Natriuretic peptides, body mass index and heart failure risk: Pooled analyses of SAVOR-TIMI 53, DECLARE-TIMI 58 and CAMELLIA-TIMI 61

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations are lower in patients with obesity. The interaction between body mass index (BMI) and NT-proBNP with respect to heart failure (HF) risk remains incompletely defined.Methods: Data were pooled across three randomized clinical trials enrolling predominantly patients who were overweight or obese with established cardiometabolic disease: SAVOR-TIMI 53, DECLARE-TIMI 58 and CAMELLIA-TIMI 61. Hospitalization for heart failure (HHF) was examined across strata of baseline BMI and NT-proBNP. The effect of dapagliflozin vs. placebo was assessed for a treatment interaction across BMI categories in patients with or without an elevated baseline NT-proBNP (>= 125 pg/mL).Results: Among 24,455 patients, the median NT-proBNP was 96 (IQR: 43-225) pg/mL and the median BMI was 33 (IQR 29-37) kg/m(2) , respectively, with 68% of patients having a BMI >= 30 kg/m(2) . There was a significant association between NT-proBNP and BMI which persisted after adjustment for all clinical variables (5.8 pg/mL lower NT-proBNP per 1 kg/m(2) higher BMI; p<0.001). Within any range of NT-proBNP, those at higher BMI had higher risk of HHF at 2 years (comparing BMI <30 vs. >= 40 kg/m(2) for NT-proBNP ranges of <125, 125-<450 and >= 450 pg/mL: 0.0% vs. 0.6%, 1.3% vs. 4.0%, and 8.1% vs. 13.8%, respectively), which persisted after multivariable adjustment (HRadj 7.47 [95% CI 3.16-17.66], HRadj 3.22 [95% CI 2.13-4.86], and HRadj 1.87 [95% CI 1.35-2.60], respectively). In DECLARE-TIMI 58, dapagliflozin vs. placebo consistently reduced HHF across BMI categories in those with an elevated NT-proBNP (p-trend for HR across BMI = 0.60), with a pattern of greater absolute risk reduction (ARR) at higher BMI (ARR for BMI <30 to >= 40 kg/m(2) : 2.2% to 4.7%; p-trend = 0.059).Conclusions: The risk of HHF varies across BMI categories for any given range of circulating NT-proBNP. These findings showcase the importance of considering BMI when applying NT-proBNP for HF risk stratification, particularly for patients with low-level elevations in NT-proBNP (125-<450 pg/mL) where there appears to be a clinically meaningful absolute and relative risk gradient. This article is protected by copyright. All rights reserved.