While attention went to GLP-1 analogues, a second pancreatic hormone quietly built a research line of its own. The state of that research, from molecular design to phase 3a.
MVMichel van der VeenRegistered Nurse · Science Editor, Peptalis Sources checked via PubMed · 5 referencesReviewed September 2026 · 9 MIN READGLP-1 dominates the conversation in metabolic peptide research. That focus is understandable, but incomplete. Pancreatic beta cells co-secrete a second hormone alongside insulin: amylin, a 37-amino-acid peptide released with every meal.
The beta cell's second hormone
Amylin slows gastric emptying, suppresses glucagon release and contributes to the satiety signal in the brain. The reference review by Hay and colleagues in Pharmacological Reviews (2015) lays out its unusual receptor biology: the calcitonin receptor only becomes amylin-selective once it assembles with accessory proteins called RAMPs. Those composite receptors are a research field of their own, and one reason amylin pharmacology lagged behind GLP-1 pharmacology for years.
Why amylin is a difficult molecule
Amylin has a notorious chemical flaw: it aggregates. The native peptide readily forms amyloid fibrils. The same property that makes it a pathological hallmark in type 2 diabetes islets makes it an unstable starting point for drug design. Kruse and colleagues at Novo Nordisk describe in Journal of Medicinal Chemistry (2021) how cagrilintide was engineered around this: a stabilised, lipidated amylin analogue whose fatty-acid side chain enables albumin binding. In the phase 1b study by Enebo and colleagues (The Lancet, 2021), cagrilintide showed a half-life of 159 to 195 hours, the pharmacokinetic basis for once-weekly dosing in the trials.
What the human studies did and showed
The clinical line is compact and well documented; the doses below are facts about the respective studies.
Phase 1b (Enebo et al., The Lancet 2021). 95 participants with overweight received once-weekly cagrilintide (0.16–4.5 mg, ascending) or placebo for 20 weeks, each alongside semaglutide 2.4 mg. Primarily a safety and pharmacokinetics study; gastrointestinal complaints made up 37% of reported events.
Phase 2 (Lau et al., The Lancet 2021). 706 participants, 26 weeks, once-weekly cagrilintide 0.3–4.5 mg as monotherapy versus placebo and versus daily liraglutide 3.0 mg. Weight reductions ranged from 6.0% to 10.8% versus 3.0% on placebo; the highest dose exceeded liraglutide (10.8% versus 9.0%).
Phase 3a REDEFINE 1 (Garvey et al., NEJM 2025). 3,417 participants, 68 weeks, cagrilintide 2.4 mg combined with semaglutide 2.4 mg (“CagriSema”) versus each alone and placebo. The combination produced a mean body-weight change of −20.4% versus −3.0% on placebo. Gastrointestinal events occurred in 79.6% of the combination group versus 39.9% on placebo, mostly transient and mild to moderate.
What makes this series notable: it is one of the few peptide research lines where the path from molecular design to a large phase 3 cohort can be followed publicly, peer-reviewed, within five years.
What remains open
Evidence for cagrilintide as monotherapy stops at phase 2; the phase 3 data concern the combination with semaglutide. How much the amylin mechanism contributes independently to the combined effect has therefore not been dissected. The receptor pharmacology itself also remains incompletely mapped: which RAMP assemblies carry the satiety signal, and where in the brain. For laboratories working on receptor pharmacology or peptide stabilisation, two concrete follow-up paths sit here: subtype-selective ligands, and the question of how lipidation changes the tissue distribution of this class of analogues.
About the authorMVMichel van der VeenRegistered Nurse · Science Editor, PeptalisRegistered nurse with eleven years in psychiatry and founder of Peptalis. Writes the platform's knowledge layer: compound profiles, evidence reviews and the quality methodology. Works from primary literature (PubChem for chemistry, PubMed for studies) and states where evidence is absent.
Sources checked via PubMed · 5 references
Compound profilesEvidence reviewsQualityIN THIS ARTICLE- The beta cell's second hormone
- Why amylin is a difficult molecule
- What the human studies did and showed
- What remains open
Compounds in this article
- Cagrilintide · Not in catalogue · Research profile
For laboratory research use only. Not for human use.
SCIENTIFIC REFERENCES
These references are provided for informational and research purposes only. They do not constitute medical advice.
- 01In vitro / chemistryDevelopment of Cagrilintide, a Long-Acting Amylin Analogue.Kruse T, Hansen JL, Dahl K, et al. J Med Chem. 2021;64(15):11183-11194.doi 10.1021/acs.jmedchem.1c00565View on PubMed →
- 02Human RCT (phase 1b)Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management.Enebo LB, Berthelsen KK, Kankam M, et al. Lancet. 2021;397(10286):1736-1748.doi 10.1016/S0140-6736(21)00845-XView on PubMed →
- 03Human RCT (phase 2)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, Erichsen L, Francisco AM, et al. Lancet. 2021;398(10317):2160-2172.doi 10.1016/S0140-6736(21)01751-7View on PubMed →
- 04Human RCT (phase 3)Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity.Garvey WT, Blüher M, Osorto Contreras CK, et al. N Engl J Med. 2025;393(7):635-647.REDEFINE 1 · doi 10.1056/NEJMoa2502081View on PubMed →
- 05ReviewAmylin: Pharmacology, Physiology, and Clinical Potential.Hay DL, Chen S, Lutz TA, Parkes DG, Roth JD. Pharmacol Rev. 2015;67(3):564-600.doi 10.1124/pr.115.010629View on PubMed →