Semaglutide Reduces Cardiovascular Outcomes in Non-Diabetes Patients With Established Cardiovascular Disease, Obesity
BA Candidate, Department of Neuroscience, Dartmouth College
Michael Bloch, MD, FACP, FASH, FNLA, FAHA, FSVM
Associate Professor, University of Nevada/Reno School of Medicine
Medical Director, Vascular Care, Renown Institute for Heart and Vascular Health
Medications in the glucagon-like peptide 1 (GLP-1) receptor agonist class have become increasingly popular for their efficacy in type 2 diabetes treatment, demonstrating consistent reductions in glycosylated hemoglobin and substantial weight loss group. Additionally, GLP-1 agonists have been shown to significantly reduce cardiovascular events in patients with type 2 diabetes, but whether GLP-1 receptor agonists’ ability to reduce the risk of cardiovascular events associated with overweight and obesity in patients without diabetes has been unknown.1 The Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial was designed to investigate if GLP-1 receptor agonist treatment would be superior to placebo in reducing the risk of major cardiovascular events in patients with overweight and obesity, preexisting cardiovascular disease, and without diabetes.2
SELECT was a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial performed at 804 clinical sites in 41 countries. Of note, the trial was designed and funded by the developers of semaglutide (a GLP-1 receptor agonist), Novo Nordisk, in addition to the academic steering committee.
Eligible patients for the trial were older than 40 years of age with a body mass index (BMI) of 27 or greater and established cardiovascular disease, defined as previous myocardial infarction, previous stroke, or symptomatic peripheral arterial disease. Exclusion criteria included any previous diagnosis of diabetes, glycated hemoglobin levels of 6.5% (48 mmol per mole) or greater at screening, any glucose-lowering or GLP-1 receptor agonist treatment within the previous 90 days, end-stage kidney disease or dialysis, or New York Heart Association class IV heart failure. Additionally, any patients who had a cardiovascular or neurological event in the past 60 days or planned to undergo carotid, coronary, or peripheral revascularization were prohibited from enrollment.
Patients who were eligible were randomly assigned in a double-blind, 1:1 ratio without stratification to receive once-weekly subcutaneous injections of semaglutide at 2.4 mg dose or placebo. Semaglutide starting dose was 0.24 mg, increasing every 4 weeks until the target dose of 2.4 mg was reached after 16 weeks, with some variation in the timeline if the dose escalation led to any unacceptable adverse effects. The primary endpoint was a composite of death by cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke assessed on a time-to-first-event analysis. Confirmatory secondary endpoints were also assessed through a hierarchical analysis.
Between October 2018 and March 2021, a total of 17,604 patients with a mean BMI of 33.3±5.0 were randomly assigned—12,732 (72.3%) of which were men—and the mean exposure to semaglutide or placebo was 34.2±13.7 months. Initially, 12,580 (71.5%) of the patients met the obesity BMI (≥30) criterion, and 11,696 (66.4%) of the patients met the prediabetes criterion (5.7-6.4% glycated hemoglobin). The primary composite cardiovascular endpoint occurred in 569 of 8803 (6.5%) of the patients treated with semaglutide and 701 of 8801 (8.0%) of the patients treated with the placebo, indicating effective risk reduction of cardiovascular events in the patients treated with semaglutide. There was a trend toward a decrease in cardiovascular death with semaglutide, but it did not quite reach statistical significance, so changes in other individual components of the primary endpoint were not assessed in keeping with the prespecified methodology. Additionally, 104 weeks post-randomization, the mean change in body weight was -9.39% and -0.88% in the semaglutide and placebo groups, respectively.
The most common adverse events (gastrointestinal disorders and gallbladder-related disorders) leading to permanent discontinuation of treatment were more prevalent in the active treatment group with 16.6% and 8.2% of patients discontinuing treatment in the semaglutide and placebo groups, respectively.
Broadly, the SELECT trial should raise an interest in expanding GLP-1 receptor agonist treatment for cardiovascular disease prevention to patients who are non-diabetic, with overweight, and obesity, at least those with established cardiovascular disease. Traditionally, this class of medications has been recognized for its cardioprotective effects in patients with type 2 diabetes, but this study indicates that these medications can diminish cardiovascular risk in patients who are overweight with obesity, without a history of diabetes. The results of this study indicate that in patients who are non-diabetic, with obesity, and preexisting cardiovascular disease, once weekly 2.4mg dose semaglutide treatment reduced the risk of cardiovascular events by approximately 20% over the course of 33 months with an absolute risk reduction of 1.5% (8.0% vs 6.5%).
The beneficial effect of semaglutide is hypothesized to be directly because of weight loss and reduction of excess abnormal body fat. But significant reductions in blood pressure, lipids, glycohemoglobin, and notably, an approximately 35% reduction in c-reactive protein (CRP) were demonstrated, and it is impossible to determine whether those effects were because of weight loss alone or other pharmacological properties of GLP-1 agonism.
The magnitude of the effect seen in the SELECT trial is roughly similar to that which has been seen with other widely employed secondary prevention strategies, including psck9i monoclonal antibodies, the anti-inflammatory colchicine, and adding low-dose rivaroxaban to low-dose aspirin. Given the rates of events with the standard of care in these secondary prevention studies, we need to treat patients more aggressively. However, determining the relative benefit and safety of these different strategies is a challenge, especially given their potential cost.
The data presented in SELECT, suggest that perhaps the addition of semaglutide (and potentially other GLP-1 agonists) should be prioritized in patients with established cardiovascular disease who have obesity and have prediabetes. Whether these findings could be extended to high-risk primary prevention patients with obesity but without diabetes should also be investigated, although the budgetary implications of a positive finding in this larger population would need to be carefully assessed.
- Marx N, Husain M, Lehrke M, Verma S, Sattar N. GLP-1 receptor agonists for the reduction of atherosclerotic cardiovascular riks in patients with Type 2 diabetes. Circulation. 2022;13;146(24):1882-1894. doi:10.1161/CIRCULATIONAHA.122.059595
- Lincoff AM, Brown-Frandsen K, Colhoun HM, et al; SELECT Trial Investigators. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023. doi:10.1056/NEJMoa2307563