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

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 <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.