Key Points:
- Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, has previously been shown to reduce body weight among overweight or obese individuals. However, data on whether the medication reduces cardiovascular events among overweight or obese individuals with established cardiovascular disease in the absence of diabetes are lacking.
- The SELECT trial enrolled 17,604 overweight or obese patients (BMI ≥ 27 kg/m2) with established cardiovascular disease who do not have diabetes and randomized them to once weekly subcutaneous semaglutide 2.4 mg or placebo.
- Over approximately 3 years of follow-up, treatment with semaglutide resulted in a 20% relative reduction in the composite primary endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.
Currently, approximately 40% of the U.S. population are considered obese. To date, no pharmacological intervention for weight loss has been shown to reduce cardiovascular events among overweight or obese patients. Glucagon-like peptide-1 (GLP-1) agonists have previously been shown to reduce body weight among overweight or obese patients and cardiovascular events among individuals with type 2 diabetes mellitus. However, data on whether semaglutide, a GLP-1 agonist, reduces cardiovascular events among overweight or obese patients with established cardiovascular disease but without diabetes has been lacking.
The SELECT trial (NCT03574597) was a global, randomized, placebo-controlled trial which enrolled 17,604 patients from 41 countries across six continents and evaluated the effect of 2.4mg of weekly subcutaneous semaglutide on major adverse cardiovascular events (defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) as compared to placebo. The trial enrolled individuals aged 45 years or older who were overweight or obese (BMI ≥ 27 kg/m2) and had established cardiovascular disease (prior MI, prior stroke, or symptomatic PAD). Notable exclusions included individuals with a history of diabetes, pancreatitis, severe psychiatric disorder, recent cardiovascular events (within 60 days) or planned revascularization, end-stage renal disease, malignancy within the past 5 years, advanced heart failure (NYHA Class IV), and pregnant women. The mean age of the participants was 62 years, 28% were women, the average BMI was 33 kg/m2, and the majority of patients had a prior MI (76%).
The mean (±SD) age of the patients was 61.6±8.9 years, and 72.3% were male. The mean BMI was 33.3±5.0, and 71.5% met the BMI criterion for obesity (≥30). The mean glycated hemoglobin level was 5.8±0.3%, and 66.4% had a level between 5.7 to 6.4%. More than three quarters of the patients had had a previous myocardial infarction, and nearly one quarter had chronic heart failure. The use of evidence-based medical therapies for cardiovascular disease was well balanced between the groups.
Over approximately 3 years of follow-up, the primary endpoint occurred among 6.5% participants in the semaglutide group and among 8% of individuals in the placebo arm (hazard ratio, 0.80; 95% CI 0.72 to 0.90; p<0.001). Event reduction was consistent across subgroups stratified by age, sex, BMI, and HbA1c level. The incidence of the secondary endpoint of all-cause mortality was also reduced with semaglutide as compared to placebo (4.3% vs. 5.2%; hazard ratio, 0.81; 95% CI 0.71 to 0.93). Secondary endpoints of non-fatal MI, coronary revascularization, and a nephropathy composite were also reduced with semaglutide. Over 104 weeks, there was a 9% greater reduction in body weight among individuals randomized to semaglutide as compared to placebo. Adverse events leading to drug discontinuation were more common among individuals randomized to semaglutide as compared to placebo (16.6% vs. 8.2%, p<0.001).
The authors commented that semaglutide is the first weight management therapy proven to reduce cardiovascular events and establishes overweight and obesity as a modifiable risk factor for cardiovascular disease.
