Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus

Abstract

Background: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. Methods: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality. Results: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45–0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76–1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66–1.17]) and those without HF (HR, 0.88 [95% CI, 0.74–1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43–0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62–0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34–0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89–1.31]; P for interaction=0.012). Likewise, dapagliflozin 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]; P for interaction=0.016). Conclusions: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

Impact of diabetes on mortality and rehospitalization in acute heart failure patients stratified by ejection fraction

“…The DECLARE‐TIMI 58 trial has demonstrated that diabetic HF patients will benefit with dapagliflozin treatment in terms of reduced all‐cause mortality and cardiovascular death in HFrEF. Furthermore, there was also a noted reduction in HF‐related hospitalizations in both HFrEF and HFpEF patients . SGLT2 inhibitors were associated with reductions in HF hospitalizations in diabetic patients .…”

Dapagliflozin and DAPA‐HF: from glycaemic control to heart failure therapy

“…Between 10–14% of subjects in EMPA‐REG OUTCOME, CANVAS and DECLARE‐TIMI were recorded to have heart failure at baseline by their local investigator. Although hospitalisation for heart failure as an endpoint was blindly adjudicated according to pre‐specified criteria, the diagnostic criteria for heart failure at baseline and the type of heart failure are unknown, although here have been some post hoc attempts to identify information on ejection fraction in DECLARE and CANVAS subjects …”

Seventh World congress on controversies to consensus in diabetes, obesity, and hypertension

“…The seventh World Congress on Controversies to Consensus in Diabetes, Obesity, and Hypertension (CODHy 2019) took place in Sorrento, Italy from April 12 to 13. There, Professor Stefano Del Prato provided interesting counterpoints to growing enthusiasm for the use of sodium‐glucose cotransporter 2 (SGLT2) inhibitors in primary prevention, pointing to a recent analysis of the DECLARE‐TIMI 58 trial of dapagliflozin that shows modest benefits of treatment in those without established heart failure. Professor Del Prato first lamented the lack of generalizability of SGLT2 inhibitor cardiovascular (CV) outcomes trials before critiquing the risk‐benefit profile of these treatments in the primary prevention of heart failure.…”

“…Professor Del Prato first lamented the lack of generalizability of SGLT2 inhibitor cardiovascular (CV) outcomes trials before critiquing the risk‐benefit profile of these treatments in the primary prevention of heart failure. He used this new analysis of DECLARE of the effects of dapagliflozin on heart failure outcomes in those with and without established heart failure to demonstrate that the absolute risk reduction in primary prevention populations (only 0.5% on heart failure hospitalizations) is troublingly low and raises important questions as to whether such treatment is justified. This absolute risk reduction amounts to a relatively high number needed to treat (NNT) value of 200 that may be impractical in clinical practice.…”

“…This absolute risk reduction amounts to a relatively high number needed to treat (NNT) value of 200 that may be impractical in clinical practice. For context, the NNT for dapagliflozin in those with heart failure with reduced ejection fraction (HFrEF) is a much smaller 18 . As a result, Professor Del Prato wondered whether the real risks associated with SGLT2 inhibitors (namely genital infections, euglycemic diabetic ketoacidosis [DKA], potential bone fractures and amputations) may outweigh the small benefits in this context.…”