New findings from the landmark SELECT trial reveal that semaglutide’s cardiovascular benefits are only partly explained by reductions in waist size, suggesting broader protective effects beyond fat loss.
Study: Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial. Image Credit: Liya Graphics / Shutterstock
In a recent study published in The Lancet, researchers examined the associations between baseline adiposity measures, treatment-induced adiposity changes, and the risk of major adverse cardiovascular events (MACE) in the semaglutide effects on cardiovascular outcomes in people with overweight and obesity (SELECT) trial.
Glucagon-Like Peptide 1 Receptor Agonists">GLP-1RAs were initially developed for glycemic control in type 2 diabetes, and some have been effective in reducing cardiovascular risk and weight in people without diabetes. Obesity is a risk factor for cardiovascular mortality and morbidity, operating through metabolic, inflammatory, and hemodynamic pathways.
Weight alone fails to capture differences between subcutaneous and visceral fat or distinguish between lean and fat mass. Visceral adiposity has been causally implicated in adverse cardiovascular outcomes. The relationship between baseline adiposity, treatment-induced changes in adiposity, and subsequent MACE is unclear in GLP-1RA trials.
About the study
In the present study, researchers investigated associations between baseline adiposity measures, treatment-induced adiposity changes, and MACE risk in the SELECT trial. SELECT was a randomized, placebo-controlled, phase 3 trial evaluating whether semaglutide as an adjunct to standard of care was superior to placebo in decreasing MACE risk in 17,604 non-diabetic patients with obesity or overweight and cardiovascular disease (CVD).
Eligible patients were aged ≥ 45 years, with a body mass index (BMI) ≥ 27 kg/m² and established CVD (prior stroke, symptomatic peripheral artery disease, or myocardial infarction). Participants were randomized to increasing doses of once-weekly semaglutide or placebo. Participants were randomized to receive a 16-week semaglutide dose-escalation or placebo injection. Semaglutide doses were 0.24 mg, 0.5 mg, 1 mg, and 1.7 mg, with the target dose (2.4 mg) starting at week 17.
The primary outcome was MACE, defined as a composite of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. Changes in waist circumference (WC) and body weight were estimated from baseline, and treatment arms were compared. MACE risk was summarized based on baseline adiposity measures and changes in adiposity after randomization.
Analyses of changes after randomization used a landmark approach, beginning at week 20 and excluding events before that point, and were observational rather than causal. The association between changes in adiposity during the first 20 weeks and subsequent MACE risk was assessed. In addition, MACE risk was analyzed based on changes in adiposity throughout the trial, up to death or week 104. A Cox proportional hazards model evaluated the extent to which adiposity changes might be markers or mediators of the effect of semaglutide on MACE reduction.
Findings
Higher BMI was associated with female sex, younger age, and non-Asian nationality. Prediabetes prevalence, blood pressure, and inflammatory burden showed an increase from the lowest to the highest BMI categories. The mean exposure duration was 33.3 and 35.1 months for semaglutide and placebo, respectively, and the mean follow-up period was 39.8 months. Semaglutide reduced MACE incidence, with no heterogeneity in effect across baseline body habitus measures.
Within each group, MACE risk was lower among those with lower baseline adiposity measures. In the semaglutide arm, risk fell by about 4% per 5 kg lower baseline weight (HR 0.96), whereas this trend was not significant in the placebo arm; for waist circumference, both arms showed about 4% lower risk per 5 cm smaller baseline WC. By 20 weeks, first-event MACE had already diverged between arms (HR 0.58), supporting an early treatment effect.
At week 20, the mean changes in body weight and WC were −6.4% and −5.0 cm for the semaglutide group, and −0.8% and −1.1 cm for the placebo group, respectively. Adiposity changes at week 20 in the semaglutide arm accounted for 68% of the reduction in WC and 71% of the weight loss observed at week 104. Further, 11% of the total MACE occurred within the first 20 weeks. In the semaglutide arm, there was no linear or non-linear trend in subsequent MACE risk by the amount of weight loss at week 20; however, a linear association was observed between greater WC reduction and lower subsequent MACE risk (HR 0.91, 95% CI 0.84–0.98, p = 0.02). Non-linear effects were observed in the placebo group, driven by higher MACE incidence among participants with at least 5% weight loss, consistent with possible unintentional or illness-related weight loss.
Among those who lost weight at week 20, the semaglutide group had a lower MACE incidence than the placebo group. At week 104, placebo recipients with the greatest weight loss had the highest MACE incidence, whereas semaglutide recipients with the greatest weight reduction had the lowest incidence. The semaglutide group showed a linear trend towards reduced in-trial MACE risk with increasing weight loss.
Moreover, the semaglutide group showed a linear trend towards lower MACE with changes in WC at week 20. Notably, there was no evidence that time-varying weight loss mediated the effect of semaglutide on MACE. Accounting for early WC change attenuated the treatment HR from 0.80 to 0.86, indicating partial rather than complete mediation. Early WC reduction accounted for an estimated 33% of the effect. Among placebo recipients, those with at least 5% weight loss had higher all-cause mortality than placebo participants with smaller losses or weight gain.
Conclusions
In sum, semaglutide was superior to placebo in reducing MACE across all baseline WC or weight levels from early in the study. However, early in-trial body weight reduction was not related to cardiovascular benefits after 20 weeks. Further, WC was linearly associated with semaglutide effects. Mediation analyses showed that WC reduction accounted for 33% of the effect. Analyses after randomization were exploratory and cannot confirm causation, and the authors noted that the predominantly White, male population may limit generalizability. These results indicate that the cardioprotective effects of semaglutide extend beyond adiposity reduction. Funding: Novo Nordisk; ClinicalTrials.gov NCT03574597.