Turning the (Semaglu)tide in Cardiovascular Prevention: The SELECT Trial

Glucagon-like peptide-1 receptor agonists, such as semaglutide, are currently recommended for cardiovascular (CV) prevention only in patients with diabetes and high CV risk.¹ They have also shown a >15% mean weight reduction benefit in patients without diabetes; however, it was previously unknown if they reduce CV risks in this population.²

The Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity trial (SELECT) is a multicenter, double-blind, randomized, placebo-controlled trial that was presented at the American Heart Association’s Scientific Sessions on October 11, 2023, by Michael Lincoff, MD.³ SELECT enrolled 17,604 nondiabetic patients with a body mass index ≥27 and established CV disease (previous myocardial infarction, stroke, or symptomatic peripheral arterial disease). The primary CV end point (death from CV causes, nonfatal myocardial infarction, or nonfatal stroke) occurred in 569 of the 8803 patients (6.5%) in the once-weekly semaglutide 2.4-mg group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% CI, 0.72-0.90; P<.001), a 20% relative risk reduction.

The incidence of serious adverse events (AEs) was higher in the placebo group (33.4% vs 36.4%; P<.001). However, AEs leading to discontinuation of semaglutide or placebo (mainly gastrointestinal symptoms) were more common in the semaglutide group (16.6% vs 8.2%; P<.001).

Only 27.7% of the enrolled patients were women, and 3.8% of the patients were Black, a limitation that may diminish the generalizability of its results. Moreover, patients without established CV disease were not included. Therefore, these results should not be extrapolated to primary CV prevention.

While the exact mechanisms are not fully understood, the CV effects of semaglutide were noted before the maximum weight loss was observed. This finding may suggest that the mechanism of CV risk reduction with semaglutide is only partially explained by the benefits of weight loss.

Dr. Ahmed Ghoneem is a cardiology fellow at UPMC (Harrisburg) and served as a CardioNerds Conference Scholar for the American Heart Association’s Scientific Sessions 2023.

References

1. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019. doi:10.1161/CIR.0000000000000678
2. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183
3. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023. doi:10.1056/NEJMoa2307563