Renal and Cardiovascular Effects of SGLT2 Inhibition in Combination With Loop Diuretics in Patients With Type 2 Diabetes and Chronic Heart Failure

Abstract

Background: Sodium-Glucose Co-Transporter-2 (SGLT2) inhibitors improve heart failure (HF) associated-outcomes in patients with type 2 diabetes (T2D). In patients with HF, SGLT2 inhibitors will likely be co-prescribed 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 (NCT03226457) was a randomized, double-blind, placebo-controlled, cross-over trial of patients with T2D and HF 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 at week 6. Results: Twenty-three participants (mean age 69.8 years, 73.9% male, mean furosemide dose of 49.6±31.3mg/day, mean HbA1c 7.9±3.8%) were recruited. Compared to placebo, empagliflozin caused a significant increase in 24-hour urinary volume at both day 3 (mean difference 535 ml, 95% CI 133 to 936, p =0.005) and week 6, (mean difference 545 ml, 95% CI 136 to 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 non-significant 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 to 598, p=0.026) compared to 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. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT03226457

Natriuretic Effect of Two Weeks of Dapagliflozin Treatment in Patients With Type 2 Diabetes and Preserved Kidney Function During Standardized Sodium Intake: Results of the DAPASALT Trial

“…Treatment with SGLT2 inhibitors increases glucose concentration in the distal nephron, resulting in a decrease in the osmotic gradient between the tubular fluid and interstitium. This reduces passive water reabsorption, resulting in osmotic diuresis ( 13 , 14 ). In the current study, glycosuria was consistently increased, although we did not observe a clear effect on urine volume, which contrasts the findings from in silico models ( 21 ).…”

“…Previous studies of varying designs in healthy volunteers or patients with type 2 diabetes have indeed suggested that SGLT2 inhibitors cause transient increases in 24-h sodium excretion ( 8 – 11 ) along with reductions in plasma and extracellular volume ( 12 , 13 ). Studies in patients with heart failure showed either no change ( 14 ) or a modest increase in sodium excretion in parallel with a reduction in plasma volume ( 15 ). The prior studies were limited by the fact that sodium excretion was estimated from spot urine samples instead of 24-h urine collections, or dietary intake of sodium was not recorded or standardized.…”

Effect of sodium–glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis

“…A total of 21 RCTs [ 10 , 24 , 25 , 29 – 31 , 33 , 39 – 52 ] were recognized eligible in this meta-analysis, including 3 in crossover design [ 41 , 44 , 50 ]. A total of 10,978 participants were enrolled, including 6236 in the SGLT2i group and 4821 in the control group.…”

“…Seventy percent of the participants were male, and the mean age ranged from 56 to 73 years old. The mean follow-up period ranged from 14 days to one year, including three studies [ 41 , 50 , 51 ] less than 3 months. Participants with T2DM that were mostly in stage A–B HF were enrolled in 10 studies [ 24 , 25 , 39 , 40 , 44 , 46 , 48 , 49 , 51 , 52 ], and patients with T2DM and stage C HF were enrolled in 11 studies [ 10 , 29 – 31 , 33 , 41 – 43 , 45 , 47 , 50 ].…”

“…The mean follow-up period ranged from 14 days to one year, including three studies [ 41 , 50 , 51 ] less than 3 months. Participants with T2DM that were mostly in stage A–B HF were enrolled in 10 studies [ 24 , 25 , 39 , 40 , 44 , 46 , 48 , 49 , 51 , 52 ], and patients with T2DM and stage C HF were enrolled in 11 studies [ 10 , 29 – 31 , 33 , 41 – 43 , 45 , 47 , 50 ]. LVMI, LVEDVI, LVESVI, LAVI, LVEF, GLS, the E/e’ ratio, plasma NT-proBNP level, and the KCCQ score were reported in 6 [ 24 , 25 , 29 , 44 , 45 , 52 ], 3 [ 25 , 29 , 30 ], 3 [ 25 , 29 , 30 ], 4 [ 25 , 29 , 45 , 52 ], 9 [ 24 , 25 , 29 – 31 , 39 , 40 , 44 , 45 ], 4 [ 24 , 39 , 44 , 51 ], 8 [ 24 , 25 , 30 , 31 , 44 , 45 , 49 , 52 ], 11 [ 10 , 24 , 25 , 31 , 41 , 44 – 46 , 48 – 50 ] and 3 [ 10 ...…”