Lilly's triple-G agonist shows unique promise in late-stage diabetes trial

Eli Lilly's triple-G agonist candidate, retatrutide, led to significant reductions in both blood sugar levels and body weight in its first phase 3 diabetes trial, suggesting a potentially differentiated metabolic profile.

In the 40-week study, which enrolled 537 patients with type 2 diabetes and inadequate glycemic control, three doses of Lilly's triple-hormone receptor agonist (GIP, GLP-1, and glucagon) were tested. Patients who took retatrutide achieved an average A1c reduction of up to 2.0% from a baseline of 7.9%, compared to 0.8% in the placebo arm.

Retatrutide lowered hemoglobin A1c by an average of 1.9% in patients who took 12 mg, 2% in those who took 8 mg and 1.7% in those who took 4 mg, meeting the study's primary endpoint.

The trial also hit its secondary endpoint of weight loss, Lilly said.

Patients treated with the highest 12 mg dose of retatrutide lost an average of 16.8% of their body weight under the efficacy estimand, which considers only those who stayed on the drug. But when including all patients, even those who dropped out, the average weight loss dips to 15.3%, compared with 2.5% in the placebo group.

No weight loss plateau was observed through week 40, Lilly said, suggesting more weight loss potential in future testing.

These findings are particularly noteworthy because most patients taking incretin-based therapies to control blood sugar don't typically experience significant weight loss.

"For many people with type 2 diabetes, it is a struggle to achieve both A1C control and weight loss, since obesity has historically been harder to treat for those with type 2 diabetes," Kenneth Custer, Ph.D., executive vice president and president of Lilly Cardiometabolic Health, said in a company press release.

Retatrutide's safety profile was consistent with other injectable diabetes and obesity drugs, with gastrointestinal side effects most common, Lilly said.

The reported data support the "remarkable potential" of Lilly's retatrutide as a more effective weight loss therapy for people with diabetes, Custer added.

The results build on topline data from the Triumph-4 study released in December. In that phase 3 trial, retatrutide helped patients with obesity and degenerative joint disease lose nearly 29% of their body weight. It also eased knee osteoarthritis pain by 75%.

Alivia Kaylor is a scientist and the senior site editor of Pharma Life Sciences.