For people carrying rare genetic variants that predispose them to cardiomyopathy—a weakening of the heart muscle that can lead to life-threatening heart failure—there was historically little to offer beyond a warning. Identify the mutation, learn you were at high risk, and wait. But new research from Mass General Brigham Heart and Vascular Institute and the Broad Institute of MIT and Harvard has upended that bleak calculus: dapagliflozin, a medication used to treat type 2 diabetes, slashes heart failure hospitalization risk by 82% in patients carrying these dangerous variants.
The discovery matters because cardiomyopathy variants affect thousands of people worldwide who may never know they carry them until heart failure strikes. For decades, genetic screening for these conditions was largely a way to flag risk without offering prevention. The new findings, published in Nature Medicine, show that we now have a concrete tool to intercept disease before symptoms emerge—a paradigm shift in how we might approach inherited heart disease.
The research analyzed genome sequencing data from the DECLARE-TIMI 58 trial, a major phase 3 study investigating dapagliflozin in patients with type 2 diabetes. Among 12,685 trial participants, researchers identified 121 who carried cardiomyopathy-associated genetic variants. Over a median follow-up of 4.2 years, the results were striking: among variant carriers who received placebo, 16% were hospitalized for heart failure. When given dapagliflozin, that number plummeted to 3%—an 82% relative risk reduction. By contrast, the drug reduced hospitalizations by 32% in patients without cardiomyopathy variants, highlighting just how potent its protective effect is in those with genetic predisposition.
"Historically, identifying a genetic variant for cardiomyopathy mostly meant telling a patient they were at high risk and not having a specific preventive therapy to offer. These data show we do have tools to lower risk in these individuals," said Dr. Shinwan Kany, a visiting scientist at Mass General Brigham's Cardiovascular Research Center. Dapagliflozin works by increasing glucose and sodium excretion through the urine—a mechanism that, among other benefits, appears to help the heart function more efficiently.
What makes this finding especially valuable is that dapagliflozin showed protection across the board: in variant carriers with a prior history of heart failure and, critically, in those without established disease. This opens a door to early intervention—catching genetic risk before it manifests as symptoms. "Moving toward early, genetically guided intervention could allow us to protect these vulnerable patients long before they develop symptoms," said Dr. Christian T. Ruff, a cardiologist at Mass General Brigham and corresponding author on the study.
Dr. Nicholas A. Marston, another co-lead author, noted the significance for patients without diagnosed heart failure: "This is especially relevant for patients without established heart failure, where such treatment may not otherwise be initiated."
The researchers acknowledge one important limitation: all trial participants had type 2 diabetes, so further research is needed to understand whether dapagliflozin offers the same protection in cardiomyopathy variant carriers without diabetes. Still, the findings suggest a future where genetic screening isn't a death sentence—it's a map to prevention.