Orforglipron and the Kidney: A Promise or Disappointment? The Need for Trials Examining Renal Outcomes

Orforglipron, the first oral non-peptide GLP-1 receptor agonist, has a pharmacokinetic and formulation profile that may be theoretically attractive for patients with chronic kidney disease (CKD) including hepatic metabolism with minimal renal excretion and removal of potential barriers associated with current injectable and other oral formulations. We utilized a literature search utilizing PubMed/MEDLINE and ClinicalTrials. gov from their respective inceptions through May 2026 to synthesize a review on orforglipron. Phase 3 trials demonstrated significant reductions in hemoglobin A1c, body weight, and cardiovascular risk markers with stable eGFR and no indications of significant renal toxicity. These trials however were not designed or powered to evaluate renal outcomes including eGFR, albuminuria, and kidney failure progression. Additionally, previous trials were noted to have underrepresented or excluded populations of patients with advanced CKD, thus renal effects are inferential barring further clinical investigation, though a current trial examining kidney and cardiovascular outcomes in patients with both atherosclerosis and CKD is underway. Future CKD-specific trials are necessary to determine the safety, efficacy, and potential integration of orforglipron into nephrology treatment algorithms.