Genetic variants may identify patients most likely to benefit from dapagliflozin

Clinical Takeaway: Dapagliflozin may be particularly effective for preventing heart failure in patients with inherited cardiomyopathy risk and could help support a more genetically guided approach to prevention.

Pathogenic variants associated with inherited cardiomyopathies are increasingly identified through genetic testing and family screening. Yet for many asymptomatic carriers, clinicians have had few evidence-based interventions to offer beyond surveillance and risk monitoring.

In a genetic analysis of the DECLARE-TIMI 58 trial, investigators evaluated whether carriers of cardiomyopathy-associated variants derived greater benefit from dapagliflozin than noncarriers. Among more than 12,600 participants with type 2 diabetes and elevated cardiovascular risk, 121 carried a pathogenic or likely pathogenic cardiomyopathy variant.

The analysis reinforced that these variants identify a high-risk population. In the placebo group, carriers had an approximately eightfold higher risk of heart failure hospitalization than noncarriers, with event rates of 16% and 3.5%, respectively.

Dapagliflozin reduced heart failure hospitalization risk regardless of carrier status, but the benefit was substantially greater among variant carriers. Treatment was associated with an 82% reduction in risk among carriers compared with a 30% reduction among noncarriers, with an absolute risk reduction of 13% versus 1%, respectively.

The benefit was especially pronounced among participants without heart failure at baseline. Most variant carriers had no prior history of heart failure, and dapagliflozin appeared to reduce their risk to levels similar to those seen in noncarriers. No carrier treated with dapagliflozin experienced a heart failure hospitalization during follow-up.

The results suggest that cardiomyopathy-associated variants may represent an actionable genotype for heart failure prevention. However, all participants had type 2 diabetes and elevated cardiovascular risk, and only 121 variant carriers were identified. The authors emphasized that dedicated prospective trials will be needed to determine whether SGLT2 inhibitors should be initiated specifically for heart failure prevention in asymptomatic genetic variant carriers.

“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, MSc. “Moving toward early, genetically guided intervention could allow us to protect these vulnerable patients long before they develop symptoms.”

Source: Marston NA, et al. 2026 June 8. Nat Med. Effects of SGLT2 inhibition on incident heart failure in carriers of cardiomyopathy-associated genetic variants