Semaglutide helps heart failure regardless of weight loss

Low doses of the injectable weight-loss drug semaglutide may improve symptoms of a hard-to-treat type of heart failure through direct effects on the heart muscle and blood vessels, despite the lack of significant weight loss, according to preliminary results from a study presented at the American Heart Association’s Basic Cardiovascular Science Sessions (BCVS 2025), which will be held July 23-26, 2025, in Baltimore. The meeting will feature the latest advances in innovation and discovery in cardiology.

Heart failure occurs when the heart can’t pump enough oxygen-rich blood to meet the body’s needs, leading to shortness of breath, fatigue, and other symptoms. One type of left-sided heart failure, called diastolic, occurs when the left ventricle can’t relax properly due to thickening of the muscle. As a result, the heart doesn’t fill with blood properly between heartbeats. This type is known as heart failure with preserved ejection fraction (HFpEF).

“HFpEF is a major and growing public health problem, accounting for about half of all cases of heart failure. It is becoming more common as the population ages and the number of people with high blood pressure, type 2 diabetes, and obesity increases,” said study author Mahmoud Elbatreek, PhD, a research fellow in the division of cardiac surgery at the Smidt Heart Institute at Cedars-Sinai Medical Center in Los Angeles.

Many people with HFpEF are also obese. Currently, the U.S. Food and Drug Administration (FDA) has not approved semaglutide for the treatment of HFpEF. In the STEP-HFpEF clinical trial published in 2023, weekly injections of a standard dose of semaglutide significantly reduced symptoms in people with obesity and HFpEF, increased their exercise capacity, and improved their quality of life. “But a big question remained: Is the main benefit of semaglutide simply a result of weight loss, or does it also have direct benefits for the heart and blood vessels?” Elbatrik said.

In the new study, Elbatrik and colleagues used two animal models that closely mimic people with HFpEF. Rats genetically predisposed to obesity and pigs were exposed to high blood pressure and fed a salty, high-fat diet. To observe the direct effects of semaglutide on the heart and blood vessels, independent of its known weight-loss effects, the animals were divided into two groups: one group received weekly injections of a low dose of semaglutide, while the other (control) group received a placebo.

The study found that despite no significant weight loss, treatment with low doses of semaglutide resulted in:

• increase in physical endurance (by 58%);
• improving the ability of the ventricle to relax and fill with blood (by 61%);
• reduction of scarring in the heart (by 37%);
• reduction of the amount of fat in the heart and liver (by 65% and 42%, respectively);
• improving vascular function (by 52%).

“The real surprise and frankly the most exciting discovery for us was how many direct positive effects semaglutide had on cardiovascular function despite the lack of significant weight loss,” Elbatrik said.

"Our findings may offer a new treatment option for more people with HFpEF, including those who are not obese or who cannot take higher doses of semaglutide. This is encouraging as using a lower dose of the drug is likely to result in fewer side effects such as nausea, vomiting, diarrhea and abdominal pain," he added.

Amanda Vest, MD, a member of the American Heart Association's Scientific Committee on Acute Cardiac Care and General Cardiology, commented, "This animal study is interesting because the results are slightly different from the pattern seen in the STEP-HFpEF clinical trial in people with obesity and heart failure. In STEP-HFpEF, greater weight loss was associated with greater improvement in symptoms and functional capacity."