Cagrilintide Phase III

What It Is

Cagrilintide (development code AM833, NN9838) is an investigational 37-amino-acid lipidated analog of the endogenous pancreatic hormone amylin, developed by Novo Nordisk as a once-weekly subcutaneous anti-obesity therapeutic. Native human amylin is co-secreted with insulin by pancreatic β-cells in response to meals and acts at calcitonin-receptor-based amylin receptor complexes (AMY1R, AMY2R, AMY3R) to slow gastric emptying, reduce glucagon secretion, and produce centrally-mediated satiety. Amylin's therapeutic potential has been recognized for decades — pramlintide (Symlin) is an FDA-approved short-acting amylin analog for type 1 and insulin-treated type 2 diabetes since 2005 — but pramlintide's three-times-daily dosing and fibril-formation tendency limited commercial uptake.

Cagrilintide was engineered to solve both problems simultaneously. Kruse, Hansen, Dahl and colleagues (J Med Chem 2021) described the medicinal chemistry: a stabilized amylin backbone carrying a C20 fatty diacid conjugate at a lysine position, giving reversible albumin binding and a plasma half-life of roughly 160–180 hours — compatible with once-weekly dosing alongside semaglutide. The sequence also incorporates substitutions that reduce the molecule's tendency to self-associate into amyloid-like fibrils, allowing stable high-concentration SubQ formulation.

What transformed cagrilintide from "another amylin analog" into one of the most-watched investigational obesity compounds was the recognition that amylin's mechanism is substantially orthogonal to GLP-1's. Both produce satiety, but via different CNS circuits and different receptors. Combining them could theoretically produce additive or supra-additive weight loss. This is the rationale for CagriSema — the fixed-dose combination of cagrilintide 2.4 mg and semaglutide 2.4 mg — positioned as a potential best-in-class obesity therapy.

The REDEFINE Phase 3 program delivered the answer in 2025. REDEFINE 1 (NCT05567796) in 3,417 adults without diabetes showed CagriSema produced 20.4% mean weight loss at 68 weeks versus 3.0% placebo. REDEFINE 2 (NCT05394519) in 1,206 adults with type 2 diabetes showed CagriSema 13.7% weight loss versus 3.4% placebo. Both trials were published simultaneously in the New England Journal of Medicine in June 2025. These results place CagriSema roughly at parity with tirzepatide (SURMOUNT-1 −20.9% at 72 weeks) in the non-diabetic obesity setting and ahead of semaglutide alone (STEP-1 −14.9% at 68 weeks). As of April 2026, CagriSema is under FDA review; cagrilintide as a solo agent is investigational.

Mechanism of Action

Cagrilintide's mechanism recapitulates amylin physiology with extended half-life and improved stability. Combination with semaglutide yields additive effects through complementary CNS satiety circuits.

• Amylin receptor agonism (AMY1R, AMY2R, AMY3R) — Cagrilintide binds the calcitonin-receptor-based amylin receptor complexes (CTR heterodimerized with RAMP1, RAMP2, RAMP3) expressed in the area postrema, nucleus of the solitary tract, and hypothalamus. This drives central satiety signaling distinct from GLP-1R-mediated pathways.
• Calcitonin receptor activity — AM833 is a novel agonist across the calcitonin family G-protein-coupled receptors, with activity at the calcitonin receptor (CTR) alongside the amylin receptors (Kruse et al. Endocrinology 2021; PMID 33727283).
• Gastric emptying delay — Amylin receptor activation slows gastric emptying, contributing to early satiety and prolonged feelings of fullness.
• Glucagon suppression — Amylin action reduces post-prandial glucagon secretion, contributing to improved glycemic control independent of insulin.
• CNS satiety (area postrema) — The area postrema is a circumventricular organ highly responsive to amylin receptor activation. Central amylin signaling reduces meal size and meal frequency — anatomically distinct from GLP-1's primary action in the arcuate nucleus and NTS.
• C20 fatty diacid albumin binding — The lipidation strategy borrowed from semaglutide and other long-acting peptides provides reversible albumin binding, extending plasma half-life to 160–180 hours and enabling once-weekly dosing.
• Mechanistic orthogonality to GLP-1 — Amylin receptors and GLP-1 receptors are distinct; amylin-driven CNS circuits in the area postrema and GLP-1-driven circuits in the arcuate nucleus / NTS act largely independently. This is the theoretical basis for CagriSema's additive effect.
• Fibril resistance — A key engineering achievement — native amylin and pramlintide form fibrils in solution, which is the main reason pramlintide had to be delivered pre-meal at low concentrations. Cagrilintide is stable in subcutaneous depot, allowing higher-dose weekly administration.
• Body composition (fat vs lean) — Phase 2/3 data suggest cagrilintide-driven weight loss is predominantly fat mass, with relative lean-mass preservation when adequate protein intake and resistance training are in place — similar to the GLP-1 class.
• Metabolic effects — Improves fasting glucose, HbA1c, insulin sensitivity, and lipid profile consistent with broader weight-loss benefit.

What the Research Shows

Cagrilintide's clinical development has been rapid and well-documented, with multiple Phase 1, 2, and 3 trials completed by 2025.

• Discovery / chemical development (Kruse J Med Chem 2021) — Published structural development of the stable, lipidated long-acting amylin analog cagrilintide.
• Receptor pharmacology (Kruse Endocrinology 2021; PMID 33727283) — Characterized AM833 as a novel agonist across the calcitonin family GPCRs, with receptor pharmacology distinct from six comparator selective and non-selective amylin receptor agonists.
• Phase 2 dose-finding (Lau Lancet 2021) — Once-weekly cagrilintide 0.3–4.5 mg for weight management in overweight/obese adults without diabetes over 26 weeks. Dose-dependent weight loss; 4.5 mg produced −10.8% mean weight change vs −3.0% placebo. Established the 2.4 mg dose as the clinical development target (matching the semaglutide dose pair).
• Phase 1b combination with semaglutide (Enebo Lancet 2021; PMID 33894838) — Concomitant cagrilintide (0.16–4.5 mg) + semaglutide 2.4 mg for 20 weeks in 285 screened / 96 randomized adults. Weight loss: cagrilintide 1.2 mg + semaglutide −15.7%; cagrilintide 2.4 mg + semaglutide −17.1%; placebo + semaglutide −9.8%. Established the clinical additivity of the combination.
• Phase 2 CagriSema in T2D (Frias Lancet 2023) — Co-administered weekly cagrilintide 2.4 mg + semaglutide 2.4 mg in T2D showed superior weight loss and HbA1c effects vs semaglutide alone.
• REDEFINE 1 Phase 3 (Garvey et al., NEJM 2025) — 3,417 adults without diabetes, BMI ≥30 or ≥27 with comorbidity. 68 weeks. CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg): −20.4% weight loss vs −3.0% placebo. ~60% achieved ≥20% weight loss; ~23% achieved ≥30% weight loss. GI adverse events common (~80% vs ~40% placebo), mostly mild-moderate and concentrated in titration.
• REDEFINE 2 Phase 3 (Davies et al., NEJM 2025; PMID 40544432) — 1,206 adults with type 2 diabetes + BMI ≥27 + HbA1c 7–10%. 68 weeks. CagriSema: −13.7% weight loss vs −3.4% placebo. HbA1c reduction confirmed.
• Long-term cardiovascular outcomes (REDEFINE-CVOT) — Cardiovascular outcomes trial ongoing for longer-term safety and MACE endpoints.
• Amycretin (unimolecular GLP-1 / amylin) — Novo Nordisk's next-generation single-molecule combining GLP-1R and amylin receptor agonism in one peptide, Phase 1b/2a data (Lancet 2025). Represents the strategic successor to CagriSema.

Human Data

Cagrilintide has accumulated one of the largest Phase 3 datasets of any investigational obesity drug:

• Phase 1 (multiple) — Pharmacokinetics, safety, dose tolerability. Established 160–180 hr half-life and once-weekly dosing.
• Phase 1b combination (Enebo 2021, PMID 33894838) — 96 participants; CagriSema proof-of-concept.
• Phase 2 dose-finding (Lau 2021) — 706 participants; established 2.4 mg dose target.
• Phase 2 CagriSema in T2D (Frias 2023) — Multicentre Phase 2 active-controlled trial.
• REDEFINE 1 Phase 3 — 3,417 adults without diabetes; pivotal non-diabetic obesity trial (NCT05567796).
• REDEFINE 2 Phase 3 — 1,206 adults with T2D; pivotal T2D trial (NCT05394519; PMID 40544432).
• REDEFINE-CVOT — Ongoing cardiovascular outcomes trial.
• Gray-market early-adopter experience — Community use ahead of approval has generated informal experience reports; not published clinical data.

Dosing from the Literature

Cagrilintide dosing is defined by the Phase 2/3 program.

Reconstitution & Storage

In Phase 3 clinical trials, cagrilintide is delivered via autoinjector pens. Research-chemical gray-market cagrilintide is typically supplied as lyophilized powder for reconstitution.

• Reconstitution — Inject BAC water slowly down vial wall at 45°. Swirl; do not shake. Clear colorless solution. Gray-market cagrilintide may be particularly sensitive to fibril formation — handle with care.
• Storage — Unreconstituted: 2–8°C strictly preferred. Reconstituted: 2–8°C, use within 21–28 days. Do not freeze.
• Injection sites — SubQ into abdomen (2" from navel), thigh, or upper arm. Rotate weekly.
• Timing — Once weekly, same day each week. If paired with semaglutide (CagriSema-style), administer together or on the same day.
• Inspection — Particularly important for amylin analogs — discard if cloudy, has particulates, or shows any aggregation. Fibril formation can occur if the peptide is destabilized.

→ Use the Kalios Peptide Calculator for exact dosing volumes

Side Effects & Risks

Cagrilintide's side effect profile from the Phase 3 REDEFINE program is well-characterized.

• Nausea — Most common; dose-dependent. ~40% of REDEFINE 1 CagriSema recipients; mostly mild-moderate and transient, concentrated in titration phase.
• Vomiting — Dose-dependent.
• Diarrhea — Common during titration.
• Constipation — Common; often alternating with diarrhea.
• Abdominal pain — Typically mild.
• Injection site reactions — Mild erythema or itching; self-limited.
• Gallbladder disease — Rapid weight loss raises cholelithiasis / cholecystitis risk (class effect for all obesity drugs producing rapid fat loss).
• Pancreatitis — Rare but documented in the obesity-drug class generally.
• Hypoglycemia risk — Low for cagrilintide alone; higher in T2D patients on insulin or secretagogues in combination.
• Heart rate increase — Modest; consistent with incretin-class drugs.
• Thyroid C-cell / medullary thyroid concerns — Amylin analogs do not share the GLP-1 boxed warning for MTC, but combination with semaglutide means CagriSema inherits the semaglutide warning. Personal or family history of MTC / MEN2 contraindicates semaglutide and thus CagriSema.
• Pregnancy / lactation — Not studied; avoid.
• Drug interactions — Delayed gastric emptying affects absorption of oral medications, particularly narrow-therapeutic-index drugs. Insulin dose adjustment typical in T2D patients.
• WADA status — Not specifically listed. Umbrella categories may apply for athletes.
• Purity (gray-market) — Cagrilintide's complex lipidation and fibril-sensitivity mean gray-market quality varies more than for simpler peptides. Third-party HPLC + mass spec COAs are the floor.
• Fibril formation risk — Amylin-family peptides can aggregate; appropriate storage and handling is more important than for some other peptides.

Quick Compare — Cagrilintide vs Semaglutide vs Tirzepatide vs Pramlintide vs Retatrutide

Cagrilintide sits in a dense competitive field. The relevant comparators are: (a) semaglutide, its CagriSema partner; (b) tirzepatide, the dual GIP/GLP-1 benchmark; (c) pramlintide, the predecessor amylin analog; (d) retatrutide, the triple-agonist competing for "most potent" weight loss.

Practical interpretation:

• CagriSema vs tirzepatide — Comparable magnitude of weight loss (20.4% vs 20.9% in non-diabetic Phase 3). Tirzepatide is approved and established; CagriSema is anticipated approval. Different receptor mechanisms (amylin+GLP-1 vs GIP+GLP-1); neither is clearly superior in published head-to-head data.
• CagriSema vs semaglutide — CagriSema clearly exceeds semaglutide alone (20.4% vs 14.9%) at the cost of additional injection complexity.
• Solo cagrilintide vs combination — Solo cagrilintide delivers smaller weight loss than the CagriSema combination. The commercially dominant pathway is CagriSema, not cagrilintide alone.
• Cagrilintide vs pramlintide — Pramlintide was the first-generation amylin analog; pre-meal 3×/day dosing limited adoption. Cagrilintide is the once-weekly successor that completes the amylin class's long-acting transition.
• Who should wait for CagriSema — Patients wanting maximum weight loss on an approved drug in a narrow timeline; T2D + obesity patients; users who find semaglutide alone insufficient.
• Who should not wait — Anyone with urgent obesity-related morbidity; approved tirzepatide provides comparable magnitude now.

→ See Semaglutide profile  •  → See Tirzepatide profile  •  → See Retatrutide profile  •  → See Pramlintide profile

Bloodwork & Monitoring

Monitoring is similar to other long-acting incretin drugs. CagriSema adds amylin-specific considerations to standard GLP-1 monitoring.

• Baseline CMP — Particularly ALT/AST and glucose. Repeat at 4, 12, 24, 48 weeks.
• HbA1c — Every 3 months if T2D or prediabetic.
• Fasting lipid panel — Baseline and at 24/48 weeks.
• Thyroid — Family-history-based; not routine unless indicated.
• Amylase / lipase — Baseline; repeat if new abdominal pain.
• Weight and body composition — Weekly weight; DEXA every 3–6 months if muscle preservation matters.
• Hydration / electrolytes — BUN/creatinine, sodium during titration.
• Gallbladder imaging — If new RUQ symptoms.
• Pregnancy planning — Document contraception counseling.

Commonly Stacked With

→ Check compound compatibility in the Stack Builder

Regulatory Status

Related Compounds

People researching cagrilintide often also look at these:

Next Steps

Key References

1. Enebo LB, Berthelsen KK, Kankam M, 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. DOI: 10.1016/S0140-6736(21)00845-X.
2. Lau DCW, Erichsen L, Francisco AM, 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.
3. Kruse T, Hansen JL, Dahl K, et al. Development of Cagrilintide, a Long-Acting Amylin Analogue. J Med Chem. 2021;64(15):11183-11194. DOI: 10.1021/acs.jmedchem.1c00565.
4. Kruse T, Dahl K, Frigeri P, et al. AM833 Is a Novel Agonist of Calcitonin Family G Protein-Coupled Receptors: Pharmacological Comparison with Six Selective and Nonselective Agonists. Endocrinology. 2021;162(6):bqab057. PMID: 33727283.
5. Garvey WT, Frias JP, Jastreboff AM, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity (REDEFINE 1). N Engl J Med. 2025. DOI: 10.1056/NEJMoa2502081.
6. Davies MJ, Frias JP, Jastreboff AM, et al. Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes (REDEFINE 2). N Engl J Med. 2025. PMID: 40544432. DOI: 10.1056/NEJMoa2502082.
7. Frias JP, Deenadayalan S, Erichsen L, 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.
8. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). N Engl J Med. 2022;387(3):205-216. PMID: 35658024. (Comparator.)
9. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP-1). N Engl J Med. 2021;384(11):989-1002. PMID: 33567185. (Comparator.)
10. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. PMID: 37366315. (Comparator.)
11. Hay DL, Garelja ML, Poyner DR, Walker CS. Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br J Pharmacol. 2018;175(1):3-17. PMID: 29059473.
12. Ratner RE, Dickey R, Fineman M, et al. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus. Diabet Med. 2004;21(11):1204-1212. PMID: 15498088.
13. Hollander P, Maggs DG, Ruggles JA, et al. Effect of pramlintide on weight in overweight and obese insulin-treated type 2 diabetes patients. Obes Res. 2004;12(4):661-668. PMID: 15090635.
14. ClinicalTrials.gov. REDEFINE 1 (NCT05567796) and REDEFINE 2 (NCT05394519). Novo Nordisk CagriSema Phase 3 program.
15. Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist administered subcutaneously: results from a phase 1b/2a randomised controlled study. Lancet. 2025. (Novo Nordisk next-generation successor to CagriSema.)