PracticeUpdate Diabetes June 2019

EDITOR’S PICKS 6

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

COMMENT By James L. Januzzi MD S odium/glucose cotransporter-2 (SGLT2) inhibitors reduced car- diovascular events in outcomes trials of patients with type 2 diabetes (T2D) and a hemoglobin A1c above 7.0%, with an early and particularly strong impact on heart failure (HF) hos- pitalization. It remains unclear whether the benefits of SGLT2 inhibitors vary depending on left ventricular ejection fraction (LVEF). Given that heart failure with preserved EF (HFpEF) is a diagno- sis lacking defined treatments, a benefit from SGLT2 inhibitors would be of great importance. In the present analysis from the Dapagliflozin Effect on CardiovascuLAR Events (DECLARE) TIMI-58 trial, Kato and colleagues sought to evaluate effects of dapagliflozin on risk for cardiovascular death or hospitalization for HF relative to presence of HF with reduced EF (HFrEF; defined somewhat unusually as an LVEF ≤45% compared with the usual cut-off of 40% in most studies), “HF without known reduced EF” (a mixture of HFpEF and HF without available LVEF data), and no history of HF at study entry. The investigators found that dapagliflozin reduced cardiovascular death/HF hospitalization along with all- cause death most in those with HFrEF, with less obvious benefit in patients with HFpEF (where HF hospitalization was reduced but mortality was less obviously affected). These results should be considered hypothesis-generating only as they are based on historical LVEF categorized using an unorthodox cut-point for “HFrEF.” Understanding regarding the effect of SGLT2 inhibitors across the spectrum of LVEF will be definitively addressed by ongoing randomized studies enrolling carefully phenotyped patients with HF.

Take-home message • In this study, the authors evaluated data from patients with heart failure with reduced ejection fraction (HFrEF) from the DECLARE-TIMI 58 trial in order to determine the efficacy of the SGLT2 inhibitor dapagliflozin for reducing cardiovascular (CV) death and hospitalization for HF (HHF). The use of dapagliflozin was associated with a greater reduction in the CV death/HHF composite in patients with HFrEF compared with patients without HFrEF. Further analysis revealed that dapagliflozin reduced HHF in all subgroups, but reduced CV death and all-cause mortality only in the HFrEF group. • The authors concluded that dapagliflozin shows promise for reducing overall HHF and reducing CV and all-cause mortality in patients with HFrEF.

Abstract BACKGROUND In DECLARE-TIMI 58, the sodium glucose co-transporter 2 inhibitor (SGLT2i) dapagliflozin reduced the composite endpoint of cardiovascular (CV) death/ hospitalization for heart failure (HHF) in a broad population of patients with T2DM. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of SGLT2i is unknown. METHODS In the DECLARE-TIMI 58 trial, baseline HF status was collected from all patients and EF where available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of CV death/HHF, its com- ponents, and all-cause mortality (ACM). 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 CV death/HHF more in patients with HFrEF (HR 0.62, 95% CI 0.45-0.86) than in those without HFrEF (HR 0.88, 95% CI 0.76-1.02; P-interaction 0.046), in whom the treat- ment 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 without HFrEF (HR 0.76, 95%CI 0.62-0.92), it reduced CV death only in patients with HFrEF (HR 0.55, 95% CI 0.34-0.90) but not in those with- out HFrEF (HR 1.08, 95%CI 0.89-1.31, P-interaction 0.012). Likewise, dapagliflozin reduced ACM 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-interaction 0.016). CONCLUSIONS In the first SGLT2i CV outcome trial to evaluate T2DM patients stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF, and reduced CV death and ACM in patients with HFrEF. Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus. Circula- tion 2019 Mar 18;[EPub Ahead of Print], ET Kato, MG Silverman, O Mosenzon, et al. www.practiceupdate.com/c/81405

Dr. Januzzi is a Physician in the Cardiology Division of Massachusetts General Hospital and Hutter Family Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

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