Sex Differences in Characteristics, Outcomes, and Treatment Response With Dapagliflozin Across the Range of Ejection Fraction in Patients With Heart Failure: Insights From DAPA-HF and DELIVER
Authors: Wang Xiaowen , Vaduganathan Muthiah , Claggett Brian L. , Hegde Sheila M. , Pabon Maria , Kulac Ian J. , Vardeny Orly , O’Meara Eileen , Zieroth Shelley , Katova Tzvetana , McGrath Martina M. , Pouleur Anne-Catherine , Jhund Pardeep S. , Desai Akshay S. , Inzucchi Silvio E. , Kosiborod Mikhail N. , de Boer Rudolf A. , Kober Lars , Sabatine Marc S. , Martinez Felipe A. , Ponikowski Piotr , Shah Sanjiv J. , Hernandez Adrian F. , Langkilde Anna Maria , McMurray John J.V. , Solomon Scott D. , Lam Carolyn S.P. 
Published: November 2022

Background:
Sodium-glucose cotransporter-2 inhibitors have emerged as a key pharmacotherapy in heart failure (HF) with both reduced and preserved ejection fraction. The benefit of other HF therapies may be modified by sex, but whether sex modifies the treatment effect and safety profile of sodium-glucose cotransporter-2 inhibitors remains unclear. Our analyses aim to assess the effect of sex on the efficacy and safety of dapagliflozin.

Methods:
In a prespecified patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), clinical outcomes were compared by sex (including the composite of cardiovascular death or worsening HF events, cardiovascular death, all-cause death, total events [first and recurrent HF hospitalization and cardiovascular death], and Kansas City Cardiomyopathy Questionnaire scores) across the spectrum of left ventricular ejection fraction.

Results:

Of a total of 11 007 randomized patients, 3856 (35%) were women. Women with HF were older and had higher body mass index but were less likely to have a history of diabetes and myocardial infarction or stroke and more likely to have hypertension and atrial fibrillation compared with men. At baseline, women had higher ejection fraction but worse Kansas City Cardiomyopathy Questionnaire scores than men did. After adjustment for baseline differences, women were less likely than men to experience cardiovascular death (adjusted hazard ratio, 0.69 [95% CI, 0.60–0.79]), all-cause death (adjusted hazard ratio, 0.69 [95% CI, 0.62–0.78]), HF hospitalizations (adjusted hazard ratio, 0.82 [95% CI, 0.72–0.94]), and total events (adjusted rate ratio, 0.77 [95% CI, 0.71–0.84]). Dapagliflozin reduced the primary end point in both men and women similarly (
P
interaction
=0.77) with no sex-related differences in secondary outcomes (all
P
interaction
>0.35) or safety events. The benefit of dapagliflozin was observed across the entire ejection fraction spectrum and was not modified by sex (
P
interaction
>0.40). There were no sex-related differences in serious adverse events, adverse events, or drug discontinuation attributable to adverse events.

Conclusions:
In DAPA-HF and DELIVER, the response to dapagliflozin was similar between men and women. Sex did not modify the treatment effect of dapagliflozin across the range of ejection fraction.