Nephroprotective Potential of Linagliptin and Glimepiride: a Comprehensive Review

Background: Diabetic kidney disease remains the leading cause of chronic kidney disease and end-stage kidney failure worldwide, driven by chronic hyperglycemia, intrarenal hemodynamic stress, and inflammatory–fibrotic signaling. Early detection and multifactorial interventions remain essential, yet many patients progress, underscoring the need for glucose-lowering agents with direct nephroprotective actions. Recent Findings: Linagliptin’s unique non-renal clearance permits use across all stages of chronic kidney disease without dose adjustment. Preclinical and clinical studies demonstrate reno-modulatory effects through antioxidant, anti-inflammatory, and antifibrotic pathways. In large outcome trials, linagliptin was cardiovascularly neutral and safe in patients with advanced chronic kidney disease, with consistent signals of reduced progression of albuminuria. Glimepiride lowers glucose via beta-cell stimulation and has been shown to reduce oxidative stress markers in animal and small clinical studies; however, robust evidence for renoprotection is lacking. Its primary renal excretion necessitates dose adjustment in patients with declining kidney function, increasing the complexity of use and the risk of drug accumulation. Sustained insulin secretion also elevates hypoglycemia risk — a significant concern in chronic kidney disease, where counter-regulatory responses are impaired, and drug clearance is reduced. A significant research gap exists in clarifying the roles of both agents within the modern renoprotective treatment framework, which now includes sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, and in determining whether they provide additive renoprotection when combined with these newer therapies. Conclusion: This review provides a comprehensive synthesis of the renoprotective potential of linagliptin and glimepiride, highlighting linagliptin’s unique safety profile and pleiotropic effects in advanced chronic kidney disease.