Macupatide trial separates GIP and GLP-1 effects on insulin in type 2 diabetes

A 12-week phase 1b trial in adults with type 2 diabetes found that the experimental GIP receptor agonist macupatide raised insulin sensitivity by about a third, while the GLP-1 receptor agonist dulaglutide mainly raised insulin secretion, and the two drugs given together produced the largest changes in both ^[1]. The results were published June 2, 2026, in the journal Diabetes, Obesity and Metabolism ^[1].

What the trial measured

The study ran at a single center in Germany and randomly assigned participants, double-blind, to macupatide 20 mg, dulaglutide, or both drugs for 12 weeks ^[1]. Macupatide is built from the natural GIP sequence and chemically modified to last longer in the body; it has no activity at GLP-1 or glucagon receptors ^[1]. Participants were 18 to 70 years old, had type 2 diabetes, a body mass index between 23 and 45, and were taking metformin; screening A1c was 7.0% to 10.0% for those on metformin alone ^[1]. The trial is registered as NCT05407961 ^[1].

Researchers used clamp tests before treatment and again after 12 weeks to measure three things: insulin sensitivity (the M value), the insulin secretion rate (ISR), and the clamp disposition index (cDI), which combines secretion with sensitivity ^[1]. Average starting values were an M value of 5.8 mg/kg/min, an insulin secretion rate of 116.8 pmol/min/m², and a cDI of 0.3 in the study's units ^[1].

How the three groups differed

After 12 weeks, macupatide raised the M value by 1.3 units, a 33.1% increase, and raised the insulin secretion rate by 37.6 units, or 32.2% ^[1]. The report describes the sensitivity increase as significant and the secretion increase as smaller but still significant ^[1].

Dulaglutide showed the reverse pattern: the M value rose 0.2 units, or 10.4%, while the insulin secretion rate rose 191.1 units, or 163.6% ^[1].

The combination raised the M value by 2.0 units (38.3%) and the insulin secretion rate by 225.3 units (192.9%) ^[1]. The cDI rose 0.2 (63.2%) with macupatide, 0.5 (181.0%) with dulaglutide and 1.0 (321.5%) with both drugs together ^[1]. The paper states the combination was numerically greater than either single drug on all three measures, wording that falls short of a tested statistical claim ^[1].

The most frequent side effects were injection site reactions and diarrhea; discontinuations because of side effects were uncommon, and there were no deaths during the study ^[1].

Why it matters for patients

Most GLP-1 medicines on the US market, including semaglutide (Ozempic, Wegovy, Rybelsus), act on the GLP-1 receptor alone, while tirzepatide (Mounjaro, Zepbound) acts on both the GIP and GLP-1 receptors ^[1]. Trials have shown tirzepatide outperforms semaglutide for weight and glucose control, but it was not clear how much of that came from the GIP side ^[1].

This trial offers one explanation. In people with type 2 diabetes, turning on the GIP receptor appears to work mainly by making the body respond better to insulin, while turning on the GLP-1 receptor works mainly by pushing the pancreas to release more insulin ^[1]. Understanding which receptor does what could shape how future drugs in this class are designed and combined ^[1].

Macupatide itself is not an approved medicine; it was tested as an investigational drug in this phase 1b study, and these findings do not change how any currently prescribed GLP-1 or dual-agonist medication works ^[1].

What is not yet known

The report does not state how many people were enrolled in the 12-week comparison, whether the gap between the combination and each single drug was statistically significant, or whether participants lost weight or lowered their A1c ^[1]. The study lasted 12 weeks and involved people with type 2 diabetes taking metformin, so how the results apply to other diabetes treatments, longer use, or people without diabetes has not been reported ^[1]. No plans for larger trials of macupatide have been disclosed ^[1].