CONTEXT:In phase 2 trials, retatrutide reduced body weight, hemoglobin A1c, and improved the lipid profiles of participants living with obesity, with and without T2D. OBJECTIVE:Assess plasma metabolome and lipidome changes associated with retatrutide treatment. DESIGN:Metabolomics and lipidomics were performed in fasting samples from two randomized, placebo-controlled phase 2 trials. Participants living with obesity with and without T2D were treated for 36 and 48 weeks, respectively. SETTING:Post-hoc exploratory analysis. PARTICIPANTS:282 and 213 participants in the obesity and T2D trials, respectively. INTERVENTION(S):Obesity trial; retatrutide (1, 4, 8, 12 mg) or placebo. T2D trial: retatrutide (0.5, 4, 8, 12 mg) or placebo or dulaglutide (1.5 mg). MAIN OUTCOME MEASURE(S):Changes in metabolite and lipid levels with retatrutide treatment against baseline levels and placebo using multiplicity correction. RESULTS:At both primary and study endpoints for both populations, higher doses of retatrutide were associated with changes in a cluster of metabolites comprising 3-hydroxybutyrate, acetylcarnitine, free carnitine and fatty acid-derived long-chain acylcarnitines. Mediation analyses suggested that changes in these biomarkers mediated 23.2% of the weight-reduction response in participants without T2D and that this mediation was blunted to 12.7% in participants with T2D. Retatrutide treatment was also associated with changes in metabolites associated with insulin resistance, including branched-chain amino acids and their catabolic products, 2-aminoadipic acid, 2-hydroxybutyrate, urate, and triglycerides enriched in short-chain and saturated acyl side chains. These changes were found in both study populations and sustained across study endpoints. CONCLUSIONS:Retatrutide was associated with changes in two metabolic clusters related to fatty acid oxidation and insulin resistance in a direction associated with improved metabolic health and reduced cardiovascular risk.

AIMS:To further characterise the effects of retatrutide on cardiometabolic risk, lipoprotein and inflammatory biomarkers were assessed post hoc in phase 2 trials of adults with obesity/overweight with or without type 2 diabetes (T2D). MATERIALS AND METHODS:Data were analysed from two randomised, double-blind, placebo-controlled phase 2 trials. In Study 1, adults with obesity/overweight and T2D received once-weekly retatrutide (0.5/4/8/12 mg), dulaglutide (1.5 mg) or placebo for 36 weeks; in Study 2, adults with clinical obesity without T2D received retatrutide (1/4/8/12 mg) or placebo for 48 weeks. Fasting blood samples were collected at baseline and during treatment to assess lipids, apolipoproteins, lipoprotein particle subclasses and inflammatory biomarkers. Mixed models for repeated measures estimated placebo-adjusted change from baseline. Statistical significance was defined as a false discovery rate-adjusted p < 0.05. RESULTS:Mean body mass index was 35.4 kg/m2 (Study 1) and 37.4 kg/m2 (Study 2). In both studies, retatrutide was associated with significant reductions in non-high-density lipoprotein cholesterol (Study 1: up to -21.0%, Study 2: up to -26.9%), apolipoprotein B (-21.4%, -24.2%), total triglyceride-rich lipoprotein particles (-22.5%, -33.7%), large triglyceride-rich lipoprotein particles (-84.4%, -76.6%), triglyceride-rich lipoprotein cholesterol (-29.4%, -38.6%), total low-density lipoprotein particles (-19.7%, -23.5%) and small low-density lipoprotein particles (-32.6%, -32.3%). Retatrutide was associated with significant reductions in high-sensitivity C-reactive protein (-54.8%) and interleukin-6 (-29.6%) in Study 2 but not Study 1. CONCLUSIONS:In adults with obesity/overweight, with or without T2D, retatrutide treatment was associated with reductions in atherogenic lipoproteins and inflammatory biomarkers linked to cardiovascular disease risk. TRIAL REGISTRATION:ClinicalTrials.gov numbers NCT04881760 and NCT04867785.

Introduction: Obesity and type 2 diabetes mellitus (T2D) increase the risk of kidney disease. This study assessed changes in kidney parameters with retatrutide, an agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors. Methods: A post hoc analysis of 2 retatrutide studies (dose range: 0.5–12 mg) was performed in participants (estimated glomerular filtration rate [eGFR] ≥ 45 ml/min per 1.73 m2) with T2D (n = 281) and with overweight or obesity without T2D (n = 338). Both studies were placebo-controlled; the T2D study included dulaglutide 1.5 mg as an active comparator. We assessed change from baseline at week 36 (T2D) and week 48 (overweight/obesity) in urine albumin-to-creatinine ratio (UACR) and eGFR derived from creatinine, cystatin C, or both. Results: At baseline, mean eGFR derived from creatinine and median UACR were 91 ml/min per 1.73 m2 and 13 mg/g, respectively in the T2D study, and 90 ml/min per 1.73 m2 and 7 mg/g, respectively in the obesity study. In participants with T2D, retatrutide 12 mg was associated with reduced UACR compared with placebo at 36 weeks by −37.0% (95% CI: −57.3 to −7.0); eGFR was unchanged compared with placebo. In participants with overweight or obesity, retatrutide 8 mg and 12 mg, compared with placebo at 48 weeks, was associated with decreased UACR by −28.0% (95% CI: −46.0 to −4.1) and −31.5% (95% CI: −49.3 to −7.4), respectively, and with increased eGFR derived from creatinine by 5.3 ml/min per 1.73 m2 (95% CI: 1.9–8.7) and 8.5 ml/min per 1.73 m2 (95% CI: 4.9–12.1), respectively. Similar increases in eGFR derived from cystatin C and combined creatinine-cystatin C eGFR were observed. Because most patients had normal albuminuria, the absolute reduction in UACR was modest. Conclusion: Higher doses of retatrutide were associated with reduced UACR in participants with T2D and obesity, and with increased eGFR in participants with obesity but not in those with T2D.

OBJECTIVE:To explore the relationship between metabolic and histological responses in a phase 2 trial of tirzepatide in metabolic dysfunction-associated steatohepatitis (MASH). RESEARCH DESIGN AND METHODS:This is a participant-level post hoc analysis of the 52-week, double-blind, randomized, placebo-controlled SYNERGY-NASH trial (NCT04166773). Participants (n = 190) with MASH and stage 2/3 fibrosis were randomly assigned to receive tirzepatide (5, 10, or 15 mg) or placebo once weekly. The primary end point was MASH resolution without worsening of fibrosis. Secondary end points included fibrosis improvement by at least one stage without worsening of MASH. Metabolic changes were evaluated in responders and nonresponders for histological end points in 154 participants who completed the study on treatment. RESULTS:At baseline, 59% had type 2 diabetes and mean BMI was 35.7 kg/m2. Compared with nonresponders, greater body weight reductions were observed in responders for MASH resolution (-16.0% vs. -7.0%; P < 0.001) and for fibrosis improvement (-13.6% vs. -9.8%; P = 0.023). Reductions in HbA1c were greater for MASH responders (-1.2% vs. -0.6%; P < 0.001) and fibrosis responders (-1.2% vs. -0.7%; P = 0.004) than for nonresponders. Compared with nonresponders, greater improvements in liver fat and measures of adipose tissue insulin sensitivity (adipose tissue insulin resistance index and adiponectin) were observed with MASH responders (P < 0.001). In causal mediation analyses, normalization of liver fat was a significant mediator of both MASH resolution and fibrosis improvement. CONCLUSIONS:In this post hoc exploratory analysis, MASH resolution and fibrosis improvement were associated with body weight reduction, improved glycemic control, and normalization of liver fat. Weight reduction and metabolic improvements with tirzepatide treatment potentially contributed to disease modification in MASH.

AIMS:To determine whether adults with type 2 diabetes (T2D) treated with retatrutide report greater changes in self-reported appetite, dietary restraint, and disinhibition compared to placebo or dulaglutide and to examine associations with weight change. MATERIALS AND METHODS:These pre-specified exploratory analyses examined changes from baseline in Appetite Visual Analogue Scale (VAS) and Eating Inventory (EI) scores after 24 and 36 weeks of once-weekly treatment with placebo, dulaglutide 1.5 mg, or retatrutide 0.5, 4, 8, or 12 mg in 275 adults with T2D. Changes from baseline with retatrutide were compared to those with placebo and dulaglutide. Post-hoc correlations between changes in body weight and Appetite VAS/EI scores were also examined. RESULTS:Compared with placebo, participants who received retatrutide ≥4 mg reported greater reductions from baseline in overall appetite, hunger, and prospective food consumption (l at Week 24 (all p <0.05)). Differences versus dulaglutide were less consistent. Improvements from baseline versus placebo in EI Perceived Hunger and Disinhibition were greater in participants who received retatrutide 8 and 12 mg at Weeks 24 and 36. Dietary Restraint increased from baseline versus placebo only in participants who received retatrutide 12 mg at Week 36 (all p <0.05). Reductions in Perceived Hunger and Disinhibition, and increases in Dietary Restraint were significantly correlated with reductions in body weight at Week 36 (r = 0.28, r = 0.36, and r = 0.31, respectively). CONCLUSIONS:Perceived hunger and tendency to overeat (disinhibition) were reduced with higher doses of retatrutide, compared with placebo. Greater weight reduction was associated with decreased perceived hunger and disinhibition and increased dietary restraint. PLAIN LANGUAGE SUMMARY:WHAT IS THE CONTEXT AND PURPOSE OF THIS RESEARCH STUDY?: Retatrutide is a new treatment currently being developed for people with obesity and people with type 2 diabetes. This study compared the changes in appetite and eating behaviours of adults with T2D who were treated with retatrutide, dulaglutide (an alternative treatment), or placebo (i.e., no treatment). We examined changes in feelings of hunger, satisfaction and fullness, the desire to eat certain types of foods (e.g., sweet, salty or fatty foods), the tendency to overeat (e.g., when stressed), and conscious efforts to limit food intake. We also examined the potential link between changes in appetite or eating behaviours and changes in weight during retatrutide treatment. WHAT WAS DONE?: Adults with type 2 diabetes who participated in this trial completed two questionnaires that measured their eating habits at several time points during the 36-week period in which they received treatment. The questionnaire responses of people who received retatrutide each week (1-4 different doses) were compared with the responses of people who received no treatment (i.e., placebo) and of people who received dulaglutide treatment. Any potential links between the amount of weight reduction people experienced while receiving treatment during the study and their questionnaire responses were also examined. WHAT WERE THE MAIN RESULTS?: This study showed that adults with type 2 diabetes who received higher doses of retatrutide reported being less likely to feel hungry or overeat compared to those who received no treatment (i.e., placebo) or those who received dulaglutide. On average, people who experienced greater weight reduction also reported being less hungry and less likely to overeat. WHAT IS THE ORIGINALITY AND RELEVANCE OF THIS STUDY?: This is the first study to assess changes in appetite and eating behaviours of adults with type 2 diabetes who received retatrutide. Our results suggest that enhanced modification of eating behaviours with retatrutide may assist with weight reduction in adults with type 2 diabetes.

Background & Aims:In the SYNERGY-NASH trial for metabolic dysfunction-associated steatohepatitis (MASH) with stage 2 or 3 fibrosis, tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, effectively resolved MASH without worsening fibrosis in up to 73% of patients. We explored the extent of histological improvements across clinically relevant subgroups in this trial. Methods:Participants (n = 190) were randomly assigned 1:1:1:1 to receive once-weekly subcutaneous tirzepatide (5, 10, or 15 mg) or placebo for 52 weeks. We analyzed 155 participants who completed the study on treatment with evaluable end-of-treatment biopsies. Post hoc subgroups (n = 34) were defined by demographics, histology, serum, and imaging biomarkers using the median of baseline values for continuous variables. Risk differences (RDs) vs. placebo (95% CI) were calculated using a logistic regression model. Results:Compared with placebo, tirzepatide was consistently associated with improved MASH resolution without worsening fibrosis across subgroups defined by sex, age, ethnicity, BMI, type 2 diabetes status, histological disease activity, fibrosis stage, serum aminotransferases, serum biomarkers of fibrosis and MASH, and imaging assessments of liver fat, fibroinflammation, and stiffness. For tirzepatide 5, 10 and 15 mg, RDs were statistically significant (p <0.05) for 74%, 97%, and 100% of the subgroups, respectively. While most RDs for fibrosis improvement without worsening of MASH favored tirzepatide, statistical significance was not reached in 59-79% of subgroups due to limited sample sizes. Significant fibrosis improvement (p <0.05) was observed with tirzepatide 5 and 15 mg among participants with stage 3 fibrosis. Conclusion:These post hoc analyses suggest that tirzepatide was consistently associated with improved MASH resolution without worsening of fibrosis across subgroups defined by demographics, histology, and biomarkers, compared with placebo. Impact and implications:In participants with metabolic dysfunction-associated steatohepatitis (MASH), tirzepatide demonstrated superiority to placebo for resolution of MASH without worsening of fibrosis, but the extent of MASH resolution across clinically relevant subgroups was not reported. In these post hoc analyses, we show that tirzepatide was consistently associated with improved MASH resolution without worsening of fibrosis across subgroups defined by demographics, histology, serum biomarkers, and imaging tests. These data support further investigation of tirzepatide in larger studies of participants with MASH including representation from diverse populations.

Background & Aims:The impact of metabolic dysfunction-associated steatohepatitis (MASH) on patient-reported outcomes is poorly understood. We assessed work productivity burden in a real-world population with suspected/confirmed MASH, comparing work productivity and symptoms across subgroups (risk status, age, BMI, and comorbidities) in the USA using secondary data from Adelphi Real World MASH Disease Specific Programmes™, cross-sectional surveys of physicians and consulting patients in 2019 and 2022. Methods:Physicians (hepatologists, gastroenterologists, and endocrinologists) reported sociodemographic data and signs/symptoms for eight or fewer consecutive participants with MASH. Participants voluntarily completing questionnaires that assessed work productivity, health status, and quality of life/symptoms were categorized with low-, indeterminate-, or high-risk MASH using physician-stated fibrosis stage and derived risk categories. Principal components factor analysis identified factors from MASH signs and symptoms. Elastic net regression determined features associated with work productivity impairment. Results:In total, 87 physicians and 429 individuals with MASH provided data. The impact of MASH on activities was greater in high-versus low-risk MASH (activity impairment score: high risk, 30.8%; low risk, 17%; p <0.001 across all risk categories). Overall work impairment scores were 18.8% in low-risk and 19.9% in high-risk MASH. Of the 14 physician-reported signs/symptoms, 11 were significantly associated with physician-stated fibrosis stage and/or derived risk category. Two clusters of signs and symptoms ('memory loss/swelling legs/abdomen' and 'fatigue/sleep disturbance/insomnia/general weakness') and female sex were the strongest work impact predictors. Conclusions:Activity impairment was greater in participants with high-risk MASH, whereas overall work impairment was comparable, almost 20%, in low- and high-risk MASH. Non-specific symptoms of fatigue, sleep disturbance, and general weakness associated with MASH and other conditions predicted work impact in low-risk MASH. Thus, early detection and management of MASH could ameliorate work impairment. Impact and implications:Even in its early stages, when otherwise asymptomatic, metabolic dysfunction-associated steatohepatitis (MASH) may impact the ability to work. Using the Work Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP) questionnaire, we identified activity and overall work impairment in people with high- and low-risk MASH. We found a link between difficulty working and other signs, such as tiredness, sleep disturbance, and general weakness, in low-risk MASH that are not specific to MASH but can be associated with liver health. These general, non-specific signs could represent possible early warning signs preceding reduced productivity in patients with MASH.

ABSTRACTBackground and AimsThe performance of non‐invasive liver tests (NITs) is known to vary across settings and subgroups. We systematically evaluated whether the performance of three NITs in detecting advanced fibrosis in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) varies with age, sex, body mass index (BMI), type 2 diabetes mellitus (T2DM) status or liver enzymes.MethodsData from 586 adult LITMUS Metacohort participants with histologically characterised MASLD were included. The diagnostic performance of the Fibrosis‐4 Index (FIB‐4), enhanced liver fibrosis (ELF) and vibration‐controlled transient elastography liver stiffness measurement (VCTE LSM) was evaluated. Performance was expressed as the area under the receiver operating characteristics curve (AUC). Thresholds for detecting advanced fibrosis (≥F3) were calculated for each NIT for fixed (high) sensitivity, specificity and predictive values.ResultsDifferences in AUC between all subgroups were small and statistically not significant, indicating comparable performance in detecting ≥F3, irrespective of these clinical factors. However, different thresholds were needed to achieve the same level of accuracy with each test. For example, for a fixed sensitivity and specificity, the thresholds for all three NITs were higher in patients with T2DM. Effects for sex, age and liver enzymes were less pronounced.ConclusionsPerformance of the selected NITs in detecting advanced liver fibrosis does not vary substantially with clinical characteristics. However, different thresholds have to be selected to achieve the same sensitivity, specificity and predictive values in the respective subgroups. Large prospective studies are called for to study NIT accuracy considering multiple patient characteristics.

AIMS:The aim of this study was to determine if retatrutide, a triple agonist of glucose-dependent insulinotropic polypeptide (GIP) receptor, glucagon-like peptide 1 (GLP-1) receptor and glucagon (GCG) receptor, may lower serum triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels in part by decreasing circulating concentrations of the angiopoietin-like protein 3/8 complex (ANGPTL3/8). MATERIALS AND METHODS:In post-hoc analyses of two phase 2 retatrutide trials, concentrations of ANGPTL3/8, ANGPTL4/8 complex (ANGPTL4/8), ANGPTL3 and ANGPTL4 were measured using dedicated immunoassays to determine percent changes from baseline. Correlations of ANGPTL protein and complex levels with lipid and metabolic parameters at baseline were analysed. Correlations of the changes in ANGPTL protein and complex levels versus the changes in lipid and metabolic parameters at study endpoints were also analysed. Direct effects of retatrutide itself, GIP, GLP-1, GCG and a GCG receptor (GCGR) antagonist antibody on ANGPTL3/8 secretion were studied in vitro using primary human hepatocytes. RESULTS:ANGPTL3/8 reductions were observed with 8 and 12 mg retatrutide doses in participants with type 2 diabetes, and with 1, 4, 8 and 12 mg retatrutide doses in participants with obesity or overweight but without diabetes. In both cases, ANGPTL3/8 decreases paralleled retatrutide-induced reductions in TG and LDL-C. In primary human hepatocytes, both glucagon and retatrutide decreased ANGPTL3/8 secretion, and these reductions were blocked with the GCGR antagonist antibody. CONCLUSIONS:Together, these results suggest that the GCGR agonism of retatrutide could lead to reduced circulating ANGPTL3/8 concentrations, which may then contribute to decreases in TG and LDL-C levels.

Clinical practice guidelines can facilitate diagnosis and management of patients with metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction associated steatohepatitis (MASH), although their implementation to date has been suboptimal.1,2 Using recently published 2023 American Association for the Study of Liver Diseases (AASLD) practice guidance-based recommendations as a reference,3 we assessed current real-world management of patients with MASH to identify gaps in clinical practice. We extracted data from the Adelphi Real World MASH Disease Specific Programme, a cross-sectional survey with retrospective data capture (from 85 hepatologists, gastroenterologists, and endocrinologists [Supplementary Table 1] and 633 patients [Supplementary Table 2] in the United States between January and June 2022). Two key goals of the AASLD guidance algorithm served as reference points: exclude fibrosis in low-prevalence populations (Goal A) and identify/manage people with 'at-risk' MASH or cirrhosis (Goal B).3 Patients were split into 2 groups: Goal A comprised 100 patients initially diagnosed by primary care physicians (PCPs)/endocrinologists, and Goal B included 533 patients managed by gastroenterologists/hepatologists.

In phase 2 (n=338), retatrutide (RETA), an agonist of GIP, GLP-1 and glucagon receptors, reduced body weight, fasting glucose, triglycerides (TG), LDL and VLDL cholesterol in participants with obesity. To understand changes in energy metabolism, lipidomic profiling was conducted. Adult participants with obesity (BMI ≥30 kg/m2), or overweight (BMI ≥ 27 kg/m2) with a weight related comorbidity, were randomized to RETA 1, 4, 8, 12 mg or PBO for 48 wk. Fasting plasma collected at baseline, 24 and 48 wk, was used to measure acylcarnitines and complex lipid species using targeted mass spectrometry. Data were analyzed using a mixed model for repeated measures. An increase in 3-hydroxybutyrate (3-HB) was noted after 24 wk, accompanied by an increase in 3-hydroxybutyrylcarnitine (C4OH), acetylcarnitine-to-free carnitine ratio (C2/C0), and medium-chain ACs. The decrease of TGs at 48 wk was bias towards short-chain and saturated species. RETA 12 mg decreased total dihydroceramides (DhCers) at 48 wk by −20.1%, p-value <0.001. The increase in ketone body and C2/C0 observed after 24 wk is suggestive of adipose tissue lipolysis and reliance on fat oxidation. Inverse changes in TGs and DhCers were observed which associate with improved insulin sensitivity, reduced hepatic steatosis and systemic inflammation. Evaluation of potential benefits on cardiovascular events and MASLD may merit further investigation. Disclosure V. Pirro: Employee; Eli Lilly and Company. M.J. Pearson: Employee; Eli Lilly and Company. Y. Lin: Stock/Shareholder; Eli Lilly and Company, Pfizer Inc., AstraZeneca. M.L. Hartman: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. K.D. Roth: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. K.L. Duffin: Employee; Eli Lilly and Company. J. Willency: Employee; Eli Lilly and Company. A. Haupt: Employee; Lilly Diabetes. Stock/Shareholder; Lilly Diabetes. G. Ruotolo: None. Funding Eli Lilly and Company

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most common form of chronic liver disease. It exists as either simple steatosis or its more progressive form, metabolic dysfunction-associated steatohepatitis (MASH), formerly, non-alcoholic steatohepatitis (NASH). The global prevalence of MASLD is estimated to be 32% among adults and is projected to continue to rise with increasing rates of obesity, type 2 diabetes, and metabolic syndrome. While simple steatosis is often considered benign and reversible, MASH is progressive, potentially leading to the development of cirrhosis, liver failure, and hepatocellular carcinoma. Treatment of MASH is therefore directed at slowing, stopping, or reversing the progression of disease. Evidence points to improved liver histology with therapies that result in sustained body weight reduction. Incretin-based molecules, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs), alone or in combination with glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon receptor agonists, have shown benefit here, and several are under investigation for MASLD/MASH treatment. In this review, we discuss current published data on GLP-1, GIP/GLP-1, GLP-1/glucagon, and GLP-1/GIP/glucagon RAs in MASLD/MASH, focusing on their efficacy on liver histology, liver fat, and MASH biomarkers.