In two phase 3 clinical trials, retatrutide, a novel glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and glucagon triple-hormone receptor agonist, demonstrated significant weight loss and clinically meaningful improvements in health outcomes in people living with obesity and type 2 diabetes.

These findings were shared on Saturday, June 6 during the symposium, Unlocking the Next Frontier in Treatment of Obesity and Type 2 Diabetes with Retatrutide: A Triple Agonist, Activating the GIP, GLP-1 and Glucagon Receptors (TRANSCEND-T2D-1 and TRIUMPH-1 Results). On-demand access to recorded presentations will be available to registered participants following the conclusion of the 2026 Scientific Sessions, from June 10–August 10.

When considering why activating the glucagon receptor could improve GIP and GLP-1 receptor agonism, presenters said it’s important to recognize that glucagon’s function extends beyond fasting to a much more complex role.

“The next frontier is positioning glucagon in prandial state where it contributes to metabolism. It enhances the metabolism of all macronutrients in the liver, it increases insulin secretion and sensitivity, and the consequence of all these actions is an increase in energy expenditure,” said Jonathan Campbell, PhD, Associate Professor at Duke University. “Collectively, you can see why these are attractive features when targeting glucagon in the corporation of the treatment of diabetes and obesity.”

Activation of the glucagon receptor with the triple-hormone receptor agonist retatrutide is being investigated in a large phase 3 program that includes 14 trials, among them TRANSCEND-T2D-1 and TRIUMPH-1, and more than 22,000 participants.

TRANSCEND-T2D-1

TRANSCEND-T2D-1, a randomized, double-blind, placebo-controlled phase 3 study, assessed the safety and efficacy of retatrutide monotherapy in adults with recent-onset type 2 diabetes who had inadequate glycemic management despite diet and exercise alone. Patients were randomized to 4 mg, 9 mg, or 12 mg of retatrutide, or placebo. The primary endpoint was the change in A1C from baseline at week 40.

“Retatrutide met all the primary and key secondary endpoints for both estimands in the TRANSCEND-T2D-1 trial with superior glycemic control versus placebo,” said Harpreet Singh Bajaj, MD, MPH, an endocrinologist at LMC Diabetes & Endocrinology, Toronto, Canada. “In the retatrutide arm, the A1C improvement was nearly 2% with nearly 85% reaching the A1C target of ≤6.5% and up to 46% reaching near-normoglycemia with an A1C of <5.7%. Retatrutide led to a superior weight reduction versus placebo, with a weight reduction up to 16.8%. In absolute terms, that’s nearly 17 kilograms or 37 pounds, which has not been seen with other treatments to date.”

Additionally, up to 68% of retatrutide-treated participants achieved an A1C ≤6.5% with a ≥10% weight reduction at week 40. Retatrutide also demonstrated clinically meaningful improvements in cardiometabolic markers, including systolic blood pressure, non–high-density lipoprotein cholesterol, and triglycerides.

The safety profile of retatrutide in TRANSCEND-T2D-1 was generally consistent with the GLP-1 receptor agonist class. No new safety signals were identified, and no hypoglycemia was reported. The most common adverse events with retatrutide were gastrointestinal in nature, mostly mild to moderate, and primarily happened during dose escalation.

TRIUMPH-1

TRIUMPH-1, a randomized, placebo-controlled phase 3 study, assessed the safety and efficacy of weekly retatrutide on weight reduction and health in adults with obesity or overweight, including subsets of participants with obstructive sleep apnea (OSA) or knee osteoarthritis (OA). Patients were randomized to 4 mg, 9 mg, or 12 mg of retatrutide, or placebo. The primary endpoint was percent change in weight at week 80 with retatrutide 9 mg or 12 mg.

The once-weekly triple-hormone receptor agonist was generally well tolerated and provided substantial reductions in weight, as well as clinically meaningful improvements in health outcomes for patients with obesity, OSA, and knee OA, said Ania Jastreboff, MD, PhD, Professor at Yale University School and Director of the Y-Weight Obesity Research Center.

“At 80 weeks, the average weight reduction with the 12 mg dose was 28.3%, which translated to more than 70 pounds,” she noted. “Participants in the extension lost up to an average 30% of their body weight, which was 85 pounds at 104 weeks,”

Nearly all participants lost ≥5% of their body weight, with over 85% losing ≥15% and more than 25% losing ≥35%. In terms of health outcomes, individuals with OSA experienced up to a 60% decrease in Apnea Hypopnea Index (AHI) with retatrutide treatment, and individuals with knee OA experienced up to a 70% reduction in knee pain.

The most common side effects with retatrutide in TRIUMPH-1 were gastrointestinal. Notably, a new safety signal that emerged was urinary tract infections.

“The next frontier in obesity and diabetes care is creating a future where better health for everyone becomes possible. As such, our mission is to remove roadblocks and explore new, effective treatment approaches,” said Ildiko Lingvay, MD, MPH, MSCS, Professor at the University of Texas. “The future we envision will require scientific innovation, clinical collaboration, healthcare system transformation, and patient engagement. The next frontier is not beyond our reach. It is what we create together, one mission at a time.”

Register On-site for the 2026 Scientific Sessions

You can register on-site at the Ernest N. Morial Convention Center in New Orleans to join the 2026 Scientific Sessions, taking place June 5–8. Don’t miss your chance to learn about the latest advances in diabetes research, prevention, and care. After the meeting, registered participants will have on-demand access to recorded presentations.