Can SGLT2 Inhibitors be Used in the Treatment of Hypomagnesemia?

Dr. Subashri Mohanasundaram
Assistant Professor
Department of Nephrology
Government Thoothukudi Medical College & Hospital, India
@happiedoc

SGLT2 inhibitors: Though much of the limelight of SGLT2 inhibitors is rightly focused on kidney protection and heart protection, there is less focus on the various electrolytes altered in the patients taking these drugs. Let’s focus on magnesium: an electrolyte without many therapeutic options currently. 

Mechanism of SGLT2 inhibitors and abnormalities of magnesium: Magnesium is one of the essential electrolytes involved in more than 600 enzymatic reactions, nucleic acid, nucleotide triphosphate stability, and cellular electrical activity. Hence, low levels of serum magnesium results in wide-ranging effects, including cardiovascular, neuropsychiatric, and endocrine disorders, especially type 2 diabetes.

Several mechanisms, both primary and secondary, may contribute to the increase in magnesium levels in patients taking SGLT2 inhibitors. (Figure 1)

• Positive effects on diabetes: Hypomagnesemia can result from Insulin resistance by reducing transient receptor potential ion channel 6 (TRPM6) activity in the distal convoluted tubule, resulting in magnesuria. Also, insulin causes a shift of magnesium from plasma to the intracellular space. Moreover, increased glucagon in diabetes may result in decline in fractional excretion of magnesium in the distal tubules. SGLT2 inhibitors result in diminished glucotoxicity, improving insulin resistance, and decreased insulin levels. Each of these effects can result in an increase in serum magnesium levels. Hemoconcentration effect: In the proximal convoluted tubules, SGLT2 inhibitors induced natriuresis and osmotic diuresis leads to extracellular volume depletion, which may result in a small increase in serum magnesium due to hemoconcentration. However, this extracellular volume depletion can result in secondary increase in Ang II levels, which may result in enhanced tubular magnesium absorption, while increased aldosterone levels results in magnesium wasting. 
• Other mechanisms, by which SGLT2 inhibitors may influence magnesium reabsorption include: (1) hypertrophy or hyperplasia of tubular segments that handle magnesium, (2) altered expression of magnesium transporters in kidney or gut, or (3) altered production of signaling agents (such as epidermal growth factor) that impact magnesium reabsorption.

Figure 1: Mechanism of increase in serum magnesium levels with SGLT2 inhibitors

Evidence from randomised controlled trials: A meta-analysis of 18 RCTs including 15,309 patients with four SGLT2 inhibitors (canagliflozin, empagliflozin, dapagliflozin and ipragliflozin) showed that these drugs can increase approximately increase serum magnesium levels by 0.08–0.2 mEq/ L in individuals without chronic kidney disease (Table 1).

Table 1: Effects of SGLT2 inhibitors on magnesium levels: Results of a meta-analysis of 18 randomised controlled trials (n=15,309 patients with eGFR > 60 ml/min/ 1.73 m2)

Can SGLT2 inhibitors be used in the treatment of hypomagnesemia? In the presence of evidence from RCTs that SGLT2 inhibitors increase serum magnesium levels, the question of its use in the treatment of hypomagnesemia arises. There has been a case report of 3 patients who presented with chronic refractory hypomagnesemia and diabetes. (Table 2)

Table 2: Patients with chronic refractory hypomagnesemia

It has to be noted that this change in serum magnesium was noticed after a period of 5 weeks to 3 months after the initiation of SGLT2 inhibitors. Also, how long will this increase in magnesium persist and whether these drugs can be used to treat hypomagnesemia in patients without diabetes still remains to be elucidated.

These observations demonstrate that SGLT2 inhibitors can prove to be a novel modality of management in patients with otherwise intractable hypomagnesemia.

Edited by Matthew Sparks