Dr. Subashri Mohanasundaram
Department of Nephrology
Government Thoothukudi Medical College & Hospital, India
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)
|Drug||Dosage||Change in serum magnesium|
|dapagliflozin||10 mg/d||+0.2 mEq/L|
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
|Patient 1||Patient 2||Patient 3|
|Age/Sex||~60y, Male||~60y, Female||~20y, Female|
|Genetic mutation||17p12 deletion||Unknown||Hepatocyte Nuclear Factor 1B deletion|
|Neurological||Defective cognition, cramps, falls, migraines, anxiety||Cramps, muscle weakness||Autism spectrum, learning disability, anxiety, migraines, cramping, weakness, wheelchair bound|
|Endocrine||Hypokalemia, osteopenia, avascular necrosis of hip, type 2 diabetes||Hypercalcemia, Type 2 diabetes mellitus, osteoporosis with vertebral fracture||Type 2 Diabetes|
|Cardiovascular||Coronary artery calcification||Hypertension||Hypertension|
|Treatment||Maximum tolerated oral magnesium, plus loperamide for loose stools; intravenous magnesium (5 g/d, split into AM and PM infusions); amiloride (10 mg 3×/d)||Maximum tolerated oral magnesium; intravenous infusions previously discontinued due to transient efficacy; did not tolerate amiloride due to hyperkalemia||Oral magnesium (poor adherence due to nausea and loose stools); intravenous magnesium previously discontinued due to recurrent deep vein thrombosis and superior vena cava syndrome|
|SGLT2 inhibitor (dose)||canagliflozin 300 mg/d||empagliflozin 10 mg/d||dapagliflozin 10 mg/d|
|Change in magnesium level on initiation of SGLT2i (mg/dL)||1.6 ± 0.2 -> 1.9 ± 0.1
|0.9 ± 0.1 -> 1.2 ± 0.1
|1.2 ± 0.2 -> 1.5 ± 0.1
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