What is Cagrilintide?
Cagrilintide (AM833) is a long-acting acylated amylin analogue developed by Novo Nordisk. Unlike most compounds currently in development for weight management, it is not a GLP-1 agonist. Its mechanism of action is entirely distinct: it targets amylin receptors in the central nervous system, primarily in the area postrema of the brainstem.
Amylin is a pancreatic hormone co-secreted with insulin. It acts as a postprandial satiety signal and suppresses glucagon release after meals. Native amylin has a half-life of only minutes; cagrilintide has been modified through acylation to extend its half-life to 160–195 hours, enabling once-weekly injection.
Clinical interest in cagrilintide stems from its complementary profile to GLP-1 agonists: because it acts on a different receptor system, it can be combined with semaglutide to produce additive or synergistic effects on body weight without duplicating mechanisms.
Mechanism of Action
Cagrilintide acts primarily through the amylin receptor (calcitonin receptor-based complexes, AMY1-3) in the area postrema and nucleus tractus solitarius:
- Central satiety: Activates hypothalamic and brainstem circuits that reduce appetite and caloric intake.
- Postprandial glucagon inhibition: Suppresses glucagon secretion after meals, improving postprandial glycemic control without inducing fasting hypoglycemia.
- Gastric emptying delay: Slows the rate at which food leaves the stomach, extending satiety and blunting glycemic excursions.
- No GLP-1R activity: Unlike semaglutide or tirzepatide, it does not activate the GLP-1 receptor. This is clinically relevant because when combined with GLP-1 agonists, the two mechanisms operate in parallel rather than redundantly.
This mechanistic distinction is the rationale for CagriSema, the fixed-dose combination of cagrilintide + semaglutide currently in Phase 3.
Clinical Results
Monotherapy — Phase 2 (Lancet, 2021)
The 26-week trial evaluated cagrilintide at 0.3, 0.6, 1.2, 2.4, and 4.5 mg/week versus placebo in 706 adults with overweight or obesity:
- 4.5 mg/week: average weight loss of 10.8% of body weight.
- 2.4 mg/week: weight loss of 8.7%.
- Placebo: weight loss of 3.0%.
CagriSema — Combination with semaglutide (NEJM Evidence, 2023)
The 32-week Phase 2 trial evaluated the combination of cagrilintide 2.4 mg + semaglutide 2.4 mg against each drug alone:
- CagriSema: average weight loss of ~15.6% at 32 weeks.
- Phase 3 projections at 68 weeks point to ~20% weight loss, exceeding semaglutide monotherapy (~14.9%).
The REDEFINE Phase 3 trials have completed enrollment; full results are expected in 2025–2026.
Dose Escalation (Research-Reported Protocol)
| Weeks | Weekly Dose | Volume (3.33 mg/mL) | U-100 Units |
|---|---|---|---|
| 1–2 | 0.6 mg | 0.18 mL | 18 U |
| 3–4 | 1.2 mg | 0.36 mL | 36 U |
| 5–6 | 2.4 mg | 0.72 mL | 72 U |
| 7+ | 4.5 mg | 1.35 mL | 135 U |
Important note on maintenance dose: The 4.5 mg dose (135 units) exceeds the capacity of a standard 1 mL U-100 insulin syringe. A 3 mL syringe is required. This is a practical safety consideration that must be discussed with a physician before starting.
Slow titration is essential for minimizing nausea and gastrointestinal side effects.
Storage and Reconstitution
- Lyophilized (powder): -20 °C, protected from light.
- Reconstituted with BAC water (3.0 mL): 2–8 °C (refrigerated), maximum 30 days.
- Concentration after reconstitution: 3.33 mg/mL.
- Do not shake; gently invert to dissolve.
Adverse Effects
Adverse effects reported in clinical trials are consistent with the drug class:
- Gastrointestinal (most frequent): nausea, vomiting, diarrhea, constipation — predominantly during the first weeks and at each dose escalation step.
- Local injection site reactions: erythema, pruritus, or induration at the injection site.
- Transient fatigue: reported at treatment initiation.
- GI effects generally decrease once a stable dose is reached.
No relevant cardiac, renal, or hepatic safety signals have been reported in Phase 3 data to date.
Regulatory Status
The REDEFINE trials have completed enrollment. If results confirm efficacy and safety, Novo Nordisk could file for FDA/EMA approval for CagriSema as a fixed-dose combination in 2025–2026. Cagrilintide monotherapy may follow an independent regulatory pathway or be developed exclusively as a component of the combination.
Mandatory legal disclaimer: This content is for educational and informational purposes only. Cagrilintide is an investigational compound that has not received approval from the FDA, EMA, or any other health authority for clinical use in humans. This material does not constitute medical advice, does not diagnose conditions, and does not recommend treatments. It should not be used to make medical decisions. Always consult a licensed physician before starting any peptide protocol or modifying your current treatment. Research use only.
Reported protocol (research reference)
| Vial sizes | 10 mg |
|---|---|
| Reported dose | Research-reported protocol: Wks 1-2: 0.6 mg | Wks 3-4: 1.2 mg | Wks 5-6: 2.4 mg | Wks 7+: 4.5 mg (weekly, subcutaneous). NOTE: the 4.5 mg maintenance dose equals 135 units on a standard U-100 syringe; a 3 mL syringe is required. Always under medical supervision. |
| Half-life | 160–195 hours (~7–8 days) — supports weekly dosing. |
| FDA status | Investigational |