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. 2022 Jan 19;3(3):477-487.
doi: 10.34067/KID.0006672021. eCollection 2022 Mar 31.

Comparative Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Serum Electrolyte Levels in Patients with Type 2 Diabetes: A Pairwise and Network Meta-Analysis of Randomized Controlled Trials

Jingjing Zhang  1 , Yonghong Huan  2 , Mark Leibensperger  3 , Bojung Seo  4 , Yiqing Song  4
Affiliations

Comparative Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Serum Electrolyte Levels in Patients with Type 2 Diabetes: A Pairwise and Network Meta-Analysis of Randomized Controlled Trials

Jingjing Zhang et al. Kidney360. .

Abstract

Background: Previous studies have reported that sodium-glucose co-transporter 2 (SGLT2) inhibitors (SGLT2is) affect levels of serum electrolytes, especially magnesium. This study aimed to integrate direct and indirect trial evidence to maximize statistical power to clarify their overall and comparative effects in patients with type 2 diabetes (T2D).

Methods: We systematically searched PubMed, EMBASE, CENTRAL, and ClinicalTrials.gov up to January 2021 to identify eligible randomized controlled trials (RCTs) of SGLT2is that reported mean changes in serum electrolytes, including magnesium, sodium, potassium, phosphate, and calcium. We performed both random-effects pairwise and network meta-analyses to calculate the weighted mean difference (WMD) and 95% confidence intervals (CI).

Results: In total, we included 25 RCTs involving 28,269 patients with T2D and 6 SGLT2is. Compared with placebo, SGLT2is were significantly associated with elevations in serum magnesium by 0.07 mmol/L (95% CI, 0.06 to 0.08 mmol/L) and serum phosphate by 0.03 mmol/L (95% CI, 0.02 to 0.04 mmol/L). Our network meta-analysis showed no evidence of significantly superior efficacy of any specific SGLT2 inhibitor over the others, although dapagliflozin was associated with a larger increment in serum magnesium (WMD=0.16 mmol/L) compared with other SGLT2is. Similarly, no statistically detectable differences among the effects of SGLT2is on serum levels of other electrolytes were detected.

Conclusions: SGLT2is significantly increased serum magnesium and phosphate levels, consistent with a class effect of SGLT2 inhibition. However, further investigations of long-term efficacy and safety in patients with T2D with different clinical phenotypes are needed.

Keywords: SGLT2 inhibitor; calcium; diabetes and the kidney; diabetes mellitus; electrolytes; magnesium; meta-analysis; phosphate; potassium; sodium; type 2 diabetes.

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Conflict of interest statement

All authors have nothing to disclose.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Flow chart of the identification of eligible trials.
Figure 2.
Figure 2.
Pairwise meta-analyses of the effects of sodium-glucose cotransporter (SGLT) 2 inhibitors (SGLT2is) on magnesium and phosphate. (A) Blood magnesium levels (mmol/L) and (B) blood phosphate levels (mmol/L). Each square indicates the WMD in each trial. The horizontal line represents the 95% CI. The pooled WMD and 95% CI is indicated by the dashed line and diamond. The black vertical line represents the null hypothesis. Heterogeneity between studies was assessed by the I2 statistics and Cochrane Q (P value). WMD, weighted mean difference; CI, confidence interval.
Figure 3.
Figure 3.
Network meta-analysis results of the effect of SGLT2is on blood magnesium levels. (A) Network of eligible comparisons for the multiple-SGLT2is meta-analysis for effects on blood magnesium levels. Each node represents one treatment. The directly compared treatments are linked with a solid line; the width of the lines is proportional to the number of randomized participants (sample size), and the size of every node is proportional to the number of trials comparing every pair of treatments. (B) Network meta-analysis combining direct and indirect evidence within a network of eligible trials for the effects of SGLT2is on blood magnesium levels (mmol/L). The black solid lines represent the confidence intervals for WMD of blood magnesium levels for each comparison, and the blue line is the line of no effect (WMD=0).
Figure 4.
Figure 4.
Network meta-analysis results of the effect of SGLT2is on blood phosphate levels. (A) Network of eligible comparisons for the multiple-SGLT2is meta-analysis for effects on blood phosphate levels. Each node represents one treatment. The directly compared treatments are linked with a solid line; the width of the lines is proportional to the number of randomized participants (sample size), and the size of every node is proportional to the number of trials comparing every pair of treatments. (B) Network meta-analysis combining direct and indirect evidence within a network of eligible trials for the effects of SGLT2is on blood phosphate levels (mmol/L). The black solid lines represent the CIs for WMD of blood magnesium levels for each comparison, and the blue line is the line of no effect (WMD=0).
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