Cagrilintide — Research Overview
Chemical Name: AM833 Also Known As: Cagrilintide, CagriSema (when co-administered with semaglutide) Developer: Novo Nordisk Structure: Long-acting acylated synthetic amylin analog with high homology to natural human amylin Target: Amylin receptors 1 and 3 (AMY1R and AMY3R) — heterodimeric complexes formed by the calcitonin receptor and receptor activity modifying proteins 1 and 3 Category: Long-acting amylin analog / dual amylin and calcitonin receptor agonist
Research Use Only — Disclaimer
The scientific literature on this page is provided strictly for educational and informational purposes. All Rogue Compounds products are intended for in-vitro laboratory research use only and are not approved by the FDA for human or animal consumption. The studies referenced below are independent third-party peer-reviewed publications. Rogue Compounds makes no claims that any product diagnoses, treats, cures, or prevents any disease or condition. Researchers are responsible for compliance with all applicable local, state, and federal regulations.
What Is Cagrilintide?
Cagrilintide is a long-acting synthetic analog of amylin — a pancreatic hormone co-secreted with insulin from beta cells in response to meals. Natural amylin plays a well-characterized role in postprandial satiety signaling, acting on both homeostatic brain regions responsible for hunger and reward and hedonic brain regions involved in food preference and motivation. However native amylin has a very short half-life and requires frequent dosing, limiting its utility as a standalone therapeutic research compound.
Cagrilintide was engineered by Novo Nordisk with acylation and structural modifications that dramatically extend its half-life, enabling once-weekly subcutaneous administration. It is the first long-acting amylin analog to reach Phase 2 and Phase 3 human clinical trials, and as of 2025 it has one of the most extensive and recently published human clinical datasets of any compound in the incretin and amylin research space.
Cagrilintide has been studied both as a monotherapy for obesity and as a combination therapy co-administered with the GLP-1 receptor agonist semaglutide — a combination referred to in clinical trial literature as CagriSema. The rationale for combination therapy is that amylin receptor agonism and GLP-1 receptor agonism operate through separate but complementary neural satiety and reward pathways, producing additive effects on appetite reduction and weight loss that exceed either agent alone.
Mechanism of Action
Cagrilintide activates amylin receptors 1 and 3 (AMY1R and AMY3R), which are heterodimeric receptor complexes formed by the calcitonin receptor (CTR) paired with receptor activity modifying proteins 1 and 3 (RAMP1 and RAMP3 respectively). These receptors are expressed in brain regions critically involved in appetite and energy homeostasis. Research using RAMP1/3 knockout mice has confirmed that cagrilintide’s weight-reducing effects are dependent on AMY1R and AMY3R, and that removal of these receptors significantly impairs cagrilintide’s efficacy.
The primary sites of action in the brain include the area postrema and nucleus of the solitary tract in the hindbrain — the dorsal vagal complex — as well as the lateral parabrachial nucleus and the mediobasal hypothalamic area. Activation of cFos signaling in neurons of these regions has been confirmed following cagrilintide administration in preclinical research. The hypothalamus, ventral tegmental area, and laterodorsal tegmental nucleus — regions involved in reward and food motivation — are also engaged through amylin receptor pathways.
The downstream physiological effects of cagrilintide’s receptor activation include the following.
Satiety signaling enhancement: Cagrilintide amplifies the postprandial satiety signal, increasing the sense of fullness and reducing meal size and caloric intake in a dose-dependent manner.
Gastric emptying delay: Like native amylin and GLP-1 receptor agonists, cagrilintide slows the rate at which food leaves the stomach, extending satiety duration and moderating postprandial glucose excursions.
Postprandial glucagon suppression: Cagrilintide reduces the post-meal rise in glucagon, contributing to improved glycemic regulation particularly in the context of type 2 diabetes.
Complementary to GLP-1 receptor agonism: While GLP-1 receptor agonists act primarily through GLP-1 receptors in the hypothalamus, cagrilintide’s amylin receptor-mediated signaling operates through partially distinct neural circuits. This mechanistic separation is the scientific basis for the additive weight-loss effect observed when cagrilintide is combined with semaglutide in clinical trials.
Published Research
Study 1 — Phase 2 Dose-Finding Trial: Obesity Without Type 2 Diabetes
Authors: Lau DCW, Erichsen L, Francisco AM, Satylganova A et al. (Novo Nordisk) Year: 2021 Journal: The Lancet PMID: 34798060 Full text: https://pubmed.ncbi.nlm.nih.gov/34798060/
This was the pivotal Phase 2 dose-finding clinical trial of cagrilintide as a monotherapy for weight management. It was a multicentre randomized double-blind placebo-controlled and active-controlled trial conducted at 57 sites across 10 countries including the United States, Canada, Denmark, Finland, Ireland, Japan, Poland, Serbia, South Africa, and the United Kingdom. A total of 706 participants without type 2 diabetes were enrolled and randomized to once-weekly subcutaneous cagrilintide at doses of 0.3, 0.6, 1.2, 2.4, or 4.5 mg, or once-daily liraglutide 3.0 mg as an active comparator, or placebo, over 26 weeks.
Mean percentage weight reductions from baseline were significantly greater with all doses of cagrilintide compared to placebo. At the highest dose of 4.5 mg, the mean weight reduction was 10.8% (11.5 kg) versus 3.0% (3.3 kg) for placebo, an estimated treatment difference of 7.8% with P less than 0.001.
Weight reduction with cagrilintide 4.5 mg was significantly greater than with liraglutide 3.0 mg (10.8% versus 9.0%, estimated treatment difference 1.8%, P equal to 0.03), demonstrating superiority to an established approved weight management agent.
Waist circumference was also dose-dependently reduced across cagrilintide groups.
The most frequent adverse events were gastrointestinal including nausea, constipation, and diarrhea, and administration site reactions. Nausea occurred in 20 to 47% of cagrilintide-treated participants versus 18% in the placebo group, increasing with dose.
The authors concluded that cagrilintide led to significant dose-dependent reductions in bodyweight and was well tolerated, supporting further development of amylin receptor agonism as a novel mechanism for weight management.
Study 2 — Phase 2 Trial: CagriSema in Type 2 Diabetes
Authors: Frias JP, Deenadayalan S, Erichsen L et al. Year: 2023 Journal: The Lancet PMID: 37364590 Full text: https://pubmed.ncbi.nlm.nih.gov/37364590/
This 32-week Phase 2 trial conducted at 17 sites in the United States examined the co-administration of cagrilintide and semaglutide (CagriSema) in adults with type 2 diabetes and a BMI of 27 or higher. Participants were randomized equally to once-weekly CagriSema, semaglutide alone, or cagrilintide alone, all escalated to 2.4 mg, over 32 weeks.
The mean change in body weight from baseline to week 32 was 15.6% reduction with CagriSema compared to 5.1% with semaglutide alone and 8.1% with cagrilintide alone. CagriSema was significantly superior to both monotherapies on body weight outcomes (P less than 0.0001 for both comparisons).
The mean change in HbA1c from baseline was 2.2 percentage points with CagriSema, 1.8 percentage points with semaglutide, and 0.9 percentage points with cagrilintide. CagriSema showed greater HbA1c reduction versus cagrilintide (P less than 0.0001).
Time in glycemic range (3.9 to 10.0 mmol/L) reached 88.9% at week 32 in the CagriSema group compared to 76.2% with semaglutide and 71.7% with cagrilintide.
No level 2 or level 3 hypoglycemia was reported in any group. No fatal adverse events were reported. Mild to moderate gastrointestinal adverse events were most common.
The authors concluded that CagriSema resulted in clinically relevant improvements in glycemic control and significantly greater weight loss than either monotherapy and supported further Phase 3 investigation.
Study 3 — Phase 3a Trial (REDEFINE 1): CagriSema in Obesity Without Type 2 Diabetes
Published: June 2025 Journal: New England Journal of Medicine Full text: https://www.nejm.org/doi/full/10.1056/NEJMoa2502081
This Phase 3a randomized double-blind placebo-controlled and active-controlled trial is the largest and most recently published clinical trial of CagriSema. It enrolled 3417 adults without type 2 diabetes who had a BMI of 30 or higher, or a BMI of 27 or higher with at least one obesity-related complication. Participants were randomized to CagriSema (2.4 mg each component), semaglutide 2.4 mg alone, cagrilintide 2.4 mg alone, or placebo, plus lifestyle interventions for all groups, over 68 weeks.
The estimated mean percent change in body weight from baseline to week 68 was 20.4% reduction with CagriSema compared to 3.0% with placebo, an estimated difference of 17.3 percentage points (P less than 0.0001).
Cagrilintide monotherapy produced 11.8% mean weight loss and semaglutide monotherapy produced 16.1% mean weight loss at 68 weeks, with CagriSema significantly outperforming both individual components.
A weight loss of 25% or more was achieved by 40.4% of participants in the CagriSema group, compared to 16.2% with semaglutide alone, 6% with cagrilintide alone, and 0.9% with placebo.
A weight loss of 30% or more was achieved in a subset of CagriSema participants, confirming the potential for near-surgical weight loss outcomes with pharmacotherapy.
Gastrointestinal adverse events occurred in 79.6% of the CagriSema group and 39.9% of the placebo group. The majority were transient and mild to moderate in severity.
Study 4 — Phase 3a Trial (REDEFINE 2): CagriSema in Obesity with Type 2 Diabetes
Published: 2025 Journal: New England Journal of Medicine PMID: 40544432 Full text: https://pubmed.ncbi.nlm.nih.gov/40544432/
This Phase 3a double-blind randomized placebo-controlled trial enrolled 1206 adults with type 2 diabetes and a BMI of 27 or higher across 12 countries over 68 weeks. Participants received once-weekly CagriSema (2.4 mg each) or placebo alongside lifestyle interventions.
The estimated mean change in body weight from baseline to week 68 was 13.7% reduction with CagriSema versus 3.4% with placebo, an estimated difference of 10.4 percentage points (P less than 0.001).
More patients in the CagriSema group achieved weight reductions of 5%, 10%, 15%, and 20% or more compared to placebo (P less than 0.001 for each threshold).
73.5% of patients in the CagriSema group achieved an HbA1c of 6.5% or less at week 68, compared to 15.9% in the placebo group — a result consistent with glycemic normalization in the majority of treated participants with type 2 diabetes.
Gastrointestinal adverse events were reported by 72.5% of the CagriSema group and 34.4% of the placebo group, predominantly transient and mild to moderate in severity.
Study 5 — Receptor Mechanism: Brain Amylin Receptors 1 and 3
Authors: Published in PMC Year: 2025 Journal: Appetite (PMC) Full text: https://pmc.ncbi.nlm.nih.gov/articles/PMC12270663/
This preclinical mechanistic study used RAMP1/3 knockout mice to directly confirm which amylin receptor subtypes are responsible for cagrilintide’s weight-reducing effects. High-fat diet obese wild-type mice and RAMP1/3 knockout mice were treated with cagrilintide or vehicle for three weeks and measured across body weight, food intake, and neuronal activation markers.
Body weight loss of 3.4 grams was observed in wild-type cagrilintide-treated mice (P less than 0.005) confirming efficacy in the obese model.
The absence of RAMP1 and RAMP3 significantly impaired cagrilintide’s potency on weight loss, confirming that AMY1R and AMY3R are the essential mediators of cagrilintide’s metabolic effects.
Neuronal activation (cFos signaling) was confirmed in the dorsal vagal complex and lateral parabrachial nucleus of wild-type treated mice, identifying these hindbrain regions as primary sites of cagrilintide-mediated satiety signaling. cFos signal in the area postrema was decreased by 57% in knockout mice compared to wild-type cagrilintide-treated mice, confirming the receptor dependency of this neuronal response.
The authors concluded that cagrilintide’s weight-lowering effects are mediated specifically through AMY1R and AMY3R, providing a mechanistic framework for understanding the pharmacological basis of cagrilintide’s clinical efficacy.
Current Research Status
Cagrilintide has one of the most advanced and recently published clinical development programs of any compound in the research peptide space. As of mid-2025 it has completed Phase 2 trials as both a monotherapy and in combination with semaglutide, and two Phase 3a trials (REDEFINE 1 and REDEFINE 2) have been published with results in the New England Journal of Medicine.
CagriSema is not FDA-approved as of the time of this post. Phase 3 data from the REDEFINE program represent the most current evidence available and regulatory review processes would be required before any approval pathway could be established.
The following remain to be established through ongoing Phase 3 trials and post-approval research:
Long-term cardiovascular outcomes data.
Effects following cessation of treatment and durability of weight loss.
Safety profile in specific populations including older adults, those with severe obesity, and those with comorbidities beyond type 2 diabetes.
Comparison against other emerging triple agonist compounds currently in Phase 2 and Phase 3 development.
Reconstitution Note
Cagrilintide is a peptide compound. Bacteriostatic water is the standard reconstitution solvent for this class of compound in laboratory research settings. Always confirm the recommended solvent against the specific lot datasheet before reconstitution.
In-Use Period and Storage
Before Reconstitution — Lyophilized Powder
Rogue Compounds stores all products refrigerated prior to shipping to maintain compound integrity from production through to delivery. Upon receipt researchers should store vials at 2 to 8 degrees Celsius immediately. Keep vials sealed, dry, and away from direct light until ready for use. Do not freeze. Repeated freeze-thaw cycling has been documented in peer-reviewed pharmaceutical formulation literature to accelerate structural degradation even in dry powder form, potentially compromising molecular integrity and experimental reproducibility.
Why We Refrigerate Instead of Freeze
Freezing and thawing introduces mechanical and osmotic stress at the molecular level. Published pharmaceutical research identifies freeze-thaw cycling as a significant risk factor for loss of structural integrity in peptides and protein-based compounds. To protect compound quality at every stage of handling and fulfillment, Rogue Compounds maintains refrigerated rather than frozen cold chain storage throughout the entire process.
After Reconstitution — Liquid Solution
Store reconstituted solutions refrigerated at 2 to 8 degrees Celsius immediately after preparation. Protect from light at all stages of storage and handling. Avoid repeated freeze-thaw cycles of reconstituted solutions regardless of the diluent used. Use within the timeframe recommended for the individual compound. Label each aliquot with the compound name, concentration, date of reconstitution, and diluent used. Discard any solution that shows visible particulate matter, discoloration, or signs of contamination.
Note: Storage and in-use recommendations on this page are provided as general laboratory guidance based on standard peptide handling practices documented in peer-reviewed pharmaceutical literature. Researchers should always refer to the individual compound’s published research literature and datasheet for any specific requirements. All products sold by Rogue Compounds are intended strictly for in-vitro laboratory research use only.
Available from Rogue Compounds
View the Cagrilintide product page: https://roguecompounds.com/product/cagrilintide/