Lilly's triple-agonist retatrutide posts record weight loss across three phase 3 trials

Eli Lilly's experimental weight-loss drug retatrutide has produced the largest body-weight reductions ever recorded for a pharmaceutical agent, according to results from three phase 3 clinical trials released this week — including one published Tuesday in the New England Journal of Medicine. Across different patient populations, participants lost between roughly 30 and 70 pounds over 80 weeks depending on dose and health status, with a subset who continued treatment reaching an average of 85 pounds lost over two years.

The drug is not a standard GLP-1 medication. Retatrutide is a once-weekly triple hormone receptor agonist, hitting three targets simultaneously: GLP-1 (glucagon-like peptide-1), GIP (glucose-dependent insulinotropic polypeptide), and glucagon. Existing drugs like semaglutide — sold as Ozempic and Wegovy — act on GLP-1 alone. Tirzepatide, sold as Mounjaro and Zepbound, targets GLP-1 and GIP. Retatrutide is the first triple agonist to reach phase 3 trials, the gold-standard testing required before the FDA considers a drug for approval.

The glucagon component is what sets retatrutide apart mechanically. While GLP-1 and GIP agonism suppresses appetite, glucagon receptor activation increases energy expenditure, pushing the body toward greater fat oxidation. That two-sided attack on the energy equation — eating less while burning more — may explain why weight loss in the trials did not plateau at 80 weeks, with participants still on a downward trajectory at the study's end, according to Pharmacy Times.

TRIUMPH-1, the trial in adults with obesity or overweight but without type 2 diabetes, enrolled participants and randomized them to retatrutide 4 mg, 9 mg, or 12 mg, or placebo. Participants assigned to the 4 mg dose — achieved through a single escalation step — shed an average of 47.2 pounds, representing 19.0% of their starting body weight, by the 80-week mark. The 9 mg group lost an average of 64.4 pounds (25.9%), and the 12 mg group lost an average of 70.3 pounds (28.3%). Among participants on the highest dose, 45.3% achieved 30% or greater weight loss — a threshold historically associated with bariatric surgery — and 65.3% fell below a BMI of 30, the clinical cutoff for obesity.

For a subset of TRIUMPH-1 participants with a baseline BMI of 35 or higher who continued on retatrutide 12 mg into a prespecified blinded extension, total weight loss reached an average of 85.0 pounds, or 30.3% of body weight, at 104 weeks — a level of sustained, progressive pharmacological weight reduction that, according to Pharmacy Times, has not previously been observed at this scale.

We achieved a new high-water mark for what's possible in terms of weight loss.— Daniel Skovronsky, Chief Scientific and Product Officer, Eli Lilly

TRIUMPH-2 tested retatrutide in a harder-to-treat population: 1,152 adults with both obesity or overweight and type 2 diabetes, who typically lose less weight on GLP-1 drugs than people without diabetes. At 80 weeks, participants on the 12 mg dose lost an average of 49.6 pounds (20.8% of body weight), those on 9 mg lost 45.4 pounds (19.1%), and those on 4 mg lost 29.8 pounds (12.7%). The placebo group lost an average of 9.3 pounds. About six in ten participants in the 12 mg group were no longer classified as having obesity by BMI at the study's end, according to Eli Lilly. Blood sugar control also improved significantly: from a baseline A1C of 7.7%, participants on the highest dose saw a mean reduction of 1.5 percentage points, compared with 0.2 points on placebo. Depending on dose, the share of retatrutide participants whose blood sugar returned to normal ranged from 28.4% to 40% by the close of the study. Results from TRIUMPH-2 were published in the Lancet.

The 1,949 adults enrolled in TRIUMPH-3 had severe obesity — class 2 or class 3, with a BMI of at least 35 — along with established cardiovascular disease, and some also had type 2 diabetes. At 80 weeks, participants on retatrutide 12 mg lost an average of 55.8 pounds (22.6% of body weight); those on 9 mg lost weight equivalent to 21.6%. The placebo group lost 3.2%. The trial also tracked cardiovascular risk markers at the highest dose: triglycerides fell by a mean of 37.0%, non-HDL cholesterol by 16.5%, systolic blood pressure by 9.3 mm Hg, waist circumference by 7.5 inches, and high-sensitivity C-reactive protein by 51.2%, according to Patient Care Online.

TRIUMPH-3 also included a prespecified analysis of major adverse cardiovascular events (MACE). For a five-component composite — all-cause death, heart attack, stroke, heart failure event, or coronary revascularization — 44 events occurred in the pooled retatrutide groups versus 52 in the placebo group, a hazard ratio of 0.82. However, for the three-component composite of cardiovascular death, heart attack, or stroke, there were 27 events with retatrutide versus 23 with placebo, a hazard ratio of 1.12. Lilly noted that MACE events occurred less frequently than anticipated in both groups, meaning the trial was not powered to draw definitive conclusions on cardiovascular outcomes.

The safety profile across trials was consistent with other drugs in the incretin class. The most common adverse events were gastrointestinal: nausea, diarrhea, constipation, and vomiting, generally mild to moderate. Across the three doses in TRIUMPH-1 — 4 mg, 9 mg, and 12 mg — the share of participants who stopped treatment because of adverse events was 4.1%, 6.9%, and 11.3%, respectively; the placebo dropout rate was 4.9%. Dysesthesia, a sensory disturbance, appeared in some patients, but cases were typically mild and most of those affected remained in the trial. According to the Lancet paper, seven deaths occurred during TRIUMPH-2, though investigators determined none was linked to the drug. Separately, anonymous study participants reported skipping doses due to side effects and concerns about rapid weight loss, according to reporting by STAT cited by Scientific American.

Particularly for reta, I think, a lot of these patients aren't going to need to get to the maximum dose.— Randy Seeley, Professor of Surgery, Internal Medicine and Nutritional Sciences, University of Michigan

Seeley, who has worked as a paid consultant for Eli Lilly and other weight-loss drug makers in the past but was not involved in TRIUMPH-2, also noted that intense weight loss carries its own risks, including a higher likelihood of gallstones and micronutrient deficiencies from reduced caloric intake.

Phase 2 findings for retatrutide, published in the New England Journal of Medicine in June 2023, showed that adults with obesity but without type 2 diabetes taking the 12 mg dose had shed a mean of 24.2% of their body weight at 48 weeks — the greatest weight reduction recorded in a randomized controlled trial for any obesity drug up to that point. The phase 3 results extend and deepen that signal across a broader and sicker population.

Detailed TRIUMPH-1 findings are set to be presented by Lilly at the 86th Annual American Diabetes Association Scientific Sessions. The company said it plans to submit a Biologics License Application to the FDA in the first quarter of 2027, according to Patient Care Online. Daniel Skovronsky said Lilly plans to submit trial data to the FDA and other health agencies around the world for approval early next year, according to Scientific American. According to Seeley, researchers are already working on drugs that target four or even five hormone receptors.

Why it matters — Retatrutide, if approved, would be the first triple-agonist obesity drug on the market, offering weight loss that approaches bariatric surgery outcomes for a population where existing medications have already transformed treatment — and the FDA submission is expected in early 2027.

Sources differ on TRIUMPH-3 cardiovascular outcomes: MACE-5 hazard ratio 0.82 (favoring retatrutide): 44 events on retatrutide vs. 52 on placebo (patientcareonline.com) vs MACE-3 hazard ratio 1.12 (numerically favoring placebo): 27 events on retatrutide vs. 23 on placebo; Lilly noted events occurred less frequently than anticipated in both groups, so the trial was not powered for definitive CV conclusions (patientcareonline.com)

Reported by nejm.org, investor.lilly.com, pharmacytimes.com, nytimes.com, yahoo.com, patientcareonline.com, reuters.com