Oral Semaglutide Approved to Reduce the Risk of Cardiovascular Events
- A total of 9650 participants were randomly assigned to the treatment groups (4825 in each group).
- The primary outcome occurred in 579 participants (3.1 events per 100 person-years) in the oral semaglutide group versus 668 (3.7 events per 100 person-years) in the placebo group...
- It is indeed well known that T2D is an independent risk factor for ASCVD and that managing this risk factor can lead to the prevention or slowing of...
Oral semaglutide (Rybelsus; Novo Nordisk) is the first and only oral glucagon-like peptide-1 (GLP-1) receptor agonist available on the market. It is indeed approved for the treatment of type 2 diabetes (T2D) in adults and works in the pancreas to reduce glucagon secretion and increase insulin secretion in a glucose-dependent manner.1 In addition to hemoglobin A1c lowering, oral semaglutide also has weight loss benefits owing to it’s effects on slowing gastric emptying in the stomach and increasing satiety in the brain. It is currently available in 2 formulations (R1 and R2) with 3 strengths available for each formulation (3 mg, 7 mg, and 14 mg and 1.5 mg, 4 mg, and 9 mg, respectively).1
The primary outcome occurred in 579 participants (3.1 events per 100 person-years) in the oral semaglutide group versus 668 (3.7 events per 100 person-years) in the placebo group (95% confidence interval (CI), 0.77 to 0.96; p=0.006). Death from cardiovascular causes (95% CI, 0.80 to 1.09) and nonfatal stroke (95% CI, 0.70 to 1.11) failed to show statistical significance; however, nonfatal myocardial infarction occurred in 4% of the oral semaglutide group versus 5.3% in placebo (95% CI, 0.61 to 0.89), which was statistically significant.The first secondary outcome in the hierarchy (major adverse kidney disease events) occurred in 403 participants (2.1 events per 100 person-years) in the semaglutide group and 435 participants (2.3 events per 100 person-years) in the placebo group (95% CI, 0.80 to 1.05; p=0.19). Since the first secondary endpoint was not statistically significant, additional outcomes in the hierarchy were not tested for significance. No new safety concerns were identified during the trial.
Place in Therapy for Oral GLP-1
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It is indeed well known that T2D is an independent risk factor for ASCVD and that managing this risk factor can lead to the prevention or slowing of ASCVD in this population.2 The current GLP-1 and GLP-1/GIP agonists with efficacy in both A1c and ASCVD reduction are only available in injectable form, which limits the potential patient population that would benefit from this therapy option.An oral option for patients with T2D with efficacy in ASCVD risk reduction irrespective of existing ASCVD is preferable to those who are needle phobic and may relieve concerns from prescribers about injection management, especially in patients with dexterity issues or othre neurologic conditions that may limit mobility.11 Furthermore, patients typically prefer once-daily oral treatment versus once-weekly injectables, regardless of the frequency of administration.12 This can be further highlighted by recent data showing that the discontinuation rates of oral semaglutide are lower than for patients taking injectable semaglutide and adherence rates are higher.13
While oral semaglutide offers a favorable option to patients who are averse to injections, it is indeed not without its limitations. The most notable is that it must be taken with no more than 4 ounces of water,on an empty stomach at least 30 minutes prior to any food or beverage,and separated from other medications.1 Patients who take other medications that have similar guidance woul“`html
Recent research continues to investigate the cardiovascular effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a class of medications primarily used to treat type 2 diabetes, but increasingly prescribed for weight management.While initial concerns existed regarding potential cardiovascular risks,current evidence suggests a neutral to beneficial impact on major adverse cardiovascular events (MACE) in many patient populations. This report summarizes the latest findings as of January 19, 2026.
GLP-1 Receptor Agonists: definition and Mechanism of Action
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of medications that mimic the effects of the naturally occurring incretin hormone GLP-1,which stimulates insulin release,suppresses glucagon secretion,slows gastric emptying,and promotes satiety. They are administered via injection or oral formulations.
Detail: GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). GLP-1 RAs are designed to be resistant to DPP-4 degradation,resulting in a longer duration of action. Different GLP-1 RAs vary in their pharmacokinetic and pharmacodynamic properties.
Example: Semaglutide (Ozempic, Wegovy) and liraglutide (Victoza, saxenda) are two commonly prescribed GLP-1 RAs. semaglutide is available in both injectable and oral forms, while liraglutide is only available as an injection.
Cardiovascular Outcomes Trials with GLP-1 RAs
multiple large-scale cardiovascular outcomes trials (CVOTs) have been conducted to assess the impact of GLP-1 RAs on major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.
Detail: These trials generally enrolled patients with type 2 diabetes and established cardiovascular disease or high cardiovascular risk. The trials were designed to demonstrate non-inferiority to placebo, with many showing a statistically significant reduction in MACE.
Example: The LEADER trial (liraglutide), the SUSTAIN-6 trial (semaglutide),and the EXAMINE trial (exenatide) all demonstrated a statistically significant reduction in MACE compared to placebo in patients with type 2 diabetes and established cardiovascular disease. specifically, SUSTAIN-6 showed a 26% reduction in the composite outcome of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke with semaglutide.
Recent Findings and ongoing Research (as of January 19, 2026)
Recent analyses and ongoing research continue to refine our understanding of the cardiovascular effects of GLP-1 RAs. Specifically, investigations are focusing on the potential benefits in heart failure and chronic kidney disease.
Detail: The FLOW trial, published in 2023, demonstrated that semaglutide reduced the risk of cardiovascular events in adults with obesity and established cardiovascular disease, regardless of the presence of type 2 diabetes. Further research is evaluating the impact of GLP-1 RAs on biomarkers of cardiovascular risk and inflammation.
Example: Data presented at the American Heart Association 2025 Scientific Sessions suggested a potential benefit of GLP-1 RAs in slowing the progression of heart failure with preserved ejection fraction (hfpef), although larger, dedicated trials are needed to confirm these findings. As of January 19, 2026, several such trials are actively recruiting participants.