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
Low-dose CagriSema: what the new trial found
Low-dose CagriSema led to an average weight loss of 21.0% over 68 weeks. In the placebo group, average weight loss was just 2.0%. These are the first results of the REDEFINE 9 trial, which Novo Nordisk announced in September. The possible implication is striking: substantial weight loss with much less medication. Still, these are early figures from a company announcement, and the full results will be presented at ObesityWeek in mid-November.
What is CagriSema and how does it work?
CagriSema is a once-weekly injection that combines two medicines. The first is semaglutide, the active ingredient in Wegovy and Ozempic. Semaglutide mimics GLP-1, a gut hormone that increases fullness and slows stomach emptying. The second is cagrilintide, a long-acting version of the hormone amylin.
Amylin is released by the pancreas together with insulin after a meal. It also signals the brain that it is time to stop eating. As a result, the combination works on two satiety pathways at once. Keep in mind that CagriSema is still investigational. To date, no regulator anywhere has approved it.
REDEFINE 9: who took part and what was tested
REDEFINE 9 is a phase 3, placebo-controlled trial in adults with obesity or overweight. The researchers tested two doses of CagriSema: 1.0 mg / 1.0 mg and 1.7 mg / 1.7 mg. All participants combined treatment with a reduced-calorie diet and increased physical activity. Treatment lasted 68 weeks.
For comparison, the full dose in earlier trials is 2.4 mg / 2.4 mg. In other words, the lowest dose in REDEFINE 9 contains less than half of each component. The trial had two main endpoints: percentage change in body weight, and the share of participants who lost at least 5% of their weight.
Low-dose CagriSema results
At 1.0 mg / 1.0 mg, participants lost an average of 21.0% of their body weight, compared with 2.0% on placebo. This figure comes from the efficacy estimand. That analysis looks at what happens when participants stay on treatment as planned. With this result, the trial met its primary goal of superiority over placebo.
Treatment also improved systolic blood pressure compared with placebo. It improved waist-to-height ratio and fasting blood lipids as well. However, the company has not yet released numbers for these measures. Nor has it released the results for the 1.7 mg / 1.7 mg dose.
In simple numbers
For example, a person weighing 100 kg who stayed on treatment lost about 21 kg on average. By contrast, the placebo group lost about 2 kg on average. An average does not predict any one person’s result: some patients lose a lot, and some lose less.
Why low-dose CagriSema matters
The REDEFINE 1 trial, which tested the full dose, enrolled 3,417 adults. In the analysis of participants who stayed on treatment, they lost an average of 22.7% of their weight after 68 weeks. The placebo group lost 2.3%.
At first glance, the low dose achieved a similar result. But two separate trials can’t be compared directly. Each one enrolled a different population, and trial conditions were not identical. Only the full data, and especially a comparison within the same trial, will show the real difference between doses.
If the finding holds up, some patients may one day do well on a lower dose. For example, a lower dose may suit people who are sensitive to side effects. Likewise, it may suit people who don’t need maximal weight loss. This is the same idea behind treat-to-target dosing, where the dose is matched to each patient’s goal.
What we know about safety
According to Novo Nordisk, low-dose CagriSema was well tolerated, and its safety profile matched earlier trials. However, the company has not yet released side-effect rates. For comparison, in REDEFINE 1 at the full dose, 79.6% of participants reported gastrointestinal side effects. In the placebo group, the rate was 39.9%.
Nausea, constipation and diarrhea are the common side effects of this drug family. In earlier CagriSema trials, most gastrointestinal effects were mild to moderate and eased over time.
Low-dose CagriSema in diabetes: REIMAGINE 5
On the same day, Novo Nordisk also announced results from REIMAGINE 5, in adults with type 2 diabetes. The trial compared CagriSema 1.0 mg / 1.0 mg with Mounjaro (tirzepatide) 5 mg. After 60 weeks, weight loss was 12.4% with CagriSema versus 9.1% with tirzepatide.
In addition, HbA1c fell by 1.71% with CagriSema versus 1.67% with tirzepatide. HbA1c reflects average blood sugar over the past three months. So blood sugar control was similar, while weight loss was considerably greater.
What this means for patients
For now, CagriSema is not available, because no regulator has approved it yet. So it makes sense to see these data as a promising direction, not a treatment you can get today. I explain what to do while waiting for CagriSema and how it works in women during menopause in separate articles. Meanwhile, effective approved medicines already exist, such as Wegovy, Mounjaro and Foundayo. In my clinic, I choose the right medication together with each patient, based on their health and goals.
What’s more, any significant weight loss calls for protecting muscle. That’s why I recommend enough protein and regular strength training alongside medication.
The bottom line
In REDEFINE 9, low-dose CagriSema produced an average weight loss of 21.0%, compared with 2.0% on placebo. If the full results confirm this, we may gain an effective option at a lower dose. Researchers will present the full data on November 15 at ObesityWeek in Washington, D.C., and I will update this article with what was shown.
This article provides general information and is not a substitute for personal medical advice. Talk to your doctor before making any change to your treatment.
References
Novo’s CagriSema delivers superior weight loss versus tirzepatide in REIMAGINE 5 trial
Adults with obesity lost 22.7% of body weight with combination GLP-1/amylin analog
Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity
