A medication already used to treat type 2 diabetes may substantially reduce the risk of heart failure hospitalization among people who carry inherited genetic variants associated with cardiomyopathy, according to researchers from the Mass General Brigham Heart and Vascular Institute and the Broad Institute of MIT and Harvard. The study, published in Nature Medicine, found that dapagliflozin reduced the risk of heart failure hospitalization by about 80% in patients carrying cardiomyopathy-associated genetic variants, compared with placebo, indicating that genetic testing could help identify people who could benefit from preventive treatments.
“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, a visiting scientist at the Cardiovascular Research Center with Mass General Brigham Heart and Vascular Institute and the Broad Institute.
Previous studies have already shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors such as dapagliflozin can reduce hospitalizations for heart failure in patients with diabetes and cardiovascular risk factors. The current study sought to find out if patients carrying rare pathogenic variants linked to cardiomyopathy might experience even more benefit from the drug.
The research was driven by an increasing body of evidence that inherited cardiomyopathies contribute to heart failure risk and that pathogenic or likely pathogenic variants are present not only in patients with diagnosed disease but also in asymptomatic individuals. The researchers noted that genetic testing is increasingly used in cardiomyopathy care and family screening, but clinician often don’t know how to proceed when identifying a relevant genetic variant in otherwise healthy carriers.
For this study, the team analyzed whole-exome sequencing data from the DECLARE-TIMI 58 trial, a randomized Phase III trial of dapagliflozin in adults with type 2 diabetes and elevated cardiovascular risk. Of the 12,685 participants with genetic sequencing data, the team identified 121 carriers of pathogenic or likely pathogenic variants in high-confidence cardiomyopathy genes.
Analysis of the data showed that the cardiomyopathy variant carriers faced substantially higher risk of heart failure hospitalization when treated with placebo and experienced an eightfold increased risk of heart failure hospitalization.
Over a median follow-up of 4.2 years, 16% of variant carriers receiving placebo were hospitalized for heart failure. Among carriers treated with dapagliflozin, that figure fell to 3%, representing an 82% relative reduction in risk. By comparison, noncarriers experienced a smaller reduction in heart failure hospitalization risk.
The findings were particularly notable among patients who had not yet developed heart failure. About 82% of the variant carriers in the study had no prior history of heart failure at enrollment. Among that group, dapagliflozin reduced the absolute risk of heart failure hospitalization by 12.8%, compared with a reduction of 0.6% among noncarriers.
“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, PhD, a cardiologist at the Brigham and Women’s Hospital. “This is especially relevant for patients without established heart failure, where such treatment may not be otherwise initiated.”
The researchers noted that the findings should be interpreted within the context of a post-hoc analysis and that the number of variant carriers was relatively small. Because all participants had type 2 diabetes and elevated cardiovascular risk, it remains uncertain whether the same degree of benefit would occur in people without diabetes.
Future research will focus on confirming the findings in prospective clinical trials specifically designed to evaluate preventive heart failure therapies in carriers of cardiomyopathy-associated genetic variants.
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