Mechanism Underlying Increase of the Serum Magnesium Concentration Observed Following Treatment with Sodium-Glucose Cotransporter 2 Inhibitors

Abstract

Aim: The EMPA-REG OUTCOME study reported that the sodium-glucose cotransporter 2 inhibitor (SGLT2-i) suppressed cardiovascular (CV) events in patients with type 2 diabetes; we recently suggested that increase of the serum magnesium (Mg) by SGLT2-i's can, in part, explain this reduction. The objective of this study was to elucidate the mechanism underlying the elevation of the serum Mg level induced by treatment with SGLT2-i's. Methods: We analyzed the data of 37 patients with type 2 diabetes who underwent clinical evaluation and laboratory assessment at baseline and the end of 3 months. To investigate the relationship between the changes in the serum Mg concentrations during 3 months' treatment (ΔMg) and other variables, we carried out simple linear regression analysis and multiple linear regression analysis. Results: Three months' treatment with the SGLT2-i resulted in a significant improvement of the body weight (BW), BMI, hemoglobin A1c (HbA1c), and fasting plasma glucose levels. The serum Mg increased significantly. Simple linear regression analysis revealed an association between the ΔMg and the serum triglyceride, serum Mg at baseline, change of the BW (ΔBW), and change of the HbA1c. Multiple linear regression analysis revealed a significant association between the ΔMg and the serum Mg level at the baseline (r = −0.55, P < 0.001) and the ΔBW (r = −0.34, P < 0.05). Conclusion: Our study revealed that a lower serum Mg level at the baseline and BW reduction were significantly associated with an increase in the serum Mg following 3 months' treatment with SGLT2-i's.

The Role of Sodium-Glucose Co-transporter 2 Inhibitors in Patients With Hypomagnesemia: A Systematic Review

“…Clinical trials have demonstrated their effectiveness in reducing hospitalizations due to heart failure, slowing the progression of chronic kidney disease, and decreasing major cardiovascular events, with consistently lower mortality rates [ 1 ]. Recent evidence suggests a class effect of SGLT2 inhibitors, with randomized controlled studies revealing a significant elevation in serum magnesium levels, ranging from 0.04-0.1 mmol/L, in patients with type 2 diabetes, regardless of baseline hypomagnesemia [ 2 , 3 ]. However, the role of SGLT2 inhibitors in treating hypomagnesemia in non-diabetic patients remains unexplored.…”

“…The potential link between hypomagnesemia and glucose intolerance, especially in the context of diabetes mellitus, warrants further investigation. SGLT2 inhibitors, established for their role in diabetes management, are associated with a significant increase in serum magnesium concentration among diabetic patients [ 2 ]. This intriguing connection highlights the potential of SGLT2 inhibitors not only for glycemic control, but also as contributors to magnesium balance.…”

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

“…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 risk observed in the EMPA-REG OUTCOME study [13], because, as mentioned above, hypomagnesemia increases the risk of CV events. We and another group reported that patients with hypomagnesemia are more likely to enjoy the beneficial effects of SGLT2 inhibitor treatment on the risk of CV events, because elevation of the serum Mg was found to be more likely to occur in patients with low serum Mg levels at the baseline [14,15]. …”