Next Step in Incretin-Based Therapy: From Single to Dual Agonism

Abstract

The twin epidemics of Type 2 diabetes (T2D) and obesity will continue to bring significant health challenges in the coming decades. Randomised controlled trials of glucagon-like peptide 1 (GLP-1)-based therapies showed high glycaemic efficacy with clinically meaningful weight loss, and have been considered as game-changers in the diabesity population. Emerging evidence has demonstrated that co-administration of glucose-dependent insulinotropic peptide (GIP) and GLP-1 results in enhanced insulinotropic effect in an additive way with significant glucagonostatic response, compared with the administration of each hormone separately. These findings have driven the choice to pursue incretin-based dual agonist therapies, known as ‘twincretin’. Observations from the global registration Phase III trials suggest that tirzepatide (a novel dual GIP/GLP-1 receptor agonist) represent advancement over current GLP-1 analogues, providing enhanced glycaemic and weight benefits with similar gastrointestinal tolerability. However, data are limited from patients with a range of ethnicities, and several questions remain unanswered.