What Has Research Described About Cagrilintide?

What is cagrilintide, and what hormone is it modelled on?

Cagrilintide is a synthetic peptide built on the sequence of amylin, a hormone whose identity was established in 1987. That year, Cooper and colleagues purified the major protein component of amyloid deposits from pancreatic tissue and reported a 37-amino-acid peptide with a calculated molecular mass of 3,905 Da, 46 percent identical in sequence to rat and human calcitonin gene-related peptide (source 1). That sequence relationship to the calcitonin peptide family turned out to matter for everything that followed, including how cagrilintide engages its receptors.

A 2015 review in Pharmacological Reviews by Hay, Chen, Lutz, Parkes and Roth summarized three decades of amylin physiology (source 2). In that account, amylin is secreted from pancreatic beta cells after a meal and circulates to receptors in the brainstem, where its activation was associated with suppressed glucagon release, reduced food intake and slower gastric emptying. The review also described pramlintide, an earlier amylin-based peptide, as already in clinical use at the time (source 2).

Cagrilintide belongs to the next generation of that line. Its developers described it in 2021 as a stable, lipidated, long-acting amylin analogue selected for clinical development (source 3). This post covers what the published record reports about its design, its receptors, where it acts in animal models and what controlled human studies measured. Like every profile on the Steadfast Research Group blog, it summarizes literature only and says nothing about research-grade material.

Why was native amylin a difficult starting point for a long-acting peptide?

The same 1987 discovery paper that identified amylin found it as the dominant component of amyloid, the insoluble fibrillar deposits seen in pancreatic islets (source 1). That tendency to aggregate is a practical problem for any attempt to formulate an amylin-based peptide as a stable solution.

Kruse and colleagues addressed it directly in the 2021 Journal of Medicinal Chemistry paper that reported cagrilintide's development (source 3). The authors identified the fibril-promoting region of the amylin sequence beyond position 20 and kept the proline substitutions at positions 25, 28 and 29 that occur naturally in rat amylin and were already used in pramlintide. Proline residues reduce the tendency of that stretch to form beta-sheet structure, and so reduce fibril formation. The paper also reported that the C-terminal amide was essential for receptor binding, so that end of the molecule was preserved.

How was cagrilintide engineered for a long half-life?

The second design goal was duration. The strategy reported in the 2021 paper was N-terminal lipidation: a fatty acid side chain attached at the start of the peptide (source 3). The authors reported that functional potency was retained when human amylin was lipidated in this way, and that structure-activity work across a series of analogues led to the compound designated cagrilintide. The paper described a non-selective agonist intended for formulation at low pH and for once-weekly subcutaneous administration in clinical studies (source 3).

The half-life that resulted was later measured in people. In a 2021 phase 1b study published in The Lancet, Enebo and colleagues reported a cagrilintide half-life of 159 to 195 hours across the dose groups studied, with a median time to maximum concentration of 24 to 72 hours (source 6). For comparison, the same study measured a semaglutide half-life of 145 to 165 hours, so both peptides in that trial persisted in circulation on a similar timescale. Plasma clearance and volume of distribution were reported as similar across groups (source 6).

Which receptors does cagrilintide activate?

Amylin does not have a single dedicated receptor. As the background to a 2025 eBioMedicine study set out, amylin binds a heterodimeric receptor built from the calcitonin receptor (CTR) paired with one of three receptor activity-modifying proteins, RAMP1, RAMP2 or RAMP3 (source 5). Each pairing forms a distinct amylin receptor subtype, giving three in total, while the calcitonin receptor alone remains a separate target.

CTR (calcitonin receptor)

The core G protein-coupled receptor. On its own it responds to calcitonin; it is also the shared component of every amylin receptor subtype.

AMY1R

CTR paired with RAMP1.

AMY2R

CTR paired with RAMP2.

AMY3R

CTR paired with RAMP3.

Dual amylin and calcitonin receptor agonist

A peptide that activates both the amylin receptor subtypes and CTR alone. The 2021 development paper reported cagrilintide's affinity for all three amylin receptor subtypes and the calcitonin receptor core, placing it in this category (source 3).

That non-selectivity was a deliberate feature rather than an accident of design, and it raised the question of whether all of those receptors contribute equally to what was observed in vivo. Two lines of work, one structural and one genetic, approached that question from opposite directions.

What did cryo-EM structures show about how cagrilintide binds?

In April 2025, Cao and colleagues reported cryo-electron microscopy structures of cagrilintide bound to each of its targets in an active, Gs protein-coupled state: AMY1R, AMY2R, AMY3R and CTR (source 4). They compared these with previously reported structures of the same receptors bound to rat amylin, salmon calcitonin and other recently developed amylin-based peptides.

The authors reported that cagrilintide adopted an amylin-like binding mode across the receptors. Where it differed was in motion: compared with the other peptides, cagrilintide induced distinct conformational dynamics in the calcitonin-family receptor complexes (source 4). The structures therefore offered a molecular explanation for why a single peptide could activate four related receptors, while leaving open how those dynamic differences translate into downstream signaling. The authors described the dynamics as something that could contribute to the clinical observations, not as a demonstrated link.

Where did cagrilintide act in mouse studies?

The genetic approach came from Carvas and colleagues, a University of Zurich and Novo Nordisk group, in their 2025 eBioMedicine paper (source 5). They used male mice lacking both RAMP1 and RAMP3, which removes the AMY1 and AMY3 receptor subtypes, alongside wild-type littermates. All animals were fed a high-fat diet for 23 weeks before a three-week study period in which they received vehicle, salmon calcitonin or cagrilintide.

In wild-type mice, cagrilintide reduced body weight by 3.4 ± 0.51 g. In mice lacking RAMP1 and RAMP3, cagrilintide's potency was impeded, while, notably, the efficacy of salmon calcitonin on body weight improved (source 5). Both peptides activated c-Fos, a marker of neuronal activation, in the dorsal vagal complex and the lateral parabrachial nucleus of wild-type mice. In the knockout animals given cagrilintide, the c-Fos signal in the area postrema, a hindbrain region, was 57 percent lower than in wild-type animals given the same peptide (source 5). The authors concluded that cagrilintide depended on the AMY1 and AMY3 receptor subtypes to lower body weight in this model, with area postrema neurons as a key site.

That result fits the brainstem-centred picture of native amylin described in the 2015 review (source 2), and it suggests that, despite activating CTR alone in receptor assays, cagrilintide's in vivo effect in these mice ran mainly through the RAMP-containing amylin receptors.

What did the first human pharmacology study report?

The 2021 phase 1b trial by Enebo and colleagues was designed to measure safety, tolerability, pharmacokinetics and pharmacodynamics when cagrilintide was given together with semaglutide (source 6). It randomized 96 adults aged 18 to 55 with a body-mass index of 27.0 to 39.9 kg/m², 95 of whom received study drug, at a single site in Kansas over a 20-week period. The mean age was 40.6 years, and 59 percent of participants were men.

Beyond the half-life figures already described, the investigators reported that adverse events were mild to moderate in severity, with gastrointestinal disturbance the most common category (207 events, 37 percent of the total), at similar rates across groups (source 6). Mean body-weight reductions of 15.7 and 17.1 percent were reported for two of the higher cagrilintide groups given with semaglutide, compared with 9.8 percent in the group given semaglutide with placebo. The authors framed the study as an early safety and pharmacology trial and called for larger and longer trials to assess the combination (source 6).

What did the phase 2 dose-finding trial measure?

Cagrilintide on its own was studied in a 26-week dose-finding trial reported in The Lancet later in 2021 by Lau and colleagues (source 7). The trial enrolled 706 adults with overweight or obesity and without type 2 diabetes across 57 sites in ten countries, and compared several once-weekly cagrilintide dose levels with placebo and with liraglutide as an active comparator.

Mean body-weight reductions from baseline ranged from 6.0 to 10.8 percent across the cagrilintide groups, compared with 3.0 percent with placebo (source 7). The highest cagrilintide group showed a 10.8 percent mean reduction versus 9.0 percent with liraglutide, an estimated difference of 1.8 percentage points (p = 0.03). Gastrointestinal adverse events were more frequent with cagrilintide than with placebo (41 to 63 percent versus 32 percent), mainly nausea (20 to 47 percent versus 18 percent), and the authors reported that most were non-serious and mild or moderate (source 7).

What did the larger phase 3 combination trial report?

The largest published study is REDEFINE 1, reported in the New England Journal of Medicine in 2025 by Garvey and colleagues (source 8). This 68-week, double-blind trial randomized 3,417 adults with overweight or obesity to cagrilintide combined with semaglutide (2,108 participants), semaglutide alone (302), cagrilintide alone (302) or placebo (705).

At week 68, the investigators reported mean body-weight changes of 20.4 percent with the combination, 11.5 percent with cagrilintide alone, 14.9 percent with semaglutide alone and 3.0 percent with placebo (source 8). For the purposes of a research profile, the most informative comparison is the cagrilintide-only arm: it gave the first long-duration, placebo-controlled measurement of the amylin analogue by itself, separate from its GLP-1 partner.

How do the published cagrilintide studies compare?

What remains unresolved in the cagrilintide literature?

Several gaps stand out. The receptor-dynamics finding from the cryo-EM work has not been tied to a specific downstream signaling difference (source 4). The knockout study used male mice only and removed two RAMPs at once, so it could not separate the contributions of AMY1R and AMY3R individually (source 5). The human trials were all conducted by investigators using a pharmaceutical product under regulatory oversight, in defined adult populations, and they are summarized here strictly as published literature. Nothing in them describes research-grade material, and none of the figures in this post should be read as applying beyond the conditions of the studies that produced them.

For laboratories working with any lipidated amylin analogue, the chemistry in source 3 also has a practical implication: the molecule is defined by a specific sequence plus an attached fatty acid side chain, so identity confirmation against that expected structure by mass spectrometry matters alongside a purity percentage. For context on the GLP-1 partner used in the combination trials, see the semaglutide mechanism post and the GLP-1 receptor agonist class overview.