Little Known Benefit in Using SGLT2 Inhibitors 

While the major impact of hypomagnesemia on cardiovascular outcomes and T2DM has been known, recent evidence suggests that SGLT2 inhibitors may normalize Mg2+ levels.  

Among the many factors that play a role in the severity of type 2 diabetes is hypomagnesemia. It is important for providers and patients to recognize this contributing abnormality, which has been shown to affect diabetes control greatly. Previous research has shown that hypomagnesemia (Mg2+ <0.7 mmol/L) is strongly associated with a more rapid disease progression, a decline in renal function and increased risk for diabetes complications. It is hypothesized that poor intestinal absorption and renal wasting of magnesium are responsible. Patients with T2DM and hypomagnesemia tend to have reduced pancreatic -cell function and are more insulin resistant. Magnesium supplementation has been shown to improve glucose metabolism and insulin sensitivity in patients with T2DM. Knowing the severity of hypomagnesemia in patients with T2DM, it is important to recognize the potential impact anti-diabetes drugs may have on magnesium levels and whether any drug classes can aid in normalizing Mg2+ levels.

New research suggests that correction of magnesium deficiency can be seen from SGLT2 inhibitor treatment in patients with T2DM. A post-hoc analysis was conducted on ten placebo-controlled trials with dapagliflozin.

Among 4,398 adult participants with T2DM from the studies combined, 773 had a serum magnesium level of less than 0.74 mmol/L (considered hypomagnesemia in this study) at baseline. Four hundred and three were randomized to dapagliflozin therapy, and 370 were assigned to placebo. The remaining participants who did not have low magnesium levels at baseline were randomized between dapagliflozin and placebo. Participants taking dapagliflozin with hypomagnesemia at baseline had an average Mg2+ level of 0.66 mmol/L at baseline and improved to 0.77 mmol/L after 24 weeks. Those in the same group that received a placebo improved from 0.66 mmol/L at baseline to 0.69 mmol/L after 24 weeks. Within the group with Mg2+ levels in the normal range (>0.74 mmol/L), the average baseline Mg2+ level was 0.84 mmol/L. Those within this group taking dapagliflozin experienced an increase to an average of 0.87 mmol/L while the placebo group experienced a decrease to 0.82 mmol/L. The rate of adverse events was similar in each treatment group.

Based on these studies, we can conclude that dapagliflozin significantly increases Mg2+ levels in patients with T2DM with or without hypomagnesemia. Dapagliflozin, more so normalizes Mg2+ in persons with hypomagnesemia, which may be a significant benefit to those struggling to achieve glycemic control and who are found to have hypomagnesemia. A previous study analyzed similar outcomes from canagliflozin and found that doses of 100mg and 300mg were associated with normalization of serum magnesium in patients with T2DM and hypomagnesemia. Several other SGLT2 inhibitors have been found to have the same effect, and therefore, this has been attributed to the drug class as a whole. 

Hypomagnesemia alone is associated with poor cardiovascular outcomes; with the added negative impact it can have on patients’ diabetes control, it is of great interest to understand this benefit SGLT2 inhibitors can provide for such patients.

It is unclear whether the cardiovascular benefit seen from SGLT2 inhibitors can be at least partially attributed to the normalization of Mg2+ levels. Further studies would be helpful to establish causation between magnesium normalization and improved cardiovascular outcomes.

Practice Pearls:

• Hypomagnesemia worsens glycemic control in patients with T2DM and is associated with worsened cardiovascular outcomes and increased T2DM complications.
• Recent studies have shown that SGLT2 inhibitors can normalize Mg2+ levels in patients with T2DM and hypomagnesemia.
• For patients with T2DM and hypomagnesemia, SGLT2 inhibitors are a good option for anti-diabetic drug therapy in patients without any contraindications.

Toto, Robert D., et al. “Correction of Hypomagnesemia by Dapagliflozin in Patients with Type 2 Diabetes: A Post Hoc Analysis of 10 Randomized, Placebo-Controlled Trials.” Journal of Diabetes and Its Complications, 2019, doi:10.1016/j.jdiacomp.2019.06.007.

Gommers, Lisanne M.m., et al. “Hypomagnesemia in Type 2 Diabetes: A Vicious Circle?” Diabetes, vol. 65, no. 1, 2015, pp. 3–13., doi:10.2337/db15-1028.

Amber Satz, PharmD Candidate, LECOM School of Pharmacy