SGLT2i in HFrEF is beneficial across all BMI categories
Efficacy of dapagliflozin in heart failure with reduced ejection fraction according to body mass index
Introduction and methods
Multiple studies have shown that an obesity-paradox exists in HFrEF. Patients with overweigt or obesity had better survival rates than non-obese patients [1-6]. In addition, it was shown that weight loss was associated with worse survival [7-11]. This analysis of the DAPA-HF trial investigated whether the risk of outcomes varied by baseline BMI. Moreover, the effects of dapagliflozin on outcomes stratified by baseline BMI and the effects of dapagliflozin on weight were studied.
DAPA-HF included adult patients with HFrEF (NYHA classes II to IV, LVEF ≤40%, elevated NT-proBNP, and standard HF drug and device therapy). Patients were randomized in a 1:1 ratio to receive either dapagliflozin (10 mg once daily) or matching placebo. A total of 4742 patients were included in the current analysis. Patients were stratified according to BMI: 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). Due to a low number of patients in the classes underweight, obesity class II and III, some classes were combined: underweight/normal weight (n=1348, 28.4%), overweight (n=1722, 36.3%), obesity class I (n=411, 9.3%), obesity class II or III (n=659, 13.9%). The primary composite outcome was first event of CV death or worsening HF event (HF hospitalization or urgent HF visit requiring IV therapy). Adverse events of interest were discontinuation of study drug due to adverse event, volume depletion, renal adverse event, bone fracture, amputation, and major hypoglycemia. Change in body weight from baseline was investigated as an exploratory endpoint. Median follow-up was 18.2 months.
- Analysis of primary outcome rates using BMI as a continuous variable showed a non-linear, U-shaped relationship, with the lowest rates in patients with BMI ~30 kg/m².
- When event rates of the primary outcome were examined using BMI categories, a similar pattern was observed: The lowest rate of primary outcome in the placebo group was found in patients with obesity class I (rate of 13.8 per 100 person-years, 95%CI 11.3-16.8). Rates in other BMI categories were 17.4 (95%CI 14.8-20.4) per 100 person-years in the underweight/ normal weight category, 14.5 (95%CI 12.5-16.9) per 100 person-years in the overweight category, and 19.2 (95%CI 15.5-23.7) per 100 person-years in the obesity class II/III category.
- Risk of primary outcome was reduced by dapagliflozin to a similar extend across all BMI categories: HR 0.74 (95%CI 0.58-0.94) for underweight/normal weight, HR 0.81 (95%CI 0.65-1.02) for overweight, HR 0.68 (95%CI 0.50-0.92) for obesity class I and 0.71 (95%CI 0.51-1.00) for obesity class II/III (P-value for interaction=0.79). Dapagliflozin also reduced the risk of all-cause mortality to a similar extend across all BMI categories (P-value for interaction =0.77).
- After 8 months follow-up, use of dapagliflozin led to a modest mean overall placebo-corrected decrease in weight of 0.9 kg (95%CI 0.7-1.1 kg, P<0.001). BMI at baseline did not modify the effect of dapagliflozin on weight (P=0.69).
- Mean KCCQ-TSS improved between baseline and 8 months follow-up with dapagliflozin, compared to placebo. This effect was observed in all BMI categories. Odds ratio’s for improvement at 8 months were: OR 1.16 (95%CI 1.03-1.30) for underweight/normal weight, OR 1.14 (95%CI 1.03-1.26) for overweight, OR 1.12 (95%CI 0.98-1.27) for obesity class I, OR 1.22 (95%CI 1.03-1.44) for obesity class II/III.
- There was no significantly different frequency of adverse events of interest across BMI categories or by randomized therapy in each category.
This analysis of the DAPA-HF trial confirmed that a obesity-paradox exists in HFrEF. A U-shaped relationship between rates of CV death or worsening HF events and BMI was found with lowest rates in patients with a BMI of ~30 kg/m². Dapagliflozin was beneficial to a similar extend in all BMI categories.