Semaglutide, a GLP-1 analog, is available in two injectable forms (Wegovy and Ozempic) and an oral tablet (Rybelsus). Wegovy and Ozempic have been proven to reduce cardiovascular events in trials, leading to FDA-approved indications for cardiovascular disease (CVD) reduction in obesity and diabetes, respectively. The effects of Rybelsus on cardiovascular events were evaluated in the 2019 PIONEER-6 Trial (N=3183), where the absolute risk of a composite CVD outcome over 16 months was 3.8% with Rybelsus and 4.8% with placebo, a 1% difference that was noninferior to placebo (p<0.001) but not superior (p=0.17). Hoping to achieve a trifecta, Novo Nordisk funded another Rybelsus trial (SOUL Study) that enrolled 9650 diabetics with an A1C between 6.5% and 10% and a history of CVD or eGFR < 60 ml/min. Participants were randomized to Rybelsus with a target dose of 14 mg/day or placebo. After 48 months, a composite of CVD events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) was lower in the Rybelsus group than the placebo group (12% vs 13.8%, p=0.006). HgA1c reduction at Week 104 was 0.71% in the Rybelsus group and 0.15% with placebo, while weight loss was 9.3 lbs and 2.8 lbs, respectively.

After missing statistical significance in the PIONEER-6 study, Novo Nordisk performed the larger and longer SOUL study, where Rybelsus was found to be superior to placebo for a composite of CVD events. Larger sample sizes and longer study durations, leading to more outcome events, help to narrow confidence intervals and increase the chance of a significant result. An analysis adjusting for changes in HgA1c and weight would be informative to see if Rybelsus has a benefit independent of its glucose-lowering and weight-loss effects.

• Rybelsus vs Placebo for CVD events in Type 2 Diabetes, NEJM (2025)
• Wegovy review