Dr Harpreet Bajaj

A triple agonist therapy has delivered substantial weight loss and glucose control in patients with type 2 diabetes inadequately controlled by diet and exercise, a phase 3 trial has found.

The 40-week Eli Lilly-funded study, published in The Lancet [link here] and presented at the American Diabetes Association (ADA) scientific sessions in New Orleans, found the 12mg dose of retatrutide produced a mean 15.3% reduction in bodyweight and a 1.94% reduction in HbA1c.

Retatrutide is a GIP, GLP-1, and glucagon receptor agonist administered by once-weekly subcutaneous injection. The 537 participants were randomised to retatrutide (4mg, 9mg, or 12mg) or placebo.

Results at week 40 showed:

• Mean HbA1c declined by 1.69% (4mg), 1.84% (9mg), and 1.94% (12mg), compared with 0.84% in the placebo group
• Mean bodyweight fell by 11.5% (4mg), 13.9% (9mg), and 15.3% (12mg), compared with 2.6% for placebo
• Between 82% and 89% of retatrutide-treated participants achieved an HbA1c target below 7%, and 75–83% reached the below-6.5% threshold
• Adverse events were predominantly gastrointestinal and consistent with other GLP-1 receptor agonist treatments, subsiding over time

Notably, weight loss had not plateaued at the 40-week mark, the authors reported.

Lead author Dr Harpreet Singh Bajaj, an endocrinologist at LMC Diabetes & Endocrinology, told media at the ADA meeting that the degree of glucose control seen with retatrutide was comparable to that of GIP/GLP-1 dual agonists, despite the addition of glucagon agonism.

“Despite having glucagon agonism, [this] was not raising glucose,” he said.

Dr Bajaj said the magnitude of weight loss seen in the trial had the potential to slow type 2 diabetes progression, with the glucagon receptor component expected to drive greater reductions in visceral adiposity, including fat in the liver and pancreas. Phase 2 data had already suggested a significant reduction in liver fat, he said, though the phase 3 study did not include MRI imaging to confirm organ-level effects.

In obesity: 28% weight loss at 80 weeks

A separate trial presented at the same meeting, TRIUMPH-1, examined retatrutide in patients with overweight or obesity without type 2 diabetes. Patients on the 12mg dose lost a mean 28.3% of baseline bodyweight at 80 weeks, with two thirds reaching a weight below the obesity threshold.

Lead author Professor Ania Jastreboff of Yale University said the benefits extended beyond weight loss.

“Treatment with retatrutide resulted in improvements in health outcomes — from decreased knee pain to fewer sleep disturbances, to clear improvements in cardiometabolic measures,” she said.