Effects of SGLT2 inhibition on incident heart failure in carriers of cardiomyopathy-associated genetic variants.

Summary

A genetic subanalysis of DECLARE-TIMI 58 shows dapagliflozin markedly reduces heart failure hospitalization in carriers of pathogenic/likely pathogenic cardiomyopathy variants, with a significant treatment-by-genotype interaction. Absolute risk reduction was 13.0% in carriers versus 1.0% in noncarriers over 4.2 years, suggesting genotype-informed early SGLT2 inhibitor use for prevention.

Key Findings

• Among 12,685 sequenced participants, 121 (≈1%) carried pathogenic/likely pathogenic cardiomyopathy variants.
• Dapagliflozin reduced HHF more strongly in carriers (HR 0.18, 95% CI 0.04–0.86) than in noncarriers (HR 0.70, 95% CI 0.57–0.86); Pinteraction=0.03.
• Absolute risk reduction was 13.0% in carriers vs 1.0% in noncarriers over a median 4.2 years.
• In carriers without prior HF (82% of carriers), dapagliflozin reduced HHF by 12.8% vs 0.6% in noncarriers (Pinteraction=0.01).

Clinical Implications

Consider genetic testing for cardiomyopathy variants in at-risk older adults with type 2 diabetes to inform early initiation of SGLT2 inhibitors for HF prevention, pending prospective validation. Clinicians should recognize greater absolute benefit in variant carriers.

Limitations

• Post hoc subgroup analysis; genotype not randomized
• Small number of variant carriers limits precision and generalizability to broader populations

Future Directions

Prospective, genotype-stratified trials to validate preventive SGLT2 inhibitor strategies in cardiomyopathy variant carriers and to explore variant-specific responses.