# SGLT2 inhibitors, GLP-1 RAs, and DPP4 inhibitors and the risk of hypomagnesemia in type 2 diabetes: A target trial emulation

## TL;DR

This study finds that SGLT2 inhibitors and GLP-1 RAs may reduce the risk of low magnesium levels in type 2 diabetes patients compared to DPP4 inhibitors.

## Contribution

The study provides real-world evidence of class-level effects of SGLT2 inhibitors and GLP-1 RAs in reducing hypomagnesemia risk in type 2 diabetes.

## Key findings

- SGLT2 inhibitors were associated with a 20% lower risk of hypomagnesemia compared to DPP4 inhibitors.
- GLP-1 RAs also showed a 11% lower risk of hypomagnesemia compared to DPP4 inhibitors.
- SGLT2 inhibitors had a 8% lower risk of hypomagnesemia compared to GLP-1 RAs.

## Abstract

Recent studies have suggested potential effects on magnesium homeostasis associated with sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA). We sought to determine whether these effects lead to a reduced risk of hypomagnesemia among adults with type 2 diabetes in clinical practice.

We conducted a target trial emulation study using the multi-institutional cohort data from the TriNetX Global Collaborative Network. We compared 1:1 propensity score-matched patients with type 2 diabetes newly initiating SGLT2 inhibitors versus dipeptidyl peptidase-4 (DPP4) inhibitors (n = 718,798), GLP-1 RAs versus DPP4 inhibitors (n = 623,390), and SGLT2 inhibitors versus GLP-1 RAs (n = 702,808) from 2016 to 2024. Propensity scores were estimated using logistic regression models that included baseline covariates such as age, sex, race, comorbidities, and medication and laboratory data. In each comparison, patients receiving DPP4 inhibitors were considered the active-comparator group. The primary outcome was incident hypomagnesemia, defined by clinical diagnosis or serum magnesium <1.80 mg/dL. Patients were followed until the occurrence of an outcome of interest, last clinical visit, death, or the end of database period (March 31, 2025), whichever came first. We found that initiation of SGLT2 inhibitors was associated with a significantly lower risk of hypomagnesemia, compared with both DPP4 inhibitors (Hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.79, 0.82; p < 0.05) and GLP-1 RAs (HR: 0.92; 95% CI: 0.91, 0.93; p < 0.05). Similarly, GLP-1 RA use was associated with a lower risk of hypomagnesemia, compared with DPP4 inhibitors (HR: 0.89; 95% CI: 0.88, 0.91; p < 0.05). These associations were consistent across individual agents within each drug class. The main limitation of our study is that residual confounding inherent to retrospective observational research cannot be completely ruled out.

Treatment with SGLT2 inhibitors and GLP-1 RAs was associated with a lower risk of hypomagnesemia, compared with DPP4 inhibitors. These findings suggest that SGLT2 inhibitors and GLP-1 RAs may be preferable options for patients at risk of hypomagnesemia.

Hypomagnesemia affects up to 25% of patients with type 2 diabetes, and it is associated with aggravated diabetes progression and a higher risk of systemic complications.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become an integral part of type 2 diabetes management due to their benefits beyond glucose control, including improvements in cardiorenal function and metabolic outcomes.

Recent studies have suggested potential effects on magnesium homeostasis associated with SGLT2 inhibitors and GLP-1 RAs. However, it is unknown whether these effects lead to a reduced risk of hypomagnesemia in clinical practice.

Using data from the TriNetX Global Collaborative Network, we found that, compared with dipeptidyl peptidase-4 (DPP4) inhibitors, SGLT2 inhibitors, and GLP-1 RAs were associated with a lower risk of hypomagnesemia in adults with type 2 diabetes.

In head-to-head comparisons of SGLT2 inhibitors versus GLP-1 RAs, initiation of SGLT2 inhibitors was also associated with a lower risk of hypomagnesemia.

Consistent findings across individual SGLT2 inhibitors and GLP-1 RAs support potential class effects in maintaining magnesium homeostasis, beyond their established cardiorenal benefits.

Our findings highlight a potentially important pleiotropic benefit of SGLT2 inhibitors and GLP-1 RAs in attenuating magnesium loss. Clinicians should consider this effect when selecting antihyperglycemic drugs, particularly for people at risk of hypomagnesemia.

Recognizing and leveraging the mineral-regulating properties of SGLT2 inhibitors and GLP-1 RAs may provide an additional strategy to optimize diabetes management beyond glycemic control.

Randomized trials are warranted to further establish causal inference, as observational studies are inherently subject to residual confounding despite rigorous design and analytical adjustment.

In a target trial emulation, Shih-Chieh Shao and colleagues investigate the risk of hypomagnesemia in type 2 diabetes when treated with GLP-1 RAs or SGLT2i compared to treatment with DDP4 inhibitors, using data from the TriNetX global collaborative network.