Eli Lilly retatrutide cuts A1C and body weight by up to 20.8 percent in Phase 3 diabetes trial

Retatrutide, an investigational medicine from Eli Lilly and Company that acts on three hormone receptors at once, moved substantially closer to the clinic on September 29, 2026, when the company released detailed Phase 3 results from the TRIUMPH-2 trial in adults who have both type 2 diabetes and obesity or overweight. The data were presented at the 62nd Annual Meeting of the European Association for the Study of Diabetes in Milan, Italy, and published simultaneously in The Lancet.

For more than a decade, weight loss medicines have underperformed in people with type 2 diabetes, a group whose condition and its treatments often work against body weight reduction. Lilly reported that participants taking the highest dose of retatrutide, 12 mg, lost an average of 49.6 lbs, or 20.8 percent of their starting body weight, after 80 weeks, compared with 9.3 lbs, or 4.0 percent, for placebo.

Retatrutide is described by Lilly as an investigational first-in-class GIP, GLP-1 and glucagon triple hormone receptor agonist. The company already markets Zepbound, known generically as tirzepatide, which targets GIP and GLP-1, and Foundayo, known generically as orforglipron. The addition of glucagon activity is one explanation researchers offer for the larger effects seen across the retatrutide program.

TRIUMPH-2 randomized 1,152 participants, and the broader TRIUMPH program has enrolled more than 5,800 people, according to the company. The results arrive as regulators, clinicians and patients weigh how much additional benefit a third receptor target can deliver on top of an already crowded market for incretin based therapies.

Key Facts

Eli Lilly announced on September 29 that in TRIUMPH-2 all three doses of retatrutide produced substantial weight loss and A1C reductions at 80 weeks. Participants taking 4 mg, 9 mg and 12 mg lost an average of 29.8 lbs (12.7 percent), 45.4 lbs (19.1 percent) and 49.6 lbs (20.8 percent) respectively, against 9.3 lbs (4.0 percent) for placebo, from an average baseline of 106.4 kg (234.6 lbs) and a BMI of 38.2.

The weight effects were larger in people who started with more severe obesity. Among participants with a baseline BMI of 35 or higher, those on 12 mg lost an average of 60.8 lbs, or 23.4 percent of body weight, and 59.5 percent of participants on that dose no longer met the BMI criteria for obesity by the end of the trial.

Glycemic control improved across doses. A1C fell by an average of 1.4 percent on 4 mg, 1.6 percent on 9 mg and 1.5 percent on 12 mg, compared with 0.2 percent for placebo. Between 79.0 and 79.2 percent of participants reached an A1C of 6.5 percent or lower, and up to 40.0 percent reached an A1C level below 5.7 percent, a range usually seen in people who do not have diabetes.

On the highest dose, 67.0 percent of participants lost at least 15 percent of body weight and 34.9 percent lost at least 25 percent. Cardiovascular and metabolic markers also moved: triglycerides fell 39.5 percent, non-HDL cholesterol 19.6 percent, systolic blood pressure 10.8 mmHg, waist circumference 6.7 in (16.9 cm) and hsCRP 58.3 percent.

Adverse events were mostly gastrointestinal and similar in kind to other incretin therapies. Diarrhea occurred in 27.4 percent, 33.5 percent and 33.6 percent of the 4 mg, 9 mg and 12 mg groups versus 13.2 percent for placebo, and nausea in 13.7 percent, 20.8 percent and 28.0 percent versus 8.0 percent. Discontinuation because of adverse events was 3.8 percent on 4 mg, 11.6 percent on 9 mg and 7.7 percent on 12 mg, compared with 4.9 percent for placebo.

Analysis

NBC News reported on September 29 that retatrutide helped people with type 2 diabetes lose up to 60 pounds, about 23 percent of body weight, the most weight loss ever recorded in a drug trial for diabetes patients. The comparison the network offered is telling: in separate trials, people with type 2 diabetes lost up to 10 percent of body weight on semaglutide and up to 15 percent on tirzepatide, though those were not head-to-head comparisons.

TIME reported on September 29 that the highest dose produced weight loss of about 18.8 percent to 25 percent of starting body weight across the two trials published that day, and quoted Dr. Juan Pablo Frias of the Los Angeles Institute for Metabolic Research, a Lancet study author, who called retatrutide the most potent drug showing the greatest percent weight loss in people with type 2 diabetes with a pharmacological agent shown to date.

What this really means is that the ceiling for drug based weight management in diabetes has moved again, and it has moved by a margin that changes how clinicians counsel patients. The trial was not designed to compare retatrutide against tirzepatide or semaglutide. Ars Technica reported on September 29 that this absence of a head to head comparison is a notable limitation of the program. A gap of roughly 6 percentage points in average weight loss, which is what separates 12 mg retatrutide from historical tirzepatide figures in this population, is clinically meaningful but is not the same as proven superiority.

The safety picture also deserves a sober reading. Gastrointestinal side effects led 11.6 percent of participants on 9 mg to stop treatment, higher than the 7.7 percent seen at 12 mg and the 4.9 percent on placebo, a non monotonic pattern that investigators will need to explain. Discontinuation rates of that size are the practical tax on potency, and they matter for real world adherence once a weekly injection leaves the controlled setting of a trial.

Why It Matters

More than half of participants on 12 mg, 59.5 percent, no longer met the BMI criteria for obesity, and up to 40.0 percent reached an A1C below 5.7 percent. Dr. Susan Spratt, an endocrinologist at Duke Health who was not involved in the trial, told NBC News that retatrutide is truly an advance in diabetes care and rivals gastric bypass surgery without the surgery. That framing, from a clinician with no stake in the sponsor, is among the strongest signals in this data set.

The benefit extends beyond glucose and weight. Lilly reported reductions in triglycerides, non-HDL cholesterol, systolic blood pressure, waist circumference and hsCRP, a marker of inflammation. For a population with elevated cardiovascular risk, those changes matter independently of the number on the scale, and they are the kind of endpoints payers and regulators examine closely.

The companion study published in the New England Journal of Medicine tested the same molecule in people with obesity or overweight who do not have diabetes. TIME reported on September 29 that the highest dose produced about 25 percent weight loss versus 3.9 percent for placebo in that population, with lower knee osteoarthritis pain scores and fewer obstructive sleep apnea episodes. Ars Technica reported on September 29 that weight loss reached an average of 25 percent at 80 weeks and 30 percent at 104 weeks, with knee pain down by up to 62 percent and sleep apnea events per hour down by up to 57 percent in subsets, and that prediabetes resolved in more than 90 percent of the participants who had it at the start.

Next Up

Lilly announced on September 29 that it plans to submit a Biologics License Application for retatrutide in the first quarter of 2027, and the company confirmed that timeline to TIME. Until then, retatrutide remains investigational, and the TRIUMPH-2 registration number is NCT05929079 for anyone who wants to read the protocol. The trial randomized participants in a 1:1:1:1 ratio across the three active doses and placebo.

One regulatory and public health question has already arrived. NBC News reported on September 29 that unauthorized copycat versions of retatrutide are being sold through wellness platforms, medical spas and compounding pharmacies, often labeled for research use only, and that Lilly has filed lawsuits against sellers of unapproved versions. The gap between a Phase 3 readout and an approved product is where those gray markets tend to grow.