Lilly’s Retatrutide Beats Ozempic in Head-to-Head Diabetes Trial, With More Than Double the Weight Loss

Eli Lilly’s experimental weekly shot retatrutide lowered blood sugar more than Novo Nordisk’s Ozempic and produced more than twice the weight loss in the first late-stage trial to pit the two drugs directly against each other, the company said Wednesday.

In the phase 3 TRANSCEND-T2D-2 study of adults with type 2 diabetes, people on retatrutide lost an average of 44.3 to 47.4 pounds over 80 weeks, depending on the dose, compared with 20.9 pounds for those taking Ozempic at its highest approved dose of 2 milligrams, Lilly said in its announcement. Both retatrutide doses cut A1C, a three-month measure of blood sugar, by an average of 2.2 percentage points, versus 1.8 points with Ozempic.

The results are topline figures released by the company. They have not yet been published in a peer-reviewed journal, and retatrutide is not approved by the Food and Drug Administration for any use.

What did the TRANSCEND-T2D-2 trial compare?

The open-label trial enrolled 1,298 adults whose type 2 diabetes was not well controlled on metformin, with or without an SGLT2 inhibitor such as Jardiance or Farxiga. Participants started with an average A1C of 8.3% and an average weight of about 226 pounds. They were randomly assigned to weekly injections of retatrutide at 9 mg or 12 mg, or Ozempic at 2 mg. The study is registered on ClinicalTrials.gov as NCT06260722.

The trial’s main goal was narrower than the headline numbers suggest. Lilly set out to show that the 12 mg dose of retatrutide was not worse than Ozempic at lowering A1C. It cleared that bar and, according to the company, also beat Ozempic on blood sugar and on weight loss, which was a key secondary goal.

Lilly said retatrutide also produced larger improvements than Ozempic in non-HDL cholesterol, triglycerides and systolic blood pressure, all risk factors for heart disease. The company has not yet released those figures in detail.

How is retatrutide different from Ozempic?

Ozempic, whose active ingredient is semaglutide, mimics one gut hormone, GLP-1, which helps the body release insulin and curbs appetite. Lilly’s current blockbuster, tirzepatide, sold as Mounjaro for diabetes and Zepbound for weight loss, acts on two hormones, GLP-1 and GIP.

Retatrutide adds a third target, the hormone glucagon, which is believed to increase the energy the body burns. That is why the drug is often nicknamed a “triple G” or triple agonist. It is a single molecule given as a once-weekly shot.

Lilly called the new study the sixth phase 3 trial in which retatrutide has delivered strong results. In March, the company reported that in an earlier diabetes trial, TRANSCEND-T2D-1, retatrutide lowered A1C by up to 2.0% and weight by up to 16.8% at 40 weeks compared with a placebo.

What side effects did patients report?

As with other drugs in this class, the most common side effects were digestive. Diarrhea affected 28.3% of people on the 9 mg dose and 32.7% on the 12 mg dose, compared with 26.4% on Ozempic. Nausea rates were similar across groups, at roughly 21% to 24%. Vomiting was reported by 10.2% and 15.0% of retatrutide patients and 13.2% of Ozempic patients, while constipation was more common with Ozempic.

Two findings stood out. Dysesthesia, an unusual or unpleasant skin sensation, occurred in 4.8% and 6.5% of people on retatrutide versus 2.7% on Ozempic. And more people stopped retatrutide because of side effects: 4.8% on the lower dose and 7.9% on the higher dose, compared with 2.7% on Ozempic. Lilly said most side effects were mild to moderate.

What does this mean for people with type 2 diabetes?

More than 40 million Americans have diabetes, and 90% to 95% of them have type 2, according to the Centers for Disease Control and Prevention. Lilly noted that weight loss has historically been harder for people living with type 2 diabetes, which is why the size of the weight drop in this trial is drawing attention.

For now, nothing changes at the pharmacy counter. Ozempic and Lilly’s Mounjaro remain among the approved weekly injections for type 2 diabetes, part of a fast-growing drug class HNC has followed since the World Health Organization’s guidance on GLP-1 drugs for obesity. Lilly said full results will be presented at a medical meeting and published in a journal. Its announcement did not say when it plans to ask the FDA for approval.

Lilly is also testing retatrutide against its own tirzepatide in a separate trial, TRIUMPH-5, in adults with obesity. That study could show whether the third hormone adds meaningful benefit over tirzepatide.

Patients should be wary of anyone offering retatrutide now. Lilly says the drug cannot legally be sold to consumers, and the FDA has warned consumers about the risks of unapproved versions of GLP-1 drugs sold online.

Key Takeaways

• Lilly said Oct. 28 that retatrutide beat Ozempic 2 mg in TRANSCEND-T2D-2, a phase 3 head-to-head trial in 1,298 adults with type 2 diabetes.
• At 80 weeks, retatrutide cut A1C by 2.2 points versus 1.8 with Ozempic, and weight by 19.5% to 20.9% versus 9.4%.
• Digestive side effects were common in all groups; more people quit retatrutide due to side effects (4.8% and 7.9% vs. 2.7%).
• Results are topline company data, not yet peer reviewed. Retatrutide is investigational and is not FDA approved.

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