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.

Empagliflozin and renal sodium handling: an intriguing smart osmotic diuretic

“…In the current mechanistic sub‐study using spot urine and plasma samples during the first four consecutive days of decongestive therapy, Boorsma et al 5 . illustrate that empagliflozin leads to an increased diuresis through an increased glycosuric effect rather than increased natriuresis.…”

“…Moreover, PRA levels can only be interpreted as an indicator of neurohumoral stimulation if plasma was taken with the patient in the supine position after an adaptation period of 30 min as PRA is very sensitive to changes in body tonus. The information on the collection of the samples was lacking in this study 5 …”

“…In this issue of the Journal, Boorsma et al 5 . describe the effects of empagliflozin on renal sodium and glucose handling in a pre‐defined sub‐analysis of the EMPA‐RESPONSE‐AHF trial.…”

“…However, PRA is depressed during episodes of acute HF with volume overload, and rise due to effective decongestion 18 . Nevertheless, one has to take into consideration the significant limitations in the interpretation of PRA as there is significant variation in the measurements between patients 5 . Moreover, PRA levels can only be interpreted as an indicator of neurohumoral stimulation if plasma was taken with the patient in the supine position after an adaptation period of 30 min as PRA is very sensitive to changes in body tonus.…”

January 2021 at a glance: focus on sex differences, acute heart failure and exercise capacity

“…Sodium–glucose co‐transporter 2 (SGLT2) inhibitors have beneficial effects in HFrEF patients with or without diabetes and may be indicated also in patients hospitalized for HF 12,13 . In a randomized trial in patients with acute HF, empagliflozin increased fractional glucose excretion and plasma osmolality, without changes in fractional sodium and chloride excretion and urinary osmolality, suggesting that it causes osmotic diuresis through increased glycosuria rather than natriuresis 14 …”