Cagrilintide

Overview

Cagrilintide (development code AM833, also identified as NN9838 / NNC0174-0833) is an investigational long-acting amylin analog developed by Novo Nordisk. Amylin is a natural hormone co-secreted with insulin by the pancreas that helps signal fullness, slow gastric emptying, and regulate appetite. Cagrilintide is engineered to mimic and extend that signal, and it has been studied for weight management and type 2 diabetes, most prominently in a fixed-dose combination with the GLP-1 agonist semaglutide, known as CagriSema.

Chemistry and structure

Cagrilintide is a synthetic peptide built on a 37-amino-acid amylin backbone similar to pramlintide (an approved amylin analog), with several amino-acid substitutions that improve stability and receptor activity. Its key engineering feature is N-terminal acylation with a long C20 fatty diacid chain attached through a gamma-glutamic acid linker.

This lipidation promotes binding to albumin in the bloodstream, which dramatically slows clearance. The reported elimination half-life is roughly 159-195 hours, long enough to support a once-weekly subcutaneous dosing schedule, in contrast to the original amylin analog pramlintide, which must be dosed at each meal.

The reported molecular formula is C194H312N54O59S2, with a free-peptide molecular weight of approximately 4,409 Da (values reported by chemical vendors vary with salt form and source).

Mechanism of action (amylin)

Native amylin is released from pancreatic beta cells alongside insulin after meals. It acts on the brain to reduce food intake and promote a sense of fullness (satiety), slows the rate at which the stomach empties, and helps suppress post-meal glucagon. Cagrilintide is designed to reproduce these effects in a longer-lasting form.

• Amylin-receptor agonism: Cagrilintide is a non-selective agonist of the amylin receptors (AMY1R, AMY2R, AMY3R), which are formed when the calcitonin receptor combines with receptor-activity-modifying proteins (RAMPs). Through these receptors it acts on appetite-regulating regions of the brain such as the area postrema and hypothalamus to reduce energy intake.
• Calcitonin-receptor activity: Because amylin and calcitonin receptors share the calcitonin receptor as a core component, cagrilintide also engages the calcitonin receptor (CTR) directly. Preclinical pharmacology work has characterized it as a broad agonist across this calcitonin receptor family.
• Complementary to GLP-1: Amylin and GLP-1 reduce appetite through distinct but complementary pathways. This is the rationale for combining cagrilintide with the GLP-1 agonist semaglutide in CagriSema: the two mechanisms are intended to add together for greater appetite suppression and weight loss than either alone.

The net pharmacological goal is to reduce energy intake and body weight by amplifying physiological satiety signaling, rather than by increasing energy expenditure (which distinguishes amylin analogs from glucagon-containing agents such as the investigational triple agonist retatrutide).

Clinical trials and evidence

Cagrilintide alone: phase 2 (Lau et al., Lancet 2021)

A 26-week, multicentre, randomized, double-blind, placebo- and active-controlled dose-finding phase 2 trial (NCT03856047) enrolled 706 adults with overweight or obesity. Participants received once-weekly cagrilintide at one of five doses (0.3, 0.6, 1.2, 2.4, or 4.5 mg), once-daily liraglutide 3.0 mg, or placebo, alongside lifestyle intervention. Weight loss was dose-dependent, with the highest dose (4.5 mg) producing a mean reduction of about 10.8% versus roughly 3.0% with placebo at week 26.

Combination with semaglutide: phase 1b (Enebo et al., Lancet 2021)

An early phase 1b trial studied co-administration of cagrilintide with semaglutide 2.4 mg in adults with a BMI of 27.0-39.9. It reported that the combination was generally tolerated (mainly gastrointestinal effects) and supported further development of the two-drug regimen later branded CagriSema.

CagriSema — phase 3 (REDEFINE 1, NEJM 2025)

REDEFINE 1 was a 68-week, double-blind, placebo-controlled phase 3 trial in 3,417 adults with obesity or overweight plus a weight-related complication, but without type 2 diabetes. It compared once-weekly CagriSema (cagrilintide 2.4 mg plus semaglutide 2.4 mg) against each component alone and placebo. Results were presented in 2025 and published in The New England Journal of Medicine.

Source: REDEFINE 1; Garvey WT et al., N Engl J Med 2025. The 22.7% figure reflects the analysis assuming full treatment adherence; an analysis regardless of adherence reported about −20.4% for CagriSema versus −3.0% placebo. In the trial, roughly 40% of CagriSema participants achieved ≥25% weight loss and about 23% achieved ≥30%.

A companion phase 3 trial, REDEFINE 2, evaluated CagriSema in adults with type 2 diabetes, and additional REDEFINE/REIMAGINE program trials addressed further populations. Reported additional effects of the combination included improvements in blood pressure, waist circumference, lipids, and glycemic control.

Strength of evidence: The phase 2 monotherapy and phase 1b combination trials are peer-reviewed in The Lancet, and the pivotal REDEFINE 1 phase 3 result is published in NEJM. This is a stronger published base than some other investigational agents in this space. Even so, cagrilintide remains investigational; long-term outcomes and the full safety profile continue to be evaluated, and any figures from press releases should be treated as preliminary until matched by peer-reviewed publication.

Safety and reported effects

Across trials, the reported safety profile of cagrilintide and CagriSema was broadly consistent with appetite-acting metabolic therapies, dominated by gastrointestinal effects that were generally most common during dose escalation:

• Nausea, vomiting, constipation, and diarrhea were the most frequently reported adverse events. In REDEFINE 1, gastrointestinal events were reported far more often with CagriSema than placebo (for example, nausea in roughly 55% versus about 13%).
• Despite this, discontinuation because of adverse events was relatively low in REDEFINE 1 (on the order of 6% for CagriSema versus about 4% for placebo).
• As an amylin analog, cagrilintide's effects are oriented toward reduced food intake and satiety, and it does not rely on the glucagon-driven energy-expenditure mechanism seen in some other investigational agents.

As with any investigational agent, the complete long-term safety and efficacy profile is not yet established, and rare or delayed risks may only emerge in larger or longer studies and in eventual regulatory review.

Regulatory status

As of June 2026, cagrilintide is not approved for any use by the FDA, the EMA, or any other regulatory authority, neither as a single agent nor as part of CagriSema.

The most advanced regulatory step is for the combination product CagriSema (cagrilintide 2.4 mg plus semaglutide 2.4 mg): Novo Nordisk announced on December 18, 2025 that it had submitted a New Drug Application (NDA) to the FDA for weight management in adults with obesity or overweight and at least one weight-related comorbidity. Public reporting indicated the FDA was expected to review the application during 2026, with commentary anticipating a possible decision in late 2026 or early 2027. Any such timeline is not a guarantee and an NDA submission is not an approval.

How it compares

Cagrilintide sits in the broader metabolic and weight-management field but works through a different mechanism than the approved incretin drugs:

• Semaglutide, an approved GLP-1 receptor agonist (Ozempic/Wegovy). It is also the partner molecule in CagriSema; cagrilintide's amylin mechanism is intended to add to, not replace, GLP-1 activity.
• Tirzepatide, an approved dual GIP/GLP-1 agonist (Mounjaro/Zepbound).
• Retatrutide, an investigational triple GIP/GLP-1/ glucagon agonist (Eli Lilly). Unlike cagrilintide, it adds glucagon-driven energy expenditure rather than amylin-based satiety.

The decisive distinction is regulatory: semaglutide and tirzepatide are approved, while cagrilintide (and CagriSema) are not: CagriSema is under FDA review and cagrilintide alone remains in trials. Cagrilintide is also notable as a leading example of the amylin approach to obesity, a different pharmacological route from the incretin-only drugs. For an approved, evidence-backed option today, the data point to the licensed incretin drugs. See the Weight management overview for the broader landscape.

Common misconceptions and unregulated-source warning

• "Cagrilintide is FDA approved / available by prescription." It is not. Approved options in the broader weight-management field include semaglutide (GLP-1) and tirzepatide (GIP/GLP-1); cagrilintide is a distinct amylin analog and is still investigational, even though CagriSema is under FDA review.
• "CagriSema and cagrilintide are the same thing." Cagrilintide is the amylin analog by itself. CagriSema is the combination of cagrilintide with semaglutide. Most of the large weight-loss figures reported in the news refer to the combination, not cagrilintide alone.
• "Amylin analogs work like GLP-1 drugs." They share appetite-reducing effects but act through different receptors (amylin/calcitonin versus GLP-1). That mechanistic difference is exactly why the two are combined in CagriSema.
• "Trial doses are a usage protocol." The doses described above are reported factually from trials for educational completeness. They are not a how-to and do not constitute medical advice or a dosing recommendation.

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This entry is educational and summarizes published trial data and public regulatory information. It is not medical advice, a recommendation, or a guide to obtaining or using any substance. Investigational drugs should only be used within an authorized clinical trial under medical supervision.