Differential Acute Kidney Injury Profiles of GLP-1RAs and SGLT2is: A Network Meta-Analysis

Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter 2 inhibitors (SGLT2is) have demonstrated protective effects against chronic kidney disease, their impact on acute kidney injury (AKI) remains unclear. AKI and chronic kidney disease share overlapping clinical features but differ in pathogenesis and risk profiles. Previous analyses often grouped diverse agents into single categories, potentially concealing medication-specific renal risks. Given the widespread assumption of renoprotection, particularly among newer agents, there is a need to evaluate the comparative AKI risk of GLP-1RAs and SGLT2is at the individual drug and dose level. We performed a Bayesian network meta-analysis (NMA) following Cochrane-recommended methodology for safety-focused assessments. A systematic literature search across eight databases identified 67 randomized controlled trials (RCTs), including 199,877 participants. Eligible trials reported AKI outcomes or sufficiently explicit acute renal injury-related events associated with GLP-1RA or SGLT2i interventions. The primary outcome was the incidence of AKI; all-cause dropout was analyzed as a general tolerability measure. Odds ratios (ORs) with 95% credible intervals (CrIs) were calculated, and surface under the cumulative ranking curves (SUCRA) were used to estimate relative safety rankings. Only high-dose tirzepatide (10-15 mg/week) was associated with a significantly increased risk of AKI compared to controls (absolute risk difference: 0.28%; number needed to harm: 357). In contrast, lixisenatide, high-dose canagliflozin (300 mg/day), empagliflozin, and dapagliflozin were associated with reduced AKI risk. Risk rankings consistently identified high-dose tirzepatide as the most likely to induce AKI. Subgroup analyses excluding patients with baseline renal impairment yielded consistent results. High-dose tirzepatide may elevate AKI risk despite its metabolic benefits. Clinicians should assess renal vulnerability when prescribing GLP-1RAs or SGLT2is, particularly in patients with preserved kidney function. Further prospective trials are needed to clarify causal mechanisms and inform clinical decision-making.