SGLT2i reduces risk of worsening HF or CV death similarly in men and women with HFrEF

Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction: A Prespecified Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial

Literature - Butt JH, Docherty KF, Petrie MC et al. - JAMA Cardiol. 2021 Mar 31;e210379. doi: 10.1001/jamacardio.2021.0379.

Introduction and methods

The DAPA-HF trial showed that addition of dapagliflozin to conventional guideline-recommended therapies reduced the composite outcome of CV death and worsening HF events in patients with HFrEF with and without diabetes in comparison to placebo [1]. It is known that women may respond differently to certain HF medications compared to men [2-8]. This prespecified subgroup analysis of DAPA-HF investigated the efficacy and safety of dapagliflozin in men and women.

DAPA-HF was a randomized, double-blind, placebo-controlled trial that randomized 4744 patients with HFrEF (1109 were women, 23.4%) to receive either dapagliflozin (10 mg, once daily) or placebo in addition to guideline-recommended therapy. Included patients were aged ≥18 years, had NYHA class II trough IV, LVEF≤40%, were optimally treated with pharmacologic or device therapy for HF and had NT-proBNP ≥600 pg/mL (≥400 pg/mL if hospitalized for HF within the last 12 months; ≥900 pg/mL in case of AF). Patients with eGFR<30 mL/min/1.73m² or rapidly declining kidney function, symptomatic hypotension, SBP <95 mmHg or type 1 diabetes were excluded. The primary outcome was the composite of worsening HF events or CV death. Secondary outcomes included HF hospitalization or CV death (and each outcome separately); total HF hospitalizations or CV death; all-cause death; an extended primary outcome (composite of the primary endpoint plus worseling HF symptoms/signs leading to initiation of new oral treatment or augmentation of existing oral treatment); change from baseline to 8 months in the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS); KCCQ overall summary score (KCCQ-OSS) and KCCQ clinical summary score (KCCQ-CSS). Follow-up was 24 months.

Main results

  • Dapagliflozin reduced the risk of the primary composite endpoint of worsening HF or CV death similarly in men and women and there was no interaction between sex and effect of treatment (men: HR 0.73, 95%CI 0.63-0.85; women: HR 0.79, 95%CI 0.59-1.06, P for interaction=0.67).
  • The effect of dapagliflozin was consistent in men and women for all studied secondary end points.
  • Dapagliflozin increased the mean KCCQ-TSS significantly from baseline to 8 months in men, compared to placebo (6.1 vs. 2.5). The mean increase in KCCQ-TTS from baseline to 8 months in women was 6.0 in the placebo group and 6.1 in the dapagliflozin group.
  • Mean increases in KCCQ-CSS and KCCQ-OSS were greater with dapagliflozin than with placebo, with consistent effects in men and women (KCCQ-CSS: 2.3 with placebo and 5.3 with dapagliflozin in men; 5.1 with placebo and 6.1 with dapagliflozin in women, P for interaction=0.22. KCCQ-OSS: 3.3 with placebo and 5.9 with dapagliflozin in men; 5.8 with placebo and 7.0 with dapagliflozin in women; P for interaction=0.34).
  • The proportion of patients with ≥5-point improvement in KCCQ-TSS was greater with dapagliflozin than with placebo in both men and women (men: OR 1.18, 95%CI 1.11-1.27; women: OR 1.06, 95%CI 0.92-1.22, P for interaction=0.14). The proportion of patients with a decrease in KCCQ-TSS of ≥5-points was smaller in the dapagliflozin group, compared with the placebo group, and consistent in men and women (men: OR 0.81, 95%CI 0.75-0.88; women: OR 0.92, 95%CI 0.79-1.06), P for interaction=0.15).
  • The proportion of patients who discontinued the study drug or experienced serious adverse events (SEA) were similar between treatment groups in both men and women, although women were more likely than men to discontinue the study drug for any reason.


Dapagliflozin added to guideline-recommended therapy reduced the risk of the primary endpoint of worsening HF events or CV death to a similar extent in men and women, compared to placebo. Dapagliflozin increased the proportion of patients with a clinically meaningful improvement of ≥5 points in KCCQ-TSS and decreased the proportion of patients with a clinically important deterioration of ≥5 points in KCCQ-TSS compared with placebo in both men and women. SEA and study drug discontinuation were similar between treatment groups, irrespective of sex.


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4. Loring Z, Caños DA, Selzman K, et al. Left bundle branch block predicts better survival in women than men receiving cardiac resynchronization therapy: long-term follow-up of ~145,000 patients. JACC Heart Fail. 2013:1(3):237-244.

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Find this article online at JAMA Cardiol.

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