Cagrilintide
Also known as: Cagri, AM833, AM-833
5 notable studies · 7 references
TLDR
Cagrilintide is a long-acting amylin and calcitonin receptor agonist with substantial human evidence for reducing body weight alone and especially when combined with semaglutide, but it remains investigational and its long-term outcomes and precise receptor contributions are still being established.
Research Supports
- Studied for effects on obesity and body-weight regulation, alone and combined with semaglutide (CagriSema)
- Investigated for effects on satiety and food-intake regulation via amylin/calcitonin receptor signaling
- Examined in people with type 2 diabetes, alone and combined with semaglutide
- Studied for effects on blood pressure and cardiometabolic risk markers
Observations Reported in Research
- Produced dose-dependent weight reductions up to 10.8% at 26 weeks versus 3.0% with placebo in a 706-person Phase 2 trial (Lau et al., 2021)
- CagriSema produced an estimated -20.4% body-weight change at 68 weeks versus -3.0% with placebo in the 3,417-person REDEFINE 1 trial (Garvey et al., 2025)
- Cryo-EM studies show cagrilintide activates AMY1R, AMY2R, AMY3R, and the calcitonin receptor rather than one selective amylin receptor (Cao et al., 2025)
- CagriSema produced a greater average HbA1c reduction than cagrilintide alone in a 92-person Phase 2 diabetes trial (Frias et al., 2023)
These are brief summaries of what the referenced research examined or reported — not conclusions about safety or effectiveness, and not medical advice. See Notable Studies and Sources & References below for the full context and citations.
At a Glance
Classification: Long-acting acylated amylin analogue; amylin and calcitonin receptor agonist
Cagrilintide is a long-acting synthetic analogue of amylin, a pancreatic peptide hormone normally released alongside insulin after eating. Amylin participates in meal-related satiation and metabolic regulation. Cagrilintide was engineered to reproduce and prolong this signaling sufficiently for once-weekly administration in clinical trials. Importantly, cagrilintide is not a GLP-1 receptor agonist. Structural and pharmacological research shows that it activates amylin receptors as well as the calcitonin receptor. PubMed In a Phase 2 obesity trial, cagrilintide alone produced dose-dependent weight reductions, reaching an average 10.8% reduction at 26 weeks with 4.5 mg, compared with 3.0% with placebo. PubMed Its development has increasingly focused on combining amylin signaling with GLP-1 signaling through cagrilintide + semaglutide (CagriSema). Phase 3 REDEFINE 1 reported an estimated mean body-weight change of −20.4% at 68 weeks with the combination versus −3.0% with placebo. PubMed Cagrilintide remains investigational and should not be described as an FDA-approved obesity medication.
What Is Cagrilintide?
Cagrilintide is an engineered, long-acting analogue of human amylin. Natural amylin is a 37-amino-acid peptide produced by pancreatic beta cells and co-secreted with insulin in response to food intake. Its physiological functions include signaling satiation and participating in post-meal metabolic regulation. Native amylin is unsuitable for once-weekly pharmacotherapy because of its physical and pharmacokinetic properties. Cagrilintide incorporates structural modifications designed to improve stability and substantially extend exposure. Its pharmacology is also broader than simply reproducing native amylin at one receptor subtype. Current structural research shows that cagrilintide can activate: • AMY1 receptors • AMY2 receptors • AMY3 receptors • Calcitonin receptors This has led researchers to describe it as a dual amylin and calcitonin receptor agonist. PubMed
What Are Researchers Studying?
Obesity and body-weight regulation
Weight management is cagrilintide's principal clinical research area. A large Phase 2 dose-ranging trial randomized 706 adults with overweight or obesity without diabetes to weekly cagrilintide, daily liraglutide, or placebo. At 26 weeks, mean weight reductions across cagrilintide groups ranged from approximately 6.0% to 10.8%, compared with 3.0% with placebo. The highest tested cagrilintide dose also produced greater average weight reduction than liraglutide 3.0 mg in that trial. PubMed
Satiety and food-intake regulation
Amylin is fundamentally a satiation hormone. It participates in meal termination through central nervous system pathways involving regions including the area postrema and nucleus tractus solitarius, with additional neural networks increasingly recognized. Cagrilintide is being studied as a pharmacological way of producing prolonged amylin-like signaling. PubMed This makes its biological approach fundamentally different from GLP-1 receptor agonists, even though both can ultimately reduce food intake and body weight.
Combination with GLP-1 receptor agonism
One of the most important questions in cagrilintide development is whether amylin and GLP-1 signaling can complement one another. Cagrilintide and semaglutide target different receptor systems. The combination known as CagriSema has consequently progressed through Phase 2 and Phase 3 clinical development. REDEFINE 1 randomized 3,417 adults with overweight or obesity without diabetes. At week 68, estimated average body-weight change was −20.4% with cagrilintide-semaglutide versus −3.0% with placebo. PubMed
Type 2 diabetes
Cagrilintide has also been studied in people with type 2 diabetes, both alone and in combination with semaglutide. A 32-week Phase 2 trial randomized 92 adults with type 2 diabetes to CagriSema, semaglutide, or cagrilintide. Average HbA1c changes were: CagriSema: −2.2 percentage points Semaglutide: −1.8 percentage points Cagrilintide: −0.9 percentage points Average body-weight changes were: CagriSema: −15.6% Semaglutide: −5.1% Cagrilintide: −8.1% The trial provided early evidence that combining the two pathways could produce greater weight reduction than either component alone. PubMed
Amylin versus calcitonin receptor signaling
An important current research question concerns exactly which receptors are responsible for cagrilintide's clinical effects. Amylin receptors are themselves unusual receptor complexes involving the calcitonin receptor combined with receptor-activity-modifying proteins. Recent cryo-electron microscopy research has visualized cagrilintide bound to several amylin receptors and the calcitonin receptor. These studies confirm that cagrilintide is not strictly selective for one amylin receptor subtype. PubMed Understanding this receptor profile may become important when comparing cagrilintide with newer amylin-based drugs designed for different degrees of receptor selectivity.
Blood pressure and cardiometabolic risk
Secondary analyses of REDEFINE 1 have investigated cardiovascular risk markers. In a 2026 analysis, average systolic blood pressure decreased 10.9 mm Hg with CagriSema versus 2.8 mm Hg with placebo, while diastolic pressure decreased 5.4 versus 1.7 mm Hg. These findings are interesting but do not establish prevention of cardiovascular events. Much of the effect may also be related to substantial weight reduction rather than a direct cardiovascular action of cagrilintide. PubMed
How Does It Work?
Cagrilintide activates amylin receptors and the calcitonin receptor. Amylin signaling participates in communication between the gastrointestinal/metabolic system and the brain following food intake. Central nervous system pathways associated with amylin include the: • Area postrema • Nucleus tractus solitarius • Parabrachial nucleus • Hypothalamic circuits • Additional reward and feeding-related neural pathways Activation of these systems contributes to satiation, helping reduce meal size and food intake. PubMed Cagrilintide's receptor pharmacology is particularly interesting. Amylin receptors consist of the calcitonin receptor associated with different receptor-activity-modifying proteins, producing AMY1R, AMY2R, and AMY3R. Structural studies published in 2025 and 2026 show that cagrilintide can activate multiple AMY receptors as well as CTR. PubMed This gives us an important Aminodex distinction: Semaglutide → GLP-1 receptor Retatrutide → GLP-1 + GIP + glucagon receptors Cagrilintide → amylin + calcitonin receptors Different upstream biology can therefore converge on reduced energy intake and body weight.
What Does the Research Show?
Human research
Cagrilintide now has a substantial human clinical evidence base. The standalone Phase 2 obesity trial included 706 participants and demonstrated dose-dependent weight reduction across cagrilintide doses. PubMed Its combination with semaglutide has subsequently generated much larger datasets. REDEFINE 1 3,417 adults with overweight or obesity without diabetes. Estimated average weight change at 68 weeks: CagriSema: −20.4% Placebo: −3.0% Gastrointestinal adverse events occurred in 79.6% of CagriSema participants versus 39.9% receiving placebo and were predominantly mild-to-moderate and transient. PubMed REDEFINE 2 Adults with overweight/obesity and type 2 diabetes. Estimated average weight change: CagriSema: −13.7% Placebo: −3.4% A substantially larger proportion of CagriSema-treated participants also reached HbA1c ≤6.5%. PubMed REDEFINE 5 A 2026 Phase 3a trial in Japan and Taiwan directly compared CagriSema with semaglutide in adults with overweight or obesity, with or without type 2 diabetes, further expanding the clinical evidence across populations. PubMed REIMAGINE 2 A large 2026 Phase 3 diabetes study randomized 2,713 participants. CagriSema 2.4/2.4 mg produced a greater average HbA1c reduction than semaglutide 2.4 mg alone, while gastrointestinal disorders remained the most common adverse events with active treatment. PubMed The important editorial distinction is that much of the strongest Phase 3 evidence concerns CagriSema, not cagrilintide monotherapy.
Animal research
Preclinical cagrilintide development included obesity models examining: • Food intake • Body weight • Energy balance • Amylin-receptor pharmacology • Combination with incretin signaling These experiments helped establish the rationale for translating cagrilintide into human obesity trials. Animal and neurobiological research remains especially important for determining which brain pathways produce therapeutic satiation versus nausea or aversive feeding responses. That question has become increasingly important as newer amylin analogues with different receptor-selectivity profiles enter development. PubMed
In-vitro research
Cagrilintide has been extensively characterized using receptor-expression systems and more recently through structural biology. Cryo-EM research published in Nature Communications in 2025 visualized cagrilintide interacting with active AMY1R, AMY2R, AMY3R, and CTR complexes. Researchers found an amylin-like binding mode but distinct receptor dynamics compared with other peptides. PubMed A separate structural analysis published for 2026 further characterized dual activation of AMY1R and CTR and demonstrated Gs signaling through both receptor systems. PubMed These studies provide unusually detailed molecular evidence for how cagrilintide engages its targets.
Notable Studies
Efficacy and Safety of Co-Administered Once-Weekly Cagrilintide 2.4 mg With Once-Weekly Semaglutide 2.4 mg in Type 2 Diabetes
humanNinety-two adults with type 2 diabetes and BMI ≥27 kg/m² were randomized to CagriSema, semaglutide, or cagrilintide. At 32 weeks, average weight change was −15.6% with CagriSema, −5.1% with semaglutide, and −8.1% with cagrilintide. CagriSema also produced a larger HbA1c reduction than cagrilintide alone. PubMed
Limitations: The trial was small and lasted 32 weeks. It could not establish long-term safety or cardiovascular outcomes.
View publication →Coadministered Cagrilintide and Semaglutide in Adults With Overweight or Obesity
humanREDEFINE 1 randomized 3,417 adults with overweight or obesity without diabetes. At 68 weeks, estimated average body-weight change was: CagriSema: −20.4% Placebo: −3.0% Participants receiving the combination were significantly more likely to reach weight-loss thresholds of ≥5%, ≥20%, ≥25%, and ≥30%. Gastrointestinal adverse events were common but predominantly mild-to-moderate and transient. PubMed
Limitations: The primary comparison was the combination versus placebo. The result should not be attributed to cagrilintide alone. Long-term cardiovascular and mortality outcomes remain to be established.
View publication →Cagrilintide-Semaglutide in Adults With Overweight or Obesity and Type 2 Diabetes
humanResearchers evaluated CagriSema in adults with obesity or overweight and type 2 diabetes. At 68 weeks, estimated average weight change was −13.7% with CagriSema versus −3.4% with placebo. Approximately 73.5% of participants receiving CagriSema achieved HbA1c ≤6.5%, compared with 15.9% receiving placebo. Gastrointestinal adverse events were again the most common tolerability issue. PubMed
Limitations: The trial evaluated the cagrilintide-semaglutide combination, not cagrilintide alone. Participants had type 2 diabetes, so weight-loss magnitude should not automatically be generalized to people without diabetes.
View publication →Structural and Dynamic Features of Cagrilintide Binding to Calcitonin and Amylin Receptors
in-vitroResearchers determined structures of cagrilintide bound to active AMY1R, AMY2R, AMY3R, and calcitonin receptor complexes. The study demonstrated broad receptor engagement and identified an amylin-like binding mode with distinctive receptor dynamics. The findings provide molecular evidence explaining why cagrilintide is better characterized as an amylin/calcitonin receptor agonist rather than a narrowly selective amylin-receptor agonist. PubMed
Limitations: Structural receptor activation does not independently establish clinical efficacy, tolerability, or long-term safety.
View publication →Once-Weekly Cagrilintide for Weight Management in People With Overweight and Obesity: A Multicentre, Randomised, Double-Blind, Placebo-Controlled and Active-Controlled, Dose-Finding Phase 2 Trial
humanResearchers randomized 706 adults without diabetes who had obesity or overweight with hypertension or dyslipidemia. Participants received several weekly cagrilintide doses, daily liraglutide 3.0 mg, or placebo. At 26 weeks, average weight reductions with cagrilintide ranged from approximately 6.0% to 10.8%, compared with 3.0% with placebo. At the highest cagrilintide dose, average weight reduction was greater than with liraglutide. The trial established substantial dose-dependent weight reduction from cagrilintide monotherapy. PubMed
Limitations: The study lasted only 26 weeks. It was not designed to establish long-term cardiovascular outcomes or lifelong safety, and the population did not include diabetes.
View publication →What We Still Don't Know
Important unanswered questions include: • Long-term cardiovascular outcomes • Long-term mortality outcomes • Durability of weight reduction over multiple years • Weight regain following discontinuation • Long-term tolerability • The relative contributions of AMY1R, AMY2R, AMY3R, and CTR activation • Whether calcitonin-receptor activation contributes primarily to efficacy, adverse effects, or both • How much cagrilintide adds independently to semaglutide during long-term combination treatment • Effects on body composition and lean mass over prolonged treatment • How cagrilintide compares directly with newer amylin analogues • Whether more receptor-selective amylin agonists can preserve efficacy with better tolerability • How amylin-based therapy compares with emerging GLP-1/GIP/glucagon multi-agonists The last question is becoming particularly interesting because newer compounds such as eloralintide have deliberately different amylin-receptor selectivity. PubMed
Related Compounds
Recent publications
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Sources & References
- Efficacy and Safety of Co-Administered Once-Weekly Cagrilintide 2.4 mg With Once-Weekly Semaglutide 2.4 mg in Type 2 Diabetes: A Multicentre, Randomised, Double-Blind, Active-Controlled, Phase 2 Trial. The Lancet. 2023.
- Garvey WT, Blüher M, Osorto Contreras CK, et al.; REDEFINE 1 Study Group. Coadministered Cagrilintide and Semaglutide in Adults With Overweight or Obesity. New England Journal of Medicine. 2025;393:635–647. doi:10.1056/NEJMoa2502081.
- REDEFINE 2 Study Group. Cagrilintide-Semaglutide in Adults With Overweight or Obesity and Type 2 Diabetes. New England Journal of Medicine. 2025.
- Cao J, et al. Structural and Dynamic Features of Cagrilintide Binding to Calcitonin and Amylin Receptors. Nature Communications. 2025. doi:10.1038/s41467-025-58680-y.
- Gu YM, Yuan QN, Li X, et al. Structural and Mechanistic Insights Into Dual Activation of Cagrilintide in Amylin and Calcitonin Receptors. Acta Pharmacologica Sinica. 2026;47:162–172.
- Yamauchi T, Becker NP, Hagemann CA, et al.; REDEFINE 5 Study Group. Efficacy and Safety of Co-Administered Cagrilintide and Semaglutide Versus Semaglutide Alone in Adults With Overweight or Obesity With or Without Type 2 Diabetes in Japan and Taiwan. Lancet Diabetes & Endocrinology. 2026;14:450–462.
- Lau DCW, Erichsen L, Francisco AM, et al. Once-Weekly Cagrilintide for Weight Management in People With Overweight and Obesity: A Multicentre, Randomised, Double-Blind, Placebo-Controlled and Active-Controlled, Dose-Finding Phase 2 Trial. The Lancet. 2021.
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