Glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor co-agonists for cardioprotection, type 2 diabetes and obesity: a review of mechanisms and clinical data

Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions. The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42]. SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None.Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions.The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42].SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None. Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions. The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42]. SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None.Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions.The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42].SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None. Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions. The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42]. SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None.Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions.The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42].SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None. Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions. The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42]. SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None.Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions.The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42].SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None. Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions. The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42]. SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None.Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions.The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42].SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None. Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions. The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42]. SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None.Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions.The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42].SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None. Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions. The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42]. SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None.Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions.The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42].SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None. Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions. The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42]. SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None.Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions.The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42].SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None. Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions. The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42]. SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None.Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions.The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42].SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None. Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions. The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42]. SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None.Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions.The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42].SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None. Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions. The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42]. SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None.Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions.The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42].SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None. Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions. The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42]. SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None.Purpose of reviewGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection.Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D.GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.Papers of particular interest, published within the annual period of review, have been highlighted as:Although the prevalence of type 2 diabetes (T2D) [1] and obesity [2] continues to soar and drive cardiovascular burden [3], obesity arguably merits more attention given the need for therapies aside from bariatric surgery that can offer clinically meaningful weight loss and the potential of T2D remission [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for T2D and obesity management in many jurisdictions, and those with proven cardiovascular benefits are recommended for people with T2D who are at high risk for cardiovascular events [5]. The strategic partnering of GLP-1RAs with other agonists that act on complementary cardiometabolic pathways to capitalize on the combined advantages is widely pursued [6]. However, it remains to be determined which GLP-1 receptor-based co-agonist combinations provide the most clinically meaningful outcomes. Furthermore, the intricacies of how co-agonists need to be combined to yield the most optimal balance of efficacy and acceptable incidence and severity of side effects still need to be resolved.Notwithstanding promising incretin effects in rats [7], glucose-dependent insulinotropic polypeptide (GIP) was for a long time the 'forgotten incretin' deemed to have limited therapeutic potential because of poor efficacy [8] and the notion that it was obesogenic as it favoured triglyceride storage in the adipose tissue of GIP receptor knockout mice [9]. It was only recently that GIP was thrust back into the spotlight following phase 2 trial findings that tirzepatide, a unimolecular acylated GLP-1/GIP receptor dual agonist, yielded superior glucose lowering and body weight loss relative to the GLP-1RA dulaglutide in people living with sub-optimally managed T2D [10].To the best of our knowledge, there are currently nine unimolecular and multimolecular GLP-1/GIP receptor dual agonists being evaluated for use in T2D and/or obesity. To date, however, tirzepatide, a 39-amino acid peptide with a half-life of approximately 5 days [11], remains the only GLP-1/GIP receptor dual agonist that is approved for managing T2D and is awaiting approval for those living with obesity or overweight (see below). no caption availableGLP-1 is released from L cells in the ileum and colon whereas GIP is secreted by K cells that are predominantly located in the duodenum and jejunum. Both GLP-1 and GIP stimulate postprandial insulin secretion from pancreatic beta-cells in a glucose-dependent fashion to manage increases in carbohydrate and lipid load, and also modulate glucagon release from pancreatic alpha-cells, albeit in opposite directions [12]. GLP-1 and GIP are metabolized by dipeptidyl peptidase-4 but unlike GLP-1 receptor activation, GIP receptor agonism does not lower glucose levels in T2D settings [13,14]. GLP-1 [15] and GIP [16] receptors are differentially expressed in the brain and while stimulation of central GLP-1 receptors by endogenous GLP-1 and GLP-1 analogues supresses food intake, increases satiety and retards gastric emptying, exactly how GIP alters the balance of energy intake remains controversial [17]. The relationship between GIP receptors and body weight is a paradox given that genetic deletion and immunological inactivation of GIP receptors, like GIP receptor agonism, have been linked with body weight loss and inhibition of diet-induced obesity [18]. Resultantly, both GIP agonism and GIP antagonism are concurrently being explored as potential weight loss therapies.The premise for the development of unimolecular GLP-1/GIP receptor dual agonists for managing T2D and obesity was founded on the observation that co-administration of GLP-1 and GIP to rodents and cynomolgus monkeys led to synergistic decreases in food intake, body weight and fat mass coupled with superior insulinotropic and antihyperglycemic effects [19,20]. The exact mechanism(s) underlying the profound preclinical metabolic benefits as well as the superior suppression of fasting glucagon [10] and weight loss (discussed in the following) observed with tirzepatide relative to GLP-1RA monotherapy remains elusive, although it has been speculated that in the presence of elevated GLP-1, GIP may serve to further enhance the actions of GLP-1 [21].GIP receptors, but not GLP-1 receptors, are expressed in white adipose tissue where GIP modulates local perfusion, insulin sensitization, glucose uptake, triglyceride storage and lipolysis [21]. Functional GIP receptors uncovered in brown adipose tissue have been associated with genes involved in thermogenesis, inflammation, mitochondrial function and lipid metabolism [22]. The high expression of GIP receptors in adipose tissue was an impetus for the design of GLP-1/GIP receptor co-agonists. Specifically, it was conceived that concomitant activation of centrally located GIP and GLP-1 receptors and peripheral GIP receptors located in the adipose tissue would augment downstream insulinotropic effects on glucose-lowering. Beyond this metabolic advantage, it is likely that proinflammatory signalling would be curtailed and lipid buffering improved, all of which would plausibly contribute to delaying the progression of weight gain, T2D and cardiovascular disease.In response to the robust evidence from cardiovascular outcome trials with GLP-1RAs, many professional organizations now endorse GLP-1RA therapy for individuals with established or who are at high risk of cardiovascular disease independent of glycaemic status [5,23,24]. It is likely that the reported cardiovascular benefits may be mediated by GLP-1 receptors expressed in the vasculature, hepatic-portal region and heart [25,26] and are believed to be a culmination of positive changes in the vascular (e.g. enhanced nitric oxide release, increased angiogenesis, greater vasodilation, lower blood pressure, decreased oxidative stress and expression of proinflammatory cytokines in mononuclear cells, less plaque formation, retarded atherosclerosis), renal (e.g. elevated glomerular filtration rate), metabolic (e.g. improved glycaemic status, declines in fasting lipids) and cardiac (e,g. improved/preserved ejection fraction as well as reduced hypertrophy and fibrosis) milieus [27].The mechanistic links between GIP and inflammation atherosclerosis have been mostly preclinical discoveries. Cell culture-based studies suggest GIP exerts both anti-atherosclerotic (increased nitric oxide and adiponectin levels; reduced endothelin-1 levels; diminished oxidative stress, migration and cell proliferation) and pro-atherosclerotic effects (decreased adiponectin levels; raised endothelin-1 and osteopontin levels) [28]. Work with atherosclerosis-prone apolipoprotein E-deficient mice suggest that GIP can modulate the entire clinical course of atherosclerosis. Specifically, chronic infusion of pharmacological doses of GIP and GIP overexpression have been associated with reduced interleukin-6 secretion, suppressed macrophage translocation into the arterial wall, inhibition of foam cell formation, decreased matrix metallopeptidase-9 activity, diminished arterial remodelling and fewer as well as less severe atherosclerotic lesions [28,29]. Notably, studies in other murine strains suggest GIP possesses both anti-atherosclerotic and pro-atherosclerotic properties [28]. GIP receptor activation in humans has been reported to lower blood pressure and increase blood flow (likely via enhanced nitric oxide release) as well as promote the release of endothelin-1, osteopontin and several pro-inflammatory chemokines [28,29].The post hoc analysis of a 26-week long phase 2b study with people living with T2D revealed that tirzepatide assignment was associated with clinically significant and meaningful reductions of several established cardiovascular risk biomarkers - high-sensitivity C-reactive protein, chitinase-3-like protein 1, growth/differentiation factor-15, intercellular adhesion molecule-1 and leptin [30]. Furthermore, the temporal fluctuations of these biomarkers in response to tirzepatide strongly suggest that this twincretin, independent of weight loss, exerts its protection in part by quashing the earlier features of atherosclerosis - inflammation and endothelial dysfunction (Fig. 1).Potential mechanisms for the cardiovascular benefits of GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonists. Adapted from Sharma and Verma [31]. GDF-15, growth/differentiation factor-15; HbA1c, glycated hemoglobin; hs-CRP, high-sensitivity C-reactive protein; ICAM-1, intercellular adhesion molecule-1; YKL-40, chitinase-3-like protein 1.There remains a substantial knowledge gap with regards to the mechanisms of action of GLP-1/GIP co-agonists and how they influence clinical changes within the different parts of the human body. The reasons behind the divergence of preclinical and clinical findings need to be resolved and there are much preclinical data that require validation in humans. Clinical trial data may offer new insights and spark new investigative directions.The clinical trial results from tirzepatide studies informs important information regarding its impact on glycemia, bodyweight and cardiometabolic parameters. The tirzepatide phase 3 program includes the SURPASS trials in people living with T2D and the SURMOUNT studies in individuals with obesity [32,33].Across the SURPASS-1 to SURPASS-5 trials using data from an efficacy estimand, HbA1c reductions from baseline ranged from 1.9 to 2.6% and occurred in a dose-dependent manner when tirzepatide was increased from 5 mg through 10 and 15 mg weekly. Importantly, HbA1C reduction with all the doses of tirazepatide was superior to both semaglutide 1.0 mg weekly and insulin glargine U100 and degludec. The proportion of participants achieving an HbA1c less than 7%, 6.5% or less and less than 5.7% was higher with all doses of tirzepatide relative to the comparators, with up to 97% of the participants achieving an HbA1c less than 7% and up to 62% attaining an HbA1c less than 5.7% with tirzepatide [34]. There were significant correlations between HbA1c reductions and body weight changes in the SURPASS-2, SURPASS-3 and SURPASS-4 studies at all doses of tirzepatide studied [35]. Of note, across the SURPASS-1 to SURPASS-5 trials, tirzepatide assignment was associated with dose-related, baseline-corrected weight reductions of 6.2-12.9 kg, all of which were superior to those observed the comparators and with up to 88% of participants losing at least 5% of baseline body weight [34]. In a substudy of SURPASS-3 with MRI-measured outcomes, all doses of tirzepatide significantly reduced the volume of visceral and abdominal subcutaneous adipose tissue as well as liver fat content [36]. Although tirzepatide allocation was associated with a higher incidence of gastrointestinal (GI) side effects in the SURPASS-1 to SURPASS-5 trials (19-36% of tirzepatide-treated participants reported experiencing nausea, vomiting or diarrhoea), a mediation analysis suggested that tirzepatide-related body weight loss was independent of gastrointestinal complaints [37]. An indirect comparison of tirzepatide 15 mg versus semaglutide 2 mg (the maximally approved dose for T2D) revealed a 0.4% improvement in HbA1c from baseline and 5.2 kg loss in body weight from baseline favouring tirzepatide [38].The decrease in SBP from baseline across the SURPASS-1 to SURPASS-5 trials ranged from 4.2 to 12.6 mmHg, and while the decline in SBP was mainly mediated through body weight loss, there were different degrees of body weight loss-independent effects on SBP across the trials [39]. For instance, in SURPASS-2, compared with the participants who had been assigned semaglutide 1.0 mg, those who were allocated tirzepatide were found to have significantly lower circulating levels of triglyceride and very low-density lipoprotein cholesterol levels alongside significantly higher high-density lipoprotein cholesterol levels [40].How tirzepatide impacts major cardiovascular events in people with T2D is currently unknown and awaits the results of SURPASS-CVOT, an active-controlled trial comparing tirzepatide 15 mg to dulaglutide 1.5 mg, a GLP-1RA with proven cardiovascular benefit, in 13 299 individuals with T2D and established cardiovascular disease [41]. In an analysis of pooled data from seven trials of tirzepatide versus comparators in people living with T2D, tirzepatide did not increase the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization due to unstable angina [hazard ratio 0.80; 95% confidence interval (CI) 0.57-1.11; P = 0.183] [42].SURMOUNT-1 and SURMOUNT-2 are the two completed and published trials with tirzepatide in people with obesity [43,44]. In the randomized SURMOUNT-1 trial with 2539 adults living with obesity (BMI >= 30 kg/m2 or >= 27 kg/m2 with at least 1 weight-related comorbidity), tirzepatide (5, 10 and 15 mg) assignment, compared with placebo, resulted in significant and substantial loss in body weight (5 mg: -13.5%, 10 mg: -17.8%, 15 mg: -20.1%); up to 96% of the cohort had documented weight reductions of more than 5% whereas up to 63% achieved at least 20% weight loss. Total fat mass was lowered by 25.7% in the pooled tirzepatide group versus the placebo-assigned group and participants randomized to tirzepatide had a three-time greater percentage reduction in fat mass than lean mass. Compared with placebo, tirzepatide improved cardiometabolic risk factors among which were decreases in waist circumference (-14.5 cm with 15 mg tirzepatide), SBP (pooled tirzepatide: -6.2 mmHg), DBP (pooled tirzepatide: -4.0 mmHg), very low-density lipoprotein cholesterol (pooled tirzepatide: -20.6 mg/dl) and free fatty acids (pooled tirzepatide: -15.6 mmol/l). All doses of tirzepatide were associated with gastrointestinal side effects that were mainly transient, mild to moderate in intensity and that primarily occurred during the dose-escalation phase (up to 33% reporting nausea, 23% diarrhoea and 17.1% constipation). An indirect comparison of tirzepatide versus semaglutide 2.4 mg in people with obesity but not living with T2D uncovered a further 4.7% loss of body weight with tirzepatide 10 mg and an additional 5.9% body weight loss with tirzepatide 15 mg [45]. SURMOUNT-2 enrolled individuals with obesity and overweight as well as coinciding T2D. The results indicate an 11.6% body weight loss with tirzepatide 15 mg weekly versus placebo and side effects were consistent with other tirzepatide trials [44]. SURMOUNT-MMO is an ongoing trial that is enrolling 15,000 individuals with overweight or obesity and has a primary endpoint of all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events [46]. Overall, the clinical data for tirzepatide demonstrates robust HbA1c lowering and weight loss in people living with T2D, and bariatric surgery-like body weight loss in individuals with obesity with encouraging benefits on cardiometabolic risk factors.There are now phase 1 data for four GLP-1/GIP receptor co-agonists. Topline phase 1 results have been reported for a subcutaneous formulation of VK2735. In short, in people with a BMI of at least 30 kg/m2 on the multiple ascending dose 28-day protocol with weekly VK2735 administration, up to 6% weight loss (versus placebo) was recorded with the maximal dose of 5/5/7.5/10 mg with 58% of those assigned to VK2735 reporting mild-moderate nausea and 19% vomiting [47]. The safety and tolerability profiles evaluated in the parallel single ascending dose arm with healthy adults were promising [47] and studies with an oral formulation of VK2735 are underway [48]. CT-388 was studied after four weekly injections with titration up to 12 mg producing a 7.6% body weight loss versus placebo in individuals with overweight or obesity without T2D and gastrointestinal side effects consistent with the GLP-1RA class [49]. In a phase 1 study of CT-868 in individuals with T2D and overweight or obesity, the primary outcome of insulin secretory rate during a graded glucose infusion following four daily subcutaneous injections was superior to placebo and similar to that with liraglutide [50]. An ongoing 26-week phase 2 study is studying individuals with T2D with a primary outcome of change in HbA1c from baseline [51]. HRS9531 has been studied in a phase 1 trial with healthy individuals with good tolerability and weight loss up to 8 kg after 4 weekly subcutaneous injections [52]. Studies with HRS9531 are ongoing in individuals with T2D (phase 1) as well as obesity without diabetes (phase 2) [53,54].GLP-1/GIP receptor co-agonists have unveiled an exciting epoch in metabolic medicine. The effect sizes of tirzepatide not only give hope that significantly more people living with T2D will be able to meet their recommended glycaemic goals but also underscore the potential of narrowing the treatment gap between weight loss pharmacotherapies and bariatric surgery. Given the pace at which the field of multiagonism is moving, it is plausible that tirzeptide may only represent the tip of the iceberg of innovative T2D and obesity pharmacotherapies. Timely achievements of glycaemic and weight control in T2D have been linked to delayed development of and less severe microvascular and macrovascular complications but despite pooled evidence supporting the cardiovascular safety of tirzepatide, there remains much to be learnt about the cardiovascular impact of long-term GLP-1 receptor and especially GIP receptor agonism. Finally, the extent to which GLP-1 and GIP agonism individually contribute towards the synergistic benefits observed with GLP-1/GIP receptor co-agonism remains unresolved and merits further work to determine if and how activities downstream of receptor activation may dictate outcomes and effect sizes.None.