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Study Summary

The DECLARE-TIMI 58 study demonstrated a reduction in the composite of cardiovascular death or hospitalization for heart failure with dapagliflozin compared to placebo in patients with type 2 diabetes. This was a pre-specified subgroup analysis of DECLARE-TIMI 58 examining the efficacy of dapagliflozin according to baseline heart failure status and systolic left ventricular ejection fraction (see accompanying Hurst's Central Illustration). Of 17,160 patients, 671 (3.9%) had heart failure with reduced ejection fraction (HFrEF), 1316 (7.7%) had heart failure without known reduced ejection fraction, and 15173 (88.4%) had no baseline history of heart failure. Dapagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure by 38% in patients with HFrEF compared to 12% in those without HFrEF (P interaction 0.046). This difference in treatment effect was driven by a reduction in cardiovascular deaths in patients with HFrEF (HR 0.55, 95% CI 0.34-0.90) that was not observed in those without HFrEF (HR 1.08, 95% CI 0.89-1.31). Dapagliflozin significantly reduced all-cause mortality in patients with HFrEF (HR 0.59, 95% CI 0.40-0.88) but not in those without HFrEF (HR 0.97, 95% CI 0.86-1.10).

Commentary

Study Strengths: DECLARE is a large trial with a long duration of follow-up in a broad population of patients. The study population included the largest group of heart failure patients among all SGLT2 inhibitor trials. Furthermore, this is the only study to date examining the relationship between baseline left ventricular function and the benefit of SGLT2 inhibition on cardiovascular outcomes.

Study Limitations: The findings should be interpreted cautiously and be considered exploratory results due to the limitations of subgroup analyses. Although heart failure status was obtained for all patients, only one-third of randomized patients had data on left ventricular ejection fraction.

Next Steps/Clinical Perspective: This pre-specified subgroup analysis of the DECLARE study demonstrated that dapagliflozin reduced hospitalization for heart failure and cardiovascular mortality in patients with diabetes and heart failure across a spectrum of left ventricular function. The greatest benefit was seen in those with HFrEF. This study extends our current understanding of the benefits of SGLT2 inhibitors on cardiovascular outcomes in patients with and without heart failure and highlights the need for further investigation.

Trial Reference

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Kato  ET, Silverman  MG, Mosenzon  O, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation doi: 10.1161/CIRCULATIONAHA.119.040130

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