Cagrilintide is a long-acting analogue of amylin, a pancreatic hormone involved in fullness and the body's response to a meal. Molecular changes help the peptide resist aggregation and remain in circulation, allowing researchers to study sustained amylin-family receptor activation for weight management. Cagrilintide has produced weight reduction on its own and is also the amylin component of CagriSema, where it is combined with semaglutide. The single-agent and combination findings answer different questions, and both remain important to its development. Kruse et al. (2021), Lau et al. (2021).
Overview
Molecular profile
Cagrilintide, previously called AM833 or NN0174-0833, is a chemically modified, lipidated amylin analogue. Native human amylin has a tendency to form amyloid fibrils, in which peptide molecules assemble into ordered fibres. That property complicates drug development. Kruse and colleagues studied sequence and chemical modifications that improved stability while retaining useful receptor activity, leading to selection of cagrilintide for clinical development. Kruse et al. (2021).
Uses and research areas
Weight management is the main area of single-agent research. Trials have enrolled adults with overweight or obesity without diabetes, initially to find an effective and tolerable exposure and later to compare cagrilintide with semaglutide and their combination. The combination programme also studies type 2 diabetes, where appetite, weight and glucose regulation can be assessed together. Lau et al. (2021), Garvey et al. (2025).
The renal and hepatic impairment studies address another practical question: whether organ dysfunction materially changes the peptide's circulating exposure. They measured pharmacokinetics after a single administration in separate groups classified by kidney or liver function. Their findings complement the efficacy trials by examining how the body handles cagrilintide in those settings. Nielsen et al. (2026).
Mechanism of action
Amylin is released from pancreatic beta cells alongside insulin after eating. It contributes to meal-ending signals, slows movement of food from the stomach and influences meal-related glucagon secretion. Cagrilintide uses the amylin receptor family to extend this kind of signalling.
An amylin receptor consists of the calcitonin receptor associated with one of three accessory proteins called RAMPs. Those partners shape peptide binding and produce the AMY1, AMY2 and AMY3 receptor complexes. Cagrilintide can activate all three and the calcitonin receptor itself. Cao and colleagues resolved cagrilintide-bound receptor structures and examined their movement, showing an amylin-like binding arrangement with distinctive interactions and dynamics. This broad receptor profile helps explain its classification as a dual amylin/calcitonin receptor agonist; the structural experiments do not determine how much each receptor contributes to weight loss in people. Cao et al. (2025).
The complementary rationale for combining cagrilintide with semaglutide follows from engaging two appetite-related receptor systems. Clinical comparisons with each component are needed to establish what the combination adds, because overlapping physiological effects cannot simply be added together mathematically.
Pharmacokinetics
Lipidation supports albumin association and prolonged exposure. Nielsen and colleagues measured plasma cagrilintide by liquid chromatography–tandem mass spectrometry after subcutaneous administration. In the renal study, the geometric mean terminal half-life in the normal-function group was 186 hours, with an observed range of 149–244 hours. Sampling continued through day 36. Nielsen et al. (2026).
Population: Adults with normal renal function (n=14) in the renal pharmacokinetic study. Administration: Subcutaneous single study administration; model begins after absorption. Analyte: Plasma cagrilintide measured by LC-MS/MS.
Nielsen and colleagues (2026) reported a 186-hour geometric mean terminal half-life in 14 adults with normal renal function after subcutaneous cagrilintide. The calculated curve starts at 100% in the elimination phase and follows C/C0 = 2^(-t/186), with time in hours. Individual estimates ranged from 149 to 244 hours; that range describes variation among participants. During repeated treatment, cagrilintide remaining from earlier administrations adds to later exposure. This single-decline illustration does not calculate that accumulation.
Nielsen MJF, Becker NP, Duus HHH, et al. (2026). Renal or Hepatic Impairment Does Not Affect Pharmacokinetics, Safety, or Tolerability of Subcutaneous Cagrilintide. Clinical pharmacokinetics 65(7):1087–1099. DOI: 10.1007/s40262-026-01654-0. Nielsen et al. (2026), Methods 2.3; Results 3.1.1 and Table 2: 186 hours, individual range 149–244 hours; sampling to day 36.
The renal study included 33 participants and the separate hepatic study 32. Neither showed a consistent impairment-related pattern in overall exposure. The small severe-impairment groups and single-administration design define the breadth of those findings. Nielsen et al. (2026).
Research findings
The single-agent weight trial
Lau and colleagues randomised 706 adults with overweight or obesity without diabetes to different doses of cagrilintide, the active medicine liraglutide, or placebo. Investigators measured body-weight change during 26 weeks of treatment and followed participants for another six weeks. The analysis estimating what would happen with continued treatment found mean weight reductions of 6.0%–10.8% across cagrilintide doses, compared with 3.0% for pooled placebo. The highest cagrilintide dose produced greater weight loss than the liraglutide regimen tested. Participants and investigators were masked to active treatment versus placebo, but knew which active medicine was being used. Lau et al. (2021).
This dose-finding trial established that sustained amylin-family activation could produce a clinically measurable weight effect by itself. Its shorter duration and adherence-assuming analysis are important when interpreting it alongside the later 68-week programme.
Direct separation of the combination and its components
The 32-week phase 2 diabetes study included 92 participants: 31 received cagrilintide plus semaglutide, 31 semaglutide and 30 cagrilintide. All had type 2 diabetes and a qualifying BMI and were using metformin with or without an SGLT2 inhibitor. Under the trial-product analysis, weight changes were −15.6%, −5.1% and −8.1%, respectively. The combination's HbA1c comparison with semaglutide was statistically inconclusive (P=0.075), even though weight loss favoured the combination. This result separates appetite-related weight effects from the study's glucose comparison. Frias et al. (2023).
REDEFINE 1 subsequently randomised 3,417 adults without diabetes, including 302 assigned cagrilintide alone and separate semaglutide, combination and placebo groups. Its four-arm structure permits direct comparisons within one trial. The main publication's prominent 20.4% weight reduction belongs to the cagrilintide–semaglutide combination under an analysis that included what happened after participants stopped or changed treatment (the treatment-policy estimand). Cagrilintide's own outcome belongs to its separate single-agent arm. REDEFINE 2 enrolled adults with type 2 diabetes and compared the combination with placebo, so it adds evidence about CagriSema without supplying another cagrilintide-alone estimate. Garvey et al. (2025), Davies et al. (2025).
Novo Nordisk's later single-agent analysis reported 11.8% mean weight reduction with cagrilintide versus 2.3% with placebo at 68 weeks, assuming all participants adhered to treatment. Its 2025 annual report also records initiation of the RENEW 1 and 2 phase 3 monotherapy trials. These are sponsor-reported findings and development updates attached to the cagrilintide arm and programme. Novo Nordisk (2025 annual report, published 2026).
The published REIMAGINE 2 diabetes trial also included 152 participants assigned cagrilintide alone within a 2,713-participant component-controlled study. Its primary comparison established a modest additional HbA1c effect for the combination versus semaglutide under the efficacy estimand. The single-agent arm provides its own safety observations: any adverse event occurred in 125 of 152 participants (82.2%), compared with 105 of 149 (70.5%) in pooled placebo. Buse et al. (2026).
Safety and tolerability
In the 26-week single-agent trial, gastrointestinal events occurred in 41%–63% of cagrilintide recipients across assignments, compared with 32% with placebo. Nausea occurred in 20%–47% versus 18%. These symptoms matter both to participants' experience and to the ability to continue treatment. The phase 2 diabetes comparison reported mainly mild or moderate gastrointestinal events and no level 2 or 3 hypoglycaemia. Lau et al. (2021), Frias et al. (2023).
Cagrilintide remains in clinical development as monotherapy as of October 13, 2026. The CagriSema application and studies concern a combination product and do not constitute approval of cagrilintide alone. Experience from relatively short trials also leaves questions about uncommon harms and long-term treatment persistence. Nielsen et al. (2026), Novo Nordisk (2026).
What the research means
Cagrilintide demonstrates that an amylin-based approach can reduce weight independently of GLP-1 receptor activation. Its engineered persistence connects the molecule's chemistry to sustained clinical exposure, while the component-controlled trials show why adding semaglutide changes the intervention being evaluated.
The important comparisons follow the actual trial groups. Single-agent findings describe the amylin analogue; CagriSema findings describe the combined treatment. Keeping that distinction allows the research to answer how much an amylin approach contributes, which outcomes change with a combination and how tolerability affects continuation.
FAQs
How does cagrilintide relate to native amylin?
It is an engineered analogue. The programme modified stability and circulating persistence to address properties such as native amylin’s fibril-forming tendency.
How does it differ from CagriSema?
Cagrilintide is one component. CagriSema combines it with semaglutide. Single-agent and combination arms describe different interventions and retain their own outcome percentages.
Why does the illustration use 186 hours?
That is the geometric mean terminal half-life in the normal renal-function group of the single-administration study. Its observed individual range of 149–244 hours is not a confidence interval.
Comparisons and related reading
Pramlintide provides an established clinical example of amylin-related pharmacology. Eloralintide and petrelintide illustrate other development approaches to long-acting amylin receptor agonism. CagriSema provides the direct combination context for cagrilintide.
References
The single-agent dose-finding trial reports cagrilintide weight change, comparator context and gastrointestinal tolerability.
The component-controlled diabetes trial distinguishes weight findings from the inconclusive HbA1c comparison with semaglutide.
REDEFINE 1 tests the combination and individual components within one randomised obesity cohort.
- Kruse T, Hansen JL, Dahl K, et al. (2021). Development of Cagrilintide, a Long-Acting Amylin Analogue. Journal of medicinal chemistry 64(15):11183–11194. DOI: 10.1021/acs.jmedchem.1c00565. · Journal record
The development report explains the stability and lipidation strategy used to select cagrilintide.
The structural study examines cagrilintide binding and dynamics at amylin and calcitonin receptors.
Two separate studies measure plasma cagrilintide across renal and hepatic function categories.
REDEFINE 2 reports combination outcomes in type 2 diabetes without separate component-only arms.
The sponsor reports cagrilintide-alone REDEFINE 1 results and RENEW initiation.
- Buse JB, Bajaj HS, Dalskov SM, et al. (2026). Cagrilintide-semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a double-blind, randomised, controlled, phase 3 study. Lancet Diabetes & Endocrinology 14(8):662–677. DOI: 10.1016/S2213-8587(26)00125-7. · PubMed record
REIMAGINE 2 finds a modest additional HbA1c effect and reports separate component safety.
The sponsor describes REIMAGINE 5 and REDEFINE 9 efficacy-estimand findings and investigational status.
Glossary
- Amylin
- A hormone released alongside insulin, involved in fullness and meal-related glucose regulation.
- RAMP
- A receptor activity-modifying protein that changes the pharmacology of its receptor partner.
- Amyloid fibril
- An ordered fibre assembled from peptide or protein molecules.
- Lipidation
- Attachment of a lipid-like group, used here to extend peptide exposure.
- Geometric mean
- An average calculated on a logarithmic scale, often used for pharmacokinetics.
- Trial-product estimand
- An intended-treatment effect assuming continued adherence under the trial’s defined conditions.
- SGLT2 inhibitor
- A glucose-lowering medicine that reduces kidney glucose reabsorption.