Dapagliflozin Reduces Heart Failure Risk by 82% in Carriers of Cardiomyopathy Genetic Variants
Key Insights
Dapagliflozin reduced heart failure (search) hospitalizations by 82% in type 2 diabetes (search) patients carrying cardiomyopathy (search) genetic variants, compared to a 32% reduction in non-carriers.
The analysis drew on genome sequencing data from 12,685 participants in the phase 3 DECLARE-TIMI 58 trial, identifying 121 cardiomyopathy (search) variant carriers.
Among carriers on placebo, 16% were hospitalized for heart failure (search) over a median 4.2-year follow-up, versus only 3% of those receiving dapagliflozin.
New research from the Mass General Brigham Heart and Vascular Institute (search) and the Broad Institute of MIT and Harvard (search) has demonstrated that dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor used to treat type 2 diabetes (search), is dramatically more effective at preventing heart failure (search) hospitalizations in individuals who carry rare genetic variants linked to cardiomyopathy (search). The findings, published in Nature Medicine, suggest that genetic screening could play a pivotal role in guiding heart failure prevention strategies.
The study found that while dapagliflozin reduced heart failure (search) hospitalizations by 32% in non-carriers compared to placebo, the drug slashed risk by approximately 82% in those harboring cardiomyopathy (search)-associated variants.
"Historically, identifying a genetic variant for cardiomyopathy (search) 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 (search) and the Broad Institute.
Genetic Analysis of a Landmark Trial
The researchers performed a post hoc analysis of genome sequencing data from the DECLARE-TIMI 58 trial, a phase 3 clinical trial that investigated dapagliflozin in patients with type 2 diabetes (search). Among 12,685 participants, 121 were identified as carriers of a cardiomyopathy (search) variant.
Over a median follow-up period of 4.2 years, 16% of cardiomyopathy (search) variant carriers who received placebo were hospitalized for heart failure (search). In stark contrast, only 3% of carriers treated with dapagliflozin experienced heart failure hospitalization—representing an 82% relative risk reduction. Notably, the protective effects of dapagliflozin were observed in participants both with and without a prior history of heart failure.
"Cardiomyopathy (search) 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 (search). "This is especially relevant for patients without established heart failure (search), where such treatment may not be otherwise initiated."
Toward Genetically Guided Prevention
The findings underscore the growing potential for incorporating genetic screening into clinical cardiovascular risk assessment. Corresponding author Christian T. Ruff, MD, MPH, a cardiologist with Mass General Brigham Heart and Vascular Institute (search) and Senior Investigator at the TIMI Study Group, emphasized the paradigm shift: "Moving toward early, genetically guided intervention could allow us to protect these vulnerable patients long before they develop symptoms."
People with diabetes are known to face elevated risk of heart disease. Dapagliflozin works by increasing urinary excretion of glucose and sodium, a mechanism that may help the heart function more efficiently. While prior studies established dapagliflozin's benefit in patients with established heart disease and its role in preventing heart failure (search) in those without known disease, the question of whether cardiomyopathy (search) variant status modulates treatment response had remained unanswered—until now.
Limitations and Future Directions
Because all participants in the DECLARE-TIMI 58 trial had type 2 diabetes (search), the researchers caution that further investigation is required to determine whether dapagliflozin confers the same degree of protection in cardiomyopathy (search) variant carriers who do not have diabetes. This represents a critical next step for translating these findings into broader clinical practice.