New Research Points to Efficacy of SGLT2 Inhibitors to Treat Hypomagnesemia in Patients with Type 2 Diabetes

Causes of hypomagnesemia are many, and can include kidney disorders or renal failure, type 2 diabetes and polyuria, excessive alcohol use, gastrointestinal disorders that prevent or limit absorption of magnesium in the body, certain medications, and others. Given the broad importance that magnesium plays in physiological processes within the body, disruption to magnesium levels—acute or chronic—can lead to a wide array of symptoms and impairments to overall health. Coupled with the fact that in many instances, cases of hypomagnesemia can be difficult to treat and manage with optimal results, new therapeutic targets or interventions are badly needed for this patient population

For individuals with type 2 diabetes and accompanying urinary magnesium wasting, the sodium glucose cotransporter 2 (SGLT2) inhibitors may be a viable treatment approach based on findings from a case report series published by Renal-Electrolyte Division researcher Evan C. Ray, MD, PhD, and colleagues in the journal Kidney Medicine in April 2020. 

Dr. Ray and colleagues research provides details from three recent cases of hypomagnesemia in individuals with type 2 diabetes (TD2) and other accompanying comorbidities. All three individuals had significant, long term cases of hypomagnesemia that was poorly controlled through standard of care measures including oral and intravenous magnesium replacement therapies.

SGLT2 inhibitors, first approved by the U.S. Food and Drug Administration (FDA) in 2013 for use in the management of T2D have been shown to help improve that condition in combination with other therapies and lifestyle modifications, but the effects of SGLT2 inhibitors on hypomagnesemia has not been rigorously studied to date in this population, or in hypomagnesemia cases attributable to other underlying causes in the absence of T2D.

Each of the three patients received a different SLGT2 inhibitor—canagliflozin, empagliflozin, and dapagliflozin, respectively. At the 8-week follow-up point, each of the individuals had statistically significant improvements in their serum magnesium levels, with noticeable changes or improvements in their symptoms, while none of the patients experienced any significant adverse reactions to the medications. The mean increase in serum magnesium was 0.36 mg/dL. This appears to be happening as a consequence of enhanced conservation of magnesium in the kidney. 

“Admittedly our study represents a small cohort of patients, but it appears that SGLT2 inhibition has the ability to modulate magnesium levels in a positive manner for individuals experiencing chronic magnesium deficiency as a result of urinary magnesium wasting in the presence of T2D,” says Dr. Ray.

There may be a number of factors contributing to these individuals’ magnesium level improvements. Moreover, it is not yet clear what the exact cellular and molecular mechanisms by which SGLT2 inhibition promotes these improvements in magnesium levels, nor is it know how durable the effects may be, though in the three-month follow-up with the patients in this study the effects did persist.

SGLT2 inhibitors may be working to enhance reabsorption of magnesium in the renal tubules, there may be GI factors associated with improvement in magnesium absorption, and changes in glucose metabolism brought on by SGLT2 inhibition.

“What we have before us is the appearance of a potential beneficial therapeutic for chronic depletion of magnesium in these kinds of cases, but we are only at the beginning of the journey to prove that definitively. There is a significant amount of scientific inquiry that needs to be developed to fully understand the mechanisms by which SGLT2 medications function with respect to magnesium, their long-term efficacy on magnesium level improvement, not to mention safety and tolerability. I suspect that our laboratory will be investigating this line of research far into the future,” says Dr. Ray.

References and Further Reading

In addition to the case report series published in Kidney Medicine, Dr. Ray also recently authored a second piece on SGLT2 inhibitors in the journal Current Opinion in Pharmacology.

1. Ray EC, Boyd-Shiwarski CR, Liu P, Novacic D, Cassiman D. SGLT2 Inhibitors for Treatment of Refractory Hypomagnesemia: A Case Report of 3 Patients. Kidney Med. 2020; 2(3): 359-364.

2. Ray EC. Evolving Understanding of Cardiovascular Protection by SGLT2 Inhibitors: Focus on Renal Protection, Myocardial Effects, Uric Acid, and Magnesium Balance. Curr Opin Pharmacol. 2020; 54: 11-17.

More About Dr. Ray and the Ray Laboratory

Evan Ray, MD, PhD, is an associate professor of medicine in the Renal-Electrolyte Division at the University of Pittsburgh School of Medicine. His laboratory is focused on the study of electrolyte balance in the body, including sodium, magnesium, potassium, calcium, and acid/base. His past and current research explores the influence of electrolytes on hypertension, bone health, and immune system function. He is a co-investigator on the Division’s NIH P30 grant, and the focus of his research is on regulation of Mg2+ homeostasis by Muc1.

Dr. Ray earned his medical degree and doctorate from the University of Pennsylvania, where he also completed his internal medicine residency. Dr. Ray completed his clinical fellowship in nephrology and a basic science fellowship in epithelial transport biology at the University of Pittsburgh School of Medicine prior to joining the Renal-Electrolyte Division as a faculty member in 2014.