Insulin Sensitivity and Beta Cell Function With Macupatide Alone or With Dulaglutide in Type 2 Diabetes: A Phase 1b,...

Area of Science:

• Endocrinology
• Metabolic Diseases
• Pharmacology

Background:

• Type 2 diabetes (T2D) is characterized by impaired insulin sensitivity and secretion.
• Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are key incretin hormones influencing glucose homeostasis.
• Understanding the individual and combined roles of GIP and GLP-1 is crucial for developing effective T2D treatments.

Purpose of the Study:

• To investigate the contribution of GIP and GLP-1 receptor agonism to insulin sensitivity and secretion in individuals with T2D on metformin.
• To compare the effects of a GIP receptor agonist (macupatide), a GLP-1 receptor agonist (dulaglutide), and their combination on key metabolic parameters.

Main Methods:

• Phase 1b, randomized, double-blind clinical trial.
• Participants received macupatide, dulaglutide, or both for 12 weeks.
• Insulin sensitivity (M value), insulin secretion rate (ISR), and clamp disposition index (cDI) were assessed using hyperinsulinemic euglycaemic clamps.

Main Results:

• Macupatide monotherapy significantly improved insulin sensitivity (M value) and insulin secretion (ISR).
• Combination therapy numerically surpassed both monotherapies in enhancing cDI, M value, and ISR.
• The most common adverse events were injection site reactions and diarrhea, with uncommon study discontinuations.

Conclusions:

• Chronic GIP receptor activation primarily increases insulin sensitivity in individuals with T2D.
• Combined GIP and GLP-1 receptor agonism offers augmented benefits for both insulin secretion and sensitivity compared to GLP-1 therapy alone.
• These findings support dual GIP/GLP-1 receptor agonism as a promising therapeutic strategy for T2D.