2024 Top Story in Diabetes: The SELECT Trial

My pick for Top Story for 2024 is the SELECT trial, published in The New England Journal of Medicine last November.¹

The Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial was the first to assess the effects of a GLP-1 receptor agonist (RA) on cardiovascular (CV) outcomes in high-risk patients with increased BMI but without diabetes. The CV benefits of this drug category in individuals with type 2 diabetes have already been proven with several GLP-1 RAs, including liraglutide, semaglutide, and dulaglutide.

The major inclusion criteria for participation in the SELECT trial were age 45 years or older, preexisting CV disease, and a BMI of 27 kg/m² or higher. The main exclusion criterion was preexisting diabetes. A total of 17,604 patients were randomized to receive either semaglutide (titrated to 2.4 mg weekly) or placebo. The mean treatment duration was approximately 34 months, and the mean follow-up duration was approximately 40 months. The average age of participants was approximately 62 years, with approximately 84% being White and approximately 72% male. The baseline mean BMI was 33.4 kg/m² and the HbA1c level was 5.8%, with 67% having prediabetes. Approximately 2 out of every 3 participants had a history of myocardial infarction (MI) and nearly 1 in 5 had a prior stroke.

At 104 weeks of therapy, patients in the semaglutide group had lost 8.51% more body weight than those in the placebo group, and their HbA1c levels were 0.32% lower. The primary outcome of major adverse CV events (MACE; composite of CV death, nonfatal MI, and nonfatal stroke) occurred in 6.5% of patients in the semaglutide group compared with 8.5% of those in the placebo group. The hazard ratio (HR) was 0.80 (95% CI, 0.72–0.90; P < .001), representing a 20% relative risk reduction in favor of semaglutide. Among the predefined secondary outcomes, the HR for CV death was 0.85 (95% CI, 0.71–1.01), for all-cause death was 0.81 (0.71–0.93), and for a heart failure composite outcome was 0.82 (0.71–0.96) — all in favor of semaglutide. Among the other components of MACE, HR for nonfatal MI was 0.72 (0.61–0.85) and for nonfatal stroke was 0.93 (0.75–1.15).

From a safety perspective, adverse events leading to the discontinuation of the study drug were more common in the semaglutide group (16.6%) than in the placebo group (8.2%), predominantly owing to gastrointestinal side effects.

The SELECT trial is a landmark study, clearly showing that the CV benefits of semaglutide extend to patients with CV disease and high BMI but without diabetes. This finding will have broad implications for the clinical care of individuals with overweight or obesity in the setting of overt CV disease. As suggested by subgroup analyses from CV outcome trials of GLP-1 RAs in patients with type 2 diabetes, reduction in hyperglycemia does not appear to be a major mediator of their CV benefits. This point is nicely supported by the SELECT trial, as its participants had either normoglycemia or just mild hyperglycemia within the prediabetes range. We look forward to follow-up reports from the SELECT trial to better understand how various subgroups within the trial responded to semaglutide.