Oral Semaglutide Lowers Heart Failure Risk

• Oral semaglutide may reduce heart failure events in high-risk individuals with type 2 diabetes.
• The benefit appeared strongest among those with a common but hard-to-treat form of heart failure.
• Type 2 diabetes and heart disease often co-occur and the findings could pave the way for new treatments.

Oral semaglutide reduced the number of significant heart failure-related events in people with type 2 diabetes (T2D), a new study has found.

The largest benefit was observed in a particularly hard-to-treat subtype of the disease.

However, that evidence stems almost entirely from studies on GLP-1 injectables rather than the oral version.

With the recent FDA approval of oral Wegovy, there is increasing excitement, and curiosity, about whether oral GLP-1s will yield comparable benefits for heart health.

Emerging evidence suggests that, like its injectable counterpart, oral semaglutide may reduce the risk of heart failure–related events in people with type 2 diabetes.

This form of heart failure has historically lacked effective treatments, but the findings of the new study, published on February 2 in JAMA Internal Medicine, could pave the way for new therapies.

“These trial findings are confirmatory, not ground-breaking,” said Nancy K. Sweitzer, editor-in-chief of Circulation: Heart Failure, a scientific journal published by the American Heart Association, and professor of cardiology at Washington University in St. Louis School of Medicine. Sweitzer wasn’t involved in the new study.

“These are important drugs for our HFpEF patients with obesity, and I hope with this additional evidence it will become easier to get insurance to cover these medications. They are clearly very important clinically in improving outcomes for patients with HFpEF,” Sweitzer told Healthline.

People with type 2 diabetes have a high lifetime risk of developing heart failure, and the two conditions frequently occur together.

In HFrEF the ejection fraction is 40% or lower, reflecting a heart muscle that is too weak to pump blood effectively. A heart with HFpEF, on the other hand, will still pump 50% or more, but indicates a stiffened left ventricle that will not fill properly

Prior research has shown injectable GLP-1s to be beneficial for CVD and heart failure, but whether those benefits extend to oral formulations has not been clear, until now.

The SOUL trial found that oral semaglutide reduced the risk of major adverse cardiovascular events (MACE), which includes heart attack, stroke, and death due to CVD in people with type 2 diabetes.

The secondary analysis explicitly investigated outcomes related to heart failure.

The average age of the cohort was 66 years, and almost one-third (29%) were females. Almost one-quarter of participants (2,229) had preexisting heart failure. Among those with heart failure, 44% had HFpEF, 27% had HFrEF, and 29% had an unknown or unclassified subtype.

The participants were randomly assigned to receive either daily oral semaglutide or a placebo.

After an average of four years of follow-up, those with preexisting heart failure who received oral semaglutide had a 22% lower risk of serious heart failure–related outcomes, including hospitalization and death. However, the study showed no significant benefit among participants without heart failure at baseline.

When the study population was divided by heart failure subtype, those with HFpEF experienced a 41% lower risk of heart failure–related events, while those with HFrEF showed no statistically significant benefit.

“The relationship between type 2 diabetes and heart failure is complex and bidirectional,” Sweitzer said. “In patients with heart failure, new diabetes develops more commonly than in populations without heart failure. This may be because of the association of both conditions with obesity.”

Cheng-Han Chen, MD, medical director of the Structural Heart Program at MemorialCare Saddleback Medical Center in Laguna Hills, CA, called the findings “extremely encouraging.”

“This is a significant development for patients with diabetes and specifically HFpEF, as we are limited in effective treatments for HFpEF,” he said.

Importantly, there was no safety signal associated with oral semaglutide; the number of serious adverse events was similar between the semaglutide and placebo groups.

Annual health care costs associated with heart failure exceed $30 billion and are projected to grow to at least $70 billion annually by 2030.

The condition is also a common complication of diabetes; more than 1 in 5 people with type 2 diabetes have heart failure, and that number is growing.

Enter GLP-1 drugs like semaglutide and tirzepatide, which are indicated to treat diabetes and obesity, but have subsequently shown to improve cardiovascular and heart-failure outcomes.

For those with type 2 diabetes and heart failure, specifically HFpEF, oral semaglutide may offer a new pharmacological option that could make it easier for some people to tolerate compared to injectables.

This study is not the first time researchers have looked at the effects of GLP-1s on heart failure; it is however, the first large randomized controlled trial to investigate the effects of oral semaglutide on the condition in people with type 2 diabetes.

Other notable trials include the SUMMIT trial, which showed a strong reduction in heart failure events in participants with HFpEF who were treated with tirzepatide. The STEP-HFpEF DM trial found that participants with HFpEF and type 2 diabetes treated with semaglutide experienced less heart failure-related symptoms and physical limitations.

While standard treatments exist for HFrEF, including ACE inhibitors, beta blockers, and SGLT2 inhibitors, HFpEF has proven harder to manage. That’s because HFpEF isn’t just one thing, and can be driven by a number of conditions, including:

The latest evidence suggests that treating some of those surrounding conditions (semaglutide improves blood sugar and aids in weight loss), extends benefits to heart failure as well.

“Given that we have very few drugs that have reduced HF hospitalization and CV death in HFpEF, any trial showing such a reduction is wonderful. However, we already saw this signal for HFpEF in SUMMIT, where it was the primary focus of the trial,” Sweitzer said.