A Review on Therapeutic Mechanisms and Pharmacological Actions of Incretin-Based Dual and Single Receptor Agonists

Review article

Abstract

Postprandial glycemic regulation and systemic energy homeostasis depend heavily on enteroendocrine hormones secreted in response to nutrient ingestion. The clinical development of glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor co-agonists has transformed treatment paradigms for type 2 diabetes mellitus and chronic obesity. Therapeutic agents like semaglutide and tirzepatide achieve exceptional glycemic control, significantly lowering glycated hemoglobin levels while driving profound, dose-dependent body weight reductions. However, the therapeutic benefits of these highly effective molecules are frequently compromised by dose-limiting toxicities. Gastrointestinal adverse events, primarily manifesting as nausea, vomiting, diarrhea, and constipation, exhibit a strict dose-dependent profile that restricts rapid dose escalation and compromises therapeutic retention. Managing these clinical interventions necessitates navigating a delicate trade-off between maximizing metabolic benefits and maintaining patient tolerability. Gradual, individualized dose titration is the primary clinical strategy to minimize gastrointestinal discomfort and preserve patient adherence. Beyond glycemic control, dual-receptor co-agonism drives metabolic improvements by activating central satiety pathways, modulating gastric emptying kinetics, and inducing white adipose tissue browning and adipogenesis. This review discusses the physiological differences, comparative trial data, and tolerability trade-offs governing incretin-based pharmacotherapies. Optimizing long-term metabolic outcomes requires integrating patient-centered management strategies that balance receptor activation kinetics against individual tolerability thresholds, ensuring sustained therapeutic efficacy without excessive treatment discontinuation.