Among incretin-based therapies, a critical evidence hierarchy has emerged: select GLP-1 receptor agonists — particularly semaglutide — carry hard cardiovascular and renal outcome trial data, while dual GIP/GLP-1 agonists (tirzepatide), triple agonists, amylin-linked compounds, and oral small-molecule GLP-1 mimetics currently rest on glycemic, weight-loss, or early mechanistic endpoints only. Semaglutide stands alone with dedicated chronic kidney disease outcome evidence. The review integrates receptor-network pharmacology across GLP-1, GIP, glucagon, and amylin signaling to explain heterogeneous efficacy and tolerability profiles across this rapidly expanding drug class.
This synthesis arrives at a pivotal inflection point in cardiometabolic medicine. The temptation to prescribe newer polyagonists based on superior weight-loss magnitude — tirzepatide produces roughly 20–22% body weight reduction versus 15% for semaglutide — must be tempered by the absence of equivalent cardiovascular mortality and renal protection trial data for those agents. The authors' insistence on outcome maturity as the primary positioning criterion is clinically sound and underappreciated in practice. Critically, real-world durability remains unresolved: discontinuation consistently reverses metabolic gains, lean mass loss during rapid weight reduction poses musculoskeletal risk in older adults, and gastrointestinal tolerability limits adherence across all agents. As a narrative review rather than meta-analysis, this work synthesizes rather than generates primary evidence, but its phenotype-stratified framework offers clinicians a more actionable decision architecture than mechanistic plausibility alone — an incremental but practically important contribution.