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

Effect of canagliflozin on N-terminal pro-brain natriuretic peptide in patients with type 2 diabetes and chronic heart failure according to baseline use of glucose-lowering agents

“…In this regard, changes in some fluid volume parameters indicative of a hemodynamic effect of SGLT2 inhibition are likely to be associated with clinical benefits [ 34 , 36 ]. Recent studies have reported a consistent reduction in ePV status in patients with HFrEF, regardless of their diabetes status, [ 20 ] and also in patients with T2D and cardiovascular diseases, regardless of their background clinical characteristics and medications [ 37 ]. The present study showed that the effect of canagliflozin treatment on ePV reduction was also consistent across the baseline use of glucose-lowering agents.…”

Empagliflozin in the treatment of heart failure and type 2 diabetes mellitus: Evidence from several large clinical trials

“…The simplest explanation for such fast and short-term effects of empagliflozin in HFpEF is its diuretic effect [43]. However, the diuretic effect of empagliflozin is different from loop diuretics in that empagliflozin caused a significant increase in 24-hour urine volume without an increase in urinary sodium and electrolyte-free water clearance [44] and a significant decrease in estimated plasma volume calculated by the Straus formula and estimated the extracellular volume determined by the body surface area [45]. A pooled analysis of both the EMPEROR-Reduced and EMPEROR-Preserved trials indicated that the magnitude of the effect of empagliflozin on HF outcomes and health status was similar in patients with ejection fractions < 25% to < 65%, but it was attenuated in patients with an ejection fraction ≥ 65% [46], which may herald the recognition of a new phenotype characterized by supra-normal left ventricular ejection fraction [47].…”

Effects of luseogliflozin on estimated plasma volume in patients with heart failure with preserved ejection fraction

“… 18 , 19 Other studies have also reported that SGLT2 inhibitors reduced the ePV in patients with T2DM complicated by cardiovascular diseases or HFrEF. 20 , 21 In addition, SGLT2 inhibitors reduced pulmonary arterial pressure in patients with heart failure. 26 These results support that SGLT2 inhibitors can reduce intracellular volume by diuretic effects related to both glycosuria and natriuresis, consistent with the results of this study.…”

“… 16 , 17 Recently, SGLT2 inhibitors have been reported to reduce estimated plasma volume (ePV). 18 , 19 , 20 , 21 Although these results suggest that SGLT2 inhibitors may be effective in reducing intravascular volume, which may improve heart failure prognosis, there is little evidence of the efficacy of SGLT2 inhibitors on intravascular volume in patients with HFpEF.…”