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 (to learn more about these concepts, take our Medical Study Analysis CME). 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