Efficacy of Dapagliflozin According to Frailty in HFrEF

Quick Takes

  • When added to standard, guideline-based therapy, dapagliflozin, compared to placebo, reduced the risk of worsening heart failure events and death, and improved symptoms, physical function, and quality of life, regardless of frailty class.
  • Improvements in health status and reductions in adverse events were larger among the class of most frail patients who received treatment with dapagliflozin compared with placebo.

Study Questions:

What was the safety and efficacy of dapagliflozin use in patients with heart failure with reduced ejection fraction (HFrEF) based on frailty status?


Data from the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), double-blind, placebo-controlled, randomized clinical trial in patients with HFrEF were analyzed. An investigator-developed instrument, the Frailty Index, was developed to classify 3 levels of frailty (class 1–not frail, 2–more frail, and 3–most frail). The Kansas City Cardiomyopathy Questionnaire (KCCQ) was used as an outcome measure for symptom burden, social and physical activity, and quality of life (QoL). New-onset type 2 diabetes was measured as a glycated hemoglobin A1c level ≥6.5%. Univariate analysis was used to describe the sample and multivariate analyses, including Kaplan-Meier and Aalen-Johansen estimates, and Cox proportional hazards were used to model outcomes data (time-to-event, fixed-effect factors for calculating hazard ratios).


Of the 4,744 patients randomly assigned in the DAPA-HF clinical trial, frailty was calculated for 4,742 cases, which were used in the ad hoc analysis. Higher (worse) frailty (as opposed to lower frailty) scores were more often White, non-Asian; and more likely to have cardiovascular (CV) and non-CV comorbidities; higher blood pressure, heart rate, body mass index, and N-terminal pro-B-type natriuretic peptide (NT-proBNP); lower glomerular filtration rate, underlying ischemic cause, and longer duration of heart failure; higher left ventricular EF; and worse New York Heart Association (NYHA) functional class, KCCQ, EuroQoL, and visual analog scores; and more likely to have defibrillating device therapy. Nearly half of the sample was classified as frail using the Frailty Index. Regardless of frailty class, dapagliflozin reduced the risk for worsening HF events and CV death. From lowest (better) to highest (worse) frailty class, the differences in event rate per 100 person-years for dapagliflozin (vs. placebo) were -3.5 (95% confidence interval [CI], -5.7 to 1.2), -3.6 (CI, -6.6 to -0.5), and -7.9 (CI, -13.9 to -1.9). Serious adverse events and study drug discontinuation were equivalent across frailty classes.


This ad hoc analysis of DAPA-HF clinical trial data showed that dapagliflozin, compared with placebo, significantly reduced the risk for worsening HF events, CV death, and all-cause death, and improved symptoms, physical function, and QoL, regardless of frailty class, with the most frail having the largest absolute reductions in clinical events and improvements in health status.


One of the major goals of HF management is to reduce symptom burden and improve physical function and QoL and achieving these goals in frail persons living with HF is especially important, as they tend to have greater symptom burden, more physical limitations, and worse QoL than patients who are not frail. In addition, goals that slow the progression of frailty and prevent frailty, altogether must be attainable. Patients in very low risk categories (e.g., NYHA functional class I and NT-proBNP <400 pg/mL) and those considered high risk were not included in the DAPA-HF clinical trial, and as such, not represented in this ad hoc analysis; thus, findings might not generalize to all HF populations. However, this analysis provides researchers and clinicians findings for clinical decision making and future research consideration.

Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Exercise

Keywords: Blood Pressure, Body Mass Index, Cardiomyopathies, Diabetes Mellitus, Type 2, Exercise, Frail Elderly, Frailty, Geriatrics, Glomerular Filtration Rate, Heart Failure, Ischemia, Natriuretic Peptide, Brain, Quality of Life, Secondary Prevention, Stroke Volume

< Back to Listings