Cagrilintide: what it is, how it works and what studies have found

Cagrilintide is a long-acting amylin analogue: a lipidated version of a pancreatic hormone that, in its natural form, lasts minutes and readily forms amyloid fibrils. It is studied on its own and, more extensively, in combination with the GLP-1 receptor agonist semaglutide. This overview covers its structure and how it differs from amylin and pramlintide, its receptor pharmacology and half-life, and the phase 1 to phase 3 findings, including the REDEFINE programme. Cagrilintide is investigational; nothing here is medical or usage guidance.

What is cagrilintide?

Cagrilintide is “the stable, lipidated long-acting amylin analogue” selected for clinical development with obesity as an indication [5]. Its starting point was the difficulty of amylin itself: “a hallmark of the pancreatic hormone amylin is its high propensity toward the formation of amyloid fibrils, which makes it a challenging drug design effort”, and the earlier analogue pramlintide “requires three daily injections due to its short half-life” [5]. Cagrilintide was engineered as a stable, lipidated, long-acting analogue and was studied with once-weekly administration [5] [10].

Most of the late-stage evidence concerns cagrilintide given together with semaglutide in the REDEFINE and REIMAGINE programmes. The monotherapy evidence base is smaller: the phase 2 dose-finding trial plus cagrilintide-alone arms inside the combination trials [11] [13] [16]. Keep that distinction in mind when reading the findings below.

Amylin is a 37-amino-acid peptide co-secreted with insulin by pancreatic beta cells. Its major role is glucoregulatory, it regulates energy metabolism, and it acts principally in the circumventricular organs of the central nervous system [6].

Cagrilintide structure and sequence

Property	Cagrilintide
INN	Cagrilintide [1]
Code	NN0174-0833 [2]
CAS number	1415456-99-3 [1] [2]
UNII	AO43BIF1U8 [1]
Molecular formula	C194H312N54O59S2 [2]
Molecular weight	About 4409 g/mol [2]
Monoisotopic mass	About 4406.25 Da [2]
Length	37 amino acids [1]
Sequence (one-letter)	KCNTATCATQRLAEFLRHSSNNFGPILPPTNVGSNTP-NH2 [1]
Disulfide	Cys2–Cys7 (cyclic disulfide) [1]
Lipidation	N-terminal amine of Lys1 acylated with a C20 fatty di-acid (19-carboxynonadecanoyl) through γ-glutamate [1]
C-terminus	Proline amide [1]

How cagrilintide differs from amylin and pramlintide

Aligning the sequences in the FDA substance record, UniProt and KEGG shows where the design changes sit [1] [3] [4]:

Position	Human amylin	Pramlintide	Cagrilintide
1 (N-terminus)	Lys, free amine	Lys, free amine	Lys, acylated with γGlu-C20 di-acid
2–7	Cys–Cys disulfide	Cys–Cys disulfide	Cys–Cys disulfide
14	Asn	Asn	Glu
17	Val	Val	Arg
25	Ala	Pro	Pro
28	Ser	Pro	Pro
29	Ser	Pro	Pro
37 (C-terminus)	Tyr-NH2	Tyr-NH2	Pro-NH2

Pramlintide’s prolines at 25, 28 and 29 are retained, and cagrilintide adds Glu14, Arg17 and a C-terminal Pro37. The cryo-EM work described below found that the Glu14 and Arg17 side chains form an intramolecular salt bridge that enhances helical stability, and that Pro37 interacts with the receptor extracellular domain [7]. The lipid sits on the N-terminus rather than on a lysine side chain, unlike semaglutide, which is acylated on lysine 26 [1] [23].

Cagrilintide mechanism of action

Amylin acts through multisubunit G protein-coupled receptors formed when a core receptor protein (the calcitonin receptor) is co-expressed with receptor activity-modifying proteins (RAMPs), giving several amylin receptor subtypes [6]. Cagrilintide is a dual amylin receptor and calcitonin receptor agonist (DACRA) [7] [8].

Finding	Evidence level	Ref
Cryo-EM structures with AMY1R-Gs and CTR-Gs show a similar binding mode at both receptors; Phe23 anchors the peptide at the transmembrane bundle	In vitro (structural)	[7]
Non-selective activation of Gs signalling through both the calcitonin receptor and AMY1R	In vitro (functional)	[7]
Acute treatment alters gene expression in area postrema Calcr/Ramp3 neurons, but activating those neurons does not change long-term food intake	Rat	[9]
Long-term treatment upregulates prolactin-releasing hormone in nucleus of the solitary tract Calcr/Prlh neurons; knocking down Prlh abolishes cagrilintide’s effects but not semaglutide’s	Rat	[9]

Because knocking down Prlh removed the effects of cagrilintide but not of semaglutide, the rat data suggest the two act through at least partly separate brainstem pathways [9]. The neural-circuit evidence is from rats; the cell populations were shown to be conserved in macaques and humans, but the mechanism has not been tested in people [9].

Cagrilintide half-life

Parameter	Value	Evidence level	Ref
Half-life	159–195 h	Phase 1b, adults with overweight or obesity	[10]
Median tmax	24–72 h	Phase 1b	[10]
Exposure	Proportional to cagrilintide dose; did not affect semaglutide exposure or elimination	Phase 1b	[10]
Comparator	Semaglutide half-life 145–165 h in the same study	Phase 1b	[10]

A half-life of 159 to 195 hours is roughly 6.5 to 8 days, close to semaglutide’s labelled elimination half-life of about 1 week [10] [23]. In the same study, cagrilintide did not alter semaglutide exposure or elimination when the two were given together [10].

Development history and timeline

Cagrilintide was developed by Novo Nordisk, which funded the trials below.

Date	Milestone	Ref
Jul 2018 to Dec 2019	Phase 1b combination study with semaglutide conducted	[10]
Mar to Aug 2019	Phase 2 monotherapy dose-finding trial randomises participants	[11]
2021	Phase 1b and phase 2 results published in the Lancet; discovery paper published in J Med Chem	[5] [10] [11]
2023	Phase 2 combination trial in type 2 diabetes published (Lancet)	[12]
Mar 2023	REDEFINE 3 cardiovascular outcomes trial starts	[17]
2025	REDEFINE 1 and REDEFINE 2 published (NEJM)	[13] [14]
Nov 2025	RENEW 1 monotherapy phase 3 trial starts	[19]
Dec 2025	Head-to-head trial versus tirzepatide reaches primary completion	[18]
2026	REDEFINE 5 and REIMAGINE 2 published	[15] [16]

Cagrilintide clinical trials: key studies and findings

Results are reported as published; dose levels are omitted, and “cagrilintide-semaglutide” is the co-administered combination studied in the trials.

Study	Phase / design	Population	n	Duration	Primary endpoint	Main finding	Ref
Phase 1b	1b, with semaglutide, placebo-controlled	Overweight or obesity, otherwise healthy	96	20 weeks + follow-up	Adverse events	Half-life 159–195 h; weight −15.4% to −17.1% in the three highest cagrilintide cohorts vs −8.0% to −9.8% (all on semaglutide)	[10]
Phase 2 monotherapy	2, placebo and liraglutide controlled	Overweight or obesity, no diabetes	706 cagrilintide + 200 controls	26 weeks	% weight change	−6.0% to −10.8% vs −3.0%	[11]
Phase 2 T2D	2, three-arm, double-blind	Type 2 diabetes, BMI ≥27	92	32 weeks	HbA1c change	Combination −2.2, semaglutide −1.8, cagrilintide −0.9 points	[12]
REDEFINE 1	3a, placebo and active controlled	Overweight or obesity, no diabetes	3,417	68 weeks	% weight change	Combination −20.4% vs −3.0%	[13]
REDEFINE 2	3a, placebo-controlled	Obesity or overweight with type 2 diabetes	1,206	68 weeks	% weight change	Combination −13.7% vs −3.4%	[14]
REDEFINE 5	3a, versus semaglutide	Japan and Taiwan, with or without diabetes	331	68 weeks	% weight change	Combination −18.4% vs −11.9%	[15]
REIMAGINE 2	3, multi-arm	Type 2 diabetes, BMI ≥25	2,713	68 weeks	HbA1c change vs semaglutide	−1.91 vs −1.75 points (difference −0.16)	[16]

Phase 2 monotherapy trial (Lancet 2021)

The dose-finding trial randomised 706 people to five once-weekly cagrilintide arms, 99 to daily liraglutide and 101 to placebo, at 57 sites in ten countries. At 26 weeks, mean weight reductions were 6.0% to 10.8% with cagrilintide versus 3.0% with placebo, and the highest cagrilintide arm exceeded liraglutide (10.8% vs 9.0%, estimated treatment difference 1.8%, p=0.03) [11]. This is the main published evidence for cagrilintide on its own; the RENEW phase 3 monotherapy trials started in November 2025 [19].

Phase 1b and phase 2 combination studies

The phase 1b trial co-administered escalating cagrilintide or placebo with semaglutide in 96 adults over 20 weeks. Its primary purpose was safety; the exploratory weight data showed greater reductions in the three highest cagrilintide cohorts (15.4% to 17.1%) than with placebo plus semaglutide (8.0% to 9.8%), and the authors called for larger and longer trials [10].

The 2023 phase 2 trial in type 2 diabetes (92 participants, 32 weeks) compared the combination with each component. HbA1c fell by 2.2 points with the combination, 1.8 with semaglutide and 0.9 with cagrilintide; the combination was better than cagrilintide but not significantly better than semaglutide (p=0.075). Body weight changed by −15.6%, −5.1% and −8.1% respectively, and time in glucose range rose to 88.9%, 76.2% and 71.7% [12]. With 30 to 31 people per arm, this is a small trial.

REDEFINE: phase 3 weight management

REDEFINE 1 enrolled 3,417 adults without diabetes with obesity, or overweight plus at least one obesity-related complication, randomised 21:3:3:7 to the combination, semaglutide alone, cagrilintide alone or placebo, plus lifestyle intervention, for 68 weeks. The estimated mean change in body weight was −20.4% with the combination versus −3.0% with placebo (difference −17.3 points, 95% CI −18.1 to −16.6) [13].

REDEFINE 2 randomised 1,206 adults with type 2 diabetes 3:1 to the combination or placebo. Body weight changed by −13.7% versus −3.4%, and 73.5% versus 15.9% reached HbA1c of 6.5% or less [14]. REDEFINE 5, in 331 participants in Japan and Taiwan, compared the combination directly with semaglutide: −18.4% versus −11.9% (difference −6.5 points) [15].

REIMAGINE: type 2 diabetes

REIMAGINE 2 randomised 2,713 people with type 2 diabetes in 30 countries to combination, semaglutide, cagrilintide or placebo arms for 68 weeks. HbA1c fell by 1.91 points with the higher combination arm versus 1.75 with matching semaglutide (difference −0.16, 95% CI −0.27 to −0.05) [16].

Ongoing trials

Trial	Question	Enrolment	Status (Oct 2026)	Ref
REDEFINE 3, NCT05669755	Cardiovascular outcomes of the combination	7,101	Active, not recruiting; primary completion expected September 2027	[17]
NCT06131437	Combination versus tirzepatide in obesity	809	Completed December 2025; results not yet published in a journal we could find	[18]
RENEW 1, NCT07220642	Cagrilintide monotherapy in overweight or obesity	300	Active, not recruiting	[19]

Safety findings reported in studies

In the phase 2 monotherapy trial, the most frequent adverse events were gastrointestinal disorders (nausea, constipation, diarrhoea) and administration-site reactions. Gastrointestinal events occurred in 41% to 63% of the cagrilintide groups versus 32% on placebo, mainly nausea (20% to 47% vs 18%); permanent discontinuation (10% overall) was similar across groups [11].

In the combination trials, gastrointestinal adverse events affected 79.6% with the combination versus 39.9% with placebo in REDEFINE 1, and 72.5% versus 34.4% in REDEFINE 2, mostly transient and mild to moderate [13] [14]. In REIMAGINE 2, adverse events were reported by 86.9% of participants in the higher combination arm, 82.2% in the cagrilintide-alone arm, 81.2% with semaglutide and 70.5% with placebo, with gastrointestinal disorders the most common [16]. In the phase 1b study, 37% of the 566 reported adverse events were gastrointestinal [10]. A 2026 review notes that nausea during initiation and up-titration is common across amylin analogues and mostly resolves with continued use [8]. Long-term cardiovascular safety will come from REDEFINE 3 [17].

Regulatory status by region

Region	Status (October 2026)	Ref
United States	Not approved, alone or in combination; no Drugs@FDA application record	[20]
European Union	Not authorised; no entry in EMA medicines data	[21]
Global	Investigational; INN assigned; phase 3 programmes completed and ongoing	[1] [17] [19]

Cagrilintide in laboratory research

Cagrilintide is a reference agonist for amylin-receptor research. Published applications include:

• Receptor pharmacology: Gs/cAMP signalling at AMY1R and the calcitonin receptor, and cryo-EM structural studies of the peptide-receptor complexes [7].
• Neuroscience: single-cell and spatial transcriptomics of the dorsal vagal complex, chemogenetic activation and gene knock-down in rats [9].
• Combination pharmacology: pairing with GLP-1 receptor agonists to study additive effects on food intake and body weight [9] [12].
• Analytical characterisation: reversed-phase HPLC or UPLC for purity, LC-MS for intact mass (monoisotopic mass about 4406.25 Da [2]), peptide mapping to confirm the N-terminal lipid, the three substitutions and the C-terminal proline amide, and a check of disulfide status (oxidised versus reduced forms differ by 2 Da). Because amylin-derived peptides are prone to fibril formation [5], an aggregation-sensitive method such as size-exclusion chromatography is a sensible addition.

Synthesis, purity and impurities

Cagrilintide is a synthetic peptide whose design started from amylin’s aggregation problem [5]. Three features shape its manufacture. The 37-residue chain is typically assembled by Fmoc solid-phase peptide synthesis (SPPS); the Cys2–Cys7 disulfide must be formed by controlled oxidation; and the γGlu-C20 di-acid is attached to the N-terminal amine. Purification is by preparative reversed-phase HPLC, followed by lyophilization. For route choices see SPPS vs LPPS.

Impurity classes to expect are deletion, insertion and truncated sequences (named in the EU synthetic peptide guideline, effective 1 June 2026 [22]), the reduced (open-chain) form and mis-bridged or dimeric disulfide species, incompletely acylated peptide, diastereomers, and deamidation at its asparagine and glutamine residues. Aggregates are a specific risk for amylin-derived sequences [5]. See peptide API impurities and specifications for how such impurities are specified.

Storage and stability of lyophilized cagrilintide

Cagrilintide for research and API use is a white to off-white lyophilized powder. Winhycare’s specification is storage at −20 °C, protected from light and moisture. Dry storage matters more than usual for this class, because amylin-derived peptides are prone to fibril formation in solution [5]. The broader science of lyophilisation and dry-powder stability is in lyophilised peptide stability and storage.

Cagrilintide versus related peptides

Property	Cagrilintide	Pramlintide	Semaglutide
Class	Long-acting amylin analogue [5]	Amylin analogue [6]	GLP-1 receptor agonist [23]
Receptors	Amylin receptors and calcitonin receptor [7]	Amylin receptors [6]	GLP-1 receptor [23]
Length	37 residues [1]	37 residues [4]	31 residues [23]
Lipid	C20 di-acid, N-terminal [1]	None [4]	C18 di-acid on Lys26 [23]
Half-life	159–195 h [10]	Short; three daily administrations [5]	About 1 week [23]
Status (Oct 2026)	Investigational [20] [21]	Approved (diabetes) [6]	Approved [23]

For the GLP-1 partner molecule see the semaglutide overview; for a different multi-receptor approach see retatrutide.

How Winhycare Pharma supplies cagrilintide

Winhycare Pharma supplies cagrilintide as research-use-only material for laboratories and, separately, as API to licensed pharmaceutical manufacturers and developers. Material is supplied at ≥99% purity by HPLC with a certificate of analysis for every batch, and custom synthesis (specified salt forms, purity grades, reference-standard quantities) is available. Specifications are on the cagrilintide supplier page; to request a quotation, use the peptide API enquiry form.

For laboratory research use only. Not for human or veterinary use.