(P103) RELEVANCE OF BODY WEIGHT AND WEIGHT CHANGE ON CARDIOVASCULAR BENEFIT WITH SEMAGLUTIDE: A PRE-SPECIFIED ANALYSIS OF THE SELECT TRIAL

Background: In the SELECT trial of people with overweight/obesity and established cardiovascular (CV) disease but no diabetes, there was both a 20% reduction in 3-point major adverse cardiovascular events, MACE (death from CV cause, nonfatal stroke or nonfatal myocardial infarction) and body weight loss (9.4%) with once-weekly subcutaneous semaglutide 2.4 mg. Here we report a pre-specified analysis of the relationship between weight measures at baseline, their change during early treatment and CV outcomes.

METHODS AND RESULTS: The SELECT trial randomized 17,604 participants aged ≥45 years with body mass index (BMI) ≥27 kg/m2 (72% males) from a geographically and racially diverse population to semaglutide or placebo for a mean of 40 months. The relationship between time to first MACE and baseline weight, BMI, waist circumference and waist to height ratio as well as changes in these parameters over the first 20-weeks of treatment were analyzed using a Cox proportional hazards model with treatment subgroup, and the interaction between treatment and subgroup as categorical fixed factors. Within each treatment arm, MACE rates were comparable across subgroups defined by baseline adiposity indices. Semaglutide reduced the risk of MACE compared to placebo, with no difference in the magnitude of benefit of semaglutide across all baseline weight or anthropometric subgroups (Figure 1). By week-20, 62% of participants on semaglutide and 10% of participants on placebo had lost ≥5% of their body weight. The reduction in the MACE rates by semaglutide versus placebo was similar in participants who lost ≥5% and in participants who lost < 5% or gained weight (hazard ratio 0.67 [95% confidence interval; 0.52–0.87] and 0.85 [0.72–1.00] respectively; interaction P-value >0.10) (Figure 2A). MACE rates among participants on semaglutide were similar in the two weight loss categories, whereas participants on placebo who lost ≥5% weight had higher MACE rates than those who lost < 5% or gained weight (Figure 2B).

Conclusion: In this CV outcomes trial of semaglutide in people with overweight/obesity but without diabetes, a reduction in MACE was achieved regardless of the level of baseline adiposity. The magnitude of this treatment effect with semaglutide was also independent of the extent of achieved weight loss. This suggests alternative mechanisms of improved CV outcomes beyond reduction in adiposity, which may benefit many people in addition to current guideline-directed care.