Compound reference
Cagrilintide
Also known as AM833
A long-acting amylin analogue that produces roughly 10% weight loss on its own and around 20% paired with semaglutide as CagriSema — investigational alone, with CagriSema now filed for FDA approval.
- CAS
- 1415456-99-3
- Formula
- C194H312N54O59S2
- Molar mass
- ≈4,409 g/mol
- Half-life
- About 7–8 days (159–195 h; once-weekly)
Investigational; not approved as a standalone medicine in the United States.
Mode of action
Cagrilintide is a long-acting analogue of amylin, the pancreatic hormone co-secreted with insulin that signals satiety. It is built on a 37-amino-acid, pramlintide-like backbone with substitutions that block the amyloid-fibril formation that limited earlier amylin drugs, plus an N-terminal C20 fatty-diacid chain that binds albumin reversibly and stretches its half-life to roughly a week — enough for once-weekly dosing.
Pharmacologically it is a non-selective agonist of the amylin receptors (AMY1–3R) and the calcitonin receptor. It acts in the hindbrain — the area postrema and nucleus of the solitary tract — to enhance satiety signalling, and it slows gastric emptying and blunts post-meal glucagon. That mechanism is complementary to GLP-1 receptor agonism, which is the rationale for combining cagrilintide with semaglutide as the fixed-dose product CagriSema: two satiety pathways rather than one.
Main intended effect
Cagrilintide is developed for weight reduction, with improved glycemic control as a secondary benefit. In practice its lead role is as the amylin half of CagriSema; as monotherapy it produces meaningful but smaller weight loss.
Areas of interest
The headline use is obesity and overweight, where CagriSema has posted some of the largest trial weight-loss numbers in the field. Type 2 diabetes is the second track, and a cardiovascular-outcomes programme and head-to-head trials against tirzepatide are underway. Interest in cagrilintide specifically is mostly interest in what amylin agonism adds on top of a GLP-1 drug.
Evidence for intended effects
Cagrilintide has a substantial, controlled human evidence base — though it is still investigational on its own, and the combination product is what is being filed for approval.
As monotherapy, a Phase 2 dose-finding trial (Lancet 2021) gave once-weekly cagrilintide at 0.3–4.5 mg and found dose-dependent weight loss of about 6–11% at 26 weeks, with the top dose beating liraglutide 3.0 mg. A Phase 1b trial then paired cagrilintide with semaglutide 2.4 mg and reported up to ~17% weight loss. The combination moved into Phase 2 in type 2 diabetes (Lancet 2023) and then into the Phase 3 REDEFINE programme: REDEFINE 1 (NEJM 2025) reported around 20% mean weight loss in adults with obesity, and REDEFINE 2 (NEJM 2025) tested it in type 2 diabetes. A 2026 head-to-head readout put CagriSema around 23% against tirzepatide, and a cardiovascular-outcomes trial is ongoing. Pooled meta-analysis supports the weight and glycemic effects.
| Setting | Strongest evidence | Result |
|---|---|---|
| Cagrilintide alone (obesity) | Phase 2 RCT (Lancet 2021) | ~10% weight loss at 26 wk |
| CagriSema — with semaglutide (obesity) | Phase 3 REDEFINE 1 (NEJM 2025) | ~20% mean weight loss |
| CagriSema (type 2 diabetes) | Phase 3 REDEFINE 2 (NEJM 2025) | weight loss + glycemic control |
| CV outcomes / head-to-head | REDEFINE 3 (ongoing); REDEFINE 4 vs tirzepatide | ~23% (REDEFINE 4 topline) |
Studied amounts (literature dosing context)
Cagrilintide is given as a once-weekly subcutaneous injection. The amounts in the trials are study facts, not recommendations: monotherapy studies tested 0.3–4.5 mg once weekly, while CagriSema uses a fixed 2.4 mg cagrilintide / 2.4 mg semaglutide dose reached by titrating both components every four weeks over about 16 weeks. There is no approved standalone dose — cagrilintide is investigational — and this page does not provide dosing guidance.
Safety and regulatory status
Across trials the safety pattern is the incretin-class norm: mostly mild-to-moderate gastrointestinal effects (nausea, constipation, diarrhea) plus injection-site reactions, generally well tolerated and managed with dose titration. Long-term and cardiovascular-outcome data are still being collected.
On regulation, cagrilintide is investigational and not approved as a standalone medicine. Its combination with semaglutide, CagriSema, was filed with the FDA in December 2025 — the first amylin-based combination submitted for approval — but no approval has been granted yet. Any cagrilintide obtained outside a clinical trial or an eventual approved product is unauthorised and of unverified content.
Sources
Development of Cagrilintide, a Long-Acting Amylin Analogue
Primary medicinal chemistry research paper by Kruse, Raun, and thirteen Novo Nordisk colleagues published in the Journal of Medicinal Chemistry (2021) describing the rational design and optimization of cagrilintide as a long-acting amylin analogue for obesity treatment. The central pharmaceutical challenge addressed is native amylin's high propensity for amyloid fibril formation, which precludes its use as a once-weekly injectable; the authors describe structural modifications — including backbone substitutions and strategic lipidation — that suppress fibrillation while adding reversible serum-albumin binding to extend plasma half-life and support once-weekly dosing. The lipidation strategy parallels that used in semaglutide and mirrors the approach enabling cagrilintide's combination with that GLP-1 receptor agonist in the CagriSema regimen. The authors conclude that the resulting compound successfully achieves the pharmacokinetic and physicochemical profile required for once-weekly subcutaneous administration in clinical obesity trials.
AM833 Is a Novel Agonist of Calcitonin Family G Protein-Coupled Receptors: Pharmacological Comparison with Six Selective and Nonselective Agonists
Fletcher and colleagues characterized AM833 (cagrilintide) across 25 endpoints using cell-based receptor assays in HEK293 and CHO cells, comparing it to six reference agonists (selective: pramlintide, human CT, rat amylin; nonselective: AM1213, AM1784, salmon CT). AM833 demonstrated a unique pharmacological profile spanning receptor binding, activation kinetics, and regulatory mechanisms across AMY1R, AMY2R, AMY3R, and the calcitonin receptor, confirming its classification as a broad-acting calcitonin family agonist. Notably, AM833's clinical efficacy in Phase 2 obesity trials despite calcitonin receptor engagement challenges assumptions that CTR activation is pharmacologically inert, underscoring that cell-based potency profiles may not predict in vivo outcomes. These are in vitro receptor pharmacology data; translation to human therapeutic effects requires clinical interpretation.
Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors
Cao and colleagues resolved cryo-EM structures of cagrilintide bound to Gs-coupled complexes of CTR, AMY1R, AMY2R, and AMY3R at 2.2–3.0 Å resolution, enabling detailed visualization of peptide–receptor contacts across all four receptor subtypes. Cagrilintide adopted an amylin-like binding mode featuring a conserved bypass motif stabilizing the mid-peptide region, but the engineered ionic salt-bridge (E14–R17) and C-terminal proline substitution imposed receptor-specific conformational dynamics — notably, the peptide locked predominantly into a bypass conformation at CTR (85% of particles) compared to the more flexible sampling seen with rat amylin. These structural distinctions from natural amylin and salmon calcitonin likely underlie cagrilintide's distinct pharmacological profile and may inform design of next-generation obesity therapeutics. The study is a structural and mechanistic investigation; clinical outcomes depend on many additional factors beyond receptor binding geometry.
Cagrilintide lowers bodyweight through brain amylin receptors 1 and 3
Carvas and colleagues administered cagrilintide subcutaneously (0.3, 3, and 30 nmol/kg once daily for 21 days) to high-fat-diet-fed male 129S2/SvEv mice alongside RAMP1/3 double-knockout (KO) mice lacking functional AMY1R and AMY3R. In wild-type animals, cagrilintide produced 3.4 ± 0.51 g body weight loss over three weeks and an acute 53% reduction in food intake on day 1, effects entirely absent in RAMP1/3 KO mice. Area postrema cFos neuronal activation was 57% lower in KO versus wild-type animals (P<0.001), localizing the anorectic signal to central amylin receptors 1 and 3 within the AP–NTS–LPBN circuit. Species-specific differences in salmon calcitonin response (weight gain in mice versus loss in humans/rats) caution against direct extrapolation, and male-only cohorts limit generalizability.
Mediators of Amylin Action in Metabolic Control
Narrative review by Boyle, Zheng, and Lutz (University of Zurich) published in the Journal of Clinical Medicine (2022) examining the mediators and circuits through which amylin (islet amyloid polypeptide) exerts its metabolic control. The authors detail how amylin limits meal size by activating area-postrema and caudal hindbrain circuits, slows the rate of gastric emptying, suppresses postprandial glucagon secretion from pancreatic alpha cells, and acts as a sensitizer for the catabolic actions of leptin in hypothalamic energy-balance pathways. Amylin receptors are described as heterodimers of the calcitonin core receptor with receptor-activity modifying proteins (RAMPs), conferring pharmacological diversity across receptor subtypes. The authors conclude that this mechanistic profile makes amylin analogues — including the long-acting cagrilintide — promising candidates for obesity and diabetes pharmacotherapy extending beyond the currently approved pramlintide.
Cagrilintide and CagriSema for weight reduction and metabolic risk modification in overweight or obesity: a systematic review and meta-analysis
Systematic review and meta-analysis published in a Springer endocrinology journal pooling data from randomized controlled trials of cagrilintide as monotherapy and in combination with semaglutide (CagriSema) in overweight or obese participants. The analysis examined effects on percentage and absolute body weight reduction alongside cardiometabolic risk markers including glycemic parameters. Results supported meaningful weight reduction with the CagriSema combination relative to semaglutide alone, while the cagrilintide monotherapy arm showed a more modest weight-loss profile; both regimens demonstrated a generally manageable safety profile with gastrointestinal events as the predominant adverse effect class. The authors conclude that cagrilintide and CagriSema represent clinically meaningful options for weight reduction and metabolic risk modification, acknowledging that the trial evidence base remains limited in size and follow-up duration, and that longer-term cardiovascular outcome data are needed.
https://link.springer.com/article/10.1007/s40200-024-01529-w
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
Multicentre, randomized, double-blind, placebo- and active-controlled dose-finding Phase 2 trial (Lau and colleagues) enrolled 706 adults with overweight or obesity across five once-weekly cagrilintide dose cohorts (0.3, 0.6, 1.2, 2.4, and 4.5 mg), liraglutide 3 mg, or placebo over 26 weeks. Mean percentage weight reductions were greater with all cagrilintide doses (6.0–10.8%) versus placebo (3.0%), with estimated treatment differences of 3.0–7.8% (p<0.001 for all doses). The 4.5 mg dose also produced significantly greater weight loss than liraglutide (10.8% vs. 9.0%; difference 1.8%; p=0.03). Adverse events were predominantly gastrointestinal and dose-dependent; the trial established the dose range for subsequent Phase 3 development.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01751-7/fulltext
Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2.4 mg for weight management: a randomised, controlled, phase 1b trial
Phase 1b randomized, placebo-controlled, multiple-ascending-dose trial (Enebo and colleagues; Novo Nordisk) enrolled 95 adults with overweight or obesity (BMI 27–39.9 kg/m²) across six sequential cohorts receiving once-weekly cagrilintide 0.16–4.5 mg co-escalated with semaglutide 2.4 mg, or placebo plus semaglutide 2.4 mg, over 20 weeks. At week 20, weight loss with cagrilintide 2.4 mg + semaglutide was 17.1% versus 9.8% with semaglutide alone (difference −7.4%; 95% CI −11.2 to −3.5%), and with cagrilintide 4.5 mg was 15.4% versus 8.0% (difference −7.4%; 95% CI −12.8 to −2.1%). Adverse events, predominantly mild-to-moderate gastrointestinal in nature, occurred in 97% of cagrilintide-treated and 96% of placebo participants; no serious safety signals were identified, supporting CagriSema Phase 2 advancement.
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
Multicentre, randomized, double-blind, active-controlled Phase 2 trial (Frias and colleagues) conducted at 17 US sites enrolled 92 adults with type 2 diabetes (BMI ≥27 kg/m², on metformin ± SGLT2 inhibitor) over 32 weeks. Participants were randomized to once-weekly subcutaneous CagriSema 2.4/2.4 mg (n=31), semaglutide 2.4 mg (n=31), or cagrilintide 2.4 mg (n=30). The primary endpoint, HbA1c change, was −2.2 percentage points with CagriSema versus −0.9 with cagrilintide (difference −1.3; 95% CI −1.7 to −0.8; p<0.0001), though not significantly different from semaglutide (−1.8 pp; p=0.075). Secondary weight-loss endpoint strongly favoured CagriSema (−15.6% vs. −5.1% semaglutide and −8.1% cagrilintide; both p<0.0001). Adverse events were mostly mild-to-moderate gastrointestinal; no severe hypoglycaemia or fatal events were reported.
Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity (REDEFINE 1)
Phase 3a randomized, double-blind, placebo-controlled trial (REDEFINE 1; Garvey and colleagues) enrolled 3,417 adults with obesity or overweight without diabetes across multiple countries; participants received once-weekly cagrilintide-semaglutide 2.4/2.4 mg (n=2,108), semaglutide 2.4 mg (n=302), cagrilintide 2.4 mg (n=302), or placebo (n=705) over 68 weeks. The combination achieved mean body-weight reduction of −20.4% versus −3.0% with placebo (difference −17.3 percentage points; 95% CI −18.1 to −16.6; p<0.001), significantly exceeding both monotherapy arms. Proportions achieving weight loss ≥5%, ≥20%, ≥25%, and ≥30% were all significantly higher with the combination versus placebo (p<0.001). Gastrointestinal adverse events occurred in 79.6% of combination-treated patients versus 39.9% on placebo, predominantly transient and mild-to-moderate.
Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes (REDEFINE 2)
Phase 3a randomized, double-blind, placebo-controlled trial (REDEFINE 2; Davies and colleagues) enrolled 1,206 adults with overweight or obesity and type 2 diabetes (HbA1c 7–10%) across 12 countries; 904 received once-weekly cagrilintide-semaglutide 2.4/2.4 mg and 302 received placebo, with lifestyle intervention in both arms, over 68 weeks. Mean body-weight change was −13.7% with the combination versus −3.4% with placebo (difference −10.4 percentage points; 95% CI −11.2 to −9.5; p<0.001). A key secondary endpoint showed 73.5% of combination-treated patients achieved HbA1c ≤6.5% versus 15.9% on placebo. Gastrointestinal adverse events were reported by 72.5% of the combination group, mostly transient and mild-to-moderate; the trial demonstrated clinically meaningful weight and glycaemic benefit in a T2DM population where weight-loss responses are typically attenuated.
Cardiovascular Safety and Efficacy of Cagrilintide-Semaglutide (CagriSema 2.4/2.4 mg) in Participants With Established Cardiovascular Disease (REDEFINE 3)
Phase 3, randomized, double-blind, placebo-controlled event-driven cardiovascular outcomes trial (REDEFINE 3; NCT05669755; Novo Nordisk) of once-weekly cagrilintide-semaglutide 2.4/2.4 mg in participants with established cardiovascular disease. The primary endpoint is time to first three-point major adverse cardiovascular event (3P-MACE: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), designed to test whether the combination's substantial weight-reduction effects translate into reduced cardiovascular event rates. The trial is ongoing; no results are yet available. This is the definitive cardiovascular safety and efficacy study required for potential broad cardiometabolic labeling of CagriSema.
Efficacy and Safety of Cagrilintide Alone and in Combination with Semaglutide (Cagrisema) as Anti-Obesity Medications: A Systematic Review and Meta-Analysis
Systematic review and meta-analysis pooling data from three randomized controlled trials enrolling 430 participants to compare cagrilintide monotherapy and the fixed combination of cagrilintide with semaglutide (CagriSema) against semaglutide or liraglutide monotherapy for obesity treatment. CagriSema produced significantly greater weight loss than semaglutide alone at 20–32 weeks, with a mean difference of approximately −9.1% body weight and −9.1 kg in absolute terms; by contrast, cagrilintide monotherapy achieved weight loss comparable to semaglutide or liraglutide (mean difference −1.8% and −1.9 kg), with significantly lower vomiting rates. Treatment-emergent and serious adverse events were broadly comparable between arms, although gastrointestinal events and vomiting were more frequent with CagriSema. The authors conclude that CagriSema outperforms semaglutide for weight reduction while cagrilintide monotherapy offers a similar weight-loss profile with a more tolerable gastrointestinal burden; notable limitations include high statistical heterogeneity (I² of 96–98%), a small number of included trials, and follow-up durations of 20–32 weeks that preclude conclusions about long-term durability.
https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15859
CagriSema demonstrated 23% weight loss in an open-label head-to-head REDEFINE 4 trial in people with obesity; the primary endpoint was not achieved
Press release (Novo Nordisk) reporting topline results from REDEFINE 4, an 84-week open-label, head-to-head phase 3 trial randomizing 809 adults with obesity (mean baseline weight 114.2 kg) to once-weekly subcutaneous CagriSema 2.4/2.4 mg or tirzepatide 15 mg. The primary endpoint — non-inferiority of CagriSema on weight loss — was not met: weight loss was 23.0% vs 25.5% (efficacy estimand) and 20.2% vs 23.6% (treatment-regimen estimand) for CagriSema and tirzepatide, respectively. Gastrointestinal adverse events were the most common finding in both arms, were predominantly mild-to-moderate, and diminished over time. Novo Nordisk characterized CagriSema as the first GLP-1/amylin combination for obesity and announced follow-on trials (REDEFINE 11 and higher-dose studies) to pursue greater weight-loss potential; full peer-reviewed publication is pending.
https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=916501
Novo Nordisk files for FDA approval of CagriSema, the first once-weekly combination of GLP‑1 and amylin analogues for weight management
Novo Nordisk press release (December 18, 2025) announcing the submission of a New Drug Application to the FDA for CagriSema — a fixed-ratio once-weekly subcutaneous combination of cagrilintide 2.4 mg (a long-acting amylin analog) and semaglutide 2.4 mg — for chronic weight management in adults with obesity or overweight and at least one weight-related comorbidity. The NDA is supported by the REDEFINE 1 trial (n=3,417), in which CagriSema produced 22.7% mean body weight loss versus 2.3% with placebo at 68 weeks, with 91.9% of participants achieving at least 5% weight reduction. Cagrilintide as a monotherapy remains investigational; its regulatory status is contingent on the outcome of this combination NDA.