Genetic testing can identify individuals at increased risk for hereditary heart muscle diseases. An international study involving the German Centre for Cardiovascular Research (DZHK) now shows that this genetic information can have concrete therapeutic implications. Published in the journal Nature Medicine, the study demonstrates that the diabetes drug dapagliflozin significantly reduces the risk of hospitalization due to heart failure in individuals with specific genetic variants.
Data from over 12,600 participants analyzed
Dapagliflozin, an SGLT2 inhibitor, is already widely used in the treatment of type 2 diabetes and heart failure. For this publication, researchers analyzed exome sequencing data from 12,685 participants in the clinical DECLARE-TIMI 58 trial. This trial originally investigated whether dapagliflozin could prevent major cardiovascular events in people with type 2 diabetes and elevated cardiovascular risk. A clear benefit in preventing heart failure had already been demonstrated. The newly published analysis went a step further by examining whether specific genetic risk factors influence therapeutic outcomes.
The researchers identified 121 individuals carrying pathogenic genetic variants associated with cardiomyopathies. At the start of the observation period, 82% of these carriers had not yet developed clinical heart failure.
The comparison revealed a markedly increased baseline risk: within just over four years, 16% of variant carriers in the placebo group were hospitalized due to heart failure, compared to only 3.5% of non-carriers. This corresponds to more than an eightfold increased risk in genetically predisposed individuals.
Treatment with dapagliflozin reduced this risk in variant carriers by 82%. The absolute rate of hospitalizations in this group dropped from 16% to 3.1%, nearly matching the level observed in the control group. Among individuals without these specific genetic variants, the risk reduction was 30%.
“Genetic testing is increasingly used to identify individuals at elevated risk for cardiomyopathies. However, it has often been unclear what concrete therapeutic consequences should follow,” says first author Dr. Shinwan Kany from the University Heart and Vascular Center Hamburg and the DZHK.
New perspectives for prevention
The results were particularly striking in the subgroup of individuals who showed no signs of heart failure at baseline. Among variant carriers treated with dapagliflozin, no one required hospitalization for heart failure during the entire observation period.
“Our findings suggest that genetic information could in the future help identify individuals who particularly benefit from early preventive treatment,” says Kany. “This opens up the possibility of preventing or at least delaying heart failure before the first symptoms occur—especially at a time when genetic testing is becoming increasingly common.”
The authors note that this is a post hoc analysis of a previously completed study with a relatively small number of identified variant carriers. Whether the preventive use of SGLT2 inhibitors in genetically predisposed but still asymptomatic individuals should be recommended in clinical guidelines must be confirmed by prospective clinical trials specifically designed for this purpose.
Nevertheless, the results provide an important indication for the future of precision medicine. Genetic testing could not only help identify high-risk individuals at an early stage but also pave the way for more individualized prevention strategies, where treatment begins even before the first symptoms of heart failure appear.
Scientific Contact: Dr. med. Shinwan Kany, University Heart and Vascular Center Hamburg, Department of Cardiology, University Medical Center Hamburg-Eppendorf, s.kany[at]uke.de
Original publication: Marston, N A, Kany, S, Melloni, G E M et al. Effects of SGLT2 inhibition on incident heart failure in carriers of cardiomyopathy-associated genetic variants. Nat Med. 2026. doi.org/10.1038/s41591-026-04439-x
