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

Summary

In DECLARE-TIMI 58 (n=12,685 sequenced), carriers of pathogenic/likely pathogenic cardiomyopathy variants (n=121) experienced a markedly greater reduction in heart-failure hospitalization with dapagliflozin versus placebo than noncarriers, with large absolute risk reductions and significant treatment-by-genotype interaction. Benefits extended to carriers without prior HF.

Key Findings

• Carriers of P/LP cardiomyopathy variants (n=121 of 12,685) had greater HHF risk reduction with dapagliflozin (HR 0.18) than noncarriers (HR 0.70); Pinteraction=0.03.
• Absolute HHF risk reduction was 13.0% in carriers vs 1.0% in noncarriers; effect persisted in carriers without prior HF.
• Median follow-up was 4.2 years in a high cardiovascular-risk T2D cohort.

Clinical Implications

Genotyping for cardiomyopathy genes could identify T2D patients who derive outsized HF-preventive benefit from dapagliflozin; prospective genotype-guided trials are warranted.

Limitations

• Genetic subgroup analysis with small carrier numbers limits precision
• Post hoc nature within an RCT; findings need confirmation in prospective genotype-guided trials

Future Directions

Prospective trials to test early SGLT2i initiation in variant carriers, mechanistic studies linking genotype to SGLT2i responsiveness, and health-economic evaluations of genotype-guided care.