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Published on: April 8, 2013
Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction
John J V McMurray1, Scott D Solomon1, Silvio E Inzucchi1
1From the BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P., K.F.D., P.S.J.); the Cardiovascular Division (S.D.S., A.S.D.) and the TIMI Study Group, Brigham and Women's Hospital and Harvard Medical School (M.S.S.) - all in Boston; Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.); Rigshospitalet Copenhagen University Hospital (L.K.) and the Department of Cardiology, Gentofte University Hospital (M. Schou), Copenhagen; the Department of Medicine, Saarland University Hospital, Homburg-Saar, Germany (M.B.); Saint Luke's Mid America Heart Institute, University of Missouri, Kansas City (M.N.K.); National University of Cordoba, Cordoba (F.A.M.), and the Division of Cardiology, Instituto Cardiovascular de Buenos Aires, Buenos Aires (M.D.) - both in Argentina; Wroclaw Medical University, Wroclaw (P.P.), and the Department of Cardiology, Medical University of Lodz, Lodz (J.D.) - both in Poland; the Department of Cardiology, University of Minnesota, Minneapolis (I.S.A.); 2nd Department of Internal Medicine, Cardiovascular Medicine, General Teaching Hospital and 1st Faculty of Medicine, Charles University, Prague, Czech Republic (J.B.); the Division of Cardiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan (C.-E.C.); the Department of Cardiology, Medanta, Gurgaon, India (V.K.C.); the Department of Cardiology, University Medical Center and University of Groningen, Groningen, the Netherlands (R.A.B.); the 5th Department of Internal Medicine, Comenius University in Bratislava, Bratislava, Slovakia (A.D.); the Department of Cardiology, Shanghai Institute of Cardiovascular Disease and Zhongshan Hospital Fudan University, Shanghai, China (J.G.); Cumming School of Medicine and Libin Cardiovascular Institute, University of Calgary, Calgary, AB (J.G.H.), the Department of Cardiology, Montreal Heart Institute, Montreal (E.O.), and the Division of Cardiac Surgery, St. Michael's Hospital, University of Toronto, Toronto (S.V.) - all in Canada; Clinic of Cardiology, National Cardiology Hospital, Sofia, Bulgaria (T.K.); the Cardiovascular Division of Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (M.K.); the Department of Molecular and Clinical Medicine and Cardiology, Sahlgrenska Academy (C.E.A.L.), and AstraZeneca (O.B., M. Sjöstrand, A.M.L.), Gothenburg, and the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University (C.H.), Uppsala - all in Sweden; the Heart and Vascular Center, Semmelweis University, Budapest, Hungary (B.M.); Instituto do Coracao, Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paolo, São Paolo (J.C.N.); the Department of Internal Medicine, Tan Tao University, Tan Duc, Vietnam (P.N.V.); the Department of Myocardial Disease and Heart Failure, National Medical Research Center of Cardiology, Moscow (S.T.); and the Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison (D.L.D.).
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 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.
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.).
Insights
Sodium-glucose cotransporter 2 (SGLT2) inhibitors like dapagliflozin significantly reduce heart failure hospitalizations and cardiovascular death in patients with reduced ejection fraction. These benefits were observed regardless of diabetes status, with similar safety profiles.
Area of Science:
- Cardiology
- Endocrinology
- Pharmacology
Background:
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors show promise in managing heart failure, potentially via glucose-independent pathways.
- Further research is needed on SGLT2 inhibitors for patients with established heart failure with reduced ejection fraction (HFrEF), irrespective of diabetes status.
Purpose of the Study:
- To evaluate the efficacy and safety of dapagliflozin in patients with symptomatic heart failure and reduced ejection fraction.
Main Methods:
- A phase 3, randomized, placebo-controlled trial involving 4744 patients with New York Heart Association class II-IV HFrEF.
- Patients received either dapagliflozin (10 mg once daily) or placebo, alongside standard heart failure therapy.
- The primary outcome was a composite of worsening heart failure events or cardiovascular death.
Main Results:
- Dapagliflozin significantly reduced the primary composite outcome (hazard ratio, 0.74; P<0.001) and individual components like worsening heart failure and cardiovascular death.
- Benefits were consistent across patients with and without type 2 diabetes.
- Adverse event rates for volume depletion, renal dysfunction, and hypoglycemia were similar between groups.
Conclusions:
- Dapagliflozin effectively lowers the risk of worsening heart failure or cardiovascular death in patients with HFrEF.
- The therapeutic benefits of dapagliflozin in HFrEF extend to patients both with and without diabetes.
- Dapagliflozin demonstrated a favorable safety profile in this patient population.
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