Lilly's Retatrutide Beats Semaglutide on A1C and Weight in Head-to-Head Phase 3 Trial

Eli Lilly said on October 28 that its investigational drug retatrutide produced larger reductions in blood sugar and body weight than semaglutide (Ozempic) at its highest approved dose for type 2 diabetes in a head-to-head Phase 3 trial in adults with type 2 diabetes, as reported by HCPLive from the company's announcement. The results are topline data reported by Lilly; detailed findings will be presented at a future medical meeting and published in a peer-reviewed journal, the company said.

Retatrutide is a once-weekly injection that activates receptors for three hormones: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon. Lilly said TRANSCEND-T2D-2 is the first Phase 3 trial comparing retatrutide with another incretin medicine and the sixth Phase 3 trial of the drug to report positive results.

Trial design

The randomized, open-label trial (NCT06260722) enrolled 1,298 adults with type 2 diabetes inadequately controlled on metformin, with or without an SGLT2 inhibitor, and a baseline A1C of 7.0% to 10.5%. Participants were randomized 2:2:1 to once-weekly retatrutide 9 mg, retatrutide 12 mg or semaglutide 2 mg. Retatrutide was started at 2 mg and increased every four weeks to the target dose.

The primary objective was to show that retatrutide 12 mg was noninferior to semaglutide 2 mg in lowering A1C, a measure of average blood sugar, at 80 weeks.

Results

From a mean baseline A1C of 8.3%, both retatrutide doses lowered A1C by 2.2 percentage points at 80 weeks, compared with 1.8 points for semaglutide, according to HCPLive's account of Lilly's data. The 12 mg dose showed statistically significant superiority with control for multiple comparisons (P < .001). The 9 mg dose met noninferiority as a key secondary endpoint and showed nominal superiority.

Participants began the trial at a mean weight of 102.4 kg. At 80 weeks, body weight fell 19.5% (20.1 kg) with retatrutide 9 mg and 20.9% (21.5 kg) with 12 mg, versus 9.4% (9.5 kg) with semaglutide. Lilly said retatrutide also produced greater improvements in non-HDL cholesterol, triglycerides and systolic blood pressure, without giving figures in the reported results. All results reflect the efficacy estimand, which assumes participants stayed on treatment without additional glucose-lowering medication.

Safety

Gastrointestinal events were the most common adverse events. Diarrhea occurred in 28.3% and 32.7% of participants on retatrutide 9 mg and 12 mg, versus 26.4% on semaglutide, and nausea in 21.2% and 23.8% versus 21.3%. Vomiting rates were 10.2% and 15.0% versus 13.2%, while constipation was less frequent with retatrutide. Dysesthesia, an abnormal skin sensation, occurred in 4.8% and 6.5% of retatrutide recipients versus 2.7% on semaglutide.

Discontinuation because of adverse events was 4.8% and 7.9% with the two retatrutide doses, versus 2.7% with semaglutide. Lilly said most events were mild to moderate and typically resolved during treatment.

"In TRANSCEND-T2D-2, the first Phase 3 trial comparing retatrutide with another incretin medicine, retatrutide delivered greater A1C reduction and more than double the weight loss of the highest approved dose of Ozempic for type 2 diabetes," said Kenneth Custer, president of Lilly Cardiometabolic Health.

An extension period will follow about 650 participants on retatrutide for an additional 24 weeks. Retatrutide is not approved by any regulator. Lilly is also comparing it with tirzepatide in TRIUMPH-5, an ongoing Phase 3 trial in adults with obesity, and is studying it in obesity, knee osteoarthritis pain, obstructive sleep apnea, cardiovascular outcomes and metabolic dysfunction-associated steatotic liver disease, HCPLive reported.