SGLT2 inhibition versus sulfonylurea treatment effects on electrolyte and acid–base balance: secondary analysis of a clinical trial reaching glycemic equipoise: Tubular effects of SGLT2 inhibition in Type 2 diabetes

Abstract

Sodium–glucose transporter (SGLT)2 inhibitors increase plasma magnesium and plasma phosphate and may cause ketoacidosis, but the contribution of improved glycemic control to these observations as well as effects on other electrolytes and acid–base parameters remain unknown. Therefore, our objective was to compare the effects of SGLT2 inhibitors dapagliflozin and sulfonylurea gliclazide on plasma electrolytes, urinary electrolyte excretion, and acid–base balance in people with Type 2 diabetes (T2D). We assessed the effects of dapagliflozin and gliclazide treatment on plasma electrolytes and bicarbonate, 24-hour urinary pH and excretions of electrolytes, ammonium, citrate, and sulfate in 44 metformin-treated people with T2D and preserved kidney function. Compared with gliclazide, dapagliflozin increased plasma chloride by 1.4 mmol/l (95% CI 0.4–2.4), plasma magnesium by 0.03 mmol/l (95% CI 0.01–0.06), and plasma sulfate by 0.02 mmol/l (95% CI 0.01–0.04). Compared with baseline, dapagliflozin also significantly increased plasma phosphate, but the same trend was observed with gliclazide. From baseline to week 12, dapagliflozin increased the urinary excretion of citrate by 0.93 ± 1.72 mmol/day, acetoacetate by 48 μmol/day (IQR 17–138), and β-hydroxybutyrate by 59 μmol/day (IQR 0–336), without disturbing acid–base balance. In conclusion, dapagliflozin increases plasma magnesium, chloride, and sulfate compared with gliclazide, while reaching similar glucose-lowering in people with T2D. Dapagliflozin also increases urinary ketone excretion without changing acid–base balance. Therefore, the increase in urinary citrate excretion by dapagliflozin may reflect an effect on cellular metabolism including the tricarboxylic acid cycle. This potentially contributes to kidney protection.

Sex-Specific Computational Models of Kidney Function in Patients With Diabetes

“…Although there is no major sex-specific differences seen in the larger clinical trials of SGLT2 inhibitors, we still find comparability in our predictions of increase in solute excretion with some trials (Sha et al, 2014;Masuda et al, 2020;van Bommel et al, 2020) and not so much with others (Kapur et al, 2013;Cherney et al, 2014;Tanaka et al, 2017;Eickhoff et al, 2019). van Bommel et al (2020) reported a chloride increase of 0.2-2.4 mmol/l in 24 h upon treatment with dapagliflozin. Masuda et al (2020) also reported an increase to 3 mM/Day in urinary chloride compared to 2.3 mM/Day in control after 8 weeks of treatment with ipragliflozin (in rats).…”

Effect of Dapagliflozin and Magnesium Supplementation on Renal Magnesium Handling and Magnesium Homeostasis in Metabolic Syndrome

“…Our results showed that dapagliflozin upregulated renal magnesium transporters, including claudin-16 and TRPM6/7, resulting in decreased magnesium excretion. It is therefore indicated that both paracellular and transcellular transport were increased [26]. Moreover, the in vitro study by monitoring intracellular magnesium concentration suggested dapagliflozin increased trans-epithelial magnesium transport via TRPM6.…”

Comparative Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Serum Electrolyte Levels in Patients with Type 2 Diabetes: A Pairwise and Network Meta-Analysis of Randomized Controlled Trials

“…In addition, correcting hypomagnesemia may help glycemic control in diabetes, but not vice versa. 17 The mechanism underlying the renal benefit of SGLT2is is likely to be independent of glucose levels and may possibly stem from a reduction in intra-glomerular pressure 18 and other possible mechanisms presently being studied. 19 SGLT2is can normalize proximal reabsorption via tubular glomerular feedback, which should have particular effects on glomerular hemodynamics, eliminate diabetic hyperfiltration, and improve hard renal end points.…”