People taking an oral formulation of the glucagon-like peptide-1 (GLP-1) agonist semaglutide were 14% less likely than those taking a placebo to experience cardiovascular death, heart attack or stroke after an average follow-up of four years, according to a study presented at the American College of Cardiology’s Annual Scientific Session (ACC.25).

The trial is the first to test the cardiovascular benefits of an oral GLP-1 inhibitor. Both injectable and oral forms of semaglutide are already approved by the U.S. Food and Drug Administration but the oral formulation’s impact on cardiovascular outcomes has not previously been assessed. The findings indicate that the drug and its benefits could be accessible to more people, including those who are hesitant to use injections.

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

GLP-1 inhibitors were initially developed as medications for Type 2 diabetes and have also been found to aid weight loss and reduce heart disease risk. Although the exact mechanism through which they improve cardiovascular health is not known, the drugs’ anti-inflammatory activity is thought to play a role.

All the GLP-1 inhibitors that are currently included in guideline-directed care are injectable formulations requiring daily or weekly self-injections, which has created a barrier for patients who have a fear of needles or cannot use injectable medications for other reasons.

The trial, called SOUL, enrolled 9,650 patients 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 semaglutide tablet daily and half took a placebo. Participants continued their assigned regimen for an average of just under four years.

By the end of the trial, 12% of participants taking semaglutide and 13.8% of those taking a placebo experienced the composite primary endpoint of death from cardiovascular causes, heart attack or stroke, representing a 14% overall reduction in risk among those taking semaglutide. According to the researchers, this level of risk reduction is in line with cardiovascular outcomes from pooled results of eight previous trials involving injectable GLP-1 inhibitors, putting the oral formulation on par with injectables in terms of cardiovascular benefit.

Developing an oral formulation of the protein-based drug was technically challenging because only a small portion of the drug, which is delivered by the tablet binding to the lining of the stomach, is absorbed and enters the bloodstream. The tablet must be taken on an empty stomach at least 30 minutes before breakfast with a small amount of water. Despite these somewhat complex requirements, McGuire said that the study results offer reassurance that patients were able to take the drug as directed and reap cardiovascular health benefits from it.

“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 said. “Whether you take it in tablet or injection, these drugs very rapidly reduce systemic inflammation.”

The 26% reduction in the rate of non-fatal heart attack among patients taking oral semaglutide was the primary driver of the improvement in the trial’s composite primary endpoint. The rate of non-fatal strokes was 12% lower in this 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.

The most common side effects reported in the study were gastrointestinal problems such as nausea, diarrhea, constipation and gas, which are also the most common side effects of injectable semaglutide. These symptoms were manageable in most cases and rarely led patients to discontinue taking the investigational product, researchers said.

Similar results were seen across all subgroups that were analyzed, showing consistent results by age, sex and among people with different health conditions at baseline. By the end of the study about half of participants had also been treated with sodium-glucose transport protein 2 (SGLT-2) inhibitors, another type of diabetes drug with cardiovascular benefits.

“There’s been a huge [open] question among clinicians about whether these drugs are complementary and whether we should use one 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.”

Researchers said that the study was limited in that Black patients were underrepresented in the study population, largely due to under-enrollment of Black participants in study sites outside of North America.

The study was funded by Novo Nordisk.

This study was simultaneously published online in the New England Journal of Medicine at the time of presentation.

ACC.25 will take place March 29-31, 2025, in Chicago, bringing together cardiologists and cardiovascular specialists from around the world to share the newest discoveries in treatment and prevention. Follow @ACCinTouch, @ACCMediaCenter and #ACC25 for the latest news from the meeting.

The American College of Cardiology (ACC) is the global leader in transforming cardiovascular care and improving heart health for all. As the preeminent source of professional medical education for the entire cardiovascular care team since 1949, ACC credentials cardiovascular professionals in over 140 countries who meet stringent qualifications and leads in the formation of health policy, standards and guidelines. Through its world-renowned family of JACC Journals, NCDR registries, ACC Accreditation Services, global network of Member Sections, CardioSmart patient resources and more, the College is committed to ensuring a world where science, knowledge and innovation optimize patient care and outcomes. Learn more at ACC.org.