McMurray JJV, Solomon SD, Inzucchi SE, et al.; DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 Nov 21;381(21):1995-2008. doi: 10.1056/NEJMoa1911303.
Koji Hasegawa, Director, Division of Translational Research, Kyoto Medical Center
Summary of the trial
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 glucose-independent 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. In this phase 3, placebo-controlled trial, the authors 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. 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.
Sodium–glucose cotransporter 2 (SGLT2) inhibitors have been primarily adopted as antidiabetic drugs to inhibit the reabsorption of glucose in the kidney. SGLT2 inhibitors possess diuretic actions, improve the lipid profile, and reduce blood pressure and body weight. The DAPA-HF trial included diabetic and nondiabetic patients with heart failure with reduced ejection fraction and clearly demonstrated that dapagliflozin markedly improved the prognosis in these patients by reducing rates of cardiovascular death and heart failure hospitalization.
These beneficial effects were seen in all subgroups (i.e., male vs. female, young vs. old, and diabetic vs. nondiabetic) and may not be explainable only by the drug’s diuretic actions or the decrease in afterload. Several other studies have suggested that SGLT2 inhibitors increase erythropoietin production, which improves oxygen supply to the heart. However, the precise mechanisms of the clinical benefits brought by SGLT2 inhibitors need to be clarified by further research. In the clinical setting, SGLT2 inhibitors should be recognized as essential drugs that can protect the heart and kidney in diabetic and nondiabetic patients.