Oral Glucagon-Like Peptide-1 Receptor Agonists for Preventing Cardiorenal Complications

This article reviews the evidence for cardiovascular and renal risk reduction with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in type 2 diabetes mellitus (T2DM), based on randomized controlled trials, including emerging oral agents. Injectable GLP-1 RAs have consistently demonstrated reductions in major adverse cardiovascular events (MACE) and clinically relevant kidney outcomes, establishing their role in cardiorenal risk reduction. Oral semaglutide, the first approved oral GLP-1 RA, met criteria for cardiovascular non-inferiority in PIONEER 6 among patients with T2DM at high cardiovascular risk. The SOUL trial (oral semaglutide) subsequently demonstrated superiority for MACE reduction versus placebo in patients with established cardiovascular disease or multiple risk factors, with benefit driven largely by fewer nonfatal myocardial infarctions. However, oral semaglutide did not significantly reduce major kidney outcomes. Orforglipron, an investigational non-peptide oral GLP-1 RA with once-daily, food-independent dosing, has shown robust glycemic and weight-loss efficacy in phase 3 trials, though cardiovascular and renal outcome data are pending. Oral semaglutide has demonstrated cardiovascular benefit, but evidence supporting prevention of renal outcomes with oral GLP-1 RAs remains limited. Injectable GLP-1 RAs currently have the strongest evidence base for cardiorenal risk reduction, and ongoing outcome trials will clarify whether newer oral agents can close this gap.