ACC 2025: Oral Semaglutide Reduces Cardiovascular Events by 14% at 4 Years

New data from the SOUL trial found that individuals taking oral semaglutide (Rybelsus; Novo Nordisk) were 14% less likely than those taking a placebo to experience cardiovascular death, heart attack, or stroke after an average follow-up of 4 years. The data were presented at the American College of Cardiology’s 2025 Scientific Session in Chicago, Illinois, from March 28 to March 31.¹

Rybelsus is an oral formulation of semaglutide | Image credit: K KStock | stock.adobe.com

According to investigators, the trial is the first to test the cardiovascular benefits of an oral glucagon-like peptide-1 (GLP-1) agonist. Injectable and oral formulations of semaglutide are already FDA-approved,² but the oral formulation’s impact on cardiovascular outcomes has not been established. The new data suggest that the medication’s benefits could be more accessible for patients, including those who are reluctant to use an injectable medication.³

GLP-1 inhibitors were initially developed for individuals with type 2 diabetes, but they have been found to have significant benefits for weight loss and reduced heart disease risk and are being investigated for benefits in kidney disease and other conditions, such as sleep apnea. Although their exact mechanism for cardiovascular improvement is unknown, the anti-inflammatory effects are believed to have a role.^1,3

Developing the oral formulation was challenging for scientists because only a small portion of the protein-based drug is absorbed and enters the bloodstream after being delivered by the tablet binding to the lining of the stomach. The tablet must be taking on an empty stomach at least 30 minutes before breakfast with a small amount of water.³ Pharmacists are well-positioned to counsel patients on these specific requirements, ensuring that they reap the full benefits of their treatment.

“We found that the oral formulation looks just like the rest of the class of GLP-1 inhibitors,” said Darren K. McGuire, MD, a professor of medicine at the University of Texas Southwestern Medical Center and Parkland Health in Dallas, and the study’s first author. “The same cardiovascular benefits can be derived from the table that we’ve seen from the injectables before.”

The SOUL trial enrolled 9650 participants aged 50 years and older with type 2 diabetes, atherosclerotic cardiovascular disease, and/or chronic kidney disease at 450 medical centers in 44 countries. Half of the participants took a daily semaglutide tablet while the other half received placebo. Participants continued their assigned regimen for an average of just less than 4 years.⁴

By the end of the trial, 12% of participants taking semaglutide and 13.8% of those taking placebo experienced the composite primary end point of death from cardiovascular causes, heart attack, or stroke, representing a 14% overall reduction in risk among those taking semaglutide. The researchers noted that this level of risk reduction aligns with cardiovascular outcomes from pooled results of 8 previous trials involving injectable GLP-1 inhibitors putting the oral formulation on par with injectables for cardiovascular benefit.^3,4

The 26% reduction in the rate of nonfatal heart attack was the primary driver of the improvement in the trial’s composite primary end point. The rate of nonfatal strokes was 12% lower in the semaglutide group, and the rate of cardiovascular death was 7% lower. There was no significant difference between groups in terms of outcomes related to kidney function.⁴

The most common adverse effects included gastrointestinal problems such as nausea, diarrhea, constipation, and gas, which are commonly reported across GLP-1s and injectable semaglutide, specifically. These symptoms were mostly manageable and rarely led to drug discontinuation.^3,4

Similar findings were seen across all subgroups, showing consistent results by age, sex, and among those with different health conditions at baseline. By the end of the study, approximately half of participants had also been treated with sodium-glucose transport protein 2 (SGLT-2) inhibitors, which also show cardiovascular benefits.³

“There’s been a huge [open] question among clinicians about whether these drugs are complementary and whether we should use 1 or the other or both,” McGuire said. “The results showed no significant difference in outcomes between patients who took SGLT-2 inhibitors, who were likely to have more advanced disease, and those who did not, suggesting that the drugs can be safely used together and are complementary in their ability to reduce cardiovascular risk.”³

The authors noted that Black patients were underrepresented in the study, largely due to under-enrollment of Black participants in study sites outside of North America.⁴ Still, the findings can give clinicians more confidence when prescribing oral semaglutide.

“This study gives us confidence that people who are resistant or reluctant to take injections can still have an option for clinical benefit with this medication in the form of a tablet,” McGuire concluded. “Whether you take it in tablet or injection, these drugs very rapidly reduce systemic inflammation.”³

REFERENCES

1. McGuire DK. Oral semaglutide reduces cardiovascular events by 14% at four years. Presented at: American College of Cardiology 2025 Scientific Session. Chicago, IL; March 29, 2025.

2. Gallagher A. FDA approves semaglutide for new indication involving cardiovascular disease. Pharmacy Times. March 8, 2024. Accessed March 30, 2025. https://www.pharmacytimes.com/view/fda-approves-semaglutide-for-new-indication-involving-cardiovascular-disease

3. Oral Semaglutide Reduces Cardiovascular Events by 14% at Four Years. News release. American College of Cardiology. March 29, 2025. Accessed March 30, 2025.

4. McGuire DK, Marx N, Mulvagh SL, et al. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes. N Engl J Med. 2025; epub online. doi:10.1056/NEJMoa2501006