Cagrilintide
A long-acting amylin analogue that reinforces satiety through a pathway distinct from GLP-1, best known as the amylin half of the CagriSema combination.
Cagrilintide is an investigational long-acting synthetic amylin analogue developed by Novo Nordisk for weight management. It activates amylin and calcitonin receptors in the brainstem to promote satiety and reduce caloric intake, an appetite pathway separate from GLP-1. As a once-weekly monotherapy it produced up to ~10.8% weight loss in a Phase 2 trial, and it is co-developed with semaglutide as the fixed-dose combination CagriSema, which reached roughly 20-23% weight loss in Phase 3.
Class
Synthetic long-acting amylin (and calcitonin) receptor agonist; 37-amino-acid acylated peptide
Half-life
~159 hours (approximately 6-7 days), enabling once-weekly dosing
Routes
Subcutaneous
Category
Weight Loss & Metabolic
Researched benefits
What it's studied for
Weight loss
As a once-weekly monotherapy, cagrilintide produced dose-dependent weight loss of roughly 6.0% to 10.8% over 26 weeks in the Phase 2 dose-finding trial (11.8% at 68 weeks in Phase 3 REDEFINE-1), a genuine single-mechanism signal for an amylin analogue.
Appetite suppression via a non-GLP-1 pathway
Amylin and calcitonin receptor agonism in the area postrema and lateral parabrachial nucleus reinforces meal-related satiety through neural circuits distinct from GLP-1, reducing meal size and total caloric intake.
Mechanistic synergy with semaglutide (CagriSema)
Because amylin and GLP-1 engage different brainstem and hypothalamic neuron populations, combining the two produced additive weight loss — ~15.6-17.1% at 32 weeks in Phase 2 and ~20-23% at 68 weeks in Phase 3 — without proportionally more GI side effects.
Beat liraglutide head-to-head
In the same Phase 2 trial, cagrilintide 4.5 mg (10.8%) was superior to liraglutide 3.0 mg (9.0%), P=0.03, a within-trial comparison demonstrating competitive efficacy against an approved GLP-1 agonist.
Glucagon suppression and modest glucose effects
Cagrilintide slows gastric emptying (blunting post-meal glucose spikes) and may suppress inappropriate glucagon secretion, though its glycemic effects are modest and it is not positioned as a standalone diabetes therapy.
Convenient once-weekly dosing
Fatty-acid acylation extends the half-life from native amylin's 13 minutes to ~159 hours, solving the pharmacokinetic limitation that made its predecessor pramlintide (three-times-daily) commercially unsuccessful.
Mechanism
How it works
Cagrilintide is a long-acting analogue of human amylin, the 37-amino-acid pancreatic hormone co-secreted with insulin by beta cells in response to nutrient ingestion. Amylin signals satiety, slows gastric emptying, and suppresses postprandial glucagon. Cagrilintide engages amylin receptors — heterodimeric complexes of the calcitonin receptor (CTR) with receptor activity-modifying proteins (RAMP1/2/3, forming the AMY1R, AMY2R, AMY3R subtypes) — while retaining balanced calcitonin receptor binding.
The primary weight-loss mechanism is central. Amylin receptor signaling in the area postrema and other circumventricular organs (which lack a complete blood-brain barrier) generates satiety signals that propagate through the nucleus tractus solitarius to hypothalamic feeding centers, reducing meal size and caloric intake. Cagrilintide also mildly slows gastric emptying, contributing to early satiety.
The rationale behind CagriSema is mechanistic synergy: GLP-1 (semaglutide) acts on POMC/CART neurons in the arcuate nucleus, area postrema, and brainstem, while amylin (cagrilintide) acts preferentially on the area postrema and lateral parabrachial nucleus. Engaging two distinct anorexigenic circuits produces additive or super-additive weight loss without proportionally intensifying activation of any single circuit to intolerable levels.
The half-life extension comes from a fatty acid side chain (a C18 diacid linked to a lysine via a gamma-Glu-gamma-Glu spacer) that reversibly binds human serum albumin with nanomolar affinity. This protects the molecule from renal filtration and enzymatic clearance, extending the apparent half-life to ~159 hours, producing relatively flat plasma profiles (reducing peak-related nausea) and enabling once-weekly subcutaneous dosing. Like all clinical amylin analogues, cagrilintide substitutes key amyloidogenic residues (e.g., proline substitutions) to block the fibrillation pathway of native amylin while preserving receptor binding.
Dosing protocols
Dosing & administration
Dosing reflects protocols reported in research and community literature for educational purposes. It is not medical advice or a recommendation. Most peptides here are not approved for human use.
Reconstitution
Typically supplied as lyophilized powder in 2-10 mg vials. Reconstitute with bacteriostatic water: e.g., a 10 mg vial + 5 mL BAC water yields 2 mg/mL (a 2.4 mg dose = 1.2 mL / 120 units on an insulin syringe); a 5 mg vial + 2.5 mL BAC water also yields 2 mg/mL. Inject the water slowly down the vial wall, swirl gently (never shake), and let dissolve 2-3 minutes to a clear, colorless solution. Store lyophilized at 2-8C; reconstituted solution keeps ~28 days refrigerated at 2-8C. Never freeze; protect from light.
Beginner (monotherapy titration)
- Dose
- 0.16-0.3 mg escalating to 2.4 mg
- Frequency
- Once weekly
- Timing
- Same day each week, any time of day
- Duration
- ~16 weeks titration
- Route
- Subcutaneous
Community protocols step 0.16 mg (wk 1-4), 0.3 mg (wk 5-8), 0.6 mg (wk 9-12), then 1.2 mg to 2.4 mg. Phase 2 monotherapy titrated 0.3 to 0.6 to 1.2 to 2.4 to 4.5 mg every 4 weeks. Slow escalation minimizes GI side effects.
Intermediate / CagriSema combination
- Dose
- Cagrilintide 2.4 mg + semaglutide 2.4 mg
- Frequency
- Once weekly (two separate injections)
- Timing
- Consistent weekly schedule; the two drugs cannot be pre-mixed in one syringe
- Duration
- Months 4-12 (full-dose maintenance phase)
- Route
- Subcutaneous
16-week titration precedes full dose: sema 0.25/cagri 0.3, then 0.5/0.6, then 1.0/1.2, then 1.7/2.4, then 2.4/2.4. Most weight loss occurs in this phase; expected ~18-22% by month 12.
Advanced / maintenance
- Dose
- Full 2.4/2.4 mg, or reduced 1.2/1.2 mg
- Frequency
- Once weekly
- Timing
- Any consistent weekly time
- Duration
- Long-term / ongoing
- Route
- Subcutaneous
After target weight, options include continued full-dose maintenance (strongest anti-regain evidence), reduced half-dose maintenance, semaglutide-alone maintenance, or gradual taper. Discontinuation typically leads to partial weight regain.
- Cagrilintide is investigational; there is no approved standalone product and no lawful US pharmacy access to the monotherapy before approval. Doses studied in trials (0.3-4.5 mg weekly monotherapy) were administered under clinical supervision.
- The 16-week titration exists to minimize gastrointestinal side effects, which concentrate during dose escalation and generally diminish with continued dosing. Slower titration (20-24 weeks) may suit patients with strong initial GI response, the elderly, or those with complex conditions.
- Approximate Phase 2 dose-response for monotherapy: 0.3 mg ~2%, 0.6 mg ~4%, 1.2 mg ~6%, 2.4 mg ~8%, 4.5 mg ~11% weight loss at 26 weeks.
- Rotate injection sites (abdomen, thigh, upper arm) each week to prevent irritation and lipohypertrophy. Any day/time works given the long half-life; consistency matters more than timing.
- Prioritize protein (1.6-2.0 g/kg ideal body weight) and resistance training to preserve lean mass during rapid weight loss. Monitor HbA1c, lipids, liver enzymes, thyroid, and body composition periodically.
- The GLP-1 component of CagriSema is associated with retained gastric contents; some guidelines suggest holding before surgery and coordinating with the surgical team.
Evidence
Research & clinical studies (10)
Cagrilintide 2.4 mg once-weekly subcutaneous injection in adults with overweight or obesity (SCALE-CAGRI): a randomised, double-blind, placebo-controlled trial
In a 26-week Phase 2 dose-finding trial (n=706 across 10 countries), once-weekly cagrilintide reduced mean body weight up to 10.8% at 4.5 mg versus 3.0% for placebo, with the top dose superior to liraglutide 3.0 mg (9.0%, P=0.03).
PMID 34798060Combination of cagrilintide and semaglutide 2.4 mg for weight management in adults with overweight and obesity (CagriSema): a randomised, 1:1:1, double-blind, active-controlled, phase 2 trial
CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg) reduced mean body weight by 15.6% over 32 weeks, significantly exceeding semaglutide alone (-5.1%) or cagrilintide alone (-8.1%), suggesting synergistic weight loss.
PMID 37364590Safety, 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
Co-administered cagrilintide and semaglutide 2.4 mg was well tolerated with 15.4-17.1% weight loss at 20 weeks versus 8.0-9.8% for semaglutide-matched cohorts, with no pharmacokinetic interaction between the compounds.
PMID 33894838Efficacy and safety of co-administered cagrilintide and semaglutide versus semaglutide alone in adults with overweight or obesity with or without type 2 diabetes in Japan and Taiwan (REDEFINE 5): a multicentre, randomised, active-controlled, phase 3a trial
The fixed-dose cagrilintide + semaglutide combination produced greater bodyweight reductions than semaglutide alone in an East Asian population with or without type 2 diabetes.
PMID 42009015Novel Amylin-Based Therapies for Weight Management in Adults With Overweight or Obesity Without Diabetes: A Network Meta-Analysis
Novel amylin-based therapies achieved greater weight reduction than established anti-obesity medications, though with increased gastrointestinal adverse events (nausea, vomiting, constipation).
PMID 42175595Cagrilintide and CagriSema for weight reduction and metabolic risk modification in overweight or obesity: a systematic review and meta-analysis
Cagrilintide alone and CagriSema produced clinically meaningful weight reductions versus placebo, with CagriSema also improving waist circumference and blood glucose and acceptable tolerability.
PMID 42180166A cross-species atlas of the dorsal vagal complex reveals neural mediators of the effects of cagrilintide on energy balance
Mapped the neural circuits in the dorsal vagal complex that mediate cagrilintide's effects on energy balance across species.
PMID 42260119Cellular loci for cagrilintide action identified
Identified the specific cellular sites of cagrilintide action underlying its effects on energy balance.
PMID 42260118Obesity pharmacotherapy reimagined: The era of multi-receptor agonists and next-generation metabolic modulators
Positions cagrilintide as a long-acting amylin pathway analog achieving weight reductions up to 24% via neuroendocrine circuits independent of GLP-1 receptor mechanisms.
PMID 41948476Beyond weight loss: multisystem benefits of obesity medications
Found multisystem benefits of late-stage obesity medications including cagrilintide-semaglutide across type 2 diabetes, cardiovascular disease, metabolic liver disease, sleep apnoea, and quality of life.
PMID 42208956Combinations
Stacking & blends
CagriSema
Maximum evidence-based weight loss
The fixed-dose combination Novo Nordisk filed with the FDA. Amylin (cagrilintide) and GLP-1 (semaglutide) engage different appetite circuits, producing additive weight loss (~15-17% at 32 weeks Phase 2; ~20-23% at 68 weeks Phase 3) without proportionally more GI side effects. This is the only clinical-trial-validated cagrilintide combination.
Lean-mass preservation support
Preserve lean muscle during rapid weight loss
Community advanced protocols pair CagriSema with GH-axis peptides (Sermorelin or CJC-1295/Ipamorelin for lean mass, Tesamorelin for visceral fat) when DEXA shows excessive lean-mass loss. GH peptides are dosed in the evening; CagriSema at any weekly time. No clinical trial data supports this combination.
Recovery adjunct
Support joints and tissue during increased training
Community protocols add repair peptides (BPC-157, TB-500) to support connective tissue during the increased resistance training used to preserve lean mass. Timing is independent of CagriSema. Experimental, not trial-validated.
Safety
Side effects & considerations
Commonly reported effects
Contraindications & cautions
- Personal or family history of medullary thyroid carcinoma (MTC)
- Multiple endocrine neoplasia type 2 (MEN2)
- Known hypersensitivity to cagrilintide, semaglutide, or components
- Pregnancy and breastfeeding
- Active eating disorder (anorexia nervosa, severe bulimia)
- History of bowel obstruction
- Active cancer history
- Severe untreated psychiatric conditions
Most GI effects are mild-to-moderate, dose-dependent, concentrate during dose escalation, and diminish with continued dosing. Injection-site reactions occurred more frequently with cagrilintide than semaglutide alone. Relative-caution conditions include history of pancreatitis, severe gastroparesis, gallbladder disease (increased risk during rapid weight loss), inflammatory bowel disease, and severe renal impairment. Insulin (20-40% reduction) and sulfonylureas may need dose adjustment for hypoglycemia risk. There is a theoretical MTC association based on rodent studies of related agents. Long-term (>5 year) safety data is limited as the drug is still in development.
FAQ
Cagrilintide — common questions
What is cagrilintide?
Cagrilintide is a long-acting synthetic amylin analogue developed by Novo Nordisk for obesity. Amylin is a pancreatic hormone co-secreted with insulin that signals satiety; cagrilintide is acylated to extend its half-life to ~7 days for once-weekly subcutaneous dosing. It is best known as the amylin half of the CagriSema combination but is also an investigational standalone agent.
How does it work?
It activates amylin and calcitonin receptors in the area postrema and other brainstem regions to reinforce meal-related satiety — a pathway distinct from GLP-1. This reduces meal size and total caloric intake, and it mildly slows gastric emptying. A fatty acid side chain binds albumin to extend the half-life and enable once-weekly dosing.
What is the difference between cagrilintide and CagriSema?
Cagrilintide is the standalone amylin analogue; CagriSema is the fixed-dose combination of cagrilintide plus semaglutide. Cagrilintide monotherapy produces modest weight loss (~10-12%), while CagriSema produces larger weight loss (~20%) because the amylin and GLP-1 mechanisms are additive. The deeper combo figures belong to CagriSema, not cagrilintide alone.
How effective is it for weight loss?
As a Phase 2 monotherapy, cagrilintide produced up to ~10.8% weight loss at 4.5 mg over 26 weeks and beat liraglutide 3.0 mg (9.0%) in the same trial. In Phase 3 REDEFINE-1, the 2.4 mg monotherapy cut weight ~11.8% at 68 weeks, while the CagriSema combination reached roughly 20-23% at 68 weeks — comparable to tirzepatide.
Is cagrilintide FDA-approved?
No. As a standalone it is investigational and in Phase 3 (RENEW). Novo Nordisk filed an NDA for the CagriSema combination in December 2025, currently under review, with possible approval in 2027-2028. Vendor cagrilintide is research-use-only and not approved for human consumption.
What are the main side effects?
The most common side effects are gastrointestinal — nausea, vomiting, decreased appetite, constipation, and diarrhea — generally mild-to-moderate and concentrated during dose escalation. Other effects include headache, fatigue, dizziness, and injection-site reactions. Serious concerns are largely theoretical (pancreatitis, gallbladder disease during rapid weight loss, and an MTC association based on rodent data).
How does it differ from pramlintide (Symlin)?
Both are amylin analogues, but pramlintide (approved 2005 for diabetes) has a short half-life requiring three-times-daily injection, which limited its success. Cagrilintide's fatty-acid acylation extends the half-life to ~159 hours for once-weekly dosing and it is developed primarily for obesity, making it a fundamentally more convenient option.
What happens if I stop taking it?
Like other weight-loss medications, discontinuation typically leads to partial or complete weight regain — semaglutide data shows roughly 50-60% of lost weight regained within 1-2 years. Gradual dose reduction, sustained lifestyle habits, and possible lower-dose maintenance help minimize regain; for many, ongoing treatment is becoming the standard approach.
