Cagrilintide

Amylin is co-secreted with insulin by pancreatic beta cells and signals satiation through amylin receptors - calcitonin receptor cores complexed with receptor activity-modifying proteins - concentrated in the area postrema. Cagrilintide is a stabilised, acylated amylin analogue that resists aggregation (native human amylin is amyloidogenic) and binds all amylin receptor subtypes plus the calcitonin receptor, with a half-life long enough for weekly dosing. Because the receptor is distinct from GLP-1R, the satiety effects are additive rather than overlapping, and phase 2 data suggested a more favourable ratio of fat to lean mass loss than GLP-1 agonists produce. The lean-mass claim is promising but not yet definitively established by DEXA-powered trials.

Targets: Amylin receptors (AMY1-3), Calcitonin receptor

• · Escalated 300, 600, 1200, 2400 then 4500 mcg weekly at four-week intervals. The 4500 mcg arm gave 10.8% weight loss at 26 weeks; 2400 mcg gave about 9%, roughly matching liraglutide 3 mg.
• · This is what CagriSema formalises - cagrilintide titrated in parallel with semaglutide to a matched 2.4 mg. Do not escalate both drugs on the same week.

Work out your exact syringe units →

• very commonNausea— Peaks after each dose increase; often described as milder and shorter than GLP-1 nausea.
• commonVomiting
• commonInjection-site reactions
• commonConstipation
• commonEarly satiety to the point of under-eating protein— The satiety is meal-terminating rather than hunger-blunting, so people stop mid-meal. Front-load protein.

• Pregnancy.
• History of pancreatitis (class caution when combined with GLP-1 agonists).
• Severe gastroparesis.

• synergysemaglutide — The defining combination - separate receptors, additive satiety, formalised as CagriSema.
• synergytirzepatide — Used the same way anecdotally; no trial data for this pairing.
• redundantpramlintide — Both are amylin analogues; pramlintide is simply the short-acting version.
• cautioninsulin-analogues — Amylin analogues plus insulin is the combination that gives pramlintide its hypoglycaemia boxed warning.

• · Weight and body composition - the lean-mass question is the whole point of using it.
• · Protein intake, which is easy to undershoot on amylin.
• · Nausea severity around dose steps.

Investigational as monotherapy; not approved in any jurisdiction. Widely sold as a research chemical.

• Lau et al. 2021, cagrilintide phase 2 dose-finding trial, The Lancet (trial)
• Enebo et al. 2021, cagrilintide plus semaglutide phase 1b, The Lancet (trial)

Amylin is co-secreted with insulin from the beta cell in roughly a 1:100 molar ratio, and it does three things that GLP-1 does not. It slows gastric emptying through a vagally mediated pathway that is distinct from the GLP-1 route. It suppresses postprandial glucagon. And it produces satiation - the meal-terminating signal - through the area postrema, using a receptor architecture that has no overlap with the incretin receptors. That architecture is worth understanding, because it explains why cagrilintide behaves the way it does: the amylin receptors are not standalone proteins but heterodimers of the calcitonin receptor with receptor activity-modifying proteins, giving AMY1R (CTR plus RAMP1), AMY2R (RAMP2) and AMY3R (RAMP3). Cagrilintide is a non-selective agonist across these and also retains meaningful activity at the calcitonin receptor itself, which is a real difference from selective amylin agonists like eloralintide and is the likely reason its tolerability profile is not as clean. The clinically interesting property is lean-mass preservation. Amylin signalling appears to reduce food intake without producing the same magnitude of counter-regulatory drop in energy expenditure and without the same lean-tissue catabolism seen with pure incretin-driven weight loss, though the evidence for this is DEXA sub-analyses rather than a dedicated trial. Cagrilintide monotherapy gave about 10.8% weight loss at 26 weeks at 4.5 mg in phase 2, which is respectable for a mechanism that nobody was taking seriously five years ago, and it is the basis for combining it with semaglutide rather than replacing it.

Escalating too fast is the main one - cagrilintide's nausea is dose-dependent and it stacks with whatever incretin is already on board, so people who add it at 2.4 mg to an existing tirzepatide dose have a bad two weeks. Second, expecting it to replace an incretin: 10.8% monotherapy at 26 weeks is real but it is not tirzepatide, and cagrilintide's role is as an addition. Third, the calcitonin receptor activity is an unmonitored risk. Chronic calcitonin agonism affects bone turnover, and nobody has run a long bone-density study in people using cagrilintide during rapid weight loss - if you are going to run it for a year, get a baseline DEXA. Fourth, everything sold direct to consumers is research-grade, unapproved and of unverifiable identity.

1. 300 mcgWeeks 1-4 — The phase 2 dose-finding trial studied 0.3, 0.6, 1.2, 2.4 and 4.5 mg weekly. Escalation was stepwise over 26 weeks.
2. 600 mcgWeeks 5-8
3. 1.2 mgWeeks 9-12
4. 2.4 mgWeeks 13-16 — This is the dose used in the CagriSema fixed combination.
5. 4.5 mgWeek 17 onward — The top phase 2 monotherapy dose, which gave about 10.8% weight loss at 26 weeks.

• AMY1R (calcitonin receptor plus RAMP1) — Not verified; described as a non-selective amylin receptor agonist

  Area postrema satiation signalling - the meal-termination signal, which feels different from GLP-1 appetite suppression and is often described as fullness arriving earlier rather than hunger being absent.

• AMY3R (calcitonin receptor plus RAMP3) — Not verified

  Contributes to central satiation and to slowed gastric emptying.

• Calcitonin receptor (CTR) — Retains meaningful activity, unlike selective amylin agonists

  Off-target relative to the intended mechanism. Calcitonin receptor activity affects bone turnover and calcium handling, and is the most likely source of the tolerability differences versus selective agonists such as eloralintide.

• Cagrilintide phase 2 dose-finding (monotherapy) Phase 2 · n=706 · 26 weeks · 2021

  Mean weight loss of 10.8% at 4.5 mg weekly versus 3.0% for placebo, with liraglutide 3.0 mg as an active comparator.

Week 1-2: satiation appears, described by most users as feeling full sooner rather than being less hungry - a qualitatively different sensation from GLP-1 appetite suppression. Weeks 4-5: approximate steady state. Weeks 8-26: weight loss accrues steadily; the phase 2 curve had not clearly plateaued at 26 weeks. Stopping: appetite returns over one to two weeks.

The intended partner is semaglutide, and that combination exists as a formal fixed-dose product rather than something you assemble. The mechanistic argument is genuinely good: amylin receptors and GLP-1 receptors are separate, the satiety signals are additive rather than redundant, and the lean-mass data point in the right direction. People routinely pair cagrilintide with tirzepatide instead, which is a reasonable extrapolation with zero trial support - REDEFINE 4 compared CagriSema against tirzepatide and failed to show non-inferiority, which is worth sitting with before assuming the combination is obviously better than tirzepatide alone. If you are running it, the same non-negotiables apply: resistance training, 1.6-2.2 g/kg protein. Consider a baseline bone density scan given the unresolved calcitonin receptor question.

Against pramlintide: same receptor family, completely different practicality - pramlintide has a 48-minute half-life and needs three injections a day, cagrilintide is weekly. Against petrelintide and eloralintide: those are the next generation, and both are selective amylin receptor agonists without cagrilintide's calcitonin receptor activity. Eloralintide's phase 2 reported around 20% weight loss with strikingly good tolerability, which if it holds up makes cagrilintide look like a first-generation compound. Against semaglutide alone: cagrilintide is not a replacement, it is an addition, and the whole point of the molecule is what it adds.

$80–$300/month. Grey market only; there is no approved monotherapy product anywhere. Market observation from mid-2026, not verified pricing.

• ?No verifiable human pharmacokinetic parameters exist - volume of distribution, clearance, protein binding, bioavailability and tmax are all unresolved.
• ?The lean-mass preservation claim rests on DEXA sub-analyses rather than a dedicated powered trial.
• ?The long-term consequences of chronic calcitonin receptor agonism on bone density have not been studied in this population.
• ?The exact sequence and the specific anti-amyloid substitutions were not verified.
• ?Whether cagrilintide adds anything on top of tirzepatide specifically has never been tested; REDEFINE 4's failure against tirzepatide is the closest evidence and it is indirect.
• ?Cost figures are market observations, not verified pricing.

• 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 Lau DCW et al., Lancet, 2021 · PMID 34798060

  The only substantial cagrilintide monotherapy dataset. Everything else is CagriSema.

• Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity Garvey WT et al., N Engl J Med, 2025 · PMID 40544433

  REDEFINE 1 - what cagrilintide adds on top of semaglutide.

• Amylin and the Renin-Angiotensin System: Risk or Opportunity in Amylin-Based Therapy? Muskiet MHA et al., Lancet, 2026 · PMID 41207308

  A commentary on an underdiscussed amylin-class question - renin-angiotensin effects - worth reading before assuming amylin analogues are mechanistically clean.