Reduction of estimated fluid volumes following initiation of empagliflozin in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the placebo-controlled, randomized EMBLEM trial

Abstract

Backgrounds/Aim: Sodium glucose co-transporter 2 inhibitors promote osmotic/natriuretic diuresis and reduce excess fluid volume, and this improves cardiovascular outcomes, including hospitalization for heart failure. We sought to assess the effect of empagliflozin on estimated fluid volumes in patients with type 2 diabetes and cardiovascular disease (CVD). Methods: The study was a post-hoc analysis of the EMBLEM trial (UMIN000024502), an investigator-initiated, multi-center, placebo-controlled, double-blinded, randomized-controlled trial designed primarily to evaluate the effect of 24 weeks of empagliflozin treatment on vascular endothelial function in patients with type 2 diabetes and established CVD. The analysis compared serial changes between empagliflozin (10 mg once daily, n = 52) and placebo (n = 53) in estimated plasma volume (ePV), calculated by the Straus formula and estimated the extracellular volume (eEV), determined by the body surface area, measured at baseline and 4, 12, and 24 weeks after initiation of treatment. Correlations were examined between the changes from baseline to week 24 in each estimated fluid volume parameter and several clinical variables of interest, including N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration. Results: In an analysis using mixed-effects models for repeated measures, relative to placebo empagliflozin reduced ePV by − 2.23% (95% CI − 5.72 to 1.25) at week 4, − 8.07% (− 12.76 to − 3.37) at week 12, and − 5.60% (− 9.87 to − 1.32) at week 24; eEV by − 70.3 mL (95% CI − 136.8 to − 3.8) at week 4, − 135.9 mL (− 209.6 to − 62.3) at week 12, and − 144.4 mL (− 226.3 to − 62.4) at week 24. The effect of empagliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in log-transformed NT-proBNP was positively correlated with change in ePV (r = 0.351, p = 0.015), but not with change in eEV. Conclusions: Our data demonstrated that initiation of empagliflozin treatment substantially reduced estimated fluid volume parameters in patients with type 2 diabetes and CVD, and that this effect was maintained for 24 weeks. Given the early beneficial effect of empagliflozin on cardiovascular outcomes seen in similar patient populations, our findings provide an important insight into the key mechanisms underlying the clinical benefit of the drug. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502