Additional treatments are needed for heart failure with reduced ejection fraction
(HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment
for patients with HFrEF, even those without diabetes.To evaluate the effects of dapagliflozin
in patients with HFrEF with and without diabetes.Exploratory analysis of a phase 3
randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart
Association classification II to IV with an ejection fraction less than or equal to
40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between
February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019.Addition
of once-daily 10 mg of dapagliflozin or placebo to recommended therapy.The primary
outcome was the composite of an episode of worsening heart failure or cardiovascular
death. This outcome was analyzed by baseline diabetes status and, in patients without
diabetes, by glycated hemoglobin level less than 5.7% vs greater than or equal to
5.7%.Among 4744 patients randomized (mean age, 66 years; 1109 [23%] women; 2605 [55%]
without diabetes), 4742 completed the trial. Among participants without diabetes,
the primary outcome occurred in 171 of 1298 (13.2%) in the dapagliflozin group and
231 of 1307 (17.7%) in the placebo group (hazard ratio, 0.73 [95% CI, 0.60-0.88]).
In patients with diabetes, the primary outcome occurred in 215 of 1075 (20.0%) in
the dapagliflozin group and 271 of 1064 (25.5%) in the placebo group (hazard ratio,
0.75 [95% CI, 0.63-0.90]) (P value for interaction = .80). Among patients without
diabetes and a glycated hemoglobin level less than 5.7%, the primary outcome occurred
in 53 of 438 patients (12.1%) in the dapagliflozin group and 71 of 419 (16.9%) in
the placebo group (hazard ratio, 0.67 [95% CI, 0.47-0.96]). In patients with a glycated
hemoglobin of at least 5.7%, the primary outcome occurred in 118 of 860 patients (13.7%)
in the dapagliflozin group and 160 of 888 (18.0%) in the placebo group (hazard ratio,
0.74 [95% CI, 0.59-0.94]) (P value for interaction = .72). Volume depletion was reported
as an adverse event in 7.3% of patients in the dapagliflozin group and 6.1% in the
placebo group among patients without diabetes and in 7.8% of patients in the dapagliflozin
group and 7.8% in the placebo group among patients with diabetes. A kidney adverse
event was reported in 4.8% of patients in the dapagliflozin group and 6.0% in the
placebo group among patients without diabetes and in 8.5% of patients in the dapagliflozin
group and 8.7% in the placebo group among patients with diabetes.In this exploratory
analysis of a randomized trial of patients with HFrEF, dapagliflozin compared with
placebo, when added to recommended therapy, significantly reduced the risk of worsening
heart failure or cardiovascular death independently of diabetes status.ClinicalTrials.gov
Identifier: NCT03036124.
