Introduction: In EMPA-REG OUTCOME®, empagliflozin significantly reduced CV death by 38% and hospitalization for heart failure and HF death by 39%. Whether empagliflozin-mediated reduction in weight and visceral adiposity may partially explain the CV benefits is unknown. We tested the hypothesis that reducing weight and indices of adiposity with empagliflozin could be related to its beneficial effects on CV outcomes.
Methods: 7020 patients with type 2 diabetes at high CV risk were randomized to receive placebo or empagliflozin (10 mg or 25 mg) in addition to standard of care. The relationships between short-term (12 week) changes in weight (kg), waist circumference (WC [cm]), and estimated total body fat (eTBF [%]) and CV death and HF hospitalization/HF death outcomes at study-end were assessed in the placebo and pooled empagliflozin groups by ≥ and < median magnitude of change at 12 weeks.
Results: At baseline, median weight, WC, and eTBF were similar in the placebo and empagliflozin groups (85.0 kg vs 85.1 kg, 104.0 cm vs. 104.0 cm, 31.9% vs 32.0%, respectively). At week 12, greater reductions in all parameters were observed with empagliflozin. The reduction in CV death appeared to be greater with more weight reduction (Table, p-interaction=0.0114), whereas the magnitude of effect on CV death was similar by degree of WC or eTBF reduction. There was a numerical trend towards a lower hazard for HF hospitalization and HF death with greater reduction in all adiposity indices.
Conclusions: Empagliflozin have a consistent effect on reducing CV death and hospitalization for HF and HF death by degree of weight and visceral adiposity reduction. However, the significant interaction p-value for CV death raises the hypothesis that weight reduction (potentially related to volume loss), rather than fat reduction per se, may contribute to the CV benefit seen with empagliflozin in patients with type 2 diabetes.