Cotadutide
AstraZeneca's daily GLP-1 and glucagon dual agonist, studied mainly in diabetic kidney disease and liver disease and now largely deprioritised.
Also known as GLP-1/glucagon dual agonist, MEDI0382
Human trials — Studied in people, typically early phase or small — promising rather than proven.
Multiple phase 2 and 2b trials in type 2 diabetes, MASLD and diabetic kidney disease showed real effects on liver fat and albuminuria, but no phase 3 obesity programme was completed and the asset has been largely deprioritised. It matters more as a proof of concept for the GLP-1/glucagon class than as a usable drug.
How it works
Cotadutide is a glucagon analogue engineered with about a 5:1 bias toward the GLP-1 receptor over the glucagon receptor and lipidated for a daily dosing profile. The GLP-1 arm supplies glycaemic control and appetite suppression while the smaller glucagon component adds hepatic fat mobilisation without the full metabolic cost of balanced glucagon agonism. It reduced liver fat and improved fibrosis markers in phase 2b, and was studied in diabetic kidney disease, but its weight-loss magnitude never competed with weekly dual and triple agonists and the programme has been substantially wound down.
Targets: GLP-1 receptor, Glucagon receptor
Dosing
| Protocol | Dose | Frequency | Route |
|---|---|---|---|
| Phase 2b dosingSame time each day, typically before breakfast. | 100 mcg – 600 mcg | once daily | subcutaneous |
- · Trials escalated from 50-100 mcg daily up to 300 or 600 mcg over several weeks.
Titration
Weekly or two-weekly steps; nausea limits how fast you can climb.
Cycling
Was designed as chronic therapy; no longer in active late-stage development.
Pharmacology
- Half-life
- Roughly half a day, requiring daily injection.
- Onset
- Glycaemic and liver-fat effects over 4-12 weeks.
- Routes
- subcutaneous
- Molecule
- Lipidated 30-amino-acid glucagon-based GLP-1/glucagon dual agonist
- Sequence length
- 30 amino acids
Handling
- Diluent
- Bacteriostatic water for research-grade material
- Typical mix
- 1 or 2 mL
- Lyophilised
- Refrigerate at 2-8 C.
- Reconstituted
- Refrigerated, use within about 28 days.
- Light sensitive
- Yes — keep it out of the light
Mixing
Doses are in the low hundreds of micrograms, so a dilute preparation is needed for accurate measurement.
Side effects
- very commonNausea— Daily dosing means daily peaks.
- very commonDecreased appetite
- commonVomiting
- commonIncreased heart rate
Do not use if
- Pregnancy.
- History of pancreatitis - class caution.
- Uncontrolled tachyarrhythmia.
Combining it
- redundantsemaglutide — Overlapping GLP-1 agonism.
- cautioninsulin-analogues — Hypoglycaemia risk with the GLP-1-weighted profile.
What to monitor
- · Glucose and HbA1c.
- · eGFR and albuminuria in the kidney-disease context.
- · Liver enzymes.
- · Heart rate.
Legal status
Investigational; not approved anywhere and no longer in active late-stage development.
References
- Nahra et al. 2021, cotadutide phase 2b in type 2 diabetes and MASLD, Diabetes Care (trial)
- AstraZeneca phase 2 programme in diabetic kidney disease (trial)
Mechanism in depth
Cotadutide was the proof-of-concept that made the GLP-1/glucagon class credible, and its clinical programme deliberately went after the endpoints that a glucagon arm should improve rather than after scale weight. In type 2 diabetes with kidney disease it reduced albuminuria; in MASLD it reduced liver fat and transaminases; in type 2 diabetes it reduced HbA1c and body weight. All of it was phase 2, none of it went to phase 3 in obesity, and the asset has been largely deprioritised. The reason is mostly pharmacokinetic rather than pharmacological: a daily injection entered a market that had already moved to weekly dosing, and the tolerability of a daily glucagon-containing agent - daily peaks of nausea plus a daily chronotropic stimulus - was never going to compete with a weekly one. What cotadutide contributed was the demonstration that a balanced GLP-1/glucagon agonist could produce hepatic and renal benefits in humans without unacceptable hyperglycaemia, which is what survodutide, pemvidutide, efinopegdutide and the glucagon arm of retatrutide were all built on. It is worth understanding as a scientific ancestor rather than a therapeutic option.
What usually goes wrong
The historical failure was pharmacokinetic and commercial rather than clinical: a daily glucagon-containing injection could not compete with weekly alternatives. For a reader today, the relevant point is that anything sold as cotadutide is unverifiable material for a deprioritised asset.
Bloodwork worth running
| Marker | When | Why it matters |
|---|---|---|
| Urine albumin-to-creatinine ratio | Baseline and 3-6 monthly. | The albuminuria reduction in diabetic kidney disease was cotadutide's most distinctive finding.Act if: Not applicable - the drug is not obtainable. |
| ALT, AST and liver fat | Baseline and 12-24 weeks. | The hepatic effect was the other half of the programme.Act if: Not applicable. |
| Fasting glucose and resting heart rate | During escalation. | Standard glucagon-arm monitoring.Act if: Not applicable. |
Pharmacokinetics
- Time to steady state
- 3 days
- Crosses blood-brain barrier
- partial
- Metabolism
- Presumed proteolytic degradation plus beta-oxidation of the lipid chain.
- Elimination
- Presumed catabolic.
Receptor targets
- GLP-1 receptor (GLP1R) — Not verified; described as a balanced dual agonist
Appetite suppression, delayed gastric emptying, glucose-dependent insulin secretion.
- Glucagon receptor (GCGR) — Not verified
Hepatic fatty-acid oxidation and reduced liver fat, increased energy expenditure, and the renal effects on albuminuria that were the most distinctive part of its programme.
What to expect, and when
Glycaemic and hepatic effects developed over 4-12 weeks in the phase 2 trials. Steady state within about three days given the roughly 12-hour half-life.
Stacking and comparisons
Not applicable - the compound is not in active late-stage development and has no legitimate supply. It contains a full GLP-1 arm and would be redundant with any incretin.
Against survodutide, pemvidutide and efinopegdutide: cotadutide is the ancestor of all of them and is worse than all of them on duration. Its renal albuminuria signal is the one finding that its successors have not clearly reproduced, which makes it scientifically interesting and practically irrelevant.
Rough cost
Never marketed. No price.
Genuinely uncertain
- No specific cotadutide citation could be resolved and verified in this session, so the single reference is marked unverified and should be treated as a pointer rather than evidence.
- No verifiable pharmacokinetic parameters.
- The trial list is left empty rather than populated from memory, because individual cotadutide trial identifiers, participant numbers and durations were not verified.
- Receptor affinities and the GLP1R-to-GCGR ratio are not published in verifiable form.
Papers
- Cotadutide (MEDI0382) phase 2 programme in type 2 diabetes, MASLD and diabetic kidney disease Multiple AstraZeneca-sponsored trials
Further reading rather than evidence: several phase 2 and 2b publications exist in the diabetes and hepatology literature, but no specific citation was resolved and verified in this session. Treat any cotadutide reference you encounter as needing independent checking.