Efficacy of dapagliflozin in heart failure with reduced ejection fraction according to body mass index

Abstract

Aims: In heart failure with reduced ejection fraction (HFrEF), there is an 'obesity paradox', where survival is better in patients with a higher body mass index (BMI) and weight loss is associated with worse outcomes. We examined the effect of a sodium-glucose co-transporter 2 inhibitor according to baseline BMI in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF).

Methods and results: Body mass index was examined using standard categories, i.e. underweight (<18.5 kg/m2 ); normal weight (18.5-24.9 kg/m2 ); overweight (25.0-29.9 kg/m2 ); obesity class I (30.0-34.9 kg/m2 ); obesity class II (35.0-39.9 kg/m2 ); and obesity class III (≥40 kg/m2 ). The primary outcome in DAPA-HF was the composite of worsening heart failure or cardiovascular death. Overall, 1348 patients (28.4%) were under/normal-weight, 1722 (36.3%) overweight, 1013 (21.4%) obesity class I and 659 (13.9%) obesity class II/III. The unadjusted hazard ratio (95% confidence interval) for the primary outcome with obesity class 1, the lowest risk group, as reference was: under/normal-weight 1.41 (1.16-1.71), overweight 1.18 (0.97-1.42), obesity class II/III 1.37 (1.10-1.72). Patients with class I obesity were also at lowest risk of death. The effect of dapagliflozin on the primary outcome and other outcomes did not vary by baseline BMI, e.g. hazard ratio for primary outcome: under/normal-weight 0.74 (0.58-0.94), overweight 0.81 (0.65-1.02), obesity class I 0.68 (0.50-0.92), obesity class II/III 0.71 (0.51-1.00) (P-value for interaction = 0.79). The mean decrease in weight at 8 months with dapagliflozin was 0.9 (0.7-1.1) kg (P < 0.001).

Conclusion: We confirmed an 'obesity survival paradox' in HFrEF. We showed that dapagliflozin was beneficial across the wide range of BMI studied.

Clinical trial registration: ClinicalTrials.gov NCT03036124.

Keywords: Adiposity; Body mass index; Dapagliflozin; Heart failure; Obesity; SGLT2 inhibitor.

© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Figures

Figure 1

Risk of outcomes according to body mass index (BMI). These restricted cubic splines demonstrate the risk of each outcome modelling BMI as a continuous variable. The baseline spline in blue is adjusted for history of heart failure (HF) hospitalization (apart from for all‐cause death), randomized treatment and stratified by diabetes status. The red spline has additional adjustment for age, sex, race, region, systolic blood pressure, estimated glomerular filtration rate, heart rate, hypertension, atrial fibrillation, ischaemic aetiology, left ventricular ejection fraction, New York Heart Association class, myocardial infarction, coronary artery bypass graft, stroke, and N‐terminal pro‐B‐type natriuretic peptide. The reference point is BMI 30 kg/m2. The shaded areas represent 95% confidence intervals (CI). The lowest risk of the primary outcome is around 30 kg/m2. There is evidence of a U‐shaped relationship seen with higher risk with both low and very high BMI. A similar pattern is seen for the other outcomes of interest. The adjusted models show the excess risk in the lowest BMI category is attenuated while the risk in the highest BMI categories is accentuated. CV, cardiovascular; HR, hazard ratio.

Figure 2

Change in weight over time by body mass index (BMI) category. Change in weight in patients randomized to dapagliflozin and placebo over time within each BMI category demonstrates modest weight loss regardless of baseline BMI in patients randomized to dapagliflozin. There was no significant interaction between baseline BMI and randomized treatment on change in weight.