Cotadutide: Two Receptors, One Daily Peptide
AstraZeneca’s MEDI0382 pairs GLP-1 appetite suppression with glucagon-driven energy expenditure and hepatic fat burning — a different metabolic lever than single-agonist semaglutide.
How It Works
Like semaglutide, the GLP-1 component stimulates glucose-dependent insulin secretion, suppresses appetite, and slows gastric emptying. This is the half of cotadutide that does the familiar GLP-1 work on blood sugar and satiety.
The differentiator. Glucagon receptor agonism raises energy expenditure and drives hepatic fat oxidation. Balancing this against the GLP-1 arm’s glucose lowering is the central design challenge of any GLP-1/glucagon dual agonist.
In the Phase 2b trial, cotadutide 300 µg improved ALT, the FIB-4 index (P=0.004), NAFLD fibrosis score (P=0.010), and PRO-C3 versus placebo — effects NOT seen with the liraglutide comparator, pointing to a glucagon-mediated liver benefit.
Unlike weekly semaglutide or tirzepatide, cotadutide is a short-acting peptide dosed once daily by subcutaneous injection, with stepwise titration to manage gastrointestinal side effects.
What the Data Shows
Daily Dosing Schedule
Key Takeaways
- Cotadutide (MEDI0382) is a balanced GLP-1 receptor / glucagon receptor dual agonist developed by AstraZeneca.
- In an 834-patient, 54-week Phase 2b trial in type 2 diabetes (Nahra 2021, Diabetes Care), 300 µg produced −4.34% placebo-adjusted weight loss vs −2.65% for liraglutide 1.8 mg (P=0.009).
- HbA1c fell by 1.26 percentage points at week 14 with the 300 µg dose; reductions were maintained at 54 weeks.
- It improved liver markers (ALT, FIB-4, NAFLD fibrosis score, PRO-C3) where liraglutide did not — consistent with a glucagon-driven hepatic effect.
- The foundational Phase 2a study (Ambery 2018, Lancet) first showed significant glucose and bodyweight reductions versus placebo.
- Most common side effects were nausea (35%) and vomiting (17%), which decreased over time with titration.
- Cotadutide is NOT FDA approved for any condition and is not available as a prescription medicine.
- AstraZeneca deprioritized cotadutide’s late-stage development — there is no Phase 3 outcomes program comparable to semaglutide or tirzepatide.
- No head-to-head data exist versus tirzepatide or retatrutide; cross-trial comparisons are not reliable.
- Long-term cardiovascular and durable weight-maintenance outcomes have not been established.
- The optimal GLP-1-to-glucagon balance for maximizing fat loss without raising glucose is still an open research question across the whole dual-agonist class.
Frequently Asked Questions
What is cotadutide?
Cotadutide (research code MEDI0382) is an investigational peptide that activates two receptors at once: the GLP-1 receptor and the glucagon receptor. It was developed by AstraZeneca and studied primarily for type 2 diabetes, obesity, and non-alcoholic fatty liver disease. It is a once-daily subcutaneous injection.
How is cotadutide different from semaglutide and tirzepatide?
Semaglutide is a pure GLP-1 agonist; tirzepatide is a GIP/GLP-1 dual agonist. Cotadutide is a GLP-1/glucagon dual agonist — the glucagon arm adds energy expenditure and direct liver-fat reduction that the others do not target the same way. Cotadutide is also short-acting and dosed daily, whereas semaglutide and tirzepatide are weekly.
Is cotadutide FDA approved?
No. Cotadutide is not approved by the FDA or any regulator and is not an available prescription medication. It reached Phase 2 trials, but AstraZeneca deprioritized its late-stage development. It is discussed here for research and educational purposes only.
How much weight loss did cotadutide produce in trials?
In the 54-week Phase 2b diabetes trial, the 300 µg dose produced 4.34% placebo-adjusted body-weight loss, compared with 2.65% for the liraglutide 1.8 mg comparator (P=0.009). These figures are from a diabetes population, not a dedicated obesity trial.
What are cotadutide’s side effects?
The most common adverse events in trials were gastrointestinal: nausea (about 35%) and vomiting (about 17%) across doses. These are typical of the incretin class and decreased over time, which is why trials used a stepwise dose-titration schedule.
Why does cotadutide help the liver?
The glucagon receptor arm promotes hepatic fat oxidation and energy expenditure. In the Phase 2b trial, the 300 µg dose improved ALT, the FIB-4 index, the NAFLD fibrosis score, and the fibrosis marker PRO-C3 versus placebo — improvements that were not seen with the GLP-1-only comparator, liraglutide.
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Educational purposes only. Not medical advice.
Cotadutide (MEDI0382) is an investigational research compound. It is not FDA approved and is not an available prescription medication. Nothing here is a recommendation to obtain or self-administer it.
All trial figures are cited from peer-reviewed publications (Nahra et al., Diabetes Care 2021, PMID 34016612; Ambery et al., Lancet 2018, PMID 29945727). Consult a qualified healthcare provider before any metabolic or weight intervention.