The Clinical Application of GLP-1RAs and GLP-1/GIP Dual Receptor Agonists Based on Pharmacological Mechanisms: A Review

📖 Top 20% JournalNov 28, 2025Drug design, development and therapy

Medical Use of GLP-1 and GLP-1/GIP Receptor Drugs Explained by How They Work

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Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with significant efficacy in managing type 2 diabetes and obesity.

GLP-1RAs stimulate insulin secretion and suppress glucagon release, leading to improved glycemic control.
These agents delay gastric emptying and reduce appetite, contributing to weight loss.
Emerging evidence suggests GLP-1RAs may provide cardiovascular protection and neuroprotective benefits.
Dual receptor agonists targeting GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) may enhance glycemic control and metabolic function.
Recent advances include the development of multi-receptor agonists, expanding therapeutic applications.

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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. , 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.

Key numbers

17.4%

Weight Loss

Mean body weight reduction with oral semaglutide in a phase III trial.

0.8%

Reduction

Average reduction with compared to baseline.

28%

Cardiovascular Event Reduction

Potential risk reduction of major adverse cardiovascular events with compared to placebo.

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Abstract

Key numbers

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