Weight change and clinical outcomes in heart failure with reduced ejection fraction: insights from EMPEROR-Reduced

Abstract

Aims: Baseline body mass index (BMI) and weight loss promoted by sodium-glucose cotransporter 2 inhibitors may impact outcomes in patients with heart failure with reduced ejection fraction (HFrEF). We assessed in the EMPEROR-Reduced population treated with empagliflozin versus placebo the relationship between baseline BMI, weight loss and effects on the primary (time to first hospitalization for heart failure [HHF] or cardiovascular death) and key secondary outcomes.

Methods and results: We categorized patients according to their baseline BMI: <20 kg/m² (n = 180); 20 to <25 kg/m² (n = 1038); 25 to <30 kg/m² (n = 1345); 30 to <35 kg/m² (n = 774) and ≥35 kg/m² (n = 393). The treatment effect of empagliflozin on the primary outcome was consistent across all BMI categories (hazard ratios in subgroups 0.66-0.88, interaction trend p = 0.32), as was the effect on total (first plus recurrent) HHF (interaction trend p = 0.31). Empagliflozin reduced the rate of estimated glomerular filtration rate decline consistently across the BMI categories (interaction trend p = 0.67). Overall, incidence rates of any or serious adverse events were comparable between the treatment groups across all BMI categories. A total of 313 (17.4%) patients treated with empagliflozin experienced a weight loss of more than 5% at week 52 versus 230 (12.8%) in placebo. When analysed separately within each treatment group, presence of weight loss was similarly associated with an increased risk of all-cause mortality.

Conclusion: The benefits of empagliflozin versus placebo were consistently present across all BMI categories in HFrEF patients. Weight loss was associated with higher risk of all-cause mortality, regardless of treatment group.

Keywords: Body mass index; Empagliflozin; Heart failure; Weight loss.

Figure 1

Risk of cardiovascular (CV) and all‐cause mortality according to baseline body mass index (BMI). The spline analyses are adjusted for age, sex, diabetes status, region, left ventricular ejection fraction, estimated glomerular filtration rate and N‐terminal pro‐B‐type natriuretic peptide. CI, confidence interval.

Figure 2

Change in weight by baseline peripheral oedema. Change from baseline in weight over time in patients without (A) and with (B) baseline peripheral oedema. Analysed by a mixed model of repeated measures. SE, standard error.

Figure 3

Effects of empagliflozin versus placebo on heart failure outcomes and mortality. BMI, body mass index; CI, confidence interval; CV, cardiovascular; HHF, hospitalization for heart failure; HR, hazard ratio; py, patient‐years.

Figure 4

Treatment effect on estimated glomerular filtration rate (eGFR) slope (A) and Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ‐CSS) (B) according to baseline body mass index (BMI) categories. Forest plot summarizing the treatment effects on eGFR slope estimates and difference in change in KCCQ‐CSS from baseline to week 52 across BMI categories. Between‐group difference in the slope of change during the treatment period in eGFR were analysed using a random intercept random model in the treated set. The model includes age, baseline eGFR, region, baseline diabetes status, sex, baseline left ventricular ejection fraction, treatment, baseline BMI categories, and treatment by baseline BMI categories interaction. CI, confidence interval; SE, standard error.

Figure 5

Effect of empagliflozin by body mass index (BMI) as a continuous variable. Spline regression models showing the treatment effect of empagliflozin versus placebo across BMI as a continuous variable for (A) the primary endpoint, (B) first hospitalization for heart failure (HHF), (C) cardiovascular (CV) death, and (D) a histogram with BMI distribution. CI, confidence interval.