Lilly's retatrutide more than doubles Ozempic's weight loss in head-to-head trial

Eli Lilly's experimental weight-loss drug retatrutide has delivered more than double the weight loss of Ozempic in the first Phase 3 trial to pit the two drugs directly against each other — results that, if they hold up through regulatory review, could redraw the landscape of obesity and diabetes treatment.

Results from the TRANSCEND-T2D-2 trial, released October 28, 2026, showed that type 2 diabetes patients on the 12 mg dose of retatrutide shed an average of 47.4 lbs — equal to 20.9% of their starting body weight — across 80 weeks. Those on the 9 mg dose lost 44.3 lbs (19.5%). Patients on Ozempic 2 mg, the highest approved dose for type 2 diabetes, lost 20.9 lbs, or 9.4%. The roughly 1,300 participants started the trial with an average weight of 225.8 lbs and a BMI of 36.8.

Retatrutide also beat Ozempic on blood sugar control: both doses reduced A1C — a standard measure of long-term blood glucose — by an average of 2.2 percentage points, compared with 1.8 points for Ozempic. The drug additionally showed greater improvements in non-HDL cholesterol, triglycerides, and systolic blood pressure, according to Lilly.

In TRANSCEND-T2D-2, the first Phase 3 trial comparing retatrutide with another incretin medicine, retatrutide delivered greater A1C reduction and more than double the weight loss of the highest approved dose of Ozempic for type 2 diabetes. Based on these results and those from across our Phase 3 program, we believe retatrutide, if approved, could shift the treatment paradigm for people living with type 2 diabetes, obesity and related cardiometabolic conditions.— Kenneth Custer, Ph.D., Executive Vice President and President of Lilly Cardiometabolic Health

To understand why these numbers matter, it helps to trace the drug's lineage. Ozempic, made by Novo Nordisk, was the first of its class — a drug that mimics a single gut hormone called GLP-1 to regulate blood sugar and suppress appetite. Eli Lilly's Mounjaro followed, targeting two hormones (GLP-1 and GIP) and producing stronger results. Retatrutide goes a step further, activating receptors for three hormones: GLP-1, GIP, and glucagon. That third target — glucagon — helps break down stored fat into energy, according to Business Insider, which is why the drug has earned nicknames like 'triple G' and 'King Kong' in online fitness communities.

TRANSCEND-T2D-2 is the sixth Phase 3 trial in which retatrutide has shown strong efficacy, according to Lilly. The company is also running TRIUMPH-5, an ongoing Phase 3 trial comparing retatrutide head-to-head with its own tirzepatide (Mounjaro) in adults with obesity. According to Business Insider, Lilly intends to submit an FDA approval application in the first quarter of 2027, and if regulators clear the drug, it could reach patients that same year for conditions including obesity, obesity-related sleep apnea, and knee osteoarthritis.

Because the trial was open-label, participants knew which drug they were receiving, and the findings have yet to undergo peer review or appear in a medical journal. Lilly has said it will present full results at a future medical meeting and submit them for publication in a peer-reviewed journal.

The safety picture is more mixed. The most common side effects on retatrutide were gastrointestinal: diarrhea affected up to 32.7% of patients on the 12 mg dose versus 26.4% on Ozempic; nausea affected up to 23.8% versus 21.3%. Constipation ran the other way — 19.8% on Ozempic versus up to 14.2% on retatrutide. A rare side effect called dysesthesia — tingling or burning skin sensations — occurred in 4.8% to 6.5% of retatrutide patients versus 2.7% on Ozempic. The majority of adverse events were mild to moderate and tended to clear up while patients remained on treatment. Critically, 7.9% of patients on the top retatrutide dose stopped treatment due to adverse events, compared with 2.7% on Ozempic.

The announcement came a day before Lilly's quarterly earnings report. In an unusual move, the company used the same release to address a gray market that has grown up around the drug before it has even been approved. Powders labeled 'reta' are being shipped from overseas and used by bodybuilders and fitness enthusiasts who say the substance shreds fat with fewer side effects than other injectable weight-loss drugs. On the matter, Lilly stated: "Retatrutide is an investigational molecule that has not been approved by FDA or any regulatory organization anywhere in the world. Anyone purporting to sell retatrutide to consumers is breaking the law."

Why it matters — Retatrutide's trial results suggest a new class of weight-loss drug could significantly outperform the current market leader, with FDA filing expected in early 2027 — potentially reshaping treatment options for the tens of millions of people living with type 2 diabetes and obesity.

Reported by prnewswire.com, businessinsider.com, fiercebiotech.com