Cagrilintide, also identified as AM833, is a long-acting amylin analog developed by Novo Nordisk for once-weekly subcutaneous dosing. Its half-life of roughly 159 to 195 hours, about seven days, comes from a C20 diacid lipid attached at the N-terminus via a gamma-glutamine linker. The primary indication under study is obesity and overweight, with a separate program in type 2 diabetes.

The molecule is built on a premlintide backbone rather than native amylin, with substitutions that stabilize an alpha helix through a salt bridge and a C-terminal Y37P change that enables calcitonin receptor agonism. This design preserves the amidated C-terminus essential for bioactivity, tolerates lipidation, and is non-fibrillating.

How it works

Cagrilintide is a dual CTR and amylin receptor agonist. It acts nonselectively across the amylin 1R, 2R, and 3R subtypes, which combine the calcitonin receptor with RAMP proteins. Its primary brain target is the area postrema, which relays to the nucleus tractus solitarius and is amplified at the lateral parabrachial nucleus. This circuit drives hindbrain satiety signaling.

Physiologically, amylin is co-secreted with insulin from pancreatic beta cells and supports glucose regulation through glucagon suppression, delayed gastric emptying, and satiety signaling. Amylin release is minimal in type 1 diabetes and dysregulated in type 2 diabetes and obesity.

Clinical evidence

Phase 2 dose-finding work reported up to about 10.8 percent body weight loss at the 4.5 mg dose over 26 weeks, with lower doses comparable to daily liraglutide. The REDEFINE program studied obesity and the REIMAGINE program studied type 2 diabetes. In phase 3, the fixed-dose combination with semaglutide, referred to as CagriSema, showed weight loss exceeding the sum of its components, while cagrilintide alone produced near 11 percent. The combination filing occurred in December 2025, with FDA approval anticipated in 2026. No clinically relevant QTc prolongation was noted.

Clinical application

Dosing follows a stepwise escalation, often starting at 0.25 mg weekly and titrating across roughly 16 weeks toward a 2.4 mg target, with up to 4.5 mg possible. The escalation can be slowed or held, and it should be tailored to each patient. GI events such as nausea, constipation, and diarrhea were most common, generally mild, and tended to diminish over time. Contraindications mirror the GLP-1 class, including personal or family history of medullary thyroid cancer or MEN 2.

Key clinical points

• Long-acting amylin analog (AM833) designed for once-weekly subcutaneous dosing, with a half-life near seven days.
• Acts as a dual CTR and nonselective amylin receptor agonist, driving hindbrain satiety through the area postrema to NTS to lateral parabrachial nucleus circuit.
• Monotherapy may support roughly 10 percent weight loss; combined with a GLP-1, reported weight loss reached about 22 percent.
• Slow, individualized dose escalation can reduce GI side effects; monitor weight, A1C, lipids, and blood pressure.
• Contraindicated with personal or family history of medullary thyroid cancer or MEN 2; use caution with pancreatitis or serious GI disease.