The Off-Target Effects, Electrolyte and Mineral Disorders of SGLT2i

Abstract

The sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic drugs that, in addition to emerging as an effective hypoglycemic treatment, have been shown to improve, in several trials, both renal and cardiovascular outcomes. In consideration of the renal site of action and the associated osmotic diuresis, a negative sodium balance has been postulated during SGLT2i administration. Although it is presumable that sodium and water depletion may contribute to some positive actions of SGLT2i, evidence is far from being conclusive and the real physiologic effects of SGLT2i on sodium remain largely unknown. Indeed, no study has yet investigated how SGLT2i change sodium balance in the long term and especially the pathways through which the natriuretic effect is expressed. Furthermore, recently, several experimental studies have identified different pathways, not directly linked to tubular sodium handling, which could contribute to the renal and cardiovascular benefits associated with SGLT2i. These compounds may also modulate urinary chloride, potassium, magnesium, phosphate, and calcium excretion. Some changes in electrolyte homeostasis are transient, whereas others may persist, suggesting that the administration of SGLT2i may affect mineral and electrolyte balances in exposed subjects. This paper will review the evidence of SGLT2i action on sodium transporters, their off-target effects and their potential role on kidney protection as well as their influence on electrolytes and mineral homeostasis.

Crosstalk between Sodium–Glucose Cotransporter Inhibitors and Sodium–Hydrogen Exchanger 1 and 3 in Cardiometabolic Diseases

“…In hypertension, there is an increase in Na + reabsorption that mainly occurs in the proximal tubule and loop of Henle. SGLT2, which is localized in the proximal tubule, is responsible for 60–90% of the renal uptake of Na+ and glucose [ 119 , 120 ].…”

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

“…Patients with lower serum magnesium levels at baseline were unexpectedly associated with an increase in magnesium levels following treatment with SGLT2 inhibitors [22]. A number of possible mechanisms have been proposed, including increased renal magnesium absorption due to increased glucagon levels, improvement of insulin resistance, and shifting of intracellular magnesium to the extracellular volume due to reduced insulin levels and increased aldosterone levels [23,24]. Although a regulating mechanism of TRPM6 by insulin or glucagon has been proposed, the direct evidence is lacking [25].…”

Empagliflozin induces apoptotic-signaling pathway in embryonic vasculature: In vivo and in silico approaches via chick’s yolk sac membrane model

“…Various studies in the literature focus on the toxicity and side effects following EMP treatment ( Bogdanffy et al, 2014 ; Halimi and Vergès, 2014 ; Taub et al, 2015 ; Neeland et al, 2016 ; Knight et al, 2018 ; Cianciolo et al, 2020 ). The toxic effect of drugs is of great concern in pregnant women.…”