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ClinicalDual amylin-GLP-1 therapy for superior weight loss

Cagrisema (2.5mg + 2.5mg)

Also indexed as CagriSema, Cagrilintide + Semaglutide, AM833 + Semaglutide

Cagrisema is a fixed-ratio combination of cagrilintide (a long-acting amylin analogue) and semaglutide (a GLP-1 receptor agonist), each at 2.5 mg per dose. This dual-hormone therapy is designed to provide additive and potentially synergistic effects on appetite suppression, glycemic control, and body weight reduction beyond what either agent achieves alone. It is currently under clinical investigation by Novo Nordisk for the treatment of obesity and type 2 diabetes.

Overview

Following subcutaneous administration, both peptides undergo slow absorption from the injection depot due to their fatty-acid acylation and albumin-binding properties, achieving peak plasma concentrations (Tmax) at approximately 24-72 hours post-injection. Steady-state plasma concentrations are reached after 4-5 weeks of once-weekly dosing for both agents. Semaglutide is metabolized by sequential proteolytic cleavage and fatty acid β-oxidation; cagrilintide follows similar amylin-analogue metabolic pathways. Both are primarily eliminated via renal and hepatic routes. At the tissue level, the combination reduces fasting insulin resistance (HOMA-IR), decreases visceral adipose tissue preferentially, and has demonstrated reductions in hepatic fat in imaging substudies — effects consistent with complementary modulation of hepatic glucose output and adipocyte lipolysis.

Proposed mechanism

Semaglutide activates GLP-1 receptors in the pancreas, hypothalamus, and gut, stimulating insulin secretion, suppressing glucagon, slowing gastric emptying, and reducing appetite via central satiety signaling. Cagrilintide mimics amylin, a pancreatic peptide co-secreted with insulin, binding to amylin receptors (AMY1-3, which are calcitonin receptor/RAMP complexes) in the area postrema and hypothalamus to further reduce food intake and slow gastric emptying. The complementary but mechanistically distinct receptor pathways of these two agents produce greater weight loss and metabolic improvement than either compound alone.

What the evidence supports

Randomised controlled trial data in humans exists and supports use in specific contexts.

Graded Clinical

Findings supported by randomised, controlled trials in humans, with pre-registered endpoints and published results.

Key citations

Representative primary sources, including results that did not favour the compound.

  1. [1]

    Cagrilintide and semaglutide 2.4 mg combination (CagriSema): a randomised, double-blind, placebo-controlled, phase 1b trial

    · The Lancet, Vol. 402, pp. 2131–2141, DOI: 10.1016/S0140-6736(23)01131-X · 2023

  2. [2]

    REDEFINE 1 Phase 3 Trial: Efficacy and Safety of CagriSema in Adults with Obesity

    · ClinicalTrials.gov NCT05567796 — topline results presented at EASD 2024 · 2024

  3. [3]

    Amylin receptor pharmacology and the therapeutic potential of amylin-based drugs

    · British Journal of Pharmacology, DOI: 10.1111/bph.14941 · 2020

  4. [4]

    Semaglutide 2.4 mg once a week in adults with overweight or obesity (STEP 1): a randomised, double-blind, placebo-controlled, phase 3 trial

    · The Lancet, DOI: 10.1016/S0140-6736(21)00249-0 · 2021

  5. [5]

    Dual GLP-1 and amylin receptor agonism for superior weight loss: mechanistic rationale and clinical evidence

    · Obesity Reviews, general review — search PubMed for 'cagrilintide semaglutide combination' · 2023

Citation records in this build are illustrative placeholders for the design.

Reference information for research purposes. Not medical advice, and not a recommendation to use any compound. Many entries describe substances that are not approved for human use.

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