1. In this randomized-controlled trial, the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide reduced the risk of cardiovascular death, myocardial infarction, and stroke in obese patients without diabetes.
2. Semaglutide was associated with a higher risk of adverse events resulting in discontinuation compared to placebo.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Obesity is an emerging epidemic and accounts for an increasing number of deaths, mainly from cardiovascular causes. Obesity not only predisposes patients to cardiovascular disease through its association with other metabolic disorders, but it is also an independent risk factor. Treating obesity has been challenging due to the lack of evidence for effective interventions. GLP-1 receptor agonists, such as semaglutide, have been shown to reduce major cardiovascular adverse events in patients with type 2 diabetes and reduce their body weight. This study was a randomized controlled trial to assess the effect of semaglutide in non-diabetic patients living with obesity and established cardiovascular disease. At the mean follow-up of 39.8 months, semaglutide resulted in a significant reduction in a composite of cardiovascular deaths, non-fatal myocardial infarction, and non-fatal stroke compared to placebo. It was also associated with a reduction in body weight and weight circumference. The semaglutide group, however, reported higher rates of adverse events, primarily gastrointestinal leading to discontinuation. Although these results were limited to those with pre-existing cardiovascular disease, semaglutide was demonstrated to improve cardiovascular outcomes among obese patients without diabetes.
Click here to read the study in NEJM
Relevant Reading: Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes
In-Depth [randomized controlled trial]: The current study was a multi-center, double-blind, randomized, placebo-controlled trial to demonstrate the superiority of semaglutide compared to placebo in treating obese patients without diabetes at cardiovascular risk. Patients aged 45 years or older who had a body mass index of 27 or greater and had established cardiovascular disease were eligible for inclusion. Exclusion criteria included diagnosed diabetes or glycated hemoglobin ≥6.5%, previous treatment with glucose-lowering medications or GLP-1 receptor agonist, New York Heart Association class IV heart failure class, and end-stage renal disease. In total, 17,604 patients were randomized 1:1 to receive once-weekly subcutaneous injections of semaglutide or placebo. The primary outcome was a composite of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. Secondary outcomes included death from cardiovascular causes, composite heart failure outcome (cardiovascular death or hospitalization for heart failure), and death from any cause. The mean follow-up was 39.8±9.4 months. The primary outcome occurred in 6.5% of patients in the semaglutide group and 8.0% in the placebo group (Hazard Ratio [HR], 0.80; 95% Confidence Interval [CI], 0.72-0.90; p<0.001). Consistent with existing evidence, semaglutide also reduced body weight and waist circumference. Although the placebo group reported a higher incidence of serious adverse events, semaglutide was associated with a significantly higher rate of adverse events resulting in discontinuation (16.6% versus 8.2%). This study demonstrated that semaglutide reduced the composite risk of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke among obese patients without diabetes.
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