Empagliflozin and Renal Sodium-Hydrogen Exchange in Healthy Subjects

• Published in: The journal of clinical endocrinology and metabolism Vol. 108; no. 8; pp. e567 - e573
• Main Authors: Biancalana, Edoardo, Rossi, Chiara, Raggi, Francesco, Distaso, Mariarosaria, Tricò, Domenico, Baldi, Simona, Ferrannini, Ele, Solini, Anna
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.08.2023
• Subjects: Antidiabetics; Clinical; Dapagliflozin; Dextrose; Electrolytes; Glucose; Glucose transporter; Healthy Volunteers; Humans; Hydrogen; Hydrogen - metabolism; Hydrogen exchange; Ketogenesis; Kidneys; Male; Membrane proteins; Na+/H+-exchanging ATPase; NHE3 protein; pH effects; Protein expression; Protein transport; Proteins; Proximal tubules; Renal tubules; Sodium; Sodium - urine; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Sodium-Hydrogen Exchanger 3; Symporters; Type 2 diabetes; empagliflozin; sodium reabsorption; NHE3; proximal tubule; SGLT2
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgad088

Abstract Context Sodium glucose co-transporter-2 inhibitors exert clinically relevant cardiorenal protection. Among several mechanisms, inhibition of sodium-hydrogen exchanger-3 (NHE3) in proximal renal tubules has been proposed in rodents. Demonstration of this mechanism with the associated electrolyte and metabolic changes in humans is lacking. Objective The present proof-of-concept study was designed to explore the involvement of NHE3 in modulating the response to sodium glucose co-transporter-2 inhibitors in humans. Methods Twenty healthy male volunteers received 2 tablets of empagliflozin 25 mg during a standardized hydration scheme; freshly voided urines and blood samples were collected at timed intervals for 8 hours. Protein expression of relevant transporters was examined in exfoliated tubular cells. Results Urine pH levels increased after empagliflozin (from 5.81 ± 0.5 to 6.16 ± 0.6 at 6 hours, P = .008) as did urinary output (from median, 1.7; interquartile range [IQR, 0.6; 2.5] to 2.5 [IQR, 1.7; 3.5] mL/min−1, P = .008) and glucose (from median, 0.03 [IQR, 0.02; 0.04] to 34.8 [IQR, 31.6; 40.2] %, P < .0001), and sodium fractional excretion rates (from median, 0.48 [IQR, 0.34; 0.65] to 0.71 [IQR, 0.55; 0.85] %, P = .0001), whereas plasma glucose and insulin concentrations decreased and plasma and urinary ketones increased. Nonsignificant changes in NHE3, phosphorylated NHE3, and membrane-associated protein 17 protein expression were detected in urinary exfoliated tubular cells. In a time-control study in 6 participants, neither urine pH nor plasma and urinary parameters changed. Conclusions In healthy young volunteers, empagliflozin acutely increases urinary pH while inducing a substrate shift toward lipid utilization and ketogenesis, without significant changes in renal NHE3 protein expression.