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

• Published in: Circulation (New York, N.Y.) N.Y.), 2020-11, Vol.142 (18), p.1713-1724
• Main Authors: Mordi, Natalie A., Mordi, Ify R., Singh, Jagdeep S., McCrimmon, Rory J., Struthers, Allan D., Lang, Chim C.
• Format: Article
• Language: English
• Subjects: Original s
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.120.048739

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:URLhttps://www.clinicaltrials.gov; Unique IdentifierNCT03226457.