Retatrutide yields substantial improvements in type 2 diabetes and obesity, phase 3 data from TRANSCEND-T2D-1 and TRIUMPH-1 show
Presenters: Harpreet S. Bajaj, MD, MPH, LMC Diabetes and Endocrinology, Brampton, ON, Canada (TRANSCEND-T2D-1)
Results of First Phase 3 Study of Retatrutide, a GIP, GLP-1, and Glucagon Receptor Agonist in Patients with T2D (TRANSCEND-T2D-1) and in Patients with Obesity (TRIUMPH-1). Presented June 6, 2026.
Ania M. Jastreboff, MD, PhD, Yale University, New Haven, CT (TRIUMPH-1)
Results of First Phase 3 Study of Retatrutide, a GIP, GLP-1, and Glucagon Receptor Agonist in Patients with Obesity (TRIUMPH-1). Presented June 6, 2026.
Treatment with retatrutide, an investigational once-weekly triple hormone receptor agonist, drove substantial improvements in weight loss and other outcomes in two first-of-their-kind phase 3 trials, one in patients with type 2 diabetes and one in patients with obesity, according to results presented at the American Diabetes Association 2026 Scientific Sessions.
In adults with early type 2 diabetes, the agent also delivered strong glycemic control as a stand-alone therapy, results of the TRANSCEND-T2D-1 trial showed.
In adults with obesity, it reduced body weight by more than a quarter at the highest dose, with reported improvements in knee osteoarthritis pain and obstructive sleep apnea, the TRIUMPH-1 trial showed.
The two trials represent some of the first phase 3 results to be reported for retatrutide, which targets the receptors for three naturally occurring hormones: glucagon-like peptide 1 (GLP-1) glucose-dependent insulinotropic polypeptide (GIP), and glucagon.
That targeting strategy is designed to curb appetite, sharpen the body's insulin response, raise energy expenditure, and drive fat breakdown, according to the authors.
“The magnitude of weight loss observed with retatrutide has the potential to slow disease progression and reshape how we treat and manage type 2 diabetes,” researcher Harpreet S. Bajaj, MD said in a statement on the findings.
About 90% of individuals with type 2 diabetes also have overweight or obesity, yet reaching both glycemic targets and meaningful weight loss on current medications remains challenging, according to the authors.
The weight loss achieved with GLP-1 receptor agonists is typically blunted in people who have type 2 diabetes relative to those who do not, pointing to a need for treatments that produce strong weight loss while also controlling blood glucose, the authors noted.
TRANSCEND-T2D-1: type 2 diabetes
TRANSCEND-T2D-1 (NCT06354660) was a 40-week, randomized, double-blind, placebo-controlled trial conducted at 48 sites in the United States, Mexico, and India. It enrolled 537 adults whose type 2 diabetes remained poorly controlled despite diet and exercise, with a hemoglobin A1c of 7.0% to 9.5% and a body mass index (BMI) of at least 23 kg/m2. The mean duration of diabetes was 2.5 years, and most participants had not previously used antihyperglycemic medication.
Participants were randomly assigned in equal groups to receive once-weekly subcutaneous injections of retatrutide 4 mg, 9 mg, or 12 mg, or placebo. The primary endpoint was the change in hemoglobin A1c from baseline to week 40, and a key secondary endpoint was the percentage change in body weight.
From a mean baseline hemoglobin A1c of 7.9%, the value fell by 1.69% with retatrutide 4 mg, 1.86% with 9 mg, and 1.94% with 12 mg, compared with 0.81% with placebo. The estimated treatment difference versus placebo for the 12-mg dose was –1.12% (95% confidence interval –1.39 to –0.85, P < .0001). A hemoglobin A1c below 7.0% was reached by 82% to 89% of retatrutide-treated participants, and a level at or below 6.5% by 75% to 83%.
Body weight fell by 11.5% with 4 mg, 13.9% with 9 mg, and 15.3% with 12 mg, versus 2.6% with placebo, a reduction of 15.1 kg at the highest dose. The estimated treatment difference versus placebo for the 12-mg dose was –12.7% (95% confidence interval –14.4 to –11.0, P < .0001). Weight loss had not reached a plateau when the 40-week trial ended.
Retatrutide also lowered triglycerides, non-HDL cholesterol, and systolic blood pressure relative to placebo, the investigators reported.
The most frequent treatment-emergent adverse events were gastrointestinal, generally mild to moderate, and eased over time, a safety profile in line with other agents that have GLP-1 agonist activity.
No severe hypoglycemia was reported. Two deaths occurred during the study, both in the 4-mg group, and both deemed unrelated to the study drug.
TRIUMPH-1: obesity
TRIUMPH-1 was a phase 3, randomized, placebo-controlled trial that enrolled 2,339 adults with obesity or overweight, including a subset of participants who also had knee osteoarthritis, obstructive sleep apnea, or both. Participants received a once-weekly injection of retatrutide 4 mg, 9 mg, or 12 mg, or placebo, for 80 weeks. The primary endpoint was weight reduction.
At 80 weeks, participants taking retatrutide 12 mg lost an average of 28.3% of body weight (70.3 lb), those taking 9 mg lost 25.9% (64.4 lb), and those taking 4 mg, with a single dose-escalation step, lost 19.0% (47.2 lb). Among participants on the 12-mg dose, 65.3% reached a BMI below 30 kg/m2, falling under the threshold for obesity.
Retatrutide also lowered triglyceride levels, systolic blood pressure, and high-sensitivity C-reactive protein levels from baseline. In addition, retatrutide lowered pain subscale scores by up 73.1% in participants with knee osteoarthritis, and reduced the apnea-hypopnea index by up to 60.6% in participants with moderate-to-severe obstructive sleep apnea.
Taken together, these findings show that retatrutide produced improvements in health outcomes ranging from decreased knee pain, to fewer sleep disturbances, to clear improvements in cardiometabolic measures, according to Dr. Jastreboff.
“Effectively treating obesity meaningfully impacts the overall health of people living with obesity,” she said in a statement discussing the results.
Longer-term phase 3 trials are underway, including head-to-head studies of retatrutide against semaglutide in patients with type 2 diabetes, type 2 diabetes with chronic kidney disease, type 2 diabetes with obesity, and cardiovascular disease with obesity, the authors noted.
Disclosures
Harpreet S. Bajaj, MD, MPH, reported research support paid to his institution from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Ionis, Novartis, Novo Nordisk, Pfizer, Roche, and Vertex, and serving as a speaker and on advisory panels for Eli Lilly, Novo Nordisk, and Roche. Retatrutide is being developed by Eli Lilly and Company, which funded TRANSCEND-T2D-1.
References
Bajaj HS, Welch M, Shah P, et al. Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial. Lancet. Published online June 6, 2026. doi:10.1016/S0140-6736(26)00967-0
Jastreboff AM. Results of first phase 3 study of retatrutide, a GIP, GLP-1, and glucagon receptor agonist in patients with obesity (TRIUMPH-1). Symposium presentation, ADA 2026 Scientific Sessions. June 6, 2026.