Retatrutide Ozempic trial shows bigger A1C drop and double the weight loss
Lilly says retatrutide cut A1C by 2.2 points and weight by up to 20.9% at 80 weeks in type 2 diabetes, against 1.8 points and 9.4% on Ozempic. More people stopped retatrutide for side effects, and the data are not yet peer reviewed.
What's new
Lilly said retatrutide beat Ozempic at its highest approved diabetes dose in the Phase 3 TRANSCEND-T2D-2 trial, cutting A1C by 2.2 points against 1.8 and weight by up to 20.9% against 9.4% at 80 weeks.
Why it matters
It is the first Phase 3 test of retatrutide against another incretin drug, and it shows both a larger effect and more side effect dropouts than the comparator.
What's next
Full data are due at a medical meeting and in a journal. An extension continues for 24 weeks, and the TRIUMPH-5 trial against tirzepatide is ongoing.
Eli Lilly said on Wednesday that its experimental peptide retatrutide beat Ozempic on blood sugar and body weight in adults with type 2 diabetes. In the retatrutide Ozempic trial, a Phase 3 head to head trial called TRANSCEND-T2D-2, both retatrutide doses cut A1C by 2.2 percentage points at 80 weeks against 1.8 points for Ozempic, the company said. The higher dose produced 20.9% average weight loss against 9.4%. More people quit retatrutide because of side effects. The figures are topline data from a company release and have not been peer reviewed.
What the TRANSCEND T2D 2 trial tested
The retatrutide Ozempic trial enrolled 1,298 adults whose type 2 diabetes was not controlled on metformin, with or without an SGLT2 inhibitor, according to Lilly. Their A1C ranged from 7.0% to 10.5% at entry, with an average of 8.3%. Average body weight was 102.4 kg and average BMI was 36.8, so most participants also had obesity. Patients were randomized in a 2:2:1 ratio to one of two retatrutide doses or to Ozempic at its highest approved dose for diabetes. All three arms used weekly injections. The trial was open label, which means patients and doctors knew which drug was given. Retatrutide was started low and raised in steps to its target level, the company said. The study is registered as NCT06260722.
The primary goal was narrow. Lilly needed to show that the higher retatrutide dose was not worse than Ozempic at lowering A1C after 80 weeks, a test called noninferiority. Weight change was a key secondary goal. Lilly said retatrutide met the primary goal and every key secondary goal. Retatrutide is a triple hormone agonist: one peptide that acts on GIP, GLP-1 and glucagon receptors. Ozempic, Novo Nordisk's semaglutide, acts on the GLP-1 receptor alone. Lilly called this the first Phase 3 trial to test retatrutide against another incretin medicine. Earlier readouts, such as the sleep apnea trials reported in The New England Journal of Medicine, compared the drug with placebo. This study measures it against a drug many patients already use.
Retatrutide Ozempic trial results on A1C and weight
Both retatrutide doses lowered A1C by 2.2 percentage points on average at 80 weeks, against 1.8 points on Ozempic, Lilly reported. For the higher dose, the gap was statistically significant with error control across the main tests. For the lower dose, A1C superiority was a prespecified secondary test that reached only nominal significance, according to a footnote in Lilly's topline release. Weight results showed a wider gap. People on the lower dose lost 19.5% of body weight, or 44.3 pounds. On the higher dose, people lost 20.9% of body weight on average, more than twice the 9.4% seen with Ozempic. The Ozempic group lost 20.9 pounds. Lilly said retatrutide also improved non-HDL cholesterol, triglycerides and systolic blood pressure more than Ozempic, but gave no figures for those measures.
On the higher dose, people lost 20.9% of body weight on average, more than twice the 9.4% seen with Ozempic.
These numbers come with caveats. Every figure in the release uses the efficacy estimand, which estimates results as if all randomized patients had stayed on treatment for the full 80 weeks without adding other glucose drugs. That approach can show larger effects than an analysis that counts everyone who stopped treatment. The release did not include those treatment regimen figures. An open label design can also shape how patients behave and report symptoms. For context, Lilly said people with type 2 diabetes and obesity on the highest retatrutide dose in its TRIUMPH-2 trial lost 20.8%. Our guide to reading weight loss headlines explains why the choice of estimand and comparator can change what a headline percentage means.
Retatrutide side effects and dropouts
The extra weight loss came with more people stopping treatment. Discontinuation because of adverse events was 4.8% on the lower retatrutide dose and 7.9% on the higher dose, against 2.7% on Ozempic, Lilly said. Gastrointestinal effects were the most common. Diarrhea affected 32.7% of people on the higher dose and 26.4% on Ozempic. Vomiting was reported by 15.0% on the higher dose and 13.2% on Ozempic. Constipation was less frequent on both retatrutide doses than on Ozempic. Lilly also reported dysesthesia, an abnormal skin sensation, in 6.5% of the higher dose group against 2.7% on Ozempic. The company said most events were mild to moderate and usually resolved while patients stayed on treatment.
Outside analysts read the tolerability gap as expected. Leerink Partners analyst David Risinger told clients the data "strengthen the case for retatrutide's long-term differentiation," BioPharma Dive reported. MedCity News reported that he called the higher side effect and dropout rates a trade off for a three target drug. He also said they were broadly in line with an earlier Phase 3 trial in people with obesity and type 2 diabetes. That view is an analyst opinion, not a trial finding. Dropout rates matter in practice because a drug that people stop taking cannot deliver its average result. Serious adverse event rates and full safety tables have not yet been published.
| Measure at 80 weeks | Retatrutide lower dose | Retatrutide higher dose | Ozempic |
|---|---|---|---|
| Average A1C drop in points | 2.2 | 2.2 | 1.8 |
| Average weight loss | 19.5% | 20.9% | 9.4% |
| Average weight loss in pounds | 44.3 | 47.4 | 20.9 |
| Diarrhea | 28.3% | 32.7% | 26.4% |
| Nausea | 21.2% | 23.8% | 21.3% |
| Vomiting | 10.2% | 15.0% | 13.2% |
| Constipation | 14.2% | 13.1% | 19.8% |
| Dysesthesia | 4.8% | 6.5% | 2.7% |
| Stopped for adverse events | 4.8% | 7.9% | 2.7% |
Unapproved status and the next readouts
Retatrutide is not approved anywhere. Lilly said in the release that no regulator has cleared it and that anyone selling it to consumers is breaking the law. BioPharma Dive noted that interest in the drug has pushed some people toward an unregulated black market. Products sold that way have no verified content, purity or sterility, and these trial results say nothing about them. The only legitimate route to the drug today is enrolment in a registered clinical trial. Lilly said it is testing retatrutide in Phase 3 studies in obesity, type 2 diabetes, knee osteoarthritis pain, obstructive sleep apnea, chronic low back pain, cardiovascular outcomes and fatty liver disease. Its TRANSCEND-T2D diabetes program alone has enrolled more than 2,050 people in three trials.
Lilly said detailed retatrutide Ozempic trial results will be presented at a medical meeting and published in a peer reviewed journal, without giving a date. About 650 participants are continuing on retatrutide for another 24 weeks in an extension to study longer term effects. The next readout analysts flagged is TRIUMPH-5, an ongoing Phase 3 trial testing retatrutide against Lilly's own tirzepatide in adults with obesity, with or without diabetes. Tirzepatide already beat semaglutide on weight in an earlier head to head comparison. Leerink models retatrutide sales of about $15 billion in 2032, above a Wall Street consensus near $10 billion, according to BioPharma Dive. Those figures are forecasts. The release did not say when Lilly plans to seek approval.
Conclusion
The retatrutide Ozempic trial gives Lilly its first Phase 3 comparison against a rival incretin medicine, with a larger A1C drop and more than twice the weight loss at 80 weeks. It also shows higher dropout rates from side effects. The figures come from a company release built on an efficacy estimand, so the full paper will show how firm the gap is. Retatrutide remains an investigational drug that is not approved for sale anywhere.
