In a diabetes trial, a heart-failure drug's benefit looked largest in 121 patients carrying a cardiomyopathy gene variant

In a diabetes trial, a heart-failure drug's benefit looked largest in 121 patients carrying a cardiomyopathy gene variant — an exploratory signal

A hypothesis-generating subgroup of the DECLARE-TIMI 58 trial linked dapagliflozin to a larger cut in heart-failure hospitalization among 121 carriers of a cardiomyopathy variant, but the confidence interval is wide, it sets no general diabetes benefit, is no reason to start the drug to prevent heart failure, and carriers are identifiable only by genetic sequencing.

Genetics may help flag who benefits most from an SGLT2 inhibitor — at least as a preliminary signal. In a whole-exome substudy of the randomized DECLARE-TIMI 58 trial, dapagliflozin (Farxiga) was associated with a larger reduction in the risk of hospitalization for heart failure among patients carrying a cardiomyopathy-associated gene variant than among everyone else. This was an exploratory subgroup comparison, not a pre-planned primary endpoint, and it turns on just 121 carriers.

Investigators sequenced 12,685 trial participants — adults with type 2 diabetes and elevated cardiovascular risk, randomized to dapagliflozin 10 mg or placebo. Among them, 121 carried a pathogenic or likely pathogenic variant in a high-confidence cardiomyopathy gene (76 dilated, 25 hypertrophic, 25 arrhythmogenic). Over a median 4.2 years, dapagliflozin was associated with a hazard ratio of 0.18 (95% CI 0.04–0.86) for hospitalization for heart failure in carriers, versus 0.70 (95% CI 0.57–0.86) in noncarriers, with a P value for interaction of 0.03. The carrier confidence interval is wide — consistent with anything from a large effect to a modest one — because the carrier group is so small.

A wide gap in absolute terms, on small numbers

The absolute risk reduction was 13.0% in carriers and 1.0% in noncarriers (P interaction 0.03). Most carriers — 82% — had no prior heart failure; among those, dapagliflozin reduced absolute risk by 12.8%, against 0.6% in noncarriers (P interaction 0.01).

As a hypothesis to be tested rather than a clinical recommendation, the authors raise the possibility that SGLT2 inhibitor treatment might be started early to prevent heart failure in carriers of cardiomyopathy variants — something they say must first be tested in a dedicated trial.

This is a small, exploratory, hypothesis-generating subgroup analysis: the carrier group is tiny, the confidence interval wide, and an association within a subgroup is not proof of causation. It does not establish that people with type 2 diabetes in general benefit, and it is not a basis for anyone to start dapagliflozin to prevent heart failure — the carrier group is genetically defined and can be identified only by sequencing. Writing in Nature Medicine, the authors say the results “need to be confirmed in a prospective, dedicated trial of preventive HF treatments in carriers.” DECLARE-TIMI 58, sponsored by AstraZeneca, enrolled 17,190 patients and completed in September 2018.