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
The TRANSCEND trial: the first head-to-head test of retatrutide
The TRANSCEND trial known as TRANSCEND-T2D-2 is the first direct comparison of retatrutide with another drug from the incretin family. On October 28, Eli Lilly released the topline results. In people with type 2 diabetes, retatrutide lowered blood sugar slightly more than Ozempic 2 mg. In contrast, weight loss was more than twice as large.
I already covered the main results in an earlier article. Here I want to look at what they mean in the clinic. What do the numbers tell a doctor treating diabetes and obesity? And what do they tell a patient weighing the options?
What did the TRANSCEND-T2D-2 trial test?
The trial enrolled 1,298 adults with type 2 diabetes. All of them were taking metformin, and some also took an SGLT2 inhibitor. Even so, their blood sugar was not under control. HbA1c, or glycated hemoglobin, reflects average blood sugar over the past few months. In these participants it ranged from 7.0% to 10.5%.
The researchers randomly assigned participants in a 2:2:1 ratio. The groups received retatrutide 9 mg, retatrutide 12 mg or Ozempic 2 mg, as a weekly injection. Retatrutide started at 2 mg, and the dose rose every four weeks to the target dose. The trial lasted 80 weeks, and the full details are listed on ClinicalTrials.gov.
The primary goal was fairly modest: to show that retatrutide 12 mg is not inferior to Ozempic in lowering blood sugar. In addition, the trial was open-label, meaning participants and doctors knew which drug was given.
Blood sugar control: a gap of 0.4 percentage points
At the start, average HbA1c was 8.3%. After 80 weeks, both retatrutide doses lowered it by 2.2 percentage points. Ozempic lowered it by 1.8 percentage points. So the gap between the drugs was 0.4 percentage points.
Clinically, both drugs work very well on blood sugar. At 12 mg, retatrutide’s advantage passed the trial’s full statistical control. At 9 mg, however, the advantage was only nominally significant, without correction for multiple testing. Therefore, for most patients the choice between the two will not rest on blood sugar alone.
Body weight: this is where the real gap lies
Average starting weight was 102.4 kg, and average BMI was 36.8. Retatrutide 12 mg reduced body weight by 20.9%, or 21.5 kg on average. At 9 mg, weight fell by 19.5%, or 20.1 kg. With Ozempic, weight fell by 9.4%, or 9.5 kg.
Put simply, the average patient on retatrutide 12 mg lost about 12 kg more than a patient on Ozempic. That is a large gap by any standard. Moreover, retatrutide also improved non-HDL cholesterol, the total cholesterol carried in “bad” particles, as well as triglycerides and systolic blood pressure, more than Ozempic did. However, the company has not yet released the figures for these measures.
The TRANSCEND trial in the wider context
These results are consistent with earlier data. In phase 2, a trial published in The Lancet showed a meaningful drop in both blood sugar and weight in people with diabetes. Then came the TRANSCEND-T2D-1 trial, against placebo, over 40 weeks. There, HbA1c fell by up to 2.0% and weight by up to 16.8%.
In addition, in the TRIUMPH-2 trial people with diabetes and obesity lost 20.8% of their weight at the highest dose. I described those data in an article on retatrutide and diabetes. In other words, across several trials, people with diabetes lose around 20% of their weight. This matters, because people with diabetes are known to find weight loss especially hard.
Safety and tolerability: what doctors should watch
As with other drugs in this family, the most common side effects were gastrointestinal. Diarrhea occurred in 28.3% and 32.7% of patients on retatrutide (9 mg and 12 mg), compared with 26.4% on Ozempic. Nausea occurred in 21.2% and 23.8%, compared with 21.3%. Interestingly, constipation was actually less common: 14.2% and 13.1%, compared with 19.8%.
Vomiting occurred in 10.2% and 15.0%, compared with 13.2%. Indigestion occurred in 10.4% and 8.5%, compared with 11.6%. Most of these effects were mild to moderate and resolved during treatment.
Treatment discontinuation
For the clinic, the key figure is the discontinuation rate. Of patients on retatrutide, 4.8% and 7.9% stopped because of side effects, compared with 2.7% on Ozempic. At 12 mg, the gap is 5.2 percentage points. As a rough calculation, for about every 19 patients on the high dose, one more will stop treatment. So careful dosing and gradual titration will be crucial.
Dysesthesia: a recurring signal
Dysesthesia is an abnormal, unpleasant skin sensation, such as tingling or sensitivity to touch. It occurred in 4.8% and 6.5% of patients on retatrutide, compared with 2.7% on Ozempic. In TRANSCEND-T2D-1 it also appeared in 2.3% to 4.5% of patients, compared with 0% on placebo. Therefore, it is worth asking about it directly and watching for it in the full publication.
How to read the TRANSCEND trial correctly
First, these data come from a press release. The full paper has not yet been peer reviewed. Second, all the figures use the efficacy estimand. This estimates what would have happened if all participants had stayed on treatment for 80 weeks, without adding other diabetes drugs. In practice, some patients stop, so the result across all participants may be slightly lower.
Third, the trial was open-label. For objective endpoints such as weight and HbA1c, this matters less. On the other hand, for subjective side effects, knowing the treatment may influence reporting. Finally, the comparator was Ozempic 2 mg, the highest approved dose for diabetes. It was not Wegovy at the 7.2 mg dose, and it was not Mounjaro.
The TRANSCEND trial and what it means in the clinic
If retatrutide is approved, it may suit people with diabetes whose obesity is also significant. For them, losing about 20% of body weight could change the whole metabolic picture. In contrast, a patient who is well controlled on Ozempic and happy with their weight has no reason to change anything.
There are several questions the trial does not answer. Participants took metformin, with or without an SGLT2 inhibitor. So there are no data here on patients taking insulin or a sulfonylurea. In addition, losing about 20% of body weight requires attention to preserving muscle. I wrote about lean body mass during weight loss in detail. The approach of treating to target is also relevant: not every patient needs the highest dose.
What is still missing?
We will need the full publication to see the treatment-regimen estimand, which also counts those who stopped treatment. Rates of reaching HbA1c targets, hypoglycemia data and body composition are also missing. In addition, about 650 participants are continuing for another 24 weeks in an extension period.
The next big question is a direct comparison with Mounjaro. The TRIUMPH-5 trial, which is still ongoing, will answer it. To understand the drug’s triple mechanism, see my complete guide to this investigational drug.
What about patients who want retatrutide now?
Retatrutide is not approved anywhere in the world. According to Lilly, anyone selling it to the public is breaking the law. Products sold online are not regulated, and no one knows what they contain. Meanwhile, approved and highly effective treatments for diabetes and obesity are already available.
Bottom line on the TRANSCEND trial
In short, the TRANSCEND trial shows that in type 2 diabetes, retatrutide’s advantage over Ozempic 2 mg is small for blood sugar but very large for weight loss. The trade-off is a higher discontinuation rate at 12 mg and a dysesthesia signal that needs monitoring. 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 trials.
