Maryam James, PharmD, Community University Health Care Center
Background: Overweight and obesity, as defined by a high body-mass index (BMI) of >25 kg/m2 and >30 kg/m2, respectively, are independently associated with an increased risk of cardiovascular (CV) events. Historically, standards of practice to decrease risks of CV events have focused on the treatment of common comorbidities, commonly dyslipidemia, hypertension, and diabetes mellitus (DM). There is a lack of data for improving CV outcomes via direct treatment for overweight or obesity. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are used in the management of type 2 DM and high BMI, and have been shown to reduce the risk of adverse CV outcomes in patients with type 2 DM. Findings from a 2022 Nature Medicine publication demonstrated that semaglutide, a long-acting GLP-1 RA, administered at a dose of 2.4 mg subcutaneously once weekly for 104 weeks reduced body weight by a mean of 15.2% among patients with overweight or obesity in the absence of DM, though its effects on the CV profile are unknown.
Objective: In the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial, semaglutide was added to standard care to assess the risk reduction in major CV events among patients who were overweight or obese with pre-existing CV disease, without a history of DM.
Study Design: The trial was a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial conducted across 804 clinical sites in 41 countries. Eligibility criteria included patients >45 years of age, BMI of >27 kg/m2, and established CV disease (defined as prior myocardial infarction, stroke, or symptomatic peripheral arterial disease). Notable exclusion criteria included the following: a previous diagnosis of DM, an A1c of >6.5%, treatment with any glucose-lowering therapy or GLP-1 RA within the last 90 days, New York Heart Association (NYHA) class IV heart failure, or end-stage kidney disease/dialysis. Patients were also ineligible if they experienced a CV or neurologic event within the previous 60 days or if they planned to undergo coronary, carotid, or peripheral revascularization. Patients were randomly assigned in a 1:1 double-blind manner to receive either once-weekly subcutaneous semaglutide or placebo. The starting dose of semaglutide was 0.24 mg once weekly, with the dose titration planned for four-week intervals at 0.5 mg, 1 mg, 1.7 mg, until the target dose of 2.4 mg was reached. In the event of GLP-1 RA-related adverse effects, dose-escalation intervals could be extended, treatment paused, or maximally tolerated maintenance doses could be used. Investigators were otherwise encouraged to follow evidence-based recommendations for medical management of underlying CV disease. Patients were permitted to continue their assigned trial product in the event that DM developed during the trial. Glucose-lowering medication could be initiated at the discretion of the investigator, with the exception of the initiation of open-label treatment with a GLP-1 RA. The primary endpoint was a composite of death from CV causes, nonfatal myocardial infarction, or non-fatal stroke. Secondary end points included death from CV causes, hospitalization or an urgent medical visit for heart failure, and death from any cause. Time-to-first-event analyses were used to assess all endpoints. In order to achieve 90% power to detect a relative-risk reduction of 17% for a primary endpoint event in the treatment group versus placebo, a minimum of 1225 primary endpoints were needed. The trial design required enrollment of 17,500 patients, with an expected trial duration of 59 months and a withdrawal or loss-to-follow-up rate of 1% in both trial arms. Efficacy of treatment was analyzed with intention-to-treat principles.
Results: From October 2018 to March 2021, 17,604 patients were enrolled in the trial: 8803 received semaglutide and 8801 received placebo. Baseline demographics and clinical characteristics of the patients were largely similar across both arms. The mean age of patients was 61.6 years, and 72.3% of patients were male. The mean BMI was 33.3 kg/m2 with 71.5% of patients meeting the BMI criterion for obesity. The mean A1c was 5.8%. The use of guideline-based medical management for CV disease was well-balanced among trial groups. Following a mean duration of 33 months of treatment with once-weekly subcutaneous semaglutide at 2.4 mg, the risk of composite of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke was reduced by 20% (hazard ratio [HR], 0.80; 95% confidence interval [CI] 0.72 to 0.90). Semaglutide was also associated with improvements in multiple biomarkers of CV risk, including blood pressure, waist circumference, glycemic control, nephropathy, and lipid levels. The mean change in body weight over the trial duration was -9.39% with semaglutide and -0.88% with placebo (95% CI, -8.75 to -8.27).
Conclusion: Cardioprotective mechanisms with semaglutide are speculated to be related to physiological benefits from reducing excess body fat, improving traditional CV risk factors, and reducing adipose tissue depots potentially contributing to atherosclerosis and myocardial dysfunction. A significant limitation of this trial was the inclusion of only patients with pre-existing CV disease; the effects of semaglutide on primary prevention of CV events in patients with overweight or obesity were not evaluated.
Key Point: The addition of weekly subcutaneous semaglutide at a targeted dose of 2.4 mg to standards of care for CV disease was shown to be superior to placebo at reducing adverse CV outcomes in patients with overweight or obesity with underlying CV disease in the absence of DM.
References:
Garvey WT, Batterham RL, Bhatta M, et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med. 2022;28(10):2083-2091.
Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232.