Generalized symptoms of weakness and muscle cramps are commonly present in patients of diabetes mellitus and despite adequate sugar control there is no significant improvement in their symptoms.¹ Type II diabetes mellitus is often accompanied by alteration in magnesium levels.² An increased prevalence of magnesium deficiency is more common in those diabetics who have uncontrolled blood sugar levels, those with longer duration of the disease and with microvascular and macrovascular complications.³ Magnesium deficiency may be present even without hypomagnesemia measurements of total serum Mg instead of the free ionized (bioactive) or the intracellular Mg concentration makes it a challenge in terms of correlation of Mg deficits to its symptoms.⁴ Intracellular free Mg levels are commonly low in patients of type II diabetes.² Mean increase in serum magnesium levels with use of SGLT₂ inhibitors is in a range from 0.01 to 0.24 mg/dl.⁵ The normal serum Magnesium level in healthy individuals ranges between 1.7 to 2.2 mg/dl. The postulated theory for increase in magnesium levels by SGLT₂ inhibitors include enhanced reabsorption of mg in renal tubules and the effect of changes in glucose metabolism which also improves serum magnesium levels.

Patients attending the hospital OPD for diabetes management were screened for study participation.Patients with type II diabetes on oral hypoglycemic agents were evaluated for generalized weakness and muscle cramps. Treatment history was further elaborated about the ongoing therapy with SGLT₂ inhibitors or magnesium supplements. Those with positive history of above medicines were excluded from the study. Furthermore, those on insulin too were not considered as study subjects.Out of the seventy-six study participants (based on sample size calculation) equal number i.e.,thirty-eight participants each were considered in two arms of the study. One group received SGLT2 inhibitors with other OHAs, while the other received all OHAs except SGLT2 inhibitors.Baseline FBS, PPBS, and serum magnesium levels were measured using standard methods. The presence of muscle cramps and generalized weakness was present in all the study subjects at the beginning of the study.The parameters were remeasured twice at 8-week intervals, resulting in a total follow-up period of 16 weeks.The sample size calculation formula for this study has expected proportion exposed in controls =0.18, assumed odds ratio = 4, confidence level = 0.95 and desired power = 0.8.After data collection, the information was entered into Excel and analyzed with epiInfo 7. Means and standard deviations were calculated for quantitative variables.

This study was conducted in seventy-six participants who reported to a tertiary care center. The Mean age in patients on SGLT2 Inhibitors was 55 ± 9.5 years while Mean age of patients on OHA Drugs was 50 ± 5.3 years (Table 1)^.The SGLT2 intervention arm thirteen patients (34.2%) had both weakness and cramps.20 patients (52.6%) had only weakness and 5patients (!3.1%) had only cramps at the beginning of the study. Serum Mg levels were normal in twenty-sixpatients (68.4%) and low in twelve patients (31.5%).

Follow-up occurred in two phases for both study arms. In Patients who were on SGLT2 only during their first follow up visit out of twelve patients only 3(25%) patients hadserum Mg level up to normal limits whilenine patients still had low Mg levels.Eight patients (21%)were having weakness and cramps, howeverfourpatients (10.5%) showed only weakness as a symptom while 1(2.6%) patient had only cramps.

At the second follow up visit out of thirty-eight patients 11 (28.9%) had weakness ,9 (23.6%) had cramps, and twopatients (5.26%) had both weakness and cramps. Serum magnesium remained lower than the baseline value in these patients.

In the second arm of the study, which included thirty-eight patients receiving oral hypoglycemic agents other than SGLT2 inhibitors, eighteen patients (47.3%) reported cramps, and weakness seen in thirty-six patients (94.7%). Serum magnesium levels at the beginningwere low in eight out of thirty-eight patients i.e.,thirty patients had normal serum magnesium levels.

In the first follow up visit thirty patients (78.9%) complained of weakness, cramps occurred in fourteenpatients (36.8%) which was eighteen in the first phase. Serum magnesium was low in titer during the first follow up.

The second follow-up visit showed improvement in weakness as twenty-five patients still had persisting weakness (65.7%) and twelvepatients (31.5%) had associated cramps also.

Table 1. Clinical Characteristics of patients

In both arms of the study Serum Magnesium levels were normal although the number of patients with complaints of weakness and cramps was high in proportion. As per Mather et al ⁶not only serum magnesium level but the intracellular magnesium and ionic Mg too play a significant role in the organ of clinical symptoms of weakness and cramps.

Hence tools to measure intracellular and ionic magnesium will be of use in future studies to signify further the role of Mg in development of these symptoms.

Magnesium deficiency can be present without hypomagnesemia. However, hypomagnesemia when present is usually indicative of systemic Mg deficit. People can have low intracellular or ionized plasma magnesium even if total magnesium levels are normal. However most of the studies till date have measured total magnesium instead of free, ionized or the intracellular Mg concentrations which makes it a challenge to correlate Mg deficits to disease.⁷ In various studies it has been proven that intracellular free Mg levels are consistently reduced in subjects with type II diabetes.^8,9

In both study groups, total serum magnesium levels increased among participants who achieved blood glucose regulation; however, these biochemical changes did not consistently align with alterations in clinical symptoms.Serum Mg often stayed constant, yet clinical symptoms improved.Total magnesium levels do not consistently correlate with clinical symptoms such as weakness and cramps. Along with it the role of blood sugar levels too is significantly important in supporting Mg levels both at intracellular and serumlevels. Improvement in blood sugar levels was associated with alleviation of weakness and cramps in a considerable proportion of participants across both study arms. Symptoms persisted even when blood sugar and serum Mg levels improved.

This showsthe possibility of other metabolic factors involved or psychogenic factors or the role of ionic Mg in the etiology of these symptoms.

By comparing the two groups it can be concluded that use of SGLT2 inhibitors alleviates symptoms of weakness and cramps but to correlate it with changes in Mg levels serum Mg levels alone may not be the best tool.

Recommendation

Assessing Serum magnesium levels only is inadequate for confirming magnesium deficiency and linking it to symptoms such as weakness and cramps. Evaluating intracellular magnesium and ionic (active) magnesium levels may provide a more exact correlation with symptoms of magnesium deficiency. Future clinical trials should include these measurements to clarify magnesium deficiency in diabetes and the impact of SGLT2 inhibitors.

Acknowledgment

Sincere thanks to the participant and my colleague who were instrumental in discussing various ideas related to the study for their support and participation in this study.

1. Chonchol M, Smogorzewski MJ, Stubbs JR, Yu ASL. Disorders of calcium, magnesium, and phosphate balance. In: Yu ASL, Chertow GM, Luyckx VA, Marsden PA, Skorecki K, Taaal MW, eds. Brenner and Rector’s The Kidney. 11^th Philadelphia, PA: Elsevier; 2020: chap 18.
2. Pfenning CL, Slovis CM. Electrolytes disorders. In: Hockberger RS, Walls RM, Gausche-Hill M, eds.Rosen; s Emergency Medicine: Concepts and Clinical Practice. 9^th Philadelphia, PA: Elsevier Saunders: 2018: chap 117.
3. Unnikrishnan, A.G., Kalra, S., Purandare, V. and Vasnawala, H., 2018. Genital infections with sodium glucose cotransporter-2 inhibitors: occurrence and management in patients with type 2 diabetes mellitus. Indian journal of endocrinology and metabolism, 22(6), pp.837-842.
4. Rosenstock J, Mathieu C, Chen H, Garcia-Sanchez R, Saraiva GL. Dapagliflozin versus saxagliptin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin. Archives of endocrinology and metabolism. 2018;62:424-30.
5. Vila G, Jørgensen JO, Luger A, Stalla GK. Insulin resistance in patients with acromegaly. Frontiers in endocrinology. 2019 Jul 30;10:509
6. Classification and diagnosis of Diabetes. Diabetes Care. 2014;38(Suppl 1): S8-16
7. International Diabetes Federation. IDF Diabetes Atlas. 20136^th ed Brussels, Belgium International Diabetes Federation.
8. Ramachandran A, Ma RC, Snehalatha C, Diabetes in Asia Lancet. 2010; 375:408-18
9. McNair P, Christensen MS, Christiansen C, Madsbad S, Transb⌀l I. Renal hypomagnesaemia in human diabetes mellitus: Its relation to glucose homeostasis Eur J Clin Invest. 1982:12:81-5