In a development that could transform the landscape of heart failure treatment, researchers have found that two widely used weight loss drugs, semaglutide and tirzepatide, can reduce the risk of hospitalization and death by more than 40% in people suffering from heart failure with preserved ejection fraction (HFpEF). The study, published on August 31, 2025, in Journal of the American Medical Association (JAMA), analyzed healthcare data from the United States spanning 2018 to 2024, making it one of the most comprehensive investigations into the efficacy of these medications for heart failure to date.
HFpEF, the most common form of heart failure, affects approximately 3 million people in the United States and more than 30 million worldwide. Patients with this condition are hospitalized an average of 1.4 times per year and face an annual mortality rate of about 15%. The rise in HFpEF cases has been closely linked to increasing rates of obesity and type 2 diabetes, both of which are major risk factors for the disease.
The study, led by researchers at Harvard Medical School and the TUM University Hospital German Heart Center, examined data from three national U.S. healthcare claims databases. The investigation included 58,333 patients in the semaglutide versus sitagliptin (another diabetes medication) cohort, 11,257 patients in the tirzepatide versus sitagliptin group, and 28,100 in a direct comparison between tirzepatide and semaglutide.
According to the researchers, both semaglutide (marketed as Ozempic, Wegovy, and Rybelsus) and tirzepatide (sold as Zepbound and Mounjaro) significantly lowered the risk of hospitalization for HFpEF and all-cause mortality compared to sitagliptin (Januvia). The hazard ratio for semaglutide was 0.58, while tirzepatide’s was 0.42, indicating a substantial reduction in risk. Interestingly, when the two drugs were compared head-to-head, tirzepatide did not show a meaningfully lower risk than semaglutide (hazard ratio of 0.86), suggesting both medications offer similar protective benefits for this patient group.
These findings are particularly noteworthy because previous clinical trials of GLP-1 agonists for heart failure were limited by small sample sizes and strict eligibility criteria. This new large-scale cohort study, encompassing nearly 100,000 patients, provides a much more robust evidence base for expanding the use of these drugs in clinical practice.
“These findings complement early results from small clinical trials and support the use of semaglutide and tirzepatide in patients with cardiometabolic heart failure with preserved ejection fraction,” the study authors wrote in JAMA. Dr. Pooja Prasad, assistant clinical professor at the University of California San Francisco, commented to Healthline, “This study further strengthens the case for using GLP-1 agonists in obese patients with HFpEF, a type of heart failure that is associated with significant morbidity and mortality.” She added, “Having these results, specifically reduction in the composite outcome of heart failure hospitalizations and all-cause mortality, replicated in a large cohort study will likely increase their utilization even before we see a change in guidelines.”
Dr. Cheng-Han Chen, an interventional cardiologist and medical director at MemorialCare Saddleback Medical Center, emphasized the practical implications: “As this condition is the most common form of heart failure and is a disease with limited treatment options, these study results offer a tremendous opportunity for us to better manage patients with this diagnosis.”
The significance of these findings extends beyond the cardiology community. Dr. Heribert Schunkert, director of the Department of Cardiovascular Diseases at TUM University Hospital German Heart Center, stated in a news release, “Together with our colleagues at Harvard Medical School, we have created a solid evidence base for using these weight-loss medications in heart failure. In patients with heart failure with preserved ejection fraction, both drugs have shown a clear protective effect that supports their use. Our analysis of around 100,000 patients provides a robust basis for reassessing an indication expansion and new indication approval in heart failure.”
While the benefits are clear, some experts urge caution and call for further research. Dr. Mir Ali, a bariatric surgeon and medical director at MemorialCare Surgical Weight Loss Center, pointed out that the study primarily focused on patients with high body mass index (BMI). “A study separating the weight loss effects (and improvement in diabetes) from other benefits, and elucidating the mechanism, would be helpful to further ascertain how these drugs are working to reduce heart failure,” he told Healthline. Dr. Ali also reminded patients and clinicians that “counseling, medications, and even surgery are tools to help the patient adopt a healthier diet and lifestyle, and like any other tool, if used properly, it works well. However, it still requires the proper effort on the part of the patient.”
The Centers for Disease Control and Prevention (CDC) estimates that about 40% of U.S. adults are obese, a factor that increases the risk for not only heart failure, but also type 2 diabetes, high blood pressure, stroke, and certain cancers. “Obesity affects every organ system in the body — from diabetes, heart disease, arthritis and even cancer. So, it is clear that reducing weight can improve or reverse the deleterious effects of obesity,” said Dr. Ali. Dr. Prasad added, “Abdominal obesity, in addition to high blood sugars, high cholesterol, and high blood pressure, is a key component of metabolic syndrome. Through a variety of mechanisms, metabolic syndrome increases our risk for cardiovascular disease, which can manifest as both acute and chronic blockages in the arteries supplying blood to our heart, strokes, heart rhythm abnormalities, and heart failure.”
Semaglutide and tirzepatide are injectable medications, with some formulations approved for weight management and others for type 2 diabetes. Past research has shown these drugs can lower the risk of heart attack and even reduce the risk of certain cancers in people with obesity. However, experts stress that lifestyle modifications remain essential. Dr. Chen advised, “Regular physical activity, a healthy balanced diet, adequate quality sleep, maintaining a healthy weight, avoiding tobacco and alcohol, and controlling blood pressure and cholesterol are all important factors for cardiovascular health.” He noted that heart-healthy diets typically avoid ultra-processed foods, sugars, and unhealthy fats, recommending foods like leafy green vegetables, whole grains, berries, beans, tomatoes, and almonds.
Looking forward, the study’s authors and many in the medical community hope these findings will prompt regulatory agencies to re-evaluate the indications for semaglutide and tirzepatide, potentially making them available to a broader population of heart failure patients. As the burden of HFpEF grows alongside rising rates of obesity and diabetes, the prospect of new, effective treatments offers hope for millions who previously had few options.
As the evidence mounts, it seems clear that the future of heart failure management may be shifting, with GLP-1 medications like semaglutide and tirzepatide taking center stage in the fight against this widespread and deadly condition.
