By Dr. Asnat Raziel, bariatric surgeon specializing in obesity treatment, metabolic health and healthy longevity; Director of the Multidisciplinary Center for Obesity Treatment, Assia Medical, Assuta Ramat HaChayal, Tel Aviv
REDEFINE trials: what they test and why it matters
The REDEFINE trials are a series of phase 3 clinical trials testing CagriSema, a once-weekly injection for obesity. In the main trial, participants lost an average of 20.4% of their body weight within 68 weeks. However, in a head-to-head comparison with Mounjaro, the drug fell short of its goal. In this article, I will go through the trials one by one: who took part, what was tested, what came out, and where things stand today.
I have previously written a general review of the CagriSema research. This time the goal is different: an organized guide to each trial, with the exact numbers from the publications themselves.
What is CagriSema and how does it work?
CagriSema combines two drugs in a single weekly injection. The first is semaglutide at 2.4 mg, the active ingredient in Wegovy. The second is cagrilintide at 2.4 mg, a long-acting analog of the hormone amylin. The pancreas releases amylin together with insulin, and it slows stomach emptying and increases the feeling of fullness.
The idea is simple: two different satiety pathways working together. I discuss the drug itself, and how it differs from other injections, in my article on CagriSema. You will also find a summary in the CagriSema entry on Wikipedia.
REDEFINE 1 and 2 trials: the key results
REDEFINE 1: obesity without diabetes
The trial enrolled 3,417 adults with obesity, or with overweight and a related condition, without diabetes. Researchers randomly assigned them to CagriSema, semaglutide alone, cagrilintide alone or placebo, alongside lifestyle support. According to the NEJM publication, after 68 weeks, weight fell by an average of 20.4% in the CagriSema group, compared with 3.0% on placebo.
Among those who stayed on treatment, weight loss reached 22.7%. In addition, about 35 in every 100 participants lost 25% or more of their weight. It is worth knowing that investigators could keep patients on a dose below the maximum if they felt this was better for them. The company published these numbers in its announcement of the REDEFINE 1 results.
REDEFINE 2: obesity and type 2 diabetes
The REDEFINE 2 trial included 1,206 adults with type 2 diabetes and a BMI of 27 or more. After 68 weeks, weight fell by 13.7% with CagriSema, compared with 3.4% on placebo. Smaller weight loss in diabetes is familiar from other drugs, too. On the other hand, 73.5% of patients reached an HbA1c (glycated hemoglobin, the average blood sugar over the past three months) of 6.5% or less, compared with 15.9% on placebo.
REDEFINE 4: a head-to-head test against tirzepatide
This is the trial that drew the most interest. A total of 809 adults with obesity received either CagriSema or tirzepatide, the active ingredient in Mounjaro, at 15 mg. The trial was open-label, meaning everyone knew which drug they were getting, and it lasted 84 weeks.
According to the company’s February 2026 announcement, among those who stayed on treatment, weight loss was 23.0% with CagriSema and 25.5% with tirzepatide. In the analysis of all participants, the results were 20.2% versus 23.6%. So the trial missed its primary goal: to show that CagriSema is not inferior to tirzepatide. I have written a full analysis comparing CagriSema with tirzepatide.
REDEFINE 5: a comparison with semaglutide alone
This trial took place in Japan and Taiwan, with 331 participants, some of them with diabetes. It was double-blind, and it tested whether adding cagrilintide gives more than semaglutide alone. According to the publication in Lancet Diabetes & Endocrinology, weight loss after 68 weeks was 18.4% with CagriSema, compared with 11.9% with semaglutide alone. In other words, adding amylin contributed about 6.5 percentage points.
REDEFINE trials still under way
First, REDEFINE 3 is a cardiovascular outcomes trial. It includes about 7,000 adults with established cardiovascular disease, and it tests CagriSema’s effect on cardiac events compared with placebo. The results have not been published yet. Second, the company reported in September 2026, in the same release as the REIMAGINE 5 results, on REDEFINE 9: at a low dose of 1.0 mg of each component, weight loss reached 21.0%, compared with 2.0% on placebo. Finally, other trials such as REDEFINE 8 and REDEFINE 11 are testing even longer treatment.
Side effects in the REDEFINE trials
As with all drugs in this family, the common side effects involved the digestive system. In REDEFINE 1, 79.6% of patients on CagriSema reported them, compared with 39.9% on placebo. Nausea occurred in about 55 out of 100 patients, constipation in about 31 and vomiting in about 26. Most of these effects were mild to moderate and eased over time.
In addition, 6% stopped treatment because of side effects, compared with 3.7% on placebo. In REDEFINE 2, the rate was 8.4% versus 3%. So, as with any treatment of this kind, gradual dose escalation and close medical follow-up are very important.
Where CagriSema stands today
The company submitted an application for FDA approval in December 2025, based on REDEFINE 1 and REDEFINE 2. According to a company update from September, a decision is expected by the end of 2026. For now, CagriSema is still an investigational drug. No country has approved it, and it is not available in Israel.
Meanwhile, patients have approved and effective options. You will find an overview of the current drugs on my page about drug treatment for obesity and metabolic disease. If this direction interests you, you can also read about the next generation of amylin drugs.
What the REDEFINE trials mean for patients
First, combining amylin with GLP-1 works. It added weight loss beyond semaglutide alone, and at the full dose it reached about 20% on average. Second, in a direct comparison, tirzepatide came out ahead by a small margin. Third, the side effects resemble those of the familiar weight-loss injections. That said, an average is only an average: some patients respond better to one drug, and others to another.
The bottom line
The REDEFINE trials show a highly effective drug, with average weight loss of about 20% and a status that is still under review. It did not overtake tirzepatide, but it adds a new mechanism of action to the toolbox. The choice of treatment should be personal, based on your medical conditions, side effects and availability. If you are considering drug treatment, talk with Dr. Asnat Raziel or your own doctor.
The information in this article is general and does not replace personal medical advice.
Frequently asked questions
When will CagriSema reach Israel?
There is no date yet. A US decision is expected by the end of 2026. After such an approval, Israel’s Ministry of Health will review the application separately.
How do the REDEFINE trials differ from the STEP trials?
The STEP trials tested semaglutide alone, meaning Wegovy. The REDEFINE trials, by contrast, test semaglutide combined with cagrilintide.
Is CagriSema better than Mounjaro?
Not according to REDEFINE 4. In a direct comparison, weight loss with tirzepatide was greater by about 2.5 to 3.4 percentage points, depending on the method of analysis.
Can I join one of the REDEFINE trials?
Some of the trials are still active in various countries. Ask your doctor whether there is a suitable research center.
Sources
Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity
Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes
Novo’s CagriSema delivers superior weight loss versus tirzepatide in REIMAGINE 5 trial
REDEFINE 3: CagriSema cardiovascular outcomes trial in participants with CVD
REDEFINE 2 – CagriSema effect in people with obesity and Type 2 diabetes
