Rare genetic variants known to cause cardiomyopathy, an inherited cause of a weak heart, can increase the risk of patients developing heart failure. However, new research from Mass General Brigham Heart and Vascular Institute and the Broad Institute of MIT and Harvard reveals that dapagliflozin, a medication used to treat type 2 diabetes, is particularly effective at reducing the risk in individuals who are genetically predisposed to developing heart failure.
The findings, published in Nature Medicine , highlight the growing potential for incorporating genetic screening into heart failure prevention strategies. While dapagliflozin reduced heart failure hospitalizations by 32% in non-carriers compared to placebo, the drug reduced risk in cardiomyopathy variant carriers by about 80%.
"Historically, identifying a genetic variant for cardiomyopathy mostly meant telling a patient they were at high risk and not having a specific preventative therapy to offer. These data show we do have tools to lower risk in these individuals," said co-lead author Shinwan Kany, MD, MSc, a visiting scientist at the Cardiovascular Research Center with Mass General Brigham Heart and Vascular Institute and the Broad Institute.
"Moving toward early, genetically guided intervention could allow us to protect these vulnerable patients long before they develop symptoms," said corresponding author Christian T. Ruff, MD, MPH, a cardiologist with Mass General Brigham Heart and Vascular Institute and Senior Investigator at the TIMI Study Group.
People with diabetes are often at higher risk of heart disease. Dapagliflozin treats diabetes by increasing the excretion of glucose and sodium in urine, a process that among other things may help the heart work more efficiently. While previous studies have established that dapagliflozin can help treat patients with established heart disease and prevent the development of heart failure in those without known disease, it remained unclear until now whether having a cardiomyopathy variant would affect the magnitude of benefit.
To assess the impact of the efficacy of dapagliflozin in cardiomyopathy variant carriers, the researchers analyzed genome sequencing data from the DECLARE-TIMI 58 trial, a phase 3 clinical trial investigating dapagliflozin treatment in patients with type 2 diabetes.
From 12,685 patients, they identified 121 who carried a cardiomyopathy variant. During a median of 4.2 years of follow-up, 16% of cardiomyopathy variant carriers who received a placebo were hospitalized for heart failure. Dapagliflozin reduced hospitalizations for heart failure to 3% in carriers, representing an 82% relative reduction in risk compared to carriers who received placebo. Importantly, dapagliflozin showed protective effects in participants both with and without a prior history of heart failure.
"Cardiomyopathy variants represent an actionable genotype which can be used to identify patients who derive a larger benefit from dapagliflozin," said co-lead author Nicholas A. Marston, MD, MPH , a cardiologist with Mass General Brigham Heart and Vascular Institute. "This is especially relevant for patients without established heart failure, where such treatment may not be otherwise initiated."
Because all participants in the trial had type 2 diabetes, researchers emphasize that further research is needed to determine if dapagliflozin is equally effective in cardiomyopathy variant carriers who do not have diabetes.
Authorship: In addition to Kany, Ruff and Marston, authors include Giorgio E. M. Melloni, Sean J. Jurgens, Frederick K. Kamanu, Yi-Pin Lai, Joel T. Rämö, Itamar Raz, Stephen D. Wiviott, Patrick T. Ellinor, and Marc S. Sabatine.
Disclosures: Marston reports research grant support from the National Institutes of Health and involvement in clinical trials with Amgen, Ionis, Pfizer, Novartis, and AstraZeneca, consultant fees from Beckman Coulter,
Cleerly, Inc. (CPC Clinical Research) and Viz.ai, and honoraria for lectures/CME Programs from Amgen, Illumina, and Medical Education Speakers Network (MESN). Ruff reports research grant through his institution from Anthos, AstraZeneca, Daiichi Sankyo, Janssen and Novartis and honoraria for scientific advisory boards and consulting from ADARx, Bayer, Novartis, Sirius, Souffle. Additional author disclosures can be found in the paper.
Funding: DECLARE-TIMI 58 (NCT01730534) was funded by AstraZeneca. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Paper cited: Marston, N et al. "Effects of SGLT2 inhibition on incident heart failure in carriers of cardiomyopathy associated genetic variants" Nature Medicine DOI: 10.1038/s41591-026-04439-x
