Semaglutide reduces MACE independent of baseline adiposity and weight loss
In a prespecified analysis of SELECT, semaglutide reduced MACE in patients with overweight or obesity with ASCVD but without diabetes compared with placebo independent of baseline adioposity and weight loss.
This summary is based on the publication of Deanfield J, Lincoff AM, Kahn SE, et al. – Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial. Lancet. 25 Nov 8;406(10516):2257-2268. doi: 10.1016/S0140-6736(25)01375-3.
Introduction and methods
Background
The SELECT trial previously demonstrated that semaglutide reduced body weight and MACE in patients with overweight or obesity and established CVD with no diabetes [1]. However, the extent to which baseline adiposity or treatment-induced weight loss mediated cardiovascular benefit remains unclear.
Aim of the study
The aim of this prespecified analysis was to examine the associations between baseline adiposity measures, changes in adiposity during treatment, and subsequent risk of MACE in the SELECT trial.
Methods
SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity) was a randomized, double-blind, placebo-controlled phase 3 trial which included 17, 604 patients aged ≥45 years with BMI ≥27 kg/m² and established ASCVD but without diabetes. Participants were randomized 1:1 to once-weekly semaglutide 2.4 mg or placebo. Adiposity measures included bodyweight and waist circumference. The risk of MACE occurring after 20 weeks was evaluated according to adiposity changes during the first 20 weeks. In a separate analysis, all in-trial MACE were assessed according to adiposity changes over 104 weeks. The mean ± SD follow-up duration was 39.8 ± 9.4 months.
Outcomes
The primary outcome was time to first MACE (CV death, non-fatal MI, or non-fatal stroke).
Main results
- Semaglutide reduced MACE compared with placebo consistently across all baseline categories of bodyweight and waist circumference, with no evidence of treatment heterogeneity (all P for interaction>0.05).
- In the semaglutide group, lower baseline bodyweight and waist circumference were associated with lower MACE risk (4% risk reduction per 5 kg lower bodyweight; HR: 0,96; 95%CI: 0.94-0.99; P=0.001; and 4% risk reduction per 5 cm smaller waist circumference; HR: 0.96; 95%CI: 0.93-0.99; P=0.004).
- In the placebo group, only lower waist circumference at baseline was associated with lower MACE risk (HR: 0.99; 95%CI: 0.97-1.01; P=0.28 for bodyweight; and HR: 0.96; 95%CI: 0.94-0.99; P=0.007 for waist circumference).
- Early weight loss at 20 weeks was not linearly associated with subsequent MACE risk in either treatment group. In contrast, there was a linear trend towards lower incidence of subsequent MACE with greater decrease in waist circumference at 20 weeks in the semaglutide group (HR: 0.91: 95%CI: 0.84-0.98; P=0.02), but not in the placebo group (HR: 0.94; 95%CI: 0.87-1.02; P=0.13).
- Greater decrease in waist circumference at week 104 was associated with lower MACE risk in the semaglutide group.
- Mediation analyses suggested that approximately 33% of the MACE reduction with semaglutide was explained by early reductions in waist circumference. There was no evidence that the treatment effect of semaglutide was mediated by time-varying weight loss.
Conclusion
This prespecified analysis of SELECT among ASCVD patients with overweight or obesity but without diabetes, semaglutide reduced MACE independently of baseline adiposity and magnitude of weight loss. Although reductions in waist circumference were associated with cardiovascular benefit, they explained only a minority of the treatment effect of semaglutide. According to the authors, “these findings suggest that the cardioprotective effects of semaglutide extend beyond its impact on adiposity”.
References
- Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med 2023; 389: 2221–32.