Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial

This phase 2 clinical trial, published in The Lancet, evaluated the efficacy and safety of retatrutide specifically in patients with type 2 diabetes. The study was randomized, double-blind, with active control (dulaglutide 1.5 mg) and placebo, in parallel groups, including patients with type 2 diabetes inadequately controlled with metformin alone or with sulfonylurea.

Participants were randomized to different doses of retatrutide (0.5 to 12 mg weekly), dulaglutide 1.5 mg weekly (active comparator), or placebo for 36 weeks. Primary endpoints included change in HbA1c and body weight.

Glycemic control results were impressive:

• HbA1c reductions of up to 2.02 percentage points at the highest doses
• A significant proportion of patients achieved HbA1c < 7.0% and even < 5.7% (normoglycemia)
• Numerical superiority over the active comparator dulaglutide at most doses

Regarding weight loss, type 2 diabetes patients showed substantial reductions, although typically smaller than in patients without diabetes:

• Weight loss of up to 16.9% at the highest dose
• Consistent dose-dependent effect

The most common adverse effects were gastrointestinal (nausea, diarrhea, vomiting) and generally decreased over time. No episodes of severe hypoglycemia were observed. The triple-action profile (GIP/GLP-1/glucagon) of retatrutide demonstrated the potential to simultaneously address hyperglycemia, excess weight, and potentially hepatic steatosis, conditions that frequently coexist in type 2 diabetes.