Gastric emptying, which exhibits a substantial interindividual, but much lesser intraindividual, variation in health and is frequently disordered (particularly delayed) in diabetes, is now appreciated to be a major determinant of postprandial glycemia. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted in the proximal and distal small intestine, respectively, in response to nutrients. GLP-1, together with peptide tyrosine-tyrosine (PYY), stimulates potent negative feedback on gastric emptying. Modulation of gastric emptying, through dietary, pharmacologic, and surgical therapies, has been utilized in current clinical practice for the treatment of hyperglycemia, particularly relating to type 2 diabetes. We review the complex, interdependent relationships between gastric emptying, small intestinal transit, glucose absorption, neurohormonal regulatory responses, and postprandial glycemia. We discuss how this has informed fundamental advances in the understanding and rational management of obesity, stress hyperglycemia, type 1 and 2 diabetes, and gestational diabetes, and we provide recommendations for research priorities that have the potential to impact practice. We also discuss the frequent complication of abnormally delayed gastric emptying (gastroparesis) in both type 1 and type 2 diabetes, the implications for management of diabetes, and the impact of treatment on gastric emptying. With the increasing recognition of the importance of gastric emptying in the management of conditions associated with disordered glucose metabolism, and the advent and increasing use of GLP-1 receptor agonists, an improved definition of the interactions between gastrointestinal motility (gastric emptying and small intestinal transit) and enteropancreatic hormonal responses is essential.

ABSTRACT Background and Aims It is appreciated that current screening tools for diabetic peripheral neuropathy (DPN) often fail to detect early disease. Sudomotor (sweat gland) dysfunction, among the earliest manifestations of DPN, can be measured objectively by the SUDOSCAN® device. We compared SUDOSCAN® with conventional validated screening (Michigan Neuropathy Screening Instrument or MNSI) in type 1 diabetes (T1D). Methods T1D participants ( n = 264, 46.2% male, mean age 26.3 years, mean diabetes duration 13.2 years) enrolled in the prospective PICTURE study (Diabetes Unit, KEM Hospital, Pune, India) underwent simultaneous assessments for sudomotor dysfunction (electrochemical skin conductance ESC <60 μS indicating dysfunction) and DPN (MNSI) and were classified as: (a) MNSI abnormal (‘clinical DPN’), (b) MNSI normal, but ESC <60 (‘subclinical DPN) and (c) Both normal (‘no neuropathy’). Results Sudomotor dysfunction was more common than clinical DPN (46.2 vs 22.3%) with a sensitivity of 72.8% and specificity of 61.4% for detecting clinical DPN. Those with sudomotor dysfunction (ESC <60 μS) were 4.3 times more likely to have clinical DPN compared with participants without sudomotor dysfunction (ESC ≥60 μS). Among participants with normal MNSI (i.e., without clinical DPN), subclinical DPN was detected in 38.5% and was associated with younger age, shorter duration of diabetes, anemia, vitamin D deficiency, and microvascular complications. Conclusion Sudomotor testing is an objective and sensitive method for DPN screening in T1D, aiding early detection.

Previous studies investigating the relationship of dietary fat intake with gestational diabetes mellitus (GDM) and impaired glucose tolerance (IGT) have yielded inconsistent findings. Therefore, the relationship between fat intake before and during pregnancy and risk of GDM and IGT was assessed. A comprehensive search was conducted using electronic databases up to June 2024. Our selection criteria focused on observational studies that reported odds ratios (ORs)/ relative risks (RRs)/ hazard ratios (HRs) and 95

Cardiovascular-kidney-metabolic (CKM) syndrome is a term that is increasingly used to describe interconnected conditions that lead to poor health outcomes, including cardiovascular disease, chronic kidney disease, type 2 diabetes, and obesity. Historically, there have been very few targeted pharmacotherapies available that have changed cardiovascular outcomes for people with CKM syndromes; however, over the past decade, new pharmacologic options have rapidly expanded, with strong evidence for cardiovascular and kidney protective benefits in CKM conditions. Of note, sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists have emerged as key therapeutic options and are now widely guideline-endorsed. However, amid a growing pipeline of therapeutic classes on the horizon, real-world use of these agents has become increasingly complex. This review will compare the efficacy of these therapies, exploring their distinct and complementary mechanisms, with consideration to their role in contemporary clinical care. Emerging classes of therapy that may confer additional benefits for people with CKM syndrome will also be highlighted.

BACKGROUND:Type 2 diabetes mellitus (T2DM) poses a significant public health challenge in Australia, particularly among underserved populations such as First Nations people and rural communities. In response, the Together Strong Connected Care (TSCC) programme was developed to address these disparities by offering a culturally appropriate, multidisciplinary approach to diabetes management in a regional hospital setting. AIMS:The aim of the study was to assess the impact of the TSCC programme on glycaemic and metabolic control in people living with diabetes. METHODS:This was a retrospective observational study. Baseline characteristics, including age, gender, ethnicity and clinical measures, were collected. The primary outcome was the change in HbA1c over 12 months. Statistical analysis included descriptive analysis, univariate comparative analysis, paired t-tests for change in outcomes and multivariate linear regression analysis. RESULTS:The study included 119 patients, divided into those who participated in the TSCC programme (n = 68) and those who declined participation (n = 51). The study participants had a mean age of 55.71 years, with 58.82% identifying as female. The mean baseline HbA1c was 8.25% (SD = 2.60) and mean baseline weight was 97.38 kg (SD = 28.81). People in the TSCC group had significantly greater reductions in HbA1c (-1.65%, P < 0.001) compared to the no-TSCC group (+0.02%, P < 0.001). After adjusting for confounders, TSCC participation remained independently associated with improved glycaemic control (β = -0.78, P < 0.001), particularly in patients with T2DM. CONCLUSIONS:The TSCC programme significantly improved glycaemic control in regional First Nations patients, supporting the effectiveness of culturally appropriate, multidisciplinary care models in managing diabetes in underserved communities. Further research is warranted to evaluate long-term outcomes of similar interventions.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used to treat obesity and diabetes. Semaglutide, a GLP-1RA, is linked to nonarteritic ischemic optic neuropathy (NAION), macular edema, and retinopathy. Because diabetic lumbosacral radiculoplexus neuropathy (DLRPN) and common fibular neuropathy (CFN) are associated with weight loss, we examined whether GLP-1RA usage is linked to these neuropathies. We conducted a retrospective case-controlled study from April 28, 2005 (the first GLP-1RA Food and Drug Administration approval), to December 25, 2024. Patients diagnosed with DLRPN or CFN were analyzed for GLP-1RA exposure and clinical characteristics. A control group, matched for age, sex, body mass index (BMI), and diabetes status, was used to assess for an association with GLP-1RA use. We identified 26 individuals who developed 27 DLRPN episodes, with median symptom onset 6 months (range 3-35 months) after GLP-1RA initiation. At onset, they had a median glycated hemoglobin A1c (HbA1c) reduction of 2.4% (range 1%-8.5%) and a BMI decrease of 4 units (range 1-15), reflecting a 13.9% (range 3.6%-28.5%) weight loss. Microvasculitis was present in 4 of 5 nerve biopsies. Among 77 individuals with CFN, 82 episodes developed, with a mean GLP-1RA duration of 15 months (range 1-112 months). In individuals with CFN, the median HbA1c reduction was 1.2% (range -0.4% to 5%) and the BMI decrease was 4 units (range 0-15), corresponding to a 15.7% (range 3.0%-37.0%) weight loss. Patients with DLRPN experienced greater HbA1c reductions than patients with CFN (2.4% vs 1.2%, p < 0.001). New NAION, macular edema, or retinopathy were not seen with episodes. Compared with controls, GLP-1RA users were 51% more likely to develop DLRPN (odds ratio [OR] 1.5, 95% CI 1.2-1.9, p = 0.0008) and 30% more likely to develop CFN (OR 1.3, 95% CI 1.0-1.5, p = 0.018). All episodes occurred after 2015, with 3 DLRPN events and 7 CFN events occurring between 2015 and 2019, rising to 24 and 70 cases in 2020-2024, reflecting increases of 700% and 900%. GLP-1RA use is associated with an increased likelihood of DLRPN and CFN. DLRPN and its associated nerve microvasculitis seem more strongly linked to metabolic changes, particularly significant HbA1c reductions, while CFN has compressive neuropathy characteristics and is more influenced by weight loss.

INTRODUCTION:While the bidirectional relationship between depression and diabetes is well recognized, the outcome of studies evaluating the potential for sex disparity, especially in low-to-middle-income (LMIC) South Asian countries, is unexplored. We evaluated sex differences in the relationship between depressive symptoms and glycemic control in individuals with type 2 diabetes in Bangladesh. METHODS:1,485 unselected individuals with, and 228 without, type 2 diabetes completed the PHQ-9 (depression screening questionnaire), and sociodemographic and clinical data were obtained. The PHQ-9 scores were categorized as mild (5-10), moderate (10-15), moderately severe (15-20), and severe (≥20) depressive symptoms, with scores ≥10 indicating clinically relevant symptoms. Descriptive statistics and ordinal and binary logistic regression analyses were performed. RESULTS:In individuals with type 2 diabetes, mean HbA1c was 9.8 ± 0.1%, with no difference between sexes (9.9 ± 0.1% vs 9.7 ± 0.2%, P = 0.39). The overall mean PHQ-9 score was 8.5 ± 0.2, with females exhibiting higher scores (9.5 ± 0.2 vs 7.1 ± 0.2, P < 0.001). Depressive symptoms correlated with older age, lower education level, longer diabetes duration (>5 years: OR: 1.5, 95% CI: 1.1-2.3), suboptimal (HbA1c 7-9%: OR: 1.8, 95% CI: 1.1-3.2), and poorer glycemic control (HbA1c ≥9%: OR, 1.7; 95% CI, 1.1-2.9). Suboptimal (OR: 2.2, 95% CI: 1.1-4.3) or poor (OR: 2.5, 95% CI: 1.3-4.9) glycemic control and diabetes duration of 1-5 years (OR: 1.9, 95% CI: 1.2-3.0) and >5 years (OR: 2.4, 95% CI: 1.5-3.9) were associated with an increased likelihood of mild-to-severe depressive symptoms in females, but not in males. CONCLUSION:The association of depressive symptoms and poor glycemic control in type 2 diabetes in South Asians is stronger in females.

ABSTRACT Background Food insecurity (FIS) affects around 25% of Bangladesh's population, and data from developed nations report higher FIS rates among individuals with type 2 diabetes (T2D), potentially worsening glycemic control. The importance of FIS to T2D has not been studied in developing countries such as Bangladesh, with substantial disparities in healthcare access, especially between rural and urban areas. We evaluated the relationships between food insecurity and glycemic control in the context of area of residence among individuals with T2D in Bangladesh. Methods A total of 849 individuals with T2D attending diabetes clinics in four districts of Bangladesh completed a validated questionnaire to assess the FIS (a score ≥ 3 is indicative of FIS), which was compared with their sociodemographic and biochemical data. Two‐way anova and multiple linear and binary logistic regression analyses were performed. Results Both HbA1c levels (10.8% vs 9.5, P < 0.001) and the prevalence of FIS (45.8% vs 31.4%, P < 0.001) were higher in rural areas. According to two‐way anova (0.87–1.78% mean difference, P < 0.05) and multiple linear regression model (β = 1.4, P < 0.001), HbA1c levels were also higher among rural than urban dwellers, irrespective of their FIS status. Rural dwellers were also more than twice as likely to have suboptimal glycemic control (HbA1c ≥7%; AOR: 2.26 (1.35–3.97), P < 0.05), irrespective of their food security status (AOR: 1.19 (0.78–1.84, P > 0.05)). Conclusions In Bangladesh, rural residence is associated with poor glycemic control, irrespective of food security status, and thus is an important social determinant of diabetes care that warrants further exploration.

BACKGROUND:Type 2 diabetes mellitus (T2DM) affects Aboriginal Australian populations six times more frequently than non-Indigenous Australians, with disparity increasing by remoteness. Contemporary guidelines recommend optimising cardiometabolic care, including achieving a target glycated haemoglobin (HbA1c) <7%, blood pressure <130/80 mmHg, and use of pharmacotherapy, including the maximal tolerated statin dose and consideration of sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in selected subpopulations. AIM:This study aimed to determine whether cardiometabolic treatment targets and pharmacological management met best practice guidelines in two rural Aboriginal Community Controlled Health Organisations. METHOD:A retrospective audit of electronic medical records was conducted in two rural Aboriginal Community Controlled Health Organisations between January 2020 and January 2021. Data were collected for people aged over 18 years who regularly attended the clinic, identified as Aboriginal, and had a documented diagnosis of T2DM. RESULTS:A total of 274 patients met the inclusion criteria, 64% of whom were female. The median age of T2DM diagnosis was 44 years (interquartile range 32-50), with a median diabetes duration of 9 years (3-17), HbA1c 8.0% (6.9-9.4), body mass index 31.6 kg/m2 (27-36.3), urine albumin-creatinine ratio (ACR) 3.8 mg/mol (1.1-20.0), and mean low density lipoprotein cholesterol 2.1 mmol/L (±0.8). Capture rates were 70% for HbA1c, 51% for urine ACR, and 51% for lipid studies. Among recorded results, 51/193 (26%) of HbA1c were <7%, 80/228 (35%) of blood pressure readings were below 130/80 mmHg. Nephropathy was present in 42% of patients, and obesity in 61%. Clinically significant albuminuria was observed in 69/140 (50%) of patients with available ACR data. Statins were prescribed in 50%, sodium-glucose co-transporter 2 inhibitors in 20%, and glucagon-like peptide-1 receptor agonists in 7% of the population. CONCLUSIONS:This study has characterised a population with an early age of T2DM diagnosis, high rates of nephropathy and obesity, and suboptimal glycaemic control. Prescription rates of modern therapies were low. These findings highlight areas for targeted improvement in the quality of cardiometabolic care, including the increased use of modern diabetes agents.

BACKGROUND AND OBJECTIVES:Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used to treat obesity and diabetes. Semaglutide, a GLP-1RA, is linked to nonarteritic ischemic optic neuropathy (NAION), macular edema, and retinopathy. Because diabetic lumbosacral radiculoplexus neuropathy (DLRPN) and common fibular neuropathy (CFN) are associated with weight loss, we examined whether GLP-1RA usage is linked to these neuropathies. METHODS:We conducted a retrospective case-controlled study from April 28, 2005 (the first GLP-1RA Food and Drug Administration approval), to December 25, 2024. Patients diagnosed with DLRPN or CFN were analyzed for GLP-1RA exposure and clinical characteristics. A control group, matched for age, sex, body mass index (BMI), and diabetes status, was used to assess for an association with GLP-1RA use. RESULTS:We identified 26 individuals who developed 27 DLRPN episodes, with median symptom onset 6 months (range 3-35 months) after GLP-1RA initiation. At onset, they had a median glycated hemoglobin A1c (HbA1c) reduction of 2.4% (range 1%-8.5%) and a BMI decrease of 4 units (range 1-15), reflecting a 13.9% (range 3.6%-28.5%) weight loss. Microvasculitis was present in 4 of 5 nerve biopsies. Among 77 individuals with CFN, 82 episodes developed, with a mean GLP-1RA duration of 15 months (range 1-112 months). In individuals with CFN, the median HbA1c reduction was 1.2% (range -0.4% to 5%) and the BMI decrease was 4 units (range 0-15), corresponding to a 15.7% (range 3.0%-37.0%) weight loss. Patients with DLRPN experienced greater HbA1c reductions than patients with CFN (2.4% vs 1.2%, p < 0.001). New NAION, macular edema, or retinopathy were not seen with episodes. Compared with controls, GLP-1RA users were 51% more likely to develop DLRPN (odds ratio [OR] 1.5, 95% CI 1.2-1.9, p = 0.0008) and 30% more likely to develop CFN (OR 1.3, 95% CI 1.0-1.5, p = 0.018). All episodes occurred after 2015, with 3 DLRPN events and 7 CFN events occurring between 2015 and 2019, rising to 24 and 70 cases in 2020-2024, reflecting increases of 700% and 900%. DISCUSSION:GLP-1RA use is associated with an increased likelihood of DLRPN and CFN. DLRPN and its associated nerve microvasculitis seem more strongly linked to metabolic changes, particularly significant HbA1c reductions, while CFN has compressive neuropathy characteristics and is more influenced by weight loss.

Autonomic dysfunction of the stomach typically manifests as delayed gastric emptying or gastroparesis and is seen in individuals with both type 1 and 2 diabetes. However, impaired gastric motility is only modestly associated with the presence of upper gastrointestinal symptoms, and the diagnosis of gastroparesis essentially requires a formal measurement of gastric emptying, ideally employing a sensitive and precise technique such as scintigraphy. There is a bidirectional relationship between gastric emptying and glycemia: insulin-induced hypoglycemia accelerates, while acute elevations in blood glucose may delay gastric emptying. On the other hand, relatively more rapid emptying is associated with a higher initial rise in postprandial glucose. The management of gastroparesis requires an individualized approach, integrating dietary modifications, nutritional supplementation, pharmacological therapies, and, in severe cases, advanced interventions including gastrojejunostomy and gastric electrical stimulation. This review provides an overview of the pathophysiology and diagnosis of autonomic neuropathy of the diabetic stomach and discusses current clinical management strategies.

Introduction To use the ‘gold standard’ technique of scintigraphy to quantify gastric emptying (GE) as soon as practicable during an admission with diabetic ketoacidosis (DKA) and following its resolution at least 7 days later.Research design and methods Five patients with type 1 diabetes, age 29±12 years; Body Mass Index 23±3 kg/m2; hemoglobin A1c 11.3%±1.9%, were studied during an admission with DKA and following its resolution. Solid and liquid GE were measured using scintigraphy. Solid emptying was assessed via the percentage intragastric retention at 100 min and that of liquid by the 50% emptying time.Results There was no difference in either solid or liquid GE at the initial study compared with the follow-up. Median (IQR) solid retention was 47±20 versus 38%±33%, respectively; p=0.31, and time to empty 50% of liquid was 37±25 min versus 35±15 min, p=0.31, at the initial and follow-up GE study, respectively.Conclusions GE of solids and liquids is not affected by moderate DKA, inferring that earlier reintroduction of oral intake may be appropriate.

CONTEXT:Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are established therapeutics for type 2 diabetes and obesity. Among other mechanisms, they slow gastric emptying and motility of the small intestine. This helps to limit postprandial glycemic excursions and reduce chylomicron formation and triglyceride absorption. Conversely, motility effects may have detrimental consequences, eg, retained gastric contents at endoscopy or general anesthesia, potentially complicated by pulmonary aspiration or bowel obstruction. DATA ACQUISITION:We searched the PubMed database for studies involving GLP-1RA therapy and adverse gastrointestinal/biliary events. DATA SYNTHESIS:Retained gastric contents at the time of upper gastrointestinal endoscopy are found more frequently with GLP-1 RAs but rarely are associated with pulmonary aspiration. Well-justified recommendations for the periprocedural management of GLP-1RAs (eg, whether to withhold these medications and for how long) are compromised by limited evidence. Important aspects to be considered are (1) their long half-lives, (2) the capacity of GLP-1 receptor agonism to slow gastric emptying even at physiological GLP-1 concentrations, (c) tachyphylaxis observed with prolonged treatment, and (d) the limited effect on gastric emptying in individuals with slow gastric emptying before initiating treatment. Little information is available on the influence of diabetes mellitus itself (ie, in the absence of GLP-1 RA treatment) on retained gastric contents and pulmonary aspiration. CONCLUSION:Prolonged fasting periods regarding solid meal components, point-of-care ultrasound examination for retained gastric content, and the use of prokinetic medications like erythromycin may prove helpful and represent an important area needing further study to increase patient safety for those treated with GLP-1 RAs.

Glucagon-like peptide-1 (GLP-1) receptor agonists and the dual GLP-1- and glucose-dependent insulinotropic polypeptide receptor co-agonist tirzepatide (referred to here collectively as "GLP-1-based therapy") are incretin-based therapies being used increasingly in the management of both type 2 diabetes and obesity. They are now recognized to have beneficial effects beyond improved glycemic control and weight loss, including cardiovascular and renal protection. GLP-1-based therapy also slows gastric emptying, which has benefits (lowering postprandial glucose), but also potential risks (eg, hypoglycemia in individuals on insulin or sulphonylurea therapy). Their effects on the gallbladder may also be beneficial, contributing to reducing postprandial triglycerides, but they also potentially increase the risk of biliary disease. In this review, we summarize the effects of GLP-1 and incretin-based therapeutics on gastric, biliary and small intestinal function. An improved understanding of these effects will optimize the use of these drugs.

Abstract Disclosure: N. Sankaran: None. R. Jalleh: None. C. Bischoff: None. C. Marathe: None. Introduction: While there is no consensus on the optimal confirmatory test for postprandial hypoglycemia, guidelines suggest evaluation with a mixed meal test that is most likely to provoke symptoms of hypoglycemia as nominated by the patient. However, studies evaluating post-bariatric surgery hypoglycemia indicate that meals with a lower carbohydrate content are less likely to be associated with postprandial hypoglycemia. It is hypothesized that a greater carbohydrate load may result in an excessive second-phase insulin response resulting in hypoglycemia. We evaluated the outcomes of consecutive mixed meal tests in individuals with suspected spontaneous postprandial hypoglycemia and the relationship with the percentage carbohydrate content of the test meal. Methods: We retrospectively analysed the data of 103 unselected patients who were referred to undergo a 5-hour mixed meal test following an overnight fast, between the years 2010 - 2023 at the Royal Adelaide Hospital. Correlations were determined using a linear regression model and Student’s t-test was used to compare the mean carbohydrate meal content in those with and without postprandial hypoglycemia. Outcomes: Outcomes that were measured included post-meal blood glucose, plasma insulin, plasma C-peptide levels and the macronutrient composition of the meal. Subjective reporting of symptoms during the test were also noted and correlated with the symptoms included in the Edinburgh Hypoglycemia Score. Results: 33/103 participants were excluded as they had previously undergone islet cell transplant or bariatric surgery. Out of the remaining 70 participants referred for confirmatory MMT testing, 51 were female and 19 were male. The ages of the participants ranged from 16 to 74, with the median age of 40 years. 9 participants (6 females and 3 males) had abnormal results with glucose below 3.0mmol/L. 34 participants experienced hypoglycemia with glucose levels recorded below 4.0mmol/L during the test. There was no difference in carbohydrate content consumed (61.1g, P=0.30) or percentage carbohydrate (64.5%, P=0.17) in the group without postprandial hypoglycemia compared with those with postprandial hypoglycemia (carbohydrate content 67.9 g, 69.6% carbohydrate). No correlation could be identified between the percentage of carbohydrate content of the meal with the glucose nadir (P=0.75), peak insulin concentration (P=0.99) or peak C-peptide concentration (P=0.40). The percentage of carbohydrate content of the meal was neither associated with hypoglycemia (P=0.17) or symptoms (P=0.41). Conclusion: On mixed meal testing, postprandial symptoms and hypoglycemia does not correlate with either carbohydrate load or the percentage carbohydrate content of the nominated meal. Presentation: 6/1/2024

Among newer classes of drugs for type 2 diabetes mellitus (T2DM), glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are incretin-based agents that lower both blood sugar levels and promote weight loss. They do so by activating pancreatic GLP-1 receptors (GLP-1R) to promote glucose-dependent insulin release and inhibit glucagon secretion. They also act on receptors in the brain and gastrointestinal tract to suppress appetite, slow gastric emptying, and delay glucose absorption. Phase 3 clinical trials have shown that GLP-1 RAs improve cardiovascular outcomes in the setting of T2DM or overweight/obesity in people who have, or are at high risk of having atherosclerotic cardiovascular disease. This is largely driven by reductions in ischemic events, although emerging evidence also supports benefits in other cardiovascular conditions, such as heart failure with preserved ejection fraction. The success of GLP-1 RAs has also seen the evolution of other incretin therapies. Tirzepatide has emerged as a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA, with more striking effects on glycemic control and weight reduction than those achieved by isolated GLP-1R agonism alone. This consists of lowering glycated hemoglobin levels by more than 2% and weight loss exceeding 15% from baseline. Here, we review the pharmacological properties of GLP-1 RAs and tirzepatide and discuss their clinical effectiveness for T2DM and overweight/obesity, including their ability to reduce adverse cardiovascular outcomes. We also delve into the mechanistic basis for these cardioprotective effects and consider the next steps in implementing existing and future incretin-based therapies for the broader management of cardiometabolic disease.