Renal and Cardiovascular Effects of SGLT2 Inhibition in Combination With Loop Diuretics in Patients With Type 2 Diabetes and Chronic Heart Failure
Supplemental Digital Content is available in the text. 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.
Circulation