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October 2026 Weight & Metabolic 7 min read

Cagrilintide and CagriSema: the amylin route explained

Cagrilintide is the first amylin analogue to reach late-stage development alongside the incretin drugs, and understanding what amylin does explains both why the combination produced larger figures than either component alone and why one of its own trials still came up short.

The short answer

  • Cagrilintide is a long-acting amylin analogue. It is not a GLP-1 receptor agonist and does not work on the same receptor as semaglutide.
  • CagriSema is the fixed combination of cagrilintide 2.4 mg and semaglutide 2.4 mg, given once weekly.
  • Evidence tier: Human trials. There is a phase 1b co-administration study, and three large phase 3 trials in the REDEFINE programme.
  • As of September 2026 CagriSema is not approved. It was submitted to FDA in December 2025 with a decision expected in the fourth quarter of 2026, and it is not authorized in Canada.
  • Cagrilintide on its own is further behind. It has a monotherapy arm in REDEFINE 1 and a high-dose monotherapy phase 3 is planned, but there is no standalone approval anywhere.
  • The results are not uniformly favourable. REDEFINE 4 compared the combination against tirzepatide 15 mg and failed to show noninferiority, per the sponsor’s February 2026 disclosure.

Amylin is the part most people skip

There are four hormones worth knowing in this area, and amylin is the one that gets left out.

GLP-1 comes from intestinal L-cells and acts on GLP-1 receptors in beta cells, brainstem, hypothalamus, stomach, heart and kidney. Its actions are glucose-dependent insulin secretion, glucagon suppression, slowed gastric emptying, and reduced food intake through central pathways. GIP comes from K-cells in the proximal gut. Glucagon comes from pancreatic alpha cells and raises hepatic glucose output, hepatic fat oxidation and energy expenditure.

Amylin is different in origin and route. It is co-secreted with insulin from pancreatic beta cells, and it acts through the calcitonin receptor together with receptor activity-modifying proteins, forming the AMY1 to AMY3 receptor complexes, with an important site of action in the area postrema of the brainstem. Its physiological actions are satiety, slowed gastric emptying, and suppression of postprandial glucagon.

The reason that matters is the pathway, not the effect list. Amylin signals satiety through a route separate from the GLP-1 pathway, in the area postrema and hypothalamus. Combining the two therefore attacks food intake at two independent points rather than pushing harder on one. That was the hypothesis, and the phase 1b co-administration study of cagrilintide with semaglutide 2.4 mg produced additive weight reduction, which is what took the pair into phase 3.

What the REDEFINE trials measured

Three numbers carry the programme, and they should be read as trial results rather than as claims about any individual.

REDEFINE 1, published by Garvey and colleagues, studied co-administered cagrilintide and semaglutide in adults with overweight or obesity. Mean body weight change at 68 weeks was -20.4% versus -3.0% on placebo.

REDEFINE 2, published by Davies and colleagues, ran the same combination in adults with overweight or obesity and type 2 diabetes. Mean body weight change was -13.7% versus -3.4%. The smaller figure in the diabetes population is not a surprise: people with type 2 diabetes lose less weight on every agent in this class, and that pattern is consistent across the GLP-1 trial literature.

REDEFINE 4 is the comparison that complicated the story. It set the combination against tirzepatide 15 mg, reported about 23% at 84 weeks, and failed to demonstrate noninferiority against the comparator, according to the sponsor’s February 2026 disclosure. A trial that produces a large number and still misses its statistical objective is a useful reminder that effect size and trial success are different questions.

For calibration against the drugs already on the market, in trials of 68 to 72 weeks without diabetes, semaglutide 2.4 mg produced about 15%, semaglutide 7.2 mg about 19%, and tirzepatide 15 mg about 21%. So the combination sits at the upper end of the current field rather than in a category of its own. Our three-way comparison sets those figures side by side.

Where cagrilintide stands as of September 2026

United States. CagriSema was submitted to FDA in December 2025, with a decision expected in the fourth quarter of 2026. It is not approved. Cagrilintide as a single agent is not approved either, and a high-dose monotherapy phase 3 was listed among the sponsor’s 2026 milestones.

Canada. Neither cagrilintide nor CagriSema is authorized. There is no Drug Product Database entry, which means no DIN.

That last point is the practical one. Health Canada’s position, stated on 2 June 2025, is that there was no GLP-1 shortage in Canada, that compounding injectable GLP-1 drugs outside unique patient-specific cases is treated as manufacturing and is subject to enforcement, and that the active ingredient must match an authorized product or a pharmacopoeial standard. Health Canada requested recalls of compounded semaglutide-pyridoxine products made with synthetic active ingredient in January 2025, and its advisories have named unauthorized injectable peptides seized from online sellers, with a separate warning about counterfeit GLP-1 products issued 21 January 2026.

Health Canada’s public advisory of 9 April 2026 also states directly that a “for research use only” label does not make a product legal or safe for human use, and that injectable peptides are generally regulated as prescription drugs in Canada. A compound with no DIN and no approval anywhere does not acquire one by being labelled for research.

On the anti-doping side, GLP-1 receptor agonists are not prohibited on WADA’s 2026 Prohibited List, and markers of semaglutide and tirzepatide sit in the 2026 Monitoring Program. Cagrilintide’s own listing status is not something the curriculum records, so athletes should confirm with their anti-doping organisation rather than assume.

Why the amylin route is interesting anyway

Two things make this worth following even with the REDEFINE 4 result in hand.

First, it is a genuinely different receptor. Most of the recent pipeline has been built by adding or subtracting incretin receptor activity: GIP agonism in tirzepatide, glucagon agonism in retatrutide and survodutide, GIP receptor antagonism in maridebart cafraglutide. Amylin is a step outside that family, acting through the calcitonin receptor complex in the brainstem. When a field is stacking variations on one mechanism, an independent mechanism is the thing most likely to add something.

Second, the same idea is being built into a single molecule. Amycretin, also identified as NNC0487-0111 and referred to by the sponsor’s 2026 reports in connection with the AMAZE programme, is a unimolecular agonist at both the GLP-1 receptor and the amylin receptor, in subcutaneous weekly and oral daily forms. Its phase 1b/2a subcutaneous data showed -24.3% at the 60 mg dose over 36 weeks versus -1.1%, and phase 3 began in 2026. That is early-stage evidence in small numbers, and a phase 1b/2a figure is not a phase 3 figure, but it is the reason the amylin pathway is not going away even if one combination trial disappointed.

What this does not change

Three things stay true regardless of how the CagriSema decision goes.

The foundations do not move. Nutrition quality, protein adequacy, physical activity including resistance training, sleep and alcohol reduction sit alongside any pharmacotherapy in this area rather than being a hurdle cleared before it. In one Danish randomised trial after an eight-week low-calorie diet, supervised exercise plus liraglutide preserved the most weight and fat loss and was the only strategy that improved HbA1c, insulin sensitivity and fitness, and a year after all treatment stopped the exercise group had regained less.

Lean mass is part of the accounting. Across the incretin trials, roughly a quarter to two fifths of weight lost is lean mass, with about 25% in one tirzepatide substudy for both drug and placebo groups. Reported proportions vary widely with population and measurement method, and lean mass includes water, organs and bone rather than muscle alone. Nothing about adding an amylin analogue is known to change that arithmetic.

Stopping matters. One year after semaglutide 2.4 mg was stopped in the STEP 1 extension, participants had regained about two thirds of lost weight, with net loss falling from 17.3% to 5.6% and metabolic improvements largely reverting. There is no reason to assume a two-hormone combination behaves differently, and no discontinuation data for it exist.

For the wider picture of how these drugs work and what their trials measured, see our overview of semaglutide and the GLP-1 explainer.

The bottom line

Cagrilintide is the first long-acting amylin analogue to reach late-stage trials, and its combination with semaglutide produced some of the largest body weight changes recorded in the field, alongside one head-to-head trial that missed its noninferiority objective. As of September 2026 nothing in this family is approved: CagriSema is under FDA review with a decision expected late in the year, and neither it nor cagrilintide alone is authorized in Canada. Anything sold as cagrilintide today is an unapproved product from an unregulated source, and the trial figures above attach to the studied product, not to it.

Education only. This page is educational. Most compounds referenced are not approved for human use, and a “research use only” label carries no legal status of its own. Nothing here constitutes medical advice, diagnosis, or treatment.

Sources

Peptides 101MetabolicRegulatory
For education only · Not medical advice