Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction

Abstract

BACKGROUND In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucoseindependent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes. METHODS In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death. RESULTS Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups. CONCLUSIONS Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF ClinicalTrials .gov number, NCT03036124.

ADVANCE in context: The benefits, risks and feasibility of providing intensive glycaemic control based on gliclazide modified release

“…The EMPA‐Reg, CANVAS, DECLARE‐TIMI and CREDENCE trials all reported the superiority of the introduction of SGLT‐2 inhibitors compared with placebo and standard care among patients with type 2 diabetes . More recently, the DAPA‐HF trial also reported the superiority of SGLT‐2 inhibitors in a mixed diabetic and non‐diabetic population with reduced ejection fraction heart failure . Similarly, the LEADER, SUSTAIN 6, HARMONY and REWIND trials all reported the superiority of the introduction of GLP‐1 agonists compared with placebo and standard care among patients with type 2 diabetes .…”

“…The emergence of new approaches to glucose lowering with proven cardiovascular and renal benefits (ie, sodium‐glucose co‐transporter‐2 [SGLT‐2] inhibitors and glucagon‐like peptide‐1 [GLP‐1] agonists) has created further uncertainty as to the value of aiming for near normal glycaemic targets without consideration of the agents used. Indeed, the growing body of trial evidence would suggest that the agents used, at least over the short term (2‐5 years), may be even more important (especially in high‐risk patients with clinically apparent cardiovascular or renal disease) . The EMPA‐Reg, CANVAS, DECLARE‐TIMI and CREDENCE trials all reported the superiority of the introduction of SGLT‐2 inhibitors compared with placebo and standard care among patients with type 2 diabetes .…”

Treatment of heart failure with sodium glucose co‐transporter‐2 inhibitors in people with type 2 diabetes mellitus: current evidence and future directions

“…Since the initial preparation of this paper, the primary results of the DAPA‐HF trial have been reported . These demonstrate a marked 26% relative risk reduction in the primary outcome of cardiovascular death or worsening heart failure, with significant reductions in both components of the primary outcome, and a reduction in all‐cause mortality.…”

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

“…In total, 4744 patients with New York Heart Association class II, III or IV heart failure and ejection fraction ≤40% were included . Forty‐two percent of subjects had a prior diagnosis of diabetes, and a small number of patients (3%) were diagnosed as having diabetes on the basis of a baseline HbA 1c measurement of 48mmol/mol or greater.…”

“…The primary outcome was a composite of worsening heart failure (hospitalisation or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death. The results were presented at the recent meeting of the EASD, with simultaneous publication online in the New England Journal of Medicine …”