Lilly's Retatrutide Lowers A1C and Weight in Its First Phase 3 Type 2 Diabetes Trial

Eli Lilly said on March 19 that retatrutide, its investigational once-weekly injection that activates the GIP, GLP-1 and glucagon receptors, met the primary and all key secondary endpoints of TRANSCEND-T2D-1, the drug's first Phase 3 trial in type 2 diabetes, according to the company's release.

The results are company-reported topline data. Lilly said detailed results will be presented at the American Diabetes Association Scientific Sessions in June and published in a peer-reviewed journal. Retatrutide is not approved for any use.

The TRANSCEND-T2D-1 trial

TRANSCEND-T2D-1 (NCT06354660) was a 40-week, randomized, double-blind, placebo-controlled study in adults with type 2 diabetes whose blood sugar was not controlled by diet and exercise alone. Participants had not taken any diabetes medicine for at least 90 days, had an A1C between 7.0% and 9.5% and a BMI of at least 23, and had had diabetes for an average of 2.5 years. The study randomized 537 participants equally to retatrutide 4 mg, 9 mg or 12 mg, or placebo. Treatment started at 2 mg weekly and stepped up every four weeks to the target dose.

For the primary endpoint, A1C fell by an average of 1.7% to 2.0% across the three doses at 40 weeks, using the efficacy estimand, which assumes all participants stayed on treatment. Lilly said retatrutide was superior to placebo on A1C and weight under both that measure and the treatment-regimen estimand, which counts participants regardless of whether they kept taking the drug.

On weight, a key secondary endpoint, participants taking 12 mg lost an average of 36.6 lbs, or 16.8% of body weight. The company said no weight-loss plateau was seen during the 40 weeks. Lilly also reported improvements from baseline in non-HDL cholesterol, triglycerides and systolic blood pressure; those results were controlled for statistical error in the 9 mg and 12 mg groups but not the 4 mg group.

"These results support the remarkable potential of this novel molecule for people living with type 2 diabetes," said Kenneth Custer, president of Lilly Cardiometabolic Health, in the release.

Safety and the wider program

The most common adverse events were gastrointestinal and occurred mainly while the dose was being increased, Lilly said. Nausea was reported in 16.4%, 19.5% and 26.5% of the 4 mg, 9 mg and 12 mg groups versus 3.7% on placebo; diarrhea in 18.7%, 26.3% and 22.8% versus 4.5%; and vomiting in 15.7%, 15.0% and 17.6% versus 2.2%.

Dysesthesia, an abnormal skin sensation, occurred in 4.5%, 2.3% and 4.4% of the three retatrutide groups and in none of the placebo group. The company said the events were generally mild and most resolved during treatment. Discontinuations because of adverse events were 2.2%, 4.5% and 5.1% on retatrutide versus 0.0% on placebo.

The TRANSCEND-T2D program includes three global registrational trials and has enrolled more than 2,050 participants since it began in 2024, with more results expected over the next year. Lilly is also studying retatrutide in Phase 3 trials in obesity, knee osteoarthritis, obstructive sleep apnea, chronic low back pain, cardiovascular and renal outcomes, and fatty liver disease.