A medication used to treat type 2 diabetes can significantly reduce the risk of heart failure in individuals who are genetically predisposed to cardiomyopathy, according to new research led by Harvard Medical School investigators at Brigham and Women’s Hospital and researchers at the Broad Institute of MIT and Harvard.
The findings, published June 8 in Nature Medicine, point to dapagliflozin as a potential preventive treatment specifically for patients with certain rare genetic variants known to cause cardiomyopathy. Treatment with dapagliflozin reduced heart failure hospitalizations by over 80 percent in trial participants carrying these genetic variants. In noncarriers, the medication reduced hospitalizations by 32 percent.
“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,” said co-first author Shinwan Kany, visiting scientist at Massachusetts General Hospital and the Broad Institute. “These data show we do have tools to lower risk in these individuals.”
The results highlight the growing potential for incorporating genetic screening into heart failure prevention strategies.
“Moving toward early, genetically guided intervention could allow us to protect these vulnerable patients long before they develop symptoms,” said senior author Christian Ruff, HMS associate professor of medicine at Brigham and Women’s.
Clinical trial data
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.
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. However, it wasn’t clear if the magnitude of these benefits would be different for someone genetically predisposed to heart failure.
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 participants, they identified 121 who carried at least one genetic variant for cardiomyopathy (76 people with dilated cardiomyopathy variants, 25 with hypertrophic cardiomyopathy variants, and 25 with arrhythmogenic cardiomyopathy variants).
The analysis showed that during a median of 4.2 years of follow-up, 16 percent of cardiomyopathy variant carriers who received a placebo were hospitalized for heart failure. Only 3 percent of carriers who received dapagliflozin were hospitalized for heart failure, representing an 82 percent relative reduction in risk compared to carriers who received placebo.
Big benefits for specific patients
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-first author Nicholas Marston, HMS assistant professor of medicine at Brigham and Women’s. “This is especially relevant for patients without established heart failure, where such treatment may not be otherwise initiated.”
The researchers emphasize that further research is needed to determine if dapagliflozin is equally effective in cardiomyopathy variant carriers who do not have diabetes.
Adapted from a Mass General Brigham news release.
Authorship, funding, disclosures
Additional 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.
The DECLARE-TIMI 58 clinical trial was funded by AstraZeneca and developed in collaboration with the TIMI Study Group. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
This work was supported by the National Institutes of Health (grants 1RO1HL092577 and K24HL105780), Deutsche Forschungsgemeinschaft (Emmy-Noether grant 571960922), the Dutch Heart Foundation (grant 03-007-2022-0035), the Sigrid Jusélius Foundation, the Fondation Leducq (14CVD01), and the American Heart Association Strategically Focused Research Networks.
Marston reports 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 grants through his institution from Anthos, AstraZeneca, Daiichi Sankyo, Janssen, and Novartis and honoraria for scientific advisory boards and consulting from ADARx, Bayer, Novartis, Sirius, and Soufflé Therapeutics. Additional author disclosures can be found in the paper.
