Cagrilintide

If you think the emergence of GLP-1 therapies has been exciting, there is another hormone that I think deserves just as much attention as we look toward the future of obesity treatment.

And that hormone is amylin.

We’ve spent the last several years talking about semaglutide, tirzepatide, and the incredible changes we’ve seen with medications targeting incretin pathways. But researchers are now looking at yet another biological system that plays an important role in hunger, satiety, and body-weight regulation.

That brings us to cagrilintide.

Cagrilintide is a long-acting amylin analogue being developed for the treatment of obesity. And while it is particularly interesting because of its combination with semaglutide in a medication called CagriSema, I actually want to start by understanding cagrilintide itself.

First, let’s talk about amylin

So, what exactly is amylin?

Amylin is a hormone produced by the beta cells of the pancreas. These are the same cells that produce insulin, and the two hormones are actually released together in response to food intake.

We tend to think of insulin as the major hormone involved in what happens after we eat, but amylin has an important role too.

While insulin helps regulate blood glucose, amylin helps regulate the amount of food we eat and how our bodies respond to a meal.

It communicates with areas of the brain involved in appetite regulation, promotes feelings of fullness, slows gastric emptying, and helps regulate post-meal glucagon secretion.

In other words, amylin is part of the body’s natural system for telling us when we’ve eaten enough.

And that’s important because hunger and satiety are not simply behavioral issues. They are regulated by an incredibly complex network of hormones and neurological signals.

This is one of the reasons obesity is so difficult to treat. The body has multiple mechanisms designed to regulate energy intake and defend body weight.

So, researchers began asking an interesting question: What if we could use the amylin pathway therapeutically to help regulate appetite and body weight?

Cagrilintide

This is where cagrilintide comes in.

Cagrilintide is a synthetic, long-acting analogue of amylin. It was designed to mimic some of the actions of naturally occurring amylin but to remain active much longer.

Unlike the natural hormone, which is released around mealtimes, cagrilintide is designed to be administered once weekly.

It acts on amylin-related receptor systems, including receptors involving the calcitonin receptor and receptor activity-modifying proteins.

And what does that actually mean for the patient?

The goal is to increase satiety, decrease hunger, reduce food intake, and ultimately help people lose weight.

I think what’s important here is that cagrilintide is not simply another version of a GLP-1 medication. It is targeting a different hormonal pathway.

And that brings us to an important distinction.

How is cagrilintide different from Wegovy?

Let’s compare cagrilintide with semaglutide, the active medication in Wegovy.

Semaglutide works by activating GLP-1 receptors. It influences appetite, food intake, gastric emptying, and glucose regulation.

Cagrilintide works through amylin-related receptors, influencing appetite and satiety through a different signaling system.

Both medications can reduce food intake, but they do not accomplish this through identical mechanisms.

I like to think of it as two different hormonal messages communicating with the brain and gastrointestinal system.

One is the GLP-1 pathway. The other is the amylin pathway.

But before we get to the combination, let’s look at what cagrilintide can accomplish by itself.

What happens when we use cagrilintide alone?

In an important Phase 2 clinical trial, researchers evaluated different doses of cagrilintide in people with overweight or obesity.

The highest dose studied, 4.5 mg weekly, produced approximately 10.8% weight loss over 26 weeks.

That was an encouraging finding because it demonstrated that activating the amylin pathway alone could produce meaningful weight reduction.

But here’s something important.

Cagrilintide alone did not outperform semaglutide in the later head-to-head Phase 3 REDEFINE 1 trial.

At 68 weeks, the treatment-policy estimates showed approximately 11.8% weight loss with cagrilintide, compared with 16.1% with semaglutide.

So, naturally, we have to ask: If cagrilintide produces less weight loss than Wegovy, why is it generating so much interest?

I think this is probably the most important question in understanding the development of this medication. 

The answer is that its potential value may be less about replacing GLP-1 therapy and more about complementing it. We know that obesity involves multiple overlapping biological systems, so targeting more than one system may produce additional benefits.

And that’s exactly what led to CagriSema.

CagriSema: Combining two different hormonal pathways

CagriSema is the combination of cagrilintide and semaglutide in a once-weekly injection.

The concept is relatively straightforward.

Why target only one hormonal pathway when we know that several systems are involved in appetite regulation?

Semaglutide activates GLP-1 receptors, while cagrilintide adds amylin-related activity.

The hope is that these two complementary mechanisms will provide greater appetite regulation and more substantial weight reduction than either medication alone.

And the clinical results have been encouraging.

In the REDEFINE 1 Phase 3 trial, which included people with overweight or obesity without diabetes, CagriSema produced approximately 20.4% average weight loss at 68 weeks using the treatment-policy analysis.

In the treatment-adherent analysis, weight loss was approximately 22.7%.

For comparison, semaglutide alone produced approximately 16.1% weight loss in the treatment-policy analysis.

So we are seeing evidence that adding the amylin pathway can produce additional weight reduction.

But I don’t think we should stop the discussion at the number on the scale.

There are several other questions worth exploring.

Why would someone choose CagriSema over Wegovy?

Let’s imagine a patient who is already taking Wegovy.

They’re losing weight, their appetite is better controlled, and their metabolic health is improving.

Why would we consider a combination medication?

Well, one reason might be that the patient has reached a weight-loss plateau or hasn’t achieved the degree of weight reduction needed to improve their obesity-related complications.

By activating another appetite-regulating pathway, CagriSema may offer additional weight-loss potential.

But we also have to consider the possibility that some patients will do very well with semaglutide alone and won’t need the additional medication.

More treatment isn’t automatically better treatment.

The real question is identifying which patients are most likely to benefit from the combination.

And this is where I think future research will become particularly important.

Beyond weight loss: What about body composition?

One of the things I really want us to pay attention to with these newer medications is body composition.

We’ve become very focused on percentages of weight loss. We hear about 15%, 20%, or even 25% weight reduction.

But what exactly are patients losing?

When someone loses a substantial amount of weight, they can lose both fat mass and lean mass, including skeletal muscle.

Muscle plays a critical role in metabolic health, glucose regulation, mobility, strength, and healthy aging. That’s why resistance training should be an essential, non-negotiable part of any weight-loss program involving GLP-1 medications. The goal isn’t just to lose weight; it’s to lose fat while preserving as much muscle as possible.

So I think we need to start asking a different question.

Are these medications simply helping people become lighter, or are they helping people become metabolically healthier?

Are they reducing visceral fat? Are they preserving muscle? Are patients maintaining physical function?

These questions are particularly relevant as we move toward combination treatments.

Interestingly, at the September 2026 European Association for the Study of Diabetes meeting, Novo Nordisk presented additional CagriSema findings that went beyond weight loss.

The company reported exploratory findings involving reductions in harmful fat around abdominal organs, including the liver and pancreas, and preliminary findings suggesting that bone health was maintained despite substantial weight loss.

There were also interesting brain-imaging findings suggesting changes in how participants responded to tempting, high-calorie foods.

The researchers described this in terms of reducing what is commonly called food noise.

Now, these findings are interesting, but we need to remember that they are still emerging research. They don’t establish that CagriSema preserves muscle or provides independent protection against bone loss or organ disease.

Nevertheless, they suggest that the next generation of obesity research is looking at much more than body weight.

What about cardiovascular and metabolic benefits?

Another question is whether targeting the amylin pathway can provide benefits beyond weight reduction.

We already know that semaglutide has demonstrated cardiovascular benefits in appropriate patient populations.

But will combining it with cagrilintide provide additional cardiovascular protection?

That remains an important question.

The REDEFINE 3 study is investigating cardiovascular outcomes in approximately 7,000 people with established cardiovascular disease, with or without type 2 diabetes.

Researchers are evaluating whether CagriSema can reduce major cardiovascular events.

This is important because we cannot assume that greater weight loss automatically translates into greater cardiovascular protection.

We need dedicated cardiovascular outcome studies to establish that benefit.

We should also consider improvements in glucose control, blood pressure, waist circumference, and other metabolic parameters.

These may all contribute to better long-term health, but we need to understand how much is attributable to the medication itself and how much is a consequence of weight reduction.

What is happening with CagriSema right now?

This is particularly interesting because CagriSema has moved well beyond the early stages of development.

Novo Nordisk submitted a New Drug Application to the FDA in December 2025 for weight management, with an FDA decision expected in the fourth quarter of 2026.

As of November 2026, that regulatory decision is still an important near-term milestone.

The company is also continuing its Phase 3 research program.

One particularly interesting direction is the investigation of different doses.

Researchers are looking at whether lower doses could provide meaningful weight reduction with potentially better tolerability, and whether higher doses could produce even greater weight loss.

A higher-dose combination of cagrilintide and semaglutide has also entered Phase 3 development.

There are additional studies investigating long-term weight maintenance and body composition.

So, the story is not finished with the initial REDEFINE results.

We are now trying to understand how to optimize the treatment, who should receive it, and what the long-term benefits might be.

Cagrilintide is not the only amylin-based medication in development

And this is where the pipeline becomes particularly exciting.

Cagrilintide is part of a much broader interest in amylin-based treatments.

There are several other investigational medications worth following.

One is petrelintide, being developed by Zealand Pharma in collaboration with Roche.

Petrelintide is another long-acting amylin analogue, but it is being investigated as a potential standalone obesity treatment rather than a component of a GLP-1 combination like CagriSema.

Its Phase 2 results have been interesting.

In the ZUPREME-1 study, petrelintide produced up to approximately 10.7% weight reduction at week 42.

What’s particularly interesting is its reported gastrointestinal tolerability profile, with relatively infrequent vomiting and very few treatment discontinuations due to gastrointestinal adverse effects.

The company plans to advance petrelintide into Phase 3 development.

Why is this important?

Because researchers are interested in whether amylin-based medications might eventually provide an alternative for patients who do not tolerate incretin-based treatments well, or who may benefit from a different approach to appetite regulation.

That is a possibility worth investigating, although we need direct comparative trials before drawing conclusions about tolerability or effectiveness relative to GLP-1 medications.

Another medication worth watching is eloralintide.

Eloralintide is an investigational amylin receptor agonist being developed by Eli Lilly.

In Phase 2 research, it demonstrated substantial weight reduction, with results reaching approximately 20.1% at 48 weeks in one study.

And then there’s zenagamtide, which was previously known as amycretin.

This is a different approach because it combines GLP-1 and amylin receptor activity in a single molecule.

Rather than administering two separate compounds, researchers are developing one molecule designed to activate both pathways.

Early studies have produced promising weight-loss results, but it remains investigational and needs larger, longer clinical trials.

So we’re beginning to see several different strategies emerge.

We have amylin analogues used alone, combinations of amylin and GLP-1 medications, and single molecules designed to activate both pathways.

I think this is a very important development in obesity medicine.

What are the questions we should be asking going forward?

When I look at this entire area of research, I think there are several questions that will determine the future of amylin-based treatment.

First, will cagrilintide have a meaningful role as a standalone treatment, or will its greatest clinical value be in combination with GLP-1 medications?

Second, which patients are most likely to benefit from targeting both pathways?

Third, can we achieve greater weight reduction while preserving muscle mass and physical function?

Fourth, will these medications provide benefits beyond weight loss, particularly in cardiovascular and metabolic health?

Fifth, could amylin-based treatments eventually offer an alternative for patients who have difficulty tolerating existing GLP-1 therapies?

And finally, how durable will the weight-loss results be over several years?

These are the questions that matter much more than simply comparing percentages of weight loss between medications.

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