Renal and Cardiovascular Effects of SGLT2 Inhibition in Combination With Loop Diuretics in Patients With Type 2 Diabetes and Chronic Heart Failure: The RECEDE-CHF Trial

Abstract

Background: SGLT2 (sodium-glucose cotransporter-2) inhibitors improve heart failure-associated outcomes in patients with type 2 diabetes. In patients with heart failure, SGLT2 inhibitors will likely be coprescribed with a loop diuretic, but this combined effect is not well-defined. Our aim was to assess the diuretic and natriuretic effect of empagliflozin in combination with loop diuretics.

Methods: The RECEDE-CHF trial (SGLT2 Inhibition in Combination With Diuretics in Heart Failure) was a randomized, double-blind, placebo-controlled, crossover trial of patients with type 2 diabetes and heart failure with reduced ejection fraction taking regular loop diuretic who were randomized to empagliflozin 25 mg once daily or placebo for 6 weeks with a 2-week washout period. The primary outcome was change in 24-hour urinary volume from baseline to week 6.

Results: Twenty-three participants (mean age, 69.8 years; 73.9% male; mean furosemide dose, 49.6±31.3 mg/d; mean HbA1c, 7.9±3.8%) were recruited. Compared with placebo, empagliflozin caused a significant increase in 24-hour urinary volume at both day 3 (mean difference, 535 mL [95% CI, 133-936]; P=0.005) and week 6 (mean difference, 545 mL [95% CI, 136-954]; P=0.005) after adjustment for treatment order, baseline 24-hour urine volume, and percentage change in loop diuretic dose. At 6 weeks, empagliflozin did not cause a significant change in 24-hour urinary sodium (mean difference, -7.85 mmol/L [95% CI, -2.43 to 6.73]; P=0.57). Empagliflozin caused a nonsignificant increase in fractional excretion of sodium at day 3, which was absent at week 6 (mean difference day 3, 0.30% [95% CI, -0.03 to 0.63]; P=0.09; week 6, 0.11% [95% CI, -0.22 to 0.44]; P>0.99), and a significant increase in electrolyte-free water clearance at week 6 (mean difference, 312 mL [95% CI, 26-598]; P=0.026) compared with placebo. Empagliflozin also caused significant reductions in body weight and serum urate at week 6.

Conclusions: Empagliflozin caused a significant increase in 24-hour urine volume without an increase in urinary sodium when used in combination with loop diuretic. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03226457.

Keywords: diabetes mellitus; diuretics; furosemide; heart failure.

Conflict of interest statement

Dr McCrimmon has received honoraria and speaker fees from Sanofi and honoraria from NovoNordisk and Lilly. Dr Struthers has received research support and lecture and consulting fees from Astra Zeneca. Dr Lang has received research support and consulting fees from Novartis; research support, lecture fees, and consulting fees from AstraZeneca; lecture fees from Merck Sharp & Dohme; and research support from Pfizer and Sanofi. The other authors report no conflicts.

Figures

Figure 1.

The RECEDE-CHF (SGLT2 Inhibition in Combination With Diuretics in Heart Failure) study design. Crossover design of the trial. RPT indicates renal physiologic test.

Figure 2.

Consolidated Standards of Reporting Trials diagram. Screening, recruitment, and study completion.

Figure 3.

Change in urine volume, urine sodium, and fractional excretion of sodium from placebo day 3. Change in urine volume (A), urine sodium (B and C), and fractional excretion of sodium (D) from placebo day 3. P values refer to the mean difference between placebo week 6 and empagliflozin day 3 and week 6.

Figure 4.

Urine volume and fractional excretion of sodium during the renal physiologic test (RPT). Mean and SD of urine volume (top row) and fractional excretion of sodium (bottom) at baseline and after administration of empagliflozin (Empa)/placebo and intravenous furosemide during the RPTs at day 3 and week 6. The red line represents the empagliflozin treatment arm, and the green line represents the placebo treatment arm.

Figure 5.

Change in serum urea, systolic blood pressure, hematocrit, and body weight. Change in serum urea (A), systolic blood pressure (SBP; B), hematocrit (C), and body weight (D). P values refer to the mean difference between empagliflozin and placebo at day 3 and week 6.