Cotadutide
Also known as: MEDI0382
Dual GLP-1/glucagon receptor agonist; fatty-acid conjugated synthetic peptide
What it is
People with type 2 diabetes and excess weight—including those with fatty liver disease—are the primary focus of cotadutide research. Developed by AstraZeneca (formerly MedImmune), it is a once-daily injectable that aims to lower blood sugar and reduce body weight simultaneously by activating two different metabolic hormone pathways.
The scientific side
cotadutide is a unimolecular dual agonist that simultaneously activates two class B1 G protein-coupled receptors: the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR). Cryo-electron microscopy structural studies determined that cotadutide (MEDI0382) engages both receptors by adopting specific conformations—its lipid moiety interacts with the TM1-TM2 cleft of GCGR, contributing to increased potency at that receptor relative to some comparators; the middle region of the peptide contacts extracellular loop 1 (ECL1) and ECL2, while distinct side-chain orientations in the first three residues govern receptor selectivity. Through these interactions cotadutide activates Gs protein signaling, leading to cAMP accumulation and ERK1/2 phosphorylation at both receptors, with biased agonism profiles that differ from the native ligands GLP-1 and glucagon. GLP-1R activation stimulates glucose-dependent insulin secretion, slows gastric emptying, reduces appetite, and promotes weight loss. GCGR activation increases hepatic glucose output under fasting conditions but is also associated with increased energy expenditure and, based on emerging mechanistic evidence, renoprotective effects mediated through a GCGR-ATP6V1A-lysosome axis that preserves tubular lysosomal acidification and autophagic flux. Together these complementary mechanisms are hypothesized to achieve glycaemic control and clinically meaningful weight reduction while also reducing hepatic steatosis. Pharmacokinetically, cotadutide is a fatty-acid conjugated peptide administered subcutaneously once daily. Phase 1 data in healthy subjects demonstrated linear pharmacokinetics with a time to maximum plasma concentration of 4.5 to 9.0 hours and an elimination half-life of approximately 9.5 to 12.1 hours, supporting once-daily dosing. Allometric scaling analyses confirm cotadutide follows standard size-related physiological scaling patterns consistent with other fatty-acid conjugated peptide therapeutics.
Class: Dual GLP-1/glucagon receptor agonist; fatty-acid conjugated synthetic peptide
Administration & storage
- Administration
- Subcutaneous injection (all reported clinical trials)
- Storage
- Specific storage conditions for cotadutide are not described in the available PubMed abstracts. As a fatty-acid conjugated peptide therapeutic, standard refrigeration conditions (2–8°C) consistent with similar agents in the class would be expected, but this is not confirmed by the fetched literature.
Legal & regulatory status
Investigational only — not approved. Phase 2 trials completed (NCT02548585; PMIDs 29945727, 29926478). A Phase 2 proof-of-concept study in non-cirrhotic NASH with fibrosis (PROXYMO-ADV, NCT05364931) was completed April…
Not specifically listed in the available abstracts. As a peptide hormone agonist acting on metabolic receptors, it falls within WADA's S2 category (Peptide Hormones, Growth Factors, Related Substances and Mimetics) by…
No approval reported in the available abstracts. Investigational status only.
What it's studied for
- Glycaemic control in type 2 diabetes (T2D) Phase 2 RCT (multiple trials, systematic review and meta-analysis)
- Body weight reduction in overweight/obese adults with T2D Phase 2 RCT (multiple trials, systematic review and meta-analysis)
- Non-alcoholic/metabolic steatohepatitis (NASH/MASH) and liver fat reduction Phase 2 RCT (proof-of-concept trial completed; included in meta-analyses)
- Renoprotective effects / chronic kidney disease (CKD) in T2D Phase 2 RCT data; mechanistic mouse studies; included in scoping reviews
- Obesity treatment (overweight/obese adults without T2D) Phase 1/2 RCT; included in class-level meta-analyses
- Potential reduction of obesity-associated cancer risk Subgroup analysis of meta-analysis of RCTs (exploratory)
- Pharmacokinetic characterisation and translational drug development Phase 1 clinical PK study; preclinical-to-clinical allometric scaling analysis
Safety signals
- Gastrointestinal adverse events (nausea, vomiting, diarrhoea, dyspepsia, constipation, decreased appetite)
- Dose-dependent increase in heart rate (pulse rate elevation)
- Increased risk of treatment-emergent adverse events and drug-related adverse events versus placebo
- Comparatively lower tolerability versus some class peers
- Gastrointestinal intolerance leading to treatment discontinuation in MASH/MASLD trials
- TEAEs more frequent at doses ≥150 µg in Phase 1 (vomiting, nausea, dizziness predominant)
No peer-reviewed studies indexed for this peptide yet.
Frequently asked
Is cotadutide approved for use in any country?
No. Based on the available clinical literature, cotadutide (MEDI0382) remains investigational. It has completed multiple Phase 2 trials — including a proof-of-concept study in NASH with fibrosis that finished in 2024 — but no marketing approval has been reported in the US, EU, Canada, or any other jurisdiction as of the available evidence.
How does cotadutide differ from semaglutide or other GLP-1 drugs?
Cotadutide activates two receptors simultaneously: the GLP-1 receptor (shared with semaglutide, liraglutide, etc.) and the glucagon receptor. The additional glucagon receptor activation is associated with increased energy expenditure and hepatoprotective effects, making cotadutide of particular interest for fatty liver disease alongside diabetes and weight management. However, it also adds to gastrointestinal tolerability challenges compared with some class peers.
What dose was used in clinical trials?
Clinical trials used once-daily subcutaneous injections ranging from 100 µg to 600 µg, with uptitration from lower doses. The Phase 2a Lancet study used up to 200 µg (41 days); Japanese Phase 2a studies used 100–300 µg (48 days); the PROXYMO-ADV NASH trial tested 300 µg and 600 µg. These are investigational doses evaluated under supervised trial conditions.
Can cotadutide help with fatty liver disease (NASH/MASH)?
Early clinical evidence from meta-analyses and a completed Phase 2 proof-of-concept trial (PROXYMO-ADV) suggest that GLP-1/glucagon dual agonists including cotadutide can significantly reduce liver fat content and improve liver histology in MASH. Results from PROXYMO-ADV were posted in August 2025. Cotadutide is not approved for this indication; larger Phase 3 trials are needed to confirm efficacy and long-term safety.
Is cotadutide safe? What are the main side effects?
In Phase 1 and Phase 2 clinical trials, the most common side effects were gastrointestinal — nausea, vomiting, diarrhoea, dyspepsia, constipation, and decreased appetite — and a dose-dependent increase in heart rate. These were mostly mild to moderate. The rate of serious adverse events was not significantly higher than placebo in meta-analyses. Tolerability was comparatively lower than some other agents in the same drug class.