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

Circulation. 2020 Nov 3;142(18):1713-1724. doi: 10.1161/CIRCULATIONAHA.120.048739. Epub 2020 Aug 29.

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.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Benzhydryl Compounds / administration & dosage*
  • Chronic Disease
  • Diabetes Complications / drug therapy*
  • Diabetes Complications / urine
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / urine
  • Double-Blind Method
  • Female
  • Glucosides / administration & dosage*
  • Heart Failure / drug therapy*
  • Heart Failure / urine
  • Humans
  • Male
  • Sodium Potassium Chloride Symporter Inhibitors / administration & dosage*
  • Sodium-Glucose Transporter 2 Inhibitors / administration & dosage*

Substances

  • Benzhydryl Compounds
  • Glucosides
  • Sodium Potassium Chloride Symporter Inhibitors
  • Sodium-Glucose Transporter 2 Inhibitors
  • empagliflozin

Associated data

  • ClinicalTrials.gov/NCT03226457