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Cagrilintide and amylin: the other satiety hormone

  • MDside
  • October 9, 2026

Key points

  • Amylin is a 37-amino-acid peptide co-secreted with insulin by the β-cell. It slows gastric emptying, suppresses glucagon and promotes meal termination [1][12].
  • Pramlintide, approved by the FDA in 2005, proved the concept but required injections with every meal [2][7].
  • In phase 2 (26 weeks), cagrilintide alone was associated with 6.0 to 10.8% weight reduction versus 3.0% with placebo, and the 4.5 mg dose outperformed liraglutide 3.0 mg [9].
  • In phase 3, the combination with semaglutide was associated with a 20.4% reduction (REDEFINE 1) and a 13.7% reduction in type 2 diabetes (REDEFINE 2) at 68 weeks [10][11].
  • Gastrointestinal events are the class’s main limit, and almost all data come from manufacturer-sponsored trials [9][10][14].

US status (October 2026): See the peptide status tracker.

Amylin is the other satiety hormone

Obesity pharmacology conversations usually start and end with GLP-1. Amylin is the other piece. It is a 37-amino-acid peptide that pancreatic β-cells release together with insulin after a meal [1][12]. It slows gastric emptying, suppresses postprandial glucagon secretion and promotes meal termination through central mechanisms [12].

Its receptor is unusual. There is no single “amylin receptor.” The calcitonin receptor combines with receptor activity-modifying proteins (RAMPs) to form several subtypes. Amylin acts mainly in the circumventricular organs of the central nervous system and interacts with other metabolic hormones such as cholecystokinin, leptin and estradiol [1]. This biology differs from that of GLP-1, which is why the field treats it as a complementary pathway.

Pramlintide proved the concept

Human amylin tends to form amyloid fibrils, which makes it hard to use as a drug [7]. The answer was pramlintide, a stable analog the FDA approved on March 16, 2005 as a new molecular entity (Symlin) [2]. Its indication was as an adjunct to mealtime insulin in type 1 and type 2 diabetes when desired control is not reached [3].

  • Type 1 diabetes (651 patients, 52 weeks): HbA1c reduction of 0.29 to 0.34 points versus 0.04 with placebo, and a 0.4 kg loss versus a 0.8 kg gain [4].
  • Insulin-treated type 2 diabetes (656 patients, 52 weeks): HbA1c down 0.62 points with 120 µg twice daily, and a 1.4 kg loss versus a 0.7 kg gain with placebo [5].
  • Obesity without diabetes (411 participants): at 12 months (146 evaluable), placebo-corrected loss was 5.6% and 6.8% with 120 µg three times daily and 360 µg twice daily, and 40 to 43% of those two arms reached at least 10% loss versus 12% with placebo [6].

The limit was practical. Its short half-life required three daily injections [7]. Drugs@FDA now lists all its presentations as discontinued [2]. It still showed that activating the amylin pathway is associated with lower weight.

Cagrilintide was built for weekly dosing

Cagrilintide was designed to solve the dosing problem. It is a stable, lipidated amylin analog designed for once-weekly administration [7], and it activates both amylin and calcitonin receptors (a dual agonist, or DACRA) [12]. In a phase 1b trial its half-life was 159 to 195 hours, roughly 7 days [8].

  • 2005: FDA approval of pramlintide [2]
  • 159 to 195 h: cagrilintide half-life in phase 1b [8]
  • 10.8%: weight loss with cagrilintide 4.5 mg alone at 26 weeks [9]

Cagrilintide alone beat liraglutide in phase 2

The reference trial for the molecule alone is the phase 2 study by Lau and colleagues, published in The Lancet in 2021 [9]. It randomized 906 adults without diabetes: 706 to five once-weekly cagrilintide doses (0.3 to 4.5 mg; 100 to 102 per group), 99 to daily liraglutide 3.0 mg and 101 to placebo, for 26 weeks.

With the trial product estimand, every dose was associated with greater reduction than placebo: 6.0 to 10.8% (6.4 to 11.5 kg) versus 3.0% (3.3 kg). The 4.5 mg dose outperformed liraglutide: 10.8% versus 9.0% (difference 1.8%, p = 0.03). The treatment policy estimand gave similar results [9]. Permanent discontinuation was 10% and was similar across groups [9].

In type 2 diabetes (92 patients, 32 weeks), cagrilintide alone was associated with an HbA1c reduction of 0.9 points and weight reduction of 8.1%. The combination with semaglutide reached 2.2 points and 15.6% [13].

CagriSema carried the combination into phase 3

The first hint of synergy came from phase 1b. With semaglutide 2.4 mg, cagrilintide 4.5 mg was associated with a 15.4% reduction versus 8.0% with semaglutide plus placebo at 20 weeks, in 96 participants [8]. Phase 3 confirmed it at scale.

  • REDEFINE 1 (3417 adults without diabetes, 68 weeks): a 20.4% reduction with the combination versus 3.0% with placebo (treatment policy). Gastrointestinal events occurred in 79.6% versus 39.9%, mostly transient and mild to moderate [10].
  • REDEFINE 2 (1206 adults with type 2 diabetes, 68 weeks): a 13.7% reduction versus 3.4%. 73.5% reached an HbA1c of 6.5% or less, versus 15.9% [11].

REDEFINE 1 also included a cagrilintide-alone arm (302 participants) [10]. A 2026 review summarizing that trial describes roughly 11 to 12% weight loss at 68 weeks with monotherapy [12]. For how to read estimands and compare with other next-generation drugs, see After semaglutide. For the approved GLP-1 products you can prescribe today, see the semaglutide and tirzepatide status pages.

A new wave of amylin drugs is in trials

  • Amycretin (now zenagamtide): a single molecule that agonizes both GLP-1 and amylin receptors [15]. In phase 1b/2a (125 participants), the 60 mg subcutaneous dose was associated with a 24.3% reduction versus 1.1% at 36 weeks [14].
  • Petrelintide: a long-acting human amylin analog. In the phase 2 ZUPREME 1 trial (485 treated participants), it was associated with a 7.9 to 9.8% reduction versus 1.7% at 28 weeks (efficacy estimand), with up to 10.7% at 42 weeks. Nausea occurred in 20% versus 6%, and vomiting in 3% versus 6% [16].
  • A 2026 review also lists eloralintide, MET-233i, ABBV-295 and AZD6234 among amylin analogs in clinical development [12].

The evidence has clear limits

The signal is consistent. Read it precisely. Gastrointestinal events are common: in phase 2 they affected 41 to 63% with cagrilintide versus 32% with placebo, mainly nausea [9]. Pramlintide with insulin carries a boxed warning for severe hypoglycemia, particularly in type 1 diabetes [3]. In the amycretin study a large number of participants withdrew [14].

Long-term data on cagrilintide alone come from a secondary arm of REDEFINE 1, not from a dedicated phase 3 trial [10][12]. Every cagrilintide, amycretin and petrelintide trial cited here was funded by its manufacturer [8][9][10][11][14][16]. The open question is no longer whether the pathway works. It is which receptor profile, selective amylin or dual amylin-calcitonin, offers the best balance of efficacy and tolerability [12].

If a patient asks for cagrilintide before it reaches the market, check the status tracker and read what research-use-only labeling means. For the programs MDside supports today, see weight management.

References

  1. Hay DL, et al. Amylin: Pharmacology, Physiology, and Clinical Potential. Pharmacol Rev. 2015;67(3):564-600. PMID 26071095. Link
  2. U.S. Food and Drug Administration. Drugs@FDA: Symlin (pramlintide acetate), NDA 021332 (original approval 16 March 2005, new molecular entity; marketing status). Link
  3. Symlin (pramlintide acetate) injection. Prescribing information. Revised 2019. Link
  4. Ratner RE, et al. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabet Med. 2004;21(11):1204-1212. PMID 15498087. Link
  5. Hollander PA, et al. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care. 2003;26(3):784-790. PMID 12610038. Link
  6. Smith SR, et al. Sustained weight loss following 12-month pramlintide treatment as an adjunct to lifestyle intervention in obesity. Diabetes Care. 2008;31(9):1816-1823. PMID 18753666. Link
  7. Kruse T, et al. Development of Cagrilintide, a Long-Acting Amylin Analogue. J Med Chem. 2021;64(15):11183-11194. PMID 34288673. Link
  8. Enebo LB, et al. Safety, 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. Lancet. 2021;397(10286):1736-1748. PMID 33894838. Link
  9. Lau DCW, et al. 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. Lancet. 2021;398(10317):2160-2172. PMID 34798060. Link
  10. Garvey WT, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity (REDEFINE 1). N Engl J Med. 2025;393(7):635-647. PMID 40544433. Link
  11. Davies MJ, et al. Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes (REDEFINE 2). N Engl J Med. 2025;393(7):648-659. PMID 40544432. Link
  12. Alhazmi A, le Roux CW. Amylin Analogs: The Next Major Class of Weight Loss Therapy: A Review of Experimental Data and Early-Phase Clinical Trials. Diabetes Obes Metab. 2026;28(Suppl 5):42-50. PMID 42452898. Link
  13. Frias JP, et al. Efficacy and safety of co-administered once-weekly cagrilintide 2.4 mg with once-weekly semaglutide 2.4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet. 2023;402(10403):720-730. PMID 37364590. Link
  14. Dahl K, et al. Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist administered subcutaneously: results from a phase 1b/2a randomised controlled study. Lancet. 2025;406(10499):149-162. PMID 40550231. Link
  15. Panou T, et al. New Amylin-Based Agonists for the Treatment of Obesity and Type 2 Diabetes Mellitus. Diabetes Ther. 2026. Online ahead of print. PMID 42803913. Link
  16. Garvey WT, et al. Petrelintide, a human amylin analogue for the treatment of obesity (ZUPREME 1): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 2026. Online ahead of print. PMID 42810355. Link

This is general information, not medical or legal advice. Rules vary by state and change. Confirm your own facts with counsel.

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