The lancet. Diabetes & endocrinology

Substantial weight reduction is often associated with loss of muscle mass. Tirzepatide has been associated with significant reductions in body weight in type 2 diabetes trials and a beneficial effect on body fat distribution in the SURPASS-3 MRI substudy. This post-hoc exploratory analysis studied the association of tirzepatide treatment with changes in thigh muscle volume, muscle volume Z score, and muscle fat infiltration, and aimed to contextualise the results using longitudinal MRI data from UK Biobank participants. SURPASS-3 was a randomised, open-label, parallel-group, phase 3 trial. The multicentre (45 sites) and multinational (eight countries) MRI substudy of SURPASS-3 enrolled insulin-naive adults (aged &#x2265;18 years) with type 2 diabetes who were on treatment with metformin with or without a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, had an HbA 1c of 7&#xb7;0-10&#xb7;5% (53-91 mmol/mol), a BMI of at least 25 kg/m 2 , and a fatty liver index of at least 60. Participants were randomly assigned (1:1:1:1) to receive subcutaneous injection once per week of tirzepatide (5, 10, or 15 mg), or subcutaneous injection once per day of titrated insulin degludec. Thigh muscle fat infiltration, muscle volume, and muscle volume Z score (invariant to sex, height, weight, and BMI) were quantified by MRI at baseline and week 52. In this post-hoc analysis, we assessed the differences between mean baseline and week 52 muscle composition values in the tirzepatide groups (pooled 5 mg, 10 mg, and 15 mg group, and per dose group) and insulin degludec group using paired t tests, and the differences in muscle composition changes with pooled tirzepatide versus insulin degludec via adjusted ANCOVA models. Observed changes in muscle fat infiltration, muscle volume, and muscle volume Z scores were compared using paired t tests to population-based estimates calculated from multiple linear regression models fitted to UK Biobank data (n=2942), capturing associations with change in body weight. Analyses were done by modified intention to treat, in the participants enrolled in the MRI substudy with a valid MRI scan at week 52. The SURPASS-3 clinical trial is registered with ClinicalTrials.gov, NCT03882970, and is complete. Participants were assessed for eligibility and recruited from April 1, 2019, to Nov 15, 2019. Among 502 participants assessed for eligibility to participate in the MRI substudy, 296 were enrolled, and 246 had a valid week 52 MRI scan and were included in the post-hoc analyses (tirzepatide 5 mg, n=63; tirzepatide 10 mg, n=60; tirzepatide 15 mg, n=67; insulin degludec, n=56; 147 [59&#xb7;8%] male participants and 99 [40&#xb7;2%] female participants). At baseline, overall mean age was 56&#xb7;0 years (SD 9&#xb7;9), median duration of type 2 diabetes was 6&#xb7;7 years (IQR 3&#xb7;7 to 10&#xb7;7), mean HbA 1c was 8&#xb7;3% (SD 0&#xb7;9), mean BMI was 33&#xb7;4 kg/m 2 (SD 4&#xb7;8), and 76 (30&#xb7;9%) were on an SGLT-2 inhibitor. Mean baseline muscle fat infiltration, muscle volume, and muscle volume Z scores were similar between the pooled tirzepatide group and insulin degludec group. For the pooled and individual tirzepatide dose groups, significant reductions were observed from baseline to week 52 in muscle fat infiltration (for pooled tirzepatide, mean change -0&#xb7;36 percentage points [95% CI -0&#xb7;48 to -0&#xb7;25], p<0&#xb7;0001), muscle volume (-0&#xb7;64 L [95% CI -0&#xb7;74 to -0&#xb7;54], p<0&#xb7;0001), and muscle volume Z score (-0&#xb7;22 [95% CI -0&#xb7;29 to -0&#xb7;15], p<0&#xb7;0001), which occurred in the context of significant weight reduction. Insulin degludec was associated with a modest and significant increase in bodyweight and muscle volume, but no significant change in the other variables. The changes in all three muscle composition variables with pooled tirzepatide were significantly different compared to those with insulin degludec. In tirzepatide-treated participants, observed muscle volume changes across all tirzepatide doses were similar to population-based estimated changes (for pooled tirzepatide, mean difference vs population-based estimate, -0&#xb7;04 L [95% CI -0&#xb7;11 to 0&#xb7;03], p=0&#xb7;22); whereas, observed reductions in muscle fat infiltration across all doses were significantly greater than population-based estimates (for pooled tirzepatide, mean difference -0&#xb7;42 percentage points [95% CI -0&#xb7;54 to -0&#xb7;31], p<0&#xb7;0001), and the observed reduction in muscle volume Z score with tirzepatide 15 mg was significantly greater than the population-based estimate (mean difference -0&#xb7;18 [95% CI -0&#xb7;29 to -0&#xb7;07], p=0&#xb7;0016). In the SURPASS-3 MRI substudy, in the context of significant improvements in bodyweight and fat distribution, tirzepatide treatment was associated with potentially favourable changes in muscle fat infiltration and reductions in muscle volume broadly in accordance with the general association between changes in muscle volume and bodyweight. The present findings provide additional information on the potential effect of tirzepatide on muscle health that might help health-care providers when deciding among treatment options for individual patients. Eli Lilly and Company.

Obesity is increasingly managed with medications as disease-modifying therapies, reflecting its role as a gateway disease driving metabolic, cardiovascular, reproductive, neuropsychiatric, and mechanical conditions. This Review synthesises evidence from randomised controlled trials and high-quality meta-analyses on approved and late-stage investigational obesity medications, including phentermine-topiramate, naltrexone-bupropion, glucagon-like peptide-1 (GLP-1) receptor agonists (eg, liraglutide, semaglutide, subcutaneously and orally), and newer GLP-1 receptor agonist-based agents (eg, tirzepatide, survodutide, mazdutide, retatrutide, cagrilintide-semaglutide, and amycretin). We evaluated the effects of obesity medications across major obesity-related conditions, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, heart failure, cardiovascular disease, obstructive sleep apnoea syndrome, polycystic ovary syndrome (recently named polyendocrine metabolic ovarian syndrome), osteoarthritis, muscle mass, depression, quality of life, and food cravings, along with binge-eating disorders, substance use disorders, and neurodegenerative diseases. Overall, GLP-1-based and multiagonist therapies show beneficial effects across these comorbid conditions. While many benefits of obesity medications are mediated by weight loss, accumulating evidence indicates important weight loss-independent effects, particularly with GLP-1 receptor agonist-based therapies. A broader understanding of these pleiotropic effects is essential to inform personalised obesity management and optimise long-term clinical outcomes.