Macupatide, a GIP agonist, primarily boosts insulin sensitivity; combination with dulaglutide significantly augments both insulin secretion and sensitivity in T2D.

Effective management of Type 2 Diabetes (T2D) often requires strategies beyond metformin to address both insulin resistance and impaired beta-cell function. While GLP-1 receptor agonists like dulaglutide are established, the distinct and synergistic contributions of glucose-dependent insulinotropic polypeptide (GIP) receptor agonism to these metabolic parameters have been less clear. Understanding the specific roles of GIP and GLP-1, alone and in combination, is crucial for developing more comprehensive and potent therapeutic approaches that can improve both insulin sensitivity and insulin secretion in T2D patients.

This Phase 1b, randomised, double-blind clinical trial investigated the effects of GIP and GLP-1 agonism in people with Type 2 Diabetes on metformin. Participants were randomised to receive either the long-acting GIP receptor agonist macupatide, the GLP-1 receptor agonist dulaglutide, or a combination of both. Insulin sensitivity (M value), insulin secretion rate (ISR), and the corresponding clamp disposition index (cDI) were meticulously assessed using hyperinsulinemic euglycaemic clamps at baseline and after 12 weeks of treatment to quantify changes in metabolic function.

Baseline means across all participants were cDI 0.3 pmolm-2Lmin-2kg-1, M value 5.8 mgkg-1min-1, and ISR 116.8 pmolmin-1m-2. After 12 weeks, the macupatide, dulaglutide, and combination arms showed distinct improvements. Macupatide alone significantly increased the M value by 1.3 mgkg-1min-1 (33.1%) and, to a lesser yet significant extent, ISR by 37.6 pmolmin-1m-2 (32.2%). Dulaglutide primarily boosted ISR by 191.1 pmolmin-1m-2 (163.6%). The most pronounced effects were observed with combination therapy:

Combination therapy led to the largest increases in all indices, with cDI rising by 1.0 (321.5%), M value by 2.0 (38.3%), and ISR by 225.3 (192.9%), numerically surpassing both monotherapies. The most frequent adverse events were injection site reactions and diarrhoea, with study discontinuations due to treatment-emergent adverse events being uncommon, and no deaths reported.