Is the Renoprotective Effect of SGLT2 Inhibitors due to their Beneficial Effect on Hypomagnesemia?

Abstract

Magnesium (Mg) deficiency is linked to diabetes and cardiovascular (CV) events. Treatment with the sodiumglucose cotransporter 2 (SGLT2) inhibitor was associated with a suppressed occurrence of CV events in patients with type 2 diabetes. We recently suggested that the increase of the serum Mg level associated with SGLT2 inhibitor treatment could explain, at least in part, the reduction of the CV events. Recently SGLT2 inhibitors have also been reported to exert a renoprotective effect and various hypotheses have been proposed regarding the mechanism. Now we would like to propose another possible mechanism, namely, the role of Mg.Keywords: Magnesium; Sodium-glucose cotransporter 2 inhibitor; Diabetic nephropathy; Renoprotection Magnesium Deficiency is linked to Diabetes, Hypertension and Cardiovascular EventsMagnesium (Mg) acts as a coenzyme in the insulin secretion pathway, influences the insulin sensitivity, and acts as a modulator of Na-K ATPase. Insufficient intake of Mg can cause diabetes [1] and hypertension.Mg exerts favorable effects on the cardiovascular (CV) system, including an anti-inflammatory effect on the vascular endothelium and smooth muscle, vascular relaxant activity, and sympatholytic activity [2]. Of the total Mg content of the body, 99% is present within the cells, and only 1% is present outside cells. Thus, while hypomagnesemia reflects Mg deficiency in the whole body, Mg deficiency could be present even in the presence of serum Mg levels within the normal range [3]. Subjects with hypomagnesemia are known to be at an elevated risk of developing CV disease [4]. According to the findings of the Framingham Heart Study, hypomagnesemia is a risk factor for atrial fibrillation [5]; hypomagnesemia has also been reported to be associated with a risk of premature ventricular contractions, particularly in diabetic patients [6]. In addition, animal experiments have shown that hypomagnesemia causes reduced cardiac function [7]. Furthermore, hypomagnesemia has been reported to increase platelet aggregation, thereby facilitating thrombus formation, and to enhance coronary artery constriction, thereby increasing the risk of development of myocardial infarction [2].A high incidence of CV events and sudden death has also been reported in patients with hypomagnesemia. A meta-analysis of relevant studies, even those including patients without diabetes, revealed that elevation of the serum Mg level by 0.2 mmol/L was associated with a 30% decrease in the risk of onset of CV disease and 40% decrease in the risk of death from CV events [8]. Adequate dietary magnesium intake has been reported to be associated with a reduced risk of cardiovascular events [9]. Thus, it might be reasonable to conclude that the risk of CV disease/events decreases as the serum Mg concentration increases. Mg Concentration Increases with SGLT2 Inhibitor TreatmentSodium-glucose cotransporter 2 (SGLT-2) is expressed in the proximal renal tubules, where it reabsorbs about 80-90% of the filtered glucose. Selective and reversible inhi...