The renal and cardiovascular effects of SGLT2 inhibition in combination with loop diuretics in patients with type 2 diabetes and chronic heart failure (RECEDE-CHF) trial
Authors: Mordi N.A , Mordi I.R , Singh J.S , McCrimmon R.J , Struthers A.D , Lang C.C 
Published: November 2020

Abstract

Introduction
The SGLT2 inhibitors have been shown to reduce heart failure (HF) hospitalisations in patients with Type 2 diabetes (T2D), and to improve outcomes in those with HF irrespective of T2D status. Given this, it is likely that they will be co-prescribed with a loop diuretic. The combined diuretic effect of SGLT2 inhibitors and loop diuretic has not been well defined.

Purpose
The aim of this study was to assess the diuretic and natriuretic effect of empagliflozin in patients with T2D and chronic HF in combination with loop diuretics.

Methods and analysis
RECEDE-CHF (Renal and Cardiovascular Effects of SGLT2 inhibition in combination with loop Diuretics in patients with T2D and Chronic HF) was a randomised, double-blind, placebo-controlled, cross-over trial. Patients were randomised to empagliflozin 25 mg once a day or placebo for 6 weeks with study assessments at day 3 and week 6. Following a 2 week washout period, patients then entered the second treatment arm. The primary outcome was change in 24-hour urinary volume, when compared to placebo at day 3 and week 6.

Results
23 participants mean age 69.8 years, (male 73.9%) with T2D and chronic HF (all ejection fraction &lt;50%) on a mean furosemide dose of 49.6 mg/day were recruited. In comparison to placebo, empagliflozin caused a significant increase in 24-hour urinary volume at both time points (day 3, mean difference of 549.3 ml, 95% confidence interval 151.4 to 947.2, p=0.004 and week 6, mean difference of 542.8 ml, 95% CI 134.9 to 950.7, p=0.005), adjusted for treatment order and baseline 24-hour urine volume. Empagliflozin did not cause a significant increase in the 24-hour urinary sodium as measured in mmol/L at both time points (day 3, mean difference compared to placebo −2.96 mmol/L, 95% CI: −21.55 to 15.64, p=1.00, week 6 mean difference compared to placebo −8.41 mmol/L, 95% CI: −27.00 to 10.18, p=0.81).
Empagliflozin caused a significant increase in electrolyte-free water clearance (cH20e) at day 3 (mean difference compared to placebo 287.36 ml/min, (95% CI 31.79 to 542.93, p=0.022) and at week 6 (mean difference when compared to placebo 255.69 ml/min (95% CI: −284.12 to 220.76, p=0.048) when corrected for furosemide dose. 21.7% (n=5) participants had to have their furosemide dose reduced by 50% whilst on the active treatment arm of empagliflozin by day 3. On discontinuation of the active treatment arm with empagliflozin, two participants experienced hospital admissions with decompensated cardiac congestion.

Conclusions
Empagliflozin caused a significant increase in 24-hour urine volume when used in combination with loop diuretic when compared to placebo. There was no increase in 24-hour urinary sodium excretion. The greater electrolyte-free water clearance induced by empagliflozin observed in this study may support a proposed hypothesis that this could result in a greater fluid clearance from the interstitial space than from the circulating volume.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): British Heart Foundation (BHF)