Effects of empagliflozin on renal sodium and glucose handling in patients with acute heart failure

Abstract

Aims: Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve clinical outcome in patients with heart failure (HF), but the mechanisms behind their beneficial effects are not yet fully understood. We examined the effects of empagliflozin on renal sodium and glucose handling in patients with acute HF.

Methods and results: This study was a pre-defined sub-study of a double-blind, randomized, placebo-controlled, multicentre study (EMPA-RESPONSE-AHF). Patients were allocated within 24 h of an acute HF admission to either empagliflozin 10 mg/day (n = 40) or placebo (n = 39) for 30 days. Markers of glucose and sodium handling were measured daily during the first 96 h and at day 30. Patients were 76 (range 38-89) years old and 33% had diabetes. The use of loop diuretics during the first 96 h was similar in both groups. Empagliflozin increased fractional glucose excretion with a peak after 24 h (21.8% vs. 0.1%; P < 0.001), without affecting plasma glucose concentration, while fractional sodium and chloride excretion and urinary osmolality remained unchanged (P >0.3 for all). However, empagliflozin increased plasma osmolality (delta osmolality at 72 h: 5 ± 8 vs. 2 ± 5 mOsm/kg; P = 0.049). Finally, there was an early decline in estimated glomerular filtration rate with empagliflozin vs. placebo (-10 ± 12 vs. -2 ± 12 mL/min/1.73 m² ; P = 0.009), which recovered within 30 days.

Conclusion: In patients with acute HF, empagliflozin increased fractional glucose excretion and plasma osmolality, without affecting fractional sodium excretion or urine osmolality and caused a temporary decline in estimated glomerular filtration rate. This suggests that empagliflozin stimulates osmotic diuresis through increased glycosuria rather than natriuresis in patients with acute HF.

Keywords: Acute heart failure; Diuresis; Empagliflozin; Kidney; Sodium-glucose co-transporter 2 inhibitors.

Figure 1

Progression of fractional excretion of sodium (A), chloride (B) and glucose (C) over the course of treatment. For each clinical variable, changes from baseline were calculated and used as outcomes in linear mixed‐effect models. Two models were performed, one adjusted for baseline values, the second model adjusted for baseline values and the interaction term between treatment and time. In each panel, the results for the ANOVA tests between the two models is depicted (likelihood ratio and P‐value). For placebo and empagliflozin, mean values are shown with dots, the bars represent standard error. A P‐value for interaction between each time point and treatment is shown.

Figure 2

Delta estimated glomerular filtration rate (GFR) (A), delta systolic blood pressure progression (B), delta urine osmolality (C) and delta plasma osmolality (D) over the course of treatment. For each clinical variable, changes from baseline were calculated and used as outcomes in linear mixed‐effect models. Two models were performed, one adjusted for baseline values, the second model adjusted for baseline values and the interaction term between treatment and time. In each panel, the results for the ANOVA tests between the two models is depicted, (likelihood ratio and P‐value). For placebo and empagliflozin, mean values are shown with dots, the bars represent standard error. A P‐value for interaction between each time point and treatment is shown.

Figure 3

Composites of urinary molecules making up osmolality. Osmolality per time point for both empagliflozin and placebo. Volumes depicted on the bars represent total urinary volume per 24 h, y axis represents spot urinary osmolality. *n = 58; ^† n = 47; ^‡ n = 44; ^§ n = 35.

Figure 4

Delta renin (A) and aldosterone (B) over the course of treatment. For renin and aldosterone (both log‐transformed), changes from baseline were calculated and used as outcomes in linear mixed‐effect models. Two models were performed, one adjusted for baseline values, the second model adjusted for baseline values and the interaction term between treatment and time. In each panel, the results for the ANOVA tests between the two models is depicted (likelihood ratio and P‐value). For placebo and empagliflozin, mean values are shown with dots, the bars represent standard error. A P‐value for interaction between each time point and treatment is shown.