Semaglutide and Cardiovascular Outcomes in People with Type 2 Diabetes: A SUSTAIN-6 Post Hoc Analysis by Weight Loss Category

INTRODUCTION: Type 2 diabetes (T2D) is a known risk factor for cardiovascular (CV) disease. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, improve glycemic control and are associated with weight loss, but the impact of weight loss on major adverse cardiovascular events (MACE) when taking semaglutide is not fully understood. This post hoc analysis of the SUSTAIN-6 trial aimed to examine the correlation between weight loss with semaglutide and the occurrence of MACE (nonfatal myocardial infarction, nonfatal ischemic stroke, and CV death). METHODS: This study is a single-arm, post hoc, observational analysis of the randomized, double-blind, placebo-controlled SUSTAIN-6 cardiovascular outcomes trial (NCT01720446). Participants in the semaglutide group (N = 1479) were stratified into four weight loss categories on the basis of the percentage change in body weight from baseline to 56 weeks: no loss/gain, < 5% loss, 5-10% loss, and > 10% loss. The occurrence of MACE during the follow-up period (weeks 56-104) was compared across weight loss categories using descriptive statistics and logistic regression adjusted for age and sex. Categorical variables were compared across groups using chi-squared tests, and continuous variables were compared using analysis of variance (ANOVA). RESULTS: Point estimates of MACE incidence did not differ by weight loss category (P = 0.73). The MACE event rate was comparable across weight loss categories (no loss/gain: 1.05%; < 5% loss: 1.69%; loss 5-10%: 1.06%, > 10% loss: 0.89%). Compared with the no weight loss/gain category, no degree of weight loss was associated with lower adjusted odds (odds ratio) of MACE (loss < 5%: 1.68; P = 0.66; loss 5-10%: 1.13; P = 0.77; loss > 10%: 1.06; P = 0.95). CONCLUSIONS: This post hoc analysis of SUSTAIN-6 did not find an association between the magnitude of weight loss achieved after 56 weeks of semaglutide treatment and subsequent MACE risk in people with T2D, suggesting that weight-independent mechanisms may mediate the cardioprotective effects of semaglutide.