High dose semaglutide 2.4 mg (once weekly) shown to reduce the risks of cardiovascular events in people without diabetes

Abstract

Diabetes, Obesity Metabolism (DOM) NOW – December 2023

Conclusive evidence have shown the cardiovascular benefits of semaglutide (1 mg weekly) in people with type 2 diabetes.¹ Recent data have also confirmed the efficacy of high dose semaglutide (2.4 mg weekly) to induce significant weight loss in people without type 2 diabetes,² but the cardiovascular benefits of semaglutide in people without type 2 diabetes remains unclear. A new study published in the New England Journal of Medicine (Select Trial)³ have now reported the cardiovascular benefits of semaglutide in overweight/obese people without type 2 diabetes.

The Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT)³ is a multicentre, double-blind, randomized, placebo-controlled, that enrolled more than 17 000 patients aged 45 years of age or older who had pre-existing cardiovascular disease and a body-mass index of 27 or greater but no history of diabetes. Patients were randomly assigned to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for an average of 3 years (mean duration of exposure to semaglutide or placebo was ~34 months, and the mean duration of follow-up was ~40 months). The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. The trial showed a significant 20% reduction of developing a primary cardiovascular end-point in the semaglutide group compared with the placebo group. Importantly, the difference in rates between the two treatment groups began to emerge within the first months of treatment. Consistent trends were also observed for each component of the composite primary outcome in addition to death from any cause (i.e., non-fatal stroke, non-fatal heart attack). The study also observed reduction in coronary revascularization and kidney function deterioration among those assigned semaglutide 2.4 mg. Not surprisingly, mean change in body weight after 104 weeks was greater in the semaglutide group −9.4%, compared with −0.9% in the placebo group. There was also a reduction in progression to diabetes and pre-diabetes with semaglutide 2.4 mg. However, adverse events leading to permanent discontinuation of the trial product occurred twice more in the semaglutide group (16.6%) compared with placebo (8.2%); which was significant. The difference was driven almost entirely by differences in gastrointestinal side effects. Reassuringly, there was no increase in adverse events of special interest, including acute pancreatitis and gallbladder-related events, cancers or psychiatric disorders.

This study is the largest and longest trial with the most data for this group of patients. How much can we generalize the findings from this study in the overweight/obese patient group? Well, the mean age of participants was 61 years with a mean BMI of 33.3 kg/m²; 71.5% of whom are obese. While diabetes is an exclusion, participants were recruited only if they have pre-existing heart disease, which included prior heart attack, stroke or symptomatic peripheral arterial disease, and overweight or obesity but no diabetes. Most patients were well-treated with evidence-based therapies at baseline, including high use of lipid-lowering medications (90.1%), platelet aggregation inhibitors (86.2%) and beta-blockers (70.2%). Only 27% were women and 3.8% were Black. So as yet, we cannot genuinely translate the efficacy of semaglutide 2.4 mg to a wider group of population for example from different ethnic minorities group, among overweight/obese patients without cardiovascular diseases or in younger patients with low cardiovascular disease risk. Also, the efficacy of this therapy for bariatric patients (BMI > 35) with comorbidities remains unclear. Nonetheless, this is the first of several emerging trials that will really revolutionize how we manage people with obesity and cardiovascular disease. Assessment of efficacy in different population group will allow a more generalized translation of these findings to a more diverse group of patients living with overweight or obesity.