Our natural human biology vigourously defends our body weight, in part because we have many fullness (satiety) hormones that drop with weight loss. In the quest to develop new, innovative, and highly effective homone-based weight management medications, it makes sense to combine more than one satiety hormone to facilitate greater weight loss and improve weight-related health issues. GLP1 receptor agonists have now been available for several years as weight loss medications. Amylin is a new player on the scene – it is a satiety hormone released by the pancreas in response to nutrient intake. CagriSema is the first combination treatment of an amylin analogue (cagrilintide 2.4mg weekly) and a GLP1 (semaglutide 2.4mg weekly, aka Wegovy) that has been explored in phase 3 trials.
I was delighted and honored to present the REDEFINE 1 and REDEFINE 2 trial results of CagriSema with colleagues at a symposium today at the American Diabetes Association (ADA) meeting. These results were simultaneously published in the New England Journal of Medicine (disclaimer: I was an investigator in the REDEFINE 2 trial and senior author of that publication).
The REDEFINE 1 trial was a randomized study of 3417 people with BMI ≥ 30 or BMI ≥ 27 with obesity related health complications (without diabetes) , designed to compare the effect on weight of CagriSema 2.4mg/2.4mg (2,108 participants) weekly vs placebo (705 participants). Treatment arms of semaglutide (Wegovy, 302 participants) and cagrilintide (302 participants) were included for an interesting comparison. At 68 weeks, weight loss was 20.4% with CagriSema, 14.9% with semaglutide 2.4mg, 11.5% with cagrilintide, vs 3% with placebo. Weight loss of at least 25% was seen in 35% of people in the CagriSema group – over double than in the other treatment groups – vs 15% of people in the semaglutide group, 7% of people in the cagrilintide group, and 1% of those in the placebo group. Health improvements were seen with CagriSema, including impressive improvements in blood pressure (-9.9mmHg reduction in systolic BP with CagriSema vs -3.2mmHg with placebo), metabolic health parameters, and physical function.
The most common side effects were gastrointestinal, numerically a little more common with CagriSema than in the other treatment groups, and mostly mild to moderate in severity. Nausea, vomiting, and diarrhea were most commonly seen during dose escalation and declined thereafter, whereas constipation didn’t seem to fade. GI side effects with cagrilintide alone were notably less than with either CagriSema or semaglutide, though a little more than placebo. A slightly greater proportion of people in the CagriSema group had hepatobiliary adverse events (eg gallstones). The need to stop treatment due to adverse events/side effects was quite low in all groups (6% with CagriSema, 3.6% with semaglutide, 2.6% with cagrilintide, and 3.7% with placebo).
The REDEFINE 2 trial included 1206 people with BMI ≥ 27 with type 2 diabetes, randomized to receive either CagriSema 2.4mg/2.4mg or placebo (note: cagrilintide and semaglutide were not studied separately in this trial). At 68 weeks, weight loss was 13.7% with CagriSema vs 3.4% with placebo. Weight loss of at least 20% was seen in 29% of people with CagriSema vs 0.2% with placebo. Hemoglobin A1c (diabetes report card) was reduced by 1.8% with CagriSema vs 0.4% with placebo. Our study was the first phase 3 weight management study to include continuous glucose monitoring in a subset of patients, where we found that time in range (percentage of time in good blood sugar control) at the end of the study was 88% with CagriSema vs 51% with placebo. Greater improvements in blood pressure (systolic -6.5mmHg vs -2.4mg with placebo), metabolic health parameters, and physical function were seen with CagriSema.
The most common side effects with CagriSema in REDEFINE 2 were also gastrointestinal, mostly mild to moderate, and transient with dose escalation. The need to stop treatment due to adverse events (mostly gastrointestinal) occurred in 8% of the CagriSema group and 3% of the placebo group. Severe low blood sugars were seen in two people in the CagriSema group – these two patients were also on sulfonylurea, which is a medication known to cause low blood sugar).
In both studies, it’s important to note that there was a great deal of flexibility in dosing of medication, which reflects what we do in clinical practice in the real world. With highly effective weight management medication (including CagriSema), some people will not need the maximum dose. Also, some people may not tolerate the full dose of medication due to side effects (typically gastrointestinal). In REDEFINE 1, 57% of people in the CagriSema group were on the highest dose of treatment of CagriSema (2.4mg/2.4mg) at the end of the 68 week study, and 74% of participants in this group reached the highest dose at any time point in the trial. As discussed in our symposium today, those who ended the REDEFINE 1 trial on lower than the maximum dose of CagriSema had the greatest weight loss, again suggesting that this treatment (like any obesity medication) is variable in its effect from person to person, and we need to individualize dosing accordingly. In REDEFINE 2, 62% of people were receiving the maximum dose of CagriSema 2.4mg/2.4mg, and 76% reached the highest dose at some time point in the trial.
BOTTOM LINE: CagriSema is a combination treatment of amylin analog and GLP1 receptor agonist, which has demonstrated robust and clinically meaningful weight loss and improvement in health parameters, in people with obesity without diabetes, and in people with obesity with type 2 diabetes. The weight loss results are similar to the results in studies of other highly efficacious therapy such as tirzepatide (Mounjaro/Zepbound) in similar patient groups, and tolerability is similar to that of other GLP1-based medications. I look forward to results of studies of CagriSema currently ongoing for potential reduction in cardiovascular events, improvement in nerve pain in people with painful diabetic neuropathy, type 2 diabetes control (including here and here and here), chronic kidney disease, and more! Though not the purpose of the REDEFINE 1 trial, treatment with cagrilintide alone was notable for having good weight loss efficacy and being very well tolerated – with many amylin agonists currently under development, it will be very exciting to see what unfolds in this area as well.
Disclaimer: I am/have been an investigator in clinical trials of cagrilintide, semaglutide , CagriSema, and tirzepatide. I receive honoraria as a continuing medical education speaker and consultant from the makers of cagrilintide, semaglutide, and CagriSema (Novo Nordisk), and tirzepatide (Eli Lilly).
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