From the Guidelines
Yes, Rybelsus (semaglutide oral tablets) has been shown to decrease cardiovascular disease (CVD) risk. The PIONEER 6 trial demonstrated that Rybelsus was non-inferior to placebo for cardiovascular safety, and there was a trend toward reduction in major adverse cardiovascular events (MACE) 1. More definitively, the injectable form of semaglutide (Ozempic) showed significant cardiovascular benefits in the SUSTAIN-6 trial, with a 26% reduction in the risk of cardiovascular death, non-fatal heart attack, or non-fatal stroke compared to placebo 1.
The cardiovascular benefits of semaglutide are believed to result from multiple mechanisms including weight loss, improved glycemic control, reduced blood pressure, decreased inflammation, and improved lipid profiles. While Rybelsus is primarily prescribed for type 2 diabetes management at doses of 3,7, or 14 mg once daily, these cardiovascular benefits represent an important additional advantage, especially for patients with diabetes who have elevated cardiovascular risk or established cardiovascular disease.
Recent guidelines also support the use of semaglutide to reduce CV events in patients with T2DM and CVD, or very high/high CV risk 1. Additionally, the 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS guideline recommends the use of GLP-1 receptor agonists, including semaglutide, to reduce MACE in patients with type 2 diabetes and CVD, including underlying PAD 1.
Key points to consider:
- Rybelsus has been shown to be non-inferior to placebo for cardiovascular safety
- The injectable form of semaglutide has shown significant cardiovascular benefits in the SUSTAIN-6 trial
- Semaglutide is recommended to reduce CV events in patients with T2DM and CVD, or very high/high CV risk
- The cardiovascular benefits of semaglutide result from multiple mechanisms, including weight loss and improved glycemic control.
From the Research
Rybelsus and CVD
- Rybelsus, also known as oral semaglutide, has been studied for its effects on cardiovascular disease (CVD) in patients with type 2 diabetes.
- A study published in 2022 found that adding semaglutide to standard of care was associated with a gain in life-years free of CVD events, with a mean increase of 1.7 life-years 2.
- Another study published in 2021 found that oral semaglutide was well tolerated and had a safety profile consistent with the GLP-1RA drug class, with a low risk of hypoglycemia and gastrointestinal adverse events being the most common 3.
- A post hoc analysis of the SUSTAIN and PIONEER trials found that semaglutide reduced the risk of major adverse cardiovascular events (MACE) across the entire continuum of CV risk in a broad type 2 diabetes population 4.
- The PIONEER 6 trial demonstrated cardiovascular safety of oral semaglutide, with a significant reduction in cardiovascular and overall mortality 5.
- A recent study published in 2025 found that oral semaglutide was associated with a significantly lower risk of major adverse cardiovascular events than placebo in persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both, without an increase in the incidence of serious adverse events 6.
Key Findings
- Oral semaglutide (Rybelsus) has been shown to reduce the risk of CVD events in patients with type 2 diabetes.
- The reduction in CVD risk is associated with a gain in life-years free of CVD events.
- Oral semaglutide is well tolerated and has a safety profile consistent with the GLP-1RA drug class.
- The cardiovascular benefits of oral semaglutide are observed across the entire continuum of CV risk in a broad type 2 diabetes population.