Hyponatremia poses risks in type 2 diabetes, yet comparative electrolyte safety across glucose-lowering therapies remains unclear. We evaluated the risk of incident hyponatremia associated with sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and dipeptidyl peptidase-4 (DPP-4) inhibitors in real-world practice. Using electronic health records from 155 healthcare organizations in the TriNetX Global Collaborative Network, we conducted multicenter active-comparator, new-user target trial emulations with 1:1 propensity score matching. For each pairwise comparison, adults with type 2 diabetes initiating either drug class, with no record of either class during the preceding 365 days, were included. The primary outcome was incident hyponatremia (ICD-10-CM E87.1 or serum sodium ≤ 135 mmol/L); sensitivity outcomes included diagnosis-only, laboratory-only, and stricter laboratory thresholds. Among more than 300,000 matched pairs per comparison, SGLT2 inhibitors and GLP-1 RAs were each associated with a 15% lower hazard of hyponatremia than DPP-4 inhibitors (hazard ratio [HR], 0.850; 95% confidence interval [CI], 0.842-0.858 and HR, 0.847; 95% CI: 0.838-0.856). The lower risk persisted at stricter sodium thresholds and across clinically relevant subgroups, including patients with heart failure, chronic kidney disease, or high-risk medications use. SGLT2 inhibitors and GLP-1 RAs were broadly comparable (HR, 0.962; 95% CI: 0.952-0.971). Positive and negative control outcomes were consistent with expectations. Overall, SGLT2 inhibitors and GLP-1 RAs were associated with a lower risk of incident hyponatremia than DPP-4 inhibitors. These real-world findings provide reassurance regarding the electrolyte safety of SGLT2 inhibitors and GLP-1 RAs, complementing their established cardiorenal benefits.
