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Cagrilintide

Tags: Weight Loss, Amylin Analogue, CagriSema, Type 2 Diabetes

Quick Summary

Cagrilintide is a long-acting lipidated amylin analogue shown to produce substantial weight loss, especially when combined with semaglutide (CagriSema); weekly subcutaneous dosing.

Overview

Cagrilintide (AM833) is a long-acting, lipidated amylin analogue that activates amylin and calcitonin receptors. It was developed for weight management and type 2 diabetes, and clinical data show substantial weight loss — especially when combined with semaglutide (the combination is often referred to as "CagriSema"). Recent Phase 3 results report up to ~22.7% mean weight reduction in combination therapy.

Key Benefits

  • Once-weekly dosing (convenient maintenance)
  • Demonstrated large weight-loss efficacy in Phase 3 when combined with semaglutide
  • Designed for sustained weight maintenance and metabolic benefits in people with obesity and type 2 diabetes

Mechanism of Action

As a lipidated amylin analogue, cagrilintide targets both amylin and calcitonin receptors to increase satiety and modulate metabolic pathways. Lipidation extends circulation time, allowing weekly subcutaneous dosing.

Molecular Information

  • Weight: 4,409.01 Da
  • Length: 37 amino acids
  • Type: Amylin receptor agonist (lipidated)
Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser-Asn-Asn-Phe-Gly-Pro-Ile-Leu-Pro-Pro-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr-NH2

N-terminal lipidation with a γ-glutamic acid spacer and a C20 fatty diacid (pharmaceutical formulations).

Research Indications

  • Weight loss (most effective; particularly when used with semaglutide)
  • Type 2 diabetes with associated weight reduction and improved glycemic control
  • Sustained weight maintenance during continued therapy

Research Protocols

Goal Dose Frequency Route
Weight Loss (Monotherapy) 2.4 mg Once weekly Subcutaneous injection
Weight Loss (CagriSema) 2.4 mg + semaglutide 2.4 mg Once weekly Subcutaneous injection
Type 2 Diabetes Management 2.4 mg Once weekly Subcutaneous injection (often with metformin)
Dose Escalation 0.25 → 0.5 → 1.0 → 1.7 → 2.4 mg Weekly increases over 16 weeks Subcutaneous injection
Combination Diabetes Therapy 2.4 mg + SGLT2 inhibitor Once weekly Subcutaneous injection
Cardiovascular Risk Reduction (REDEFINE 3) 2.4 mg Once weekly Subcutaneous injection

Timing: administer on the same day each week; evening dosing may reduce morning nausea. Because the route is subcutaneous, it can be given with or without food.

Peptide Interactions

Compatible / Complementary

  • Semaglutide — Synergistic (combination = CagriSema)
  • Tirzepatide — Compatible
  • Liraglutide — Compatible
  • Metformin — Compatible
  • SGLT2 inhibitors — Compatible
  • Oral contraceptives — May require timing adjustments

Monitor

  • Insulin — Monitor when combined (adjust doses as needed)
  • Retatrutide — Use caution and monitor clinically

Avoid

  • Pramlintide — Avoid combination

How to Reconstitute (practical notes)

  1. Cagrilintide formulations require an acidic pH (optimal ~3.5–4.5) to avoid fibril formation. Standard bacteriostatic water (pH ~5.5–6) is acceptable for short-term refrigerated use (<30 days), but acidification to ~pH 4.0 (for long-term stability) is recommended in research settings.
  2. Reconstitute slowly down the vial wall and gently swirl — do not shake.
  3. Verify pH after reconstitution (3.5–4.5) and ensure the solution is clear; discard if cloudy or if particles are visible.
  4. Store frozen at -20°C and refrigerate after thawing; inspect for clarity before each injection.
  5. Allow the vial to warm to room temperature for 15–30 minutes before injection and rotate subcutaneous injection sites weekly.

Quality Indicators

Positive Signs

  • Pre-filled pen design likely for commercial formulation (post-approval)
  • Clinical-grade material shows >98% purity with correct lipidation and folding
  • Stable pharmacokinetics support 7-day dosing intervals when stored and handled properly

Warning Signs

  • Amylin analogs can form amyloid fibrils at neutral/alkaline pH; maintain acidic conditions to prevent aggregation

What to Expect (timeline)

  • Week 1–2: GI adaptation, mild nausea possible during dose escalation
  • Week 4–8: Early weight loss (approx. 2–5%), reduced appetite
  • Week 12–26: Accelerated weight loss (≈10–15%), improved satiety
  • Week 26+: Peak efficacy (≈15–23% weight loss when combined with semaglutide), sustained with ongoing therapy

Side Effects & Safety

  • Most common: gastrointestinal symptoms (nausea, vomiting, diarrhea) during early treatment
  • Anti-cagrilintide antibodies are frequently seen (46–73%) but have not been shown to affect efficacy in trials
  • No clinically meaningful QT prolongation observed in thorough QT assessments
  • Not all patients reach the 2.4 mg target dose (REDEFINE 1 achieved 2.4 mg in ~57.3% of participants)
  • Maintain acidic formulation to avoid fibril formation and deamidation; inspect reconstituted solutions before use

References

REDEFINE 1 Trial - Phase 3 Weight Loss (2025)

REDEFINE 2 Trial - Phase 3 Type 2 Diabetes (2025)

Phase 2 Type 2 Diabetes Combination Study (2023)