Positive Top-line Results for Retatrutide in Diabetes: TRANSCEND-T2D-1

Retatrutide has cleared a large hurdle in TRANSCEND-T2D-1, the first phase III trial testing the triple hormone receptor agonist in patients with type 2 diabetes, according to new top-line results released today by manufacturer Lilly.

Delivered once weekly by subcutaneous injection, retatrutide significantly reduced both glycated hemoglobin (HbA1c) and body weight over a 40-week period. The next-generation medication activates receptors for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon.

As reported in 2023, the triple agonist previously showed promise in a phase II trial. “The main message here is that we’re not done with this story, not even in the slightest. We’re just in the first generation of modifying weight and fundamentally changing cardiometabolic disease,” Michael Blaha, MD (Johns Hopkins Medicine, Baltimore, MD), commented to TCTMD at the time. “It’s extremely exciting.”

TRANSCEND-T2D-1

TRANSCEND-T2D-1 randomized 537 patients with type 2 diabetes and inadequate glycemic control in a 1:1:1:1 ratio to receive one of three retatrutide doses (4, 9, or 12 mg) or placebo. All participants had HbA1c levels between 7.0% and 9.5% plus a body mass index of at least 23 kg/m² at baseline. Mean diabetes duration was 2.5 years. Those assigned to the drug arm started at 2 mg and then increased their medication every 4 weeks to reach the target dose.

Average decrease in HbA1c from baseline, the primary endpoint, over the 40-week period ranged from 1.7% to 2.0% across retatrutide doses and was 0.8% with placebo. Body weight, a key secondary endpoint, decreased by 11.5% to 16.8% with retatrutide and by 2.5% with placebo. The drug therapy also led to clinically meaningful improvements in other cardiovascular risk factors, such as non-HDL cholesterol, triglycerides, and systolic blood pressure, according to a Lilly press release.

The most common adverse events were nausea (16.4% to 26.5% with retatrutide vs 3.7% with placebo), diarrhea (18.7% to 26.3% vs 4.5%), and vomiting (15.0% to 17.6% vs 2.2%). Most of these occurred during dose escalation. Additionally, 2.3% to 4.5% of retatrutide-treated patients across the three doses developed dysesthesia, which was generally mild and tended to resolve during treatment. Discontinuation rates ranged from 2.2% to 5.1% depending on the retatrutide dose.

Lilly says detailed results from TRANSCEND-T2D-1 will be presented at the upcoming American Diabetes Association Scientific Sessions in June. The company is also testing the medication in patients with obesity and overweight.