Oral semaglutide reduces cardiovascular event rates in high-risk patients

1. In this randomized controlled trial, oral semaglutide significantly reduced the risk of adverse cardiovascular events in patients with type 2 diabetes and coexisting cardiovascular and/or kidney disease.

2. Oral semaglutide was not associated with an increased incidence of serious adverse events.

Evidence Rating Level: 1 (Excellent)

Study Rundown: The injectable formulation of semaglutide, a GLP-1 receptor agonist, has demonstrated efficacy in reducing adverse cardiovascular events in patients with type 2 diabetes and cardiovascular or kidney disease. While the oral formulation has shown an acceptable safety profile, its cardiovascular effects were previously unclear. This trial evaluated the efficacy of oral semaglutide in patients with type 2 diabetes and established cardiovascular disease and/or chronic kidney disease. The primary outcome was the occurrence of a major adverse cardiovascular event, defined as cardiovascular death, myocardial infarction, or nonfatal stroke. Oral semaglutide was superior to placebo in reducing major adverse cardiovascular events, with consistent findings across subgroups stratified by age, sex, body mass index (BMI), baseline disease history, estimated glomerular filtration rate (eGFR), and medication use. The greatest relative risk reduction was observed in nonfatal myocardial infarction. While not statistically significant, oral semaglutide was also associated with lower risks of major kidney disease events, cardiovascular mortality, and adverse limb events. Serious adverse events occurred less frequently in the semaglutide group compared to placebo. However, gastrointestinal side effects were more common, and treatment discontinuation due to adverse events was higher. Limitations included the restriction to patients with existing cardiovascular or kidney disease, the underrepresentation of Black and female participants, and limited power to assess kidney-specific outcomes. Overall, the trial demonstrated that oral semaglutide significantly reduces cardiovascular risk in high-risk patients with type 2 diabetes.

Click here to read the study in NEJM

Relevant Reading: Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes

In-Depth [randomized controlled trial]: This randomized controlled trial evaluated the efficacy of oral semaglutide in reducing major adverse cardiovascular events in patients with type 2 diabetes and coexisting cardiovascular and/or kidney disease. Eligible participants were ≥50 years old, had type 2 diabetes with an HbA1c of 6.5–10%, and a history of either coronary artery disease, cerebrovascular disease, symptomatic peripheral arterial disease, or chronic kidney disease. Exclusion criteria included end-stage kidney disease or ongoing kidney replacement therapy. A total of 4,825 patients were randomized to receive either oral semaglutide or placebo. By the end of the study, 12.0% of patients in the semaglutide group and 13.8% in the placebo group experienced a major adverse cardiovascular event —defined as cardiovascular death, myocardial infarction, or nonfatal stroke (Hazard Ratio [HR], 0.86; 95% Confidence Interval [CI], 0.77–0.96; p=0.0006). At three years, the number needed to treat to prevent one event was 50 (95% CI, 31–125). Semaglutide also showed a trend toward benefit in key secondary outcomes, including major kidney disease (HR, 0.91; 95% CI, 0.80–1.05; p=0.19), cardiovascular death (HR, 0.93; 95% CI, 0.80–1.09), and major adverse limb events (HR, 0.71; 95% CI, 0.52–0.96), although these did not reach statistical significance. At week 104, patients receiving semaglutide had a greater mean reduction in HbA1c (−0.71% vs. −0.15%) and body weight (−2.95 kg) compared to placebo. Overall adverse event rates were slightly lower in the semaglutide group (47.9% vs. 50.3%; p = 0.02), but gastrointestinal disorders were more frequent (6.4% vs. 2.0%), and discontinuation due to adverse events was higher (15.5% vs. 11.6%). In conclusion, oral semaglutide significantly reduced the incidence of major cardiovascular events in patients with type 2 diabetes and cardiovascular or kidney comorbidities, with additional benefits in glycemic control and weight reduction.

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