Comprehensive pharmacological review of GLP-1 receptor agonists and dual GLP-1/GIP receptor agonists including tirzepatide, covering molecular receptor activation mechanisms, downstream metabolic signaling, central appetite regulation, peripheral effects on beta cells and adipose tissue, and clinical applications across T2DM, obesity, cardiovascular disease, MASLD, and emerging indications. Serves as a unified pharmacology reference. Provides clinicians and pharmacologists with a thorough mechanistic grounding for tirzepatide's multi-organ benefits—establishing the biological basis for its expanding clinical applications and guiding rational selection across patient comorbidity profiles.
Abstract
This review provides a comprehensive examination of the clinical pharmacological mechanisms and broad therapeutic applications of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual receptor agonists targeting both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. GLP-1RAs exert their effects by stimulating insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite through the activation of the GLP-1 receptor. These agents have demonstrated significant efficacy in the management of type 2 diabetes mellitus (T2DM) and obesity. Moreover, emerging evidence suggests that GLP-1RAs may confer cardiovascular protection, neuroprotective benefits, and positive effects on mental health. Dual GLP-1/GIP receptor agonists, such as tirzepatide, simultaneously activate both receptors, thereby potentiating glycemic control, promoting weight loss, and ameliorating metabolic dysfunction. This review also addresses recent advances in the development of other dual and triple receptor agonists. Distinct from prior reviews that predominantly focus on a single drug class or limited clinical indications, this article systematically contrasts the mechanistic pathways, therapeutic efficacy, and safety profiles of GLP-1RAs versus GLP-1/GIP dual receptor agonists. Notably, it integrates the most current evidence pertaining to novel domains, such as perioperative management, neuropsychiatric outcomes, and the innovation of multi-receptor agonists. This synthesis offers a timely and practical resource to inform clinical precision medicine and to guide future investigative efforts.
Authors
Liu, Zhao; Yu, Shanshan; Jin, Xinyan; Sheng, Luguang; YanMu, Mai Re; Gao, Jie; Lu, Jun; Lei, Tao