Side-by-side · Research reference
CagrilintidevsPE 22-28
Side-by-side comparison across mechanism, dosage, evidence, side effects, administration, and stack synergies. Citations on every claim where available.
APhase 3HUMAN-REVIEWED35/64 cited
BAnimal-StrongHUMAN-REVIEWED16/47 cited
PE 22-28
TREK-1 Antagonist · Pre-Clinical
IP · SQ · Once Daily (animal models)Djillani 2017Pietri 2019
01Mechanism of Action
Parameter
Cagrilintide
PE 22-28
Primary target
Amylin receptor (AMYR) and calcitonin receptor (CTR) heterodimeric complexesBailey 2026
TREK-1 two-pore-domain potassium channelDjillani 2017Ma 2020
Pathway
AMYR/CTR agonism → Central satiety signaling → Reduced food intake, delayed gastric emptying, suppressed glucagonBailey 2026
TREK-1 channel blockade → Neuronal membrane depolarisation → Enhanced hippocampal excitability → Increased neuroplasticity
Downstream effect
Central satiety induction, prandial glucagon suppression, reduced caloric intake, weight loss, improved glycemic controlBailey 2026Yamauchi 2026
Antidepressant-like activity in forced swim test and tail suspension test; reduced A1-like reactive astrocyte activation; neuroprotection via NF-κB pathway modulationDjillani 2017Cong 2023Wu 2021
Feedback intact?
Yes — acts via physiological amylin pathways
N/A — direct ion channel blockade; not receptor-mediated endocrine axis
Origin
Second-generation non-aggregating long-acting amylin analogue designed for once-weekly dosingBailey 2026
Synthetic truncation of spadin (PE 12-28), itself derived from the sortilin propeptide C-terminus. Residues 22-28: Val-Val-Arg-Gly-Trp-Leu-Arg.Djillani 2017Mazella 2018
Antibody development
—
Not reported in animal studies
02Dosage Protocols
Parameter
Cagrilintide
PE 22-28
Standard dose (combination)
Cagrilintide 2.4 mg + Semaglutide 2.4 mg (CagriSema)Yamauchi 2026
Phase 3 REDEFINE 5 trial dosing.
—
Monotherapy dosing
Dose-dependent, under investigation
Monotherapy trials reported in meta-analysis.
—
Frequency
Once weekly (subcutaneous)Bailey 2026
Long-acting formulation.
Once daily
Sustained antidepressant effect over 7+ days.
Evidence basis
Phase 3 RCT (REDEFINE 5), meta-analysis of 3 RCTs (n=3545)Yamauchi 2026Ahmed 2026
Multiple rodent RCTs; behavioral + electrophysiology endpointsDjillani 2017Qi 2018Wu 2021
Animal dose (antidepressant)
—
0.3–3 µg/kg IP
Effective in forced swim test, tail suspension test, CUMS models.
Animal dose (neuroprotection)
—
0.03 µg/kg IPPietri 2019
Low-dose TREK-1 activation post-stroke for 7 days, then high-dose blockade.
Onset (animal)
—
Within hours (acute); full effect 4–7 days
Comparison to fluoxetine
—
PE 22-28 outperforms fluoxetine in CUMS-sensitive rats by day 7
Chronic administration shows superior long-term efficacy.
Human equivalent (extrapolated)
—
Not established — no clinical trials
Allometric scaling from rodent data unavailable.
03Metabolic / Fat Loss Evidence
Parameter
Cagrilintide
PE 22-28
Weight loss vs semaglutide
7.47% greater percentage weight lossAhmed 2026
CagriSema combination vs semaglutide monotherapy (meta-analysis).
—
Absolute weight change
Significantly greater absolute weight reductionAhmed 2026
Mean difference favoring combination therapy.
—
Glycemic benefit
Reduced fasting glucose and HbA1cAhmed 2026
Synergistic effect with semaglutide in combination.
—
Body composition
Predominant fat loss with weight reduction
—
Mitochondrial function
In vitro effects on skeletal muscle mitochondria under metabolic stress conditionsOld 2026
C2C12 myotube study; clinical relevance under investigation.
—
Key publications
REDEFINE 5 (Yamauchi 2026) · Ahmed meta-analysis 2026 · Bailey review 2026Yamauchi 2026Ahmed 2026Bailey 2026
—
04Side Effects & Safety
Parameter
Cagrilintide
PE 22-28
Gastrointestinal
Nausea, diarrhea (common with incretin-based therapies)Pardali 2026
Dietary management and nutritional monitoring recommended.
—
Injection site reactions
Local reactions possible with subcutaneous administration
—
Safety profile
Generally consistent with incretin-based therapies
Phase 3 and meta-analysis safety data.
—
Tolerability
Tolerability considerations similar to GLP-1RAs
—
Muscle preservation
Lean mass considerations during weight loss
In vitro mitochondrial effects observed; clinical impact under investigation.
—
Toxicity (animal)
—
No adverse effects reported at therapeutic doses
Cardiovascular (theoretical)
—
TREK-1 expressed in cardiac tissue; arrhythmia risk unclear
Weight change
—
Not reported in animal studies
Neurological
—
No seizures or behavioral abnormalities noted
Long-term safety
—
Unknown — longest animal study 28 days
Absolute Contraindications
Cagrilintide
- ·Hypersensitivity to cagrilintide or formulation components
PE 22-28
- ·Human use — no clinical safety data available
Relative Contraindications
Cagrilintide
- ·Severe gastrointestinal disease
- ·History of pancreatitis (incretin-based therapy consideration)
PE 22-28
- ·Cardiac arrhythmia or channelopathy (theoretical TREK-1 cardiac role)
05Administration Protocol
Parameter
Cagrilintide
PE 22-28
1. Dosing frequency
Once-weekly subcutaneous injection. Long-acting formulation designed for weekly administration schedule.Bailey 2026
Dissolved in sterile saline or vehicle. Intraperitoneal injection, 0.3–3 µg/kg body weight. Once daily administration in rodent behavioral studies.
2. Combination form
Co-formulated with semaglutide as CagriSema for single weekly injection combining amylin and GLP-1 receptor agonism.Yamauchi 2026Bailey 2026
Shorter peptide length (7 AA) confers improved plasma stability vs 17-AA spadin. Exact storage conditions not detailed in published protocols.Djillani 2017
3. Injection site
Subcutaneous — typically abdomen, thigh, or upper arm. Rotate injection sites weekly to minimize local reactions.
Enhanced CNS bioavailability vs full spadin, likely due to smaller size. Mechanism (passive diffusion vs active transport) not fully characterized.
4. Storage
Refrigerate 2–8°C. Follow product-specific storage instructions for pre-filled pens or vials. Protect from light.
Not established — peptide synthesis methods for research use only. No pharmaceutical-grade formulation available.
5. Dietary considerations
Nutritional monitoring recommended during treatment. Dietary management strategies important for tolerability and outcomes.Pardali 2026
—
06Stack Synergy
Cagrilintide
+ Semaglutide
StrongCagrilintide (amylin receptor agonist) and semaglutide (GLP-1 receptor agonist) act on distinct receptor systems to produce synergistic weight loss through complementary mechanisms — central satiety via amylin pathways plus incretin-mediated glucose control and appetite suppression via GLP-1. Co-formulated as CagriSema, this combination demonstrates 7.5% greater weight loss versus semaglutide monotherapy in Phase 3 trials with additional benefits on glycemic control and lipid parameters.
- CagriSema
- Cagrilintide 2.4 mg + Semaglutide 2.4 mg
- Frequency
- Once weekly subcutaneous
- Duration
- 26–52 weeks (trial data)
- Primary benefit
- Enhanced weight loss, improved glycemic control, multi-pathway metabolic modulation
PE 22-28
— no documented stacks