Renal effects of GLP-1 receptor agonists and tirzepatide in individuals with type 2 diabetes: seeds of a promising future

Abstract Purpose Chronic kidney disease (CKD) is one of the most common complications of type 2 diabetes (T2D), and CKD-related disability and mortality are increasing despite the recent advances in diabetes management. The dual GIP/GLP-1 receptor agonist tirzepatide is among the furthest developed multi-agonists for diabetes care and has so far displayed promising nephroprotective effects. This review aims to summarize the evidence regarding the nephroprotective effects of glucagon-like peptide-1 receptor agonists (GLP-1RA) and tirzepatide and the putative mechanisms underlying the favorable renal profile of tirzepatide. Methods A comprehensive literature search was performed from inception to July 31st 2023 to select research papers addressing the renal effects of GLP-1RA and tirzepatide. Results The pathogenesis of CKD in patients with T2D likely involves many contributors besides hyperglycemia, such as hypertension, obesity, insulin resistance and glomerular atherosclerosis, exerting kidney damage through metabolic, fibrotic, inflammatory, and hemodynamic mechanisms. Tirzepatide displayed an unprecedented glucose and body weight lowering potential, presenting also with the ability to increase insulin sensitivity, reduce systolic blood pressure and inflammation and ameliorate dyslipidemia, particularly by reducing triglycerides levels. Conclusion Tirzepatide is likely to counteract most of the pathogenetic factors contributing to CKD in T2D, potentially representing a step forward in incretin-based therapy towards nephroprotection. Further evidence is needed to understand its role in renal hemodynamics, fibrosis, cell damage and atherosclerosis, as well as to conclusively show reduction of hard renal outcomes.