Worldwide, 60 million people suffer from heart failure (HF). Heart failure with preserved ejection fraction (HFpEF) is the most common form of HF, especially among people with obesity and type 2 diabetes. Recent studies have suggested that novel weight-loss drugs targeting glucagon-like peptide-1 (GLP-1) may also improve HFpEF symptoms, but their effect on important outcomes like hospitalization and death has not been evaluated in large populations. By analyzing real-world data from over 90,000 HFpEF patients with obesity and type 2 diabetes, researchers from Mass General Brigham demonstrated that GLP-1 medications may significantly reduce the risk of hospitalization due to HF and all-cause mortality. Findings are published in JAMA and presented simultaneously at the European Society of Cardiology Congress.
"Despite the widespread morbidity and mortality burden of HFpEF, current treatment options are limited," said corresponding author Nils Krüger, MD, of the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system. "Both semaglutide and tirzepatide are well-known for their effects on weight loss and blood sugar control, but our study suggests they may also offer substantial benefits to patients with obesity and type 2 diabetes by reducing adverse heart failure outcomes."
Despite promising results from existing randomized controlled trials of semaglutide and tirzepatide in those with obesity-related HFpEF, regulatory authorities and professional societies have not approved or endorsed the use of these drugs for HFpEF, due in part to the studies' relatively small sample sizes and unknown generalizability. The researchers therefore used data from three large U.S. insurance claims databases to emulate two previous, placebo-controlled trials of semaglutide and tirzepatide in new study populations that were an average of 19 times larger than those previously evaluated.
The researchers compared the one-year risk of HF hospitalization or death in new users of each GLP-1 drug to the risk of those outcomes in a "placebo" group of patients taking sitagliptin, a diabetes drug known to have no impact on HFpEF. After verifying the results of the previous, highly controlled studies, the researchers expanded their study population to make it more reflective of HFpEF cases in clinical practice, finding that overall, the drugs were associated with a greater than 40% reduction in heart failure hospitalization or all-cause mortality as compared with sitagliptin. Semaglutide and tirzepatide had similar effectiveness.
Notably, both drugs had acceptable safety profiles. In the future, the researchers hope to clarify the long-term impact of GLP-1 medications, the HFpEF subpopulations that may derive the most benefit from them, and whether the drugs are also effective in reducing other cardiovascular risks.
"By using nationwide data and an innovative methodological approach, our team was able to expand the findings of previous trials to larger populations more representative of HFpEF patients treated in clinical practice," Krüger said. "Our findings show that in the future, GLP-1 targeting medications could provide a much-needed treatment option for patients with heart failure."
Authorship: In addition to Krüger, Mass General Brigham authors include Sebastian Schneeweiss, Kenshiro Fuse, Sushama Kattinakere Sreedhara, Georg Hahn, and Shirley V. Wang. Additional authors include Sofiya Matsekyo and Heribert Schunkert.
Disclosures: Dr. Krüger has no disclosures. Dr. Schneeweiss is participating in investigator-initiated grants to the Brigham and Women's Hospital from Boehringer Ingelheim, Takeda, and UCB unrelated to the topic of this study. He is advisor to and equity holder of Aetion Inc., a software manufacturer. He is an advisor to Temedica GmbH, a patient-oriented data generation company. His interests were declared, reviewed, and approved by Mass General Brigham in accordance with their institutional compliance policies. Dr. Wang has been an ad hoc consultant to Exponent Inc, Cytel Inc, and MITRE, a federally funded research and development center for the Centers for Medicare and Medicaid on unrelated work.
Funding: This work was funded by the National Institutes of Health (R01-HL141505, R01-AR080194) and the German Heart Foundation (S/02/24, SRF-HF/24).
Paper cited: Krüger, N et al. "Semaglutide and Tirzepatide in Patients with Heart Failure with Preserved Ejection Fraction" JAMA DOI: /10.1001/jama.2025.14092
