Blockbuster Retatrutide Trial: A New Benchmark for Weight-Loss Drugs

The experimental weight-loss drug retatrutide has reached a significant milestone: a Phase 3 clinical trial showed participants with type 2 diabetes losing up to 49.6 pounds, or over 20 percent of their body weight. Eli Lilly, the drug's developer, reported this as a first for the field.

Beyond weight reduction, trial participants experienced notable improvements in blood sugar levels, along with lower cholesterol and blood pressure. These factors are all linked to cardiovascular disease risk.

Daniel Skovronsky, Eli Lilly's chief scientific and product officer, stated, "We achieved a new high-water mark for what’s possible in terms of weight loss."

Retatrutide is classified as a "triple agonist," targeting three hormone receptors: GLP-1, GIP, and glucagon. This distinguishes it from current GLP-1 receptor agonists (like semaglutide) and dual agonists (like tirzepatide) that target one or two receptors, respectively. It is the first triple agonist to undergo a Phase 3 trial, the critical testing phase for U.S. Food and Drug Administration approval consideration.

The TRIUMPH-2 trial, spanning 80 weeks, involved 1,152 individuals with obesity and type 2 diabetes. Participants received either a placebo or retatrutide at doses of 4 mg, 9 mg, or 12 mg. Average weight loss varied by dose: 29.8 pounds (13.5 kg) for the 4 mg group, 45.4 pounds (20.6 kg) for the 9 mg group, and 49.6 pounds (22.5 kg) for the 12 mg group. The placebo group lost an average of 9.3 pounds (4.2 kg).

Remarkably, at the trial's conclusion, approximately 60 percent of participants in the 12 mg retatrutide group no longer met the criteria for obesity based on their body mass index. Depending on the dosage, 28.4 to 40 percent of participants on retatrutide achieved normalized blood sugar levels. These findings were published in The Lancet.

Randy Seeley, a professor at the University of Michigan, commented that these results are particularly significant given that individuals with type 2 diabetes generally experience less weight loss with GLP-1 drugs compared to those without the condition. (Seeley has consulted for Eli Lilly and other weight-loss drug manufacturers in the past but was not involved in TRIUMPH-2.)

A separate Eli Lilly-funded trial, TRIUMPH-1, demonstrated that participants with obesity but without diabetes lost up to 25 percent of their body weight over 80 weeks using the same retatrutide doses. The results of TRIUMPH-1 were published in The New England Journal of Medicine.

Retatrutide can cause side effects, including diarrhea, constipation, nausea, and vomiting. The Lancet paper noted seven deaths occurred during the study, though they were deemed unrelated to the treatment.

Reports also indicate that some participants experienced side effects leading them to skip doses, and expressed concerns about the speed of weight loss.

Seeley noted that rapid weight loss can increase the risk of gallstones and micronutrient deficiencies. He explained, "If you're eating very few calories, it’s harder and harder to get all of the other things you need from your food."

Seeley advised that if retatrutide becomes widely available, patients should consult their physicians to determine the appropriate dose and treatment plan. He believes many patients may not need the maximum dose of retatrutide.

The development of retatrutide points to future innovations, with drugs targeting four and even five hormone receptors already in development.

"The science is moving very, very fast," Seeley observed.

Eli Lilly intends to submit the trial data to regulatory agencies globally, with approval anticipated "early next year," according to Skovronsky.