Retatrutide Delivers A1C Reduction, Weight Loss in Phase 3 TRANSCEND-T2D-1 Trial

Eli Lilly and Company have announced positive topline results from the phase 3 TRANSCEND-T2D-1 trial assessing the efficacy and safety of retatrutide, an investigational first-in-class GIP, GLP-1 and glucagon triple hormone receptor agonist, as an adjunct to diet and exercise in people with type 2 diabetes and inadequate glycemic control.

As described in a March 19, 2026, release from the Company, in the study, retatrutide met the primary and all key secondary endpoints, delivering superior A1C reduction and weight loss at 40 weeks compared to placebo, using both the efficacy and treatment-regimen estimands.

"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, PhD, executive vice president and president, Lilly Cardiometabolic Health, said in a statement. "With triple agonist retatrutide, we set out to make a molecule that could help patients achieve substantial A1C reduction and weight loss. These results support the remarkable potential of this novel molecule for people living with type 2 diabetes, with up to 2% A1C improvement and nearly 17% weight loss in 40 weeks of treatment."

Retatrutide is an investigational once-weekly triple hormone receptor agonist that activates the body's receptors for GIP, GLP-1, and glucagon. Lilly is studying retatrutide in multiple phase 3 clinical trials to evaluate its potential efficacy and safety in obesity and overweight with ≥ 1 weight-related medical problem, type 2 diabetes, knee osteoarthritis, moderate-to-severe obstructive sleep apnea, chronic low back pain, cardiovascular and renal outcomes, and metabolic dysfunction-associated steatotic liver disease.

Lilly announced positive topline results from the phase 3 TRIUMPH-4 clinical trial evaluating the safety and efficacy of retatrutide in adults with obesity or overweight and knee osteoarthritis, and without diabetes, as an adjunct to healthy diet and physical activity in December 2025. In the trial, participants taking retatrutide 12 mg lost an average of 28.7% of their body weight at 68 weeks.

Its use in people with type 2 diabetes and inadequate glycemic control is being assessed in TRANSCEND-T2D-1, a phase 3, 40-week, randomized, double-blind, placebo-controlled study comparing the efficacy and safety of retatrutide with placebo. The study randomly assigned 537 participants in a 1:1:1:1 ratio to receive either retatrutide 4 mg, 9 mg or 12 mg, or placebo.

The objective of the study was to demonstrate that retatrutide is superior to placebo in A1C reduction from baseline after 40 weeks, in adults with type 2 diabetes who have not taken any anti-diabetes medications for ≥ 90 days prior to visit 1, and are naïve to insulin therapy except for gestational diabetes. Study participants had A1C between ≥7.0% and ≤9.5% and a BMI of ≥23 kg/m2 at visit 1.

Participants randomized to retatrutide initiated treatment with 2 mg once-weekly and increased the dose in a step-wise approach every four weeks until reaching the target dose of 4 mg (via one step at 2 mg), 9 mg (via steps at 2 mg, 4 mg and 6 mg) or 12 mg (via steps at 2 mg, 4 mg, 6 mg and 9 mg).

For the primary endpoint, results showed participants taking retatrutide achieved average A1C reductions of up to 2.0%, using the efficacy estimand. For a key secondary endpoint, participants taking retatrutide lost up to an average of 36.6 lbs (16.8%), using the efficacy estimand. Weight loss continued through the end of the treatment period.

Of note, retatrutide also showed clinically meaningful improvements from baseline across key cardiovascular risk factors, including non-HDL cholesterol, triglycerides and systolic blood pressure.

Consistent with the types of adverse events seen in clinical trials for other incretin-based therapies, the most common adverse events among participants treated with retatrutide (4 mg, 9 mg, 12 mg) were nausea (16.4%, 19.5%, 26.5%, respectively vs 3.7% with placebo), diarrhea (18.7%, 26.3%, 22.8%, respectively vs 4.5% with placebo) and vomiting (15.7%, 15.0%, 17.6%, respectively vs 2.2% with placebo), and occurred primarily during dose escalation.

Incidence of dysesthesia occurred in 4.5%, 2.3% and 4.4% (4 mg, 9 mg and 12 mg, respectively) of patients treated with retatrutide, compared to 0.0% with placebo. Discontinuation rates due to adverse events were 2.2%, 4.5% and 5.1% with retatrutide 4 mg, 9 mg and 12 mg, respectively, compared to 0.0% with placebo.

Lilly described plans to present detailed TRANSCEND-T2D-1 results at the American Diabetes Association Scientific Sessions in June and publish them in a peer-reviewed journal. Additional results from the retatrutide clinical trial program are expected over the next year.

References

1. Lilly. Lilly's triple agonist, retatrutide, demonstrated significant reductions in A1C and weight in first Phase 3 trial for treatment of type 2 diabetes. March 19, 2026. Accessed March 19, 2026. https://www.prnewswire.com/news-releases/lillys-triple-agonist-retatrutide-demonstrated-significant-reductions-in-a1c-and-weight-in-first-phase-3-trial-for-treatment-of-type-2-diabetes-302718589.html

2. Lilly. Lilly's triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial. December 11, 2025. Accessed March 19, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average