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There is much buzz in the media this week about the press release results of the head-to-head trial of tirzepatide (Zepbound/Mounjaro) compared to a treatment currently under investigation for obesity (not yet available), called CagriSema. CagriSema is actually a combination of two medications: semaglutide (Wegovy, aka Ozempic) and cagrilintide, an amylin analog. (more on amylin blogged here)

The REDEFINE-4 study was a head-to-head, randomized, open label trial (everyone knew what they were taking), comparing the weight loss efficacy of CagriSema 2.4mg/2.4mg weekly vs maximum dose tirzepatide (15mg weekly). The trial included 809 people with obesity, with BMI of at least 30 kg/m2 (mean baseline body weight was 114.2kg). At 84 weeks, weight loss was 20.2% with CagriSema, compared to 23.6% with tirzepatide.

Let’s take a beat here, and rather than simply compare these results, contextualize them. We know that with greater weight loss, say from 5% to 10% to 15%, there are greater health benefits. But for many people, even 10% weight loss is plenty, and more is not needed. So given that we are in the neighborhood of 20%+ weight loss with both treatments, while there are some people who may benefit from more weight loss, most people would likely benefit from either treatment. As new and emerging medications seem to be shooting for greater and greater weight loss, let’s not lose track of an important point: in treating obesity, it should be about the health gains, not the weight loss.

As we await the full results of this trial, one thing I really want to know is, how did the medications compare on health benefits, like lowering of blood pressure, blood sugar, cholesterol, and inflammation? I also want to know how people fared regarding tolerability of each medication, as gastrointestinal side effects of GLP1-based medications can be a limitation for some people. I would also like to know more about the quality of weight loss with each medication, whether there is any difference in muscle vs fat loss, or bone loss.

On the note of potential health gains with these medications, tirzepatide has shown benefit to treat type 2 diabetes, obstructive sleep apnea, MASH (formerly ‘fatty liver disease’), heart failure (HFpEF), and prevention of type 2 diabetes (see full details on these benefits in our Obesity Canada 2025 Pharmacotherapy Clinical Practice Guideline – disclosure, I am the lead author). CagriSema is being studied as a potential treatment for type 2 diabetes. Both treatments are being evaluated in cardiovascular outcome trials to see if they may reduce the risk of heart attacks and strokes in people living with obesity.

BOTTOM LINE: Both CagriSema and tirzepatide (Zepbound/Mounjaro) each facilitated an average of more than 20% weight loss in people with obesity. While tirzepatide provided a few percent greater weight loss, more important aspects to differentiate medications are improvements in health, quality of weight loss, and tolerability. I look forward to the full trial results, and to additional future study results!

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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