Abstract
Backgrounds/AimSodium 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).MethodsThe 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.ResultsIn 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.ConclusionsOur 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
Highlights
Previous cardiovascular outcome trials (CVOTs) have demonstrated that sodium glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular and renal outcomes, including hospitalization for heart failure (HHF), in patients with type 2 diabetes and a high risk of cardiovascular events [1]
Our data demonstrated that initiation of empagliflozin treatment substantially reduced estimated fluid volume parameters in patients with type 2 diabetes and cardiovascular disease (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
Summary
Previous cardiovascular outcome trials (CVOTs) have demonstrated that sodium glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular and renal outcomes, including hospitalization for heart failure (HHF), in patients with type 2 diabetes and a high risk of cardiovascular events [1]. SGLT2 inhibitors promote osmotic/natriuretic diuresis and reduce excess plasma and interstitial volumes without affecting effective intravascular circulating volumes [9, 10] This action of SGLT2 inhibitors appears to contribute substantially to the risk reduction in HHF [11]. In this context, a mediation analysis of data from the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose) trial showed that increases in hematocrit and hemoglobin, indicative of the hemodynamic effect of SGLT2 inhibitors, were the strongest predictors of the reduction in the risk of cardiovascular death [12]. Given that the effects of SGLT2 inhibitors on erythropoietic and volume status seem largely to mediate their cardiovascular benefits, some recent clinical studies showed that treatment with SGLT2 inhibitors reduced estimated fluid volume parameters in patients with type 2 diabetes [14] or HF with reduced ejection fraction [15]
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