By Dr. Asnat Raziel, specialist in obesity treatment, metabolic health and healthy longevity; Director of the Multidisciplinary Center for Obesity Treatment, Assia Medical, Assuta Ramat HaChayal
Retatrutide vs Ozempic: the first head-to-head comparison
Retatrutide vs Ozempic is the comparison many have been waiting for. On October 28, Eli Lilly released the first results of the TRANSCEND-T2D-2 trial. The trial compared retatrutide, an investigational weekly injection, with Ozempic at its highest approved dose, 2 mg. In people with type 2 diabetes, retatrutide improved blood sugar control slightly more. However, the striking difference was in weight: weight loss with retatrutide was more than twice as large.
What does this mean for patients with diabetes and obesity? And what is still unknown? I have gathered the key data for you.
What is retatrutide and how does it work?
Retatrutide is a single molecule that activates three hormone receptors: GLP-1, GIP and glucagon. That is why it is called a “triple agonist”. In contrast, Ozempic acts on only one receptor, GLP-1. Its active ingredient is semaglutide. Mounjaro, for example, acts on two receptors.
In addition, Lilly is testing retatrutide in many phase 3 trials: obesity, diabetes, knee pain, sleep apnea, heart disease and fatty liver. You will find a detailed explanation of the mechanism in my complete guide to this investigational drug.
How was the TRANSCEND-T2D-2 trial designed?
The trial, registered on ClinicalTrials.gov, enrolled 1,298 adults with type 2 diabetes. All of them were taking metformin, and some also took a drug from the SGLT2 family. Even so, their blood sugar was not under control.
The main measure in the trial was HbA1c, or glycated hemoglobin, which reflects average blood sugar over recent months. In these participants, HbA1c ranged from 7.0% to 10.5%.
The researchers randomly assigned participants to three groups, in a 2:2:1 ratio. The groups received retatrutide 9 mg, retatrutide 12 mg or Ozempic 2 mg. Retatrutide started at 2 mg, and the dose rose every four weeks up to the target dose.
The trial lasted 80 weeks, about a year and a half. It is important to note that this was an open-label trial: participants and doctors knew which drug each person received.
Retatrutide vs Ozempic: blood sugar results
At the start, average HbA1c was 8.3%. After 80 weeks, both doses of retatrutide lowered it by an average of 2.2 percentage points. With Ozempic, the average drop was 1.8 percentage points.
In other words, both drugs greatly improved blood sugar control, and retatrutide’s advantage on blood sugar was relatively small. At 12 mg, the advantage passed the trial’s strict statistical test. At 9 mg, the researchers showed that the drug is not inferior to Ozempic. However, the advantage of this dose was only nominally significant, meaning without the full statistical correction.
Weight loss with retatrutide vs Ozempic: more than double
At the start, average weight was 102.4 kg, and average BMI was 36.8. Here the difference between the drugs stood out:
Retatrutide 12 mg: a 20.9% drop in body weight, 21.5 kg on average.
Retatrutide 9 mg: a drop of 19.5%, 20.1 kg on average.
Ozempic 2 mg: a drop of 9.4%, 9.5 kg on average.
To illustrate, for a person weighing 100 kg, a 20.9% drop equals about 21 kg, and a 9.4% drop equals about 9 kg. At both doses, retatrutide’s weight advantage was statistically significant.
Moreover, compared with Ozempic, retatrutide also improved several heart risk markers. These included non-HDL cholesterol, the total cholesterol carried in “bad” particles, triglycerides and systolic blood pressure. The company has not yet released the exact figures for these measures.
Why does weight loss matter so much in diabetes?
People with type 2 diabetes usually find it hard to lose weight, even with medication. That makes this result especially interesting. It also fits the TRIUMPH-2 trial, in which people with diabetes and obesity lost an average of 20.8% of their weight at the high dose. I described those data in an article on retatrutide and diabetes.
Beyond that, substantial weight loss improves the body’s sensitivity to insulin and makes blood sugar easier to control. You can read about the close link between the two in my guide to obesity and type 2 diabetes.
Retatrutide vs Ozempic: side effects
As with other drugs in this family, the common side effects were gastrointestinal. Here are the rates for retatrutide 9 mg and 12 mg, compared with Ozempic:
Diarrhea: 28.3% and 32.7%, compared with 26.4%.
Nausea: 21.2% and 23.8%, compared with 21.3%.
Constipation: 14.2% and 13.1%, compared with 19.8%.
Vomiting: 10.2% and 15.0%, compared with 13.2%.
Indigestion: 10.4% and 8.5%, compared with 11.6%.
In addition, dysesthesia occurred in 4.8% and 6.5% of patients on retatrutide, compared with 2.7% on Ozempic. This means an unpleasant or abnormal skin sensation, such as tingling or sensitivity to touch. Urinary tract infections occurred in 5.8% and 4.2%, compared with 5.8%.
Most side effects were mild to moderate and resolved during treatment. On the other hand, 4.8% and 7.9% of patients on retatrutide stopped treatment because of side effects, compared with 2.7% on Ozempic. At the high dose, the discontinuation rate was almost three times higher. I wrote another guide on GLP-1 side effects and how to ease them.
What should you know before drawing conclusions?
First, these are preliminary results from a company press release. The full paper has not yet been peer reviewed, and the researchers will present the data at a medical meeting later.
Second, the data describe the efficacy estimand. This is a calculation of what would have happened if all participants had stayed on treatment for 80 weeks. In practice, some patients stop treatment, so the result across all participants may be slightly lower.
Third, the trial was open-label, and everyone knew the treatment. Finally, the trial compared retatrutide with Ozempic 2 mg, the highest approved dose for diabetes. A direct comparison with Mounjaro is still under way in the TRIUMPH-5 trial.
Can you get retatrutide today?
No. Retatrutide has not been approved by the FDA or by any other regulator in the world. According to Lilly, anyone selling it to the public is breaking the law.
So it is important to beware of websites and social media accounts offering “retatrutide” for sale. Such products are unregulated, and no one knows what they really contain. Meanwhile, approved and effective drugs are available today, including Ozempic, Wegovy and Mounjaro.
Retatrutide vs Ozempic: what does it mean for you?
If you are taking Ozempic and are well controlled, there is no reason to change anything because of this trial. Retatrutide is not yet available, and Ozempic also showed a meaningful drop in blood sugar and weight here.
Still, the results point in a clear direction. If retatrutide is approved, one drug may give people with diabetes both good blood sugar control and major weight loss. Ultimately, treatment is always chosen individually, together with your doctor, based on each patient’s medical situation and goals.
The bottom line
In the head-to-head comparison of retatrutide vs Ozempic, the new drug lowered HbA1c by 2.2 percentage points compared with 1.8. Weight loss reached up to 20.9%, compared with 9.4%. On the other hand, at the high dose the discontinuation rate due to side effects was higher than with Ozempic. These are preliminary results for a drug that is not yet approved, so we will wait for the full publication.
This article provides general information and is not personal medical advice. For any question about your treatment, please consult your doctor.
References
Eli Lilly, the maker of retatrutide, funded the trial.
