Cotadutide
AstraZeneca's GLP-1 / glucagon dual agonist — discontinued in 2023 after Phase 2 in NASH and chronic kidney disease did not deliver compelling benefit-risk profile.
Investigational compounds — read carefully
This section covers peptides at the frontier of research. Most entries are preclinical, in early or mid-stage clinical trials, or theoretical. Evidence levels are explicitly marked on every entry.
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At a glance
An early dual GLP-1/glucagon agonist that helped establish the therapeutic concept later carried forward by survodutide, mazdutide, and pemvidutide. The clinical program ultimately ended; the mechanistic lessons live on.
- Class
- GLP-1 / glucagon dual agonist peptide
- Sponsor
- AstraZeneca / MedImmune
- Stage
- Phase 2 (discontinued 2023)
- Lead use cases studied
- T2D, NASH, chronic kidney disease, obesity
What it is
Cotadutide (MEDI0382) is a peptide engineered to activate both the GLP-1 receptor and the glucagon receptor — the dual-agonist concept that has since been expanded to triple agonism (retatrutide, with GIP added) and to other dual-agonist programs (survodutide, mazdutide, pemvidutide). Cotadutide was one of the earliest molecules in this class to enter sustained clinical investigation.
Current research status
AstraZeneca discontinued the cotadutide development program in 2023 after Phase 2b readouts in NASH (PROXYMO trial) and other indications did not produce the benefit-risk profile required for Phase 3 advancement. The molecule is no longer in active development. The dual-agonist therapeutic concept it helped establish is being pursued by competitor programs with second-generation molecules.
Mechanistic rationale
Simultaneous activation of GLP-1 and glucagon receptors. The GLP-1 component drives the now-familiar appetite suppression and glycemic improvement; the glucagon component is intended to add energy expenditure (raising metabolic rate) and direct hepatic effects (reducing hepatic fat). The challenge is balancing the two arms — too much glucagon activity raises blood glucose and could undermine the GLP-1 glycemic benefit; too little fails to add the energy-expenditure differentiator.
Available evidence
PROXYMO Phase 2b NASH trial (2022) — Cotadutide produced hepatic fat reductions and weight loss, but the benefit-risk profile did not meet the bar for advancement.[1]
T2D and CKD Phase 2 trials (2018–2022) — Demonstrated dose-dependent glycemic and weight effects, but with tolerability concerns particularly at higher doses needed for the glucagon-driven energy expenditure component.[2]
Why it's interesting
Cotadutide is part of the foundational evidence base for the dual-agonist concept. The lessons from its development — particularly the tradeoff between glucagon-driven thermogenesis and tolerability — directly shaped the design and dose-selection strategies of the second-generation molecules currently in late-stage trials. Anyone trying to understand why retatrutide, survodutide, and mazdutide look the way they do should know cotadutide's history.
Limitations & risks
The molecule is no longer in active development; its current relevance is historical context for understanding the broader dual/triple agonist class. The discontinuation reflects benefit-risk-balance challenges rather than a fundamental rejection of the dual-agonist concept — which is alive and well in competitor programs.
Community discussion notes
Less discussed in fitness communities than the active triple-agonist programs (retatrutide especially). Of substantial academic interest as the foundational dual-agonist clinical experience.
The takeaway
Cotadutide is a discontinued first-generation GLP-1/glucagon dual agonist whose primary current value is historical and pedagogical. The active dual-agonist development resides with second-generation molecules; cotadutide established the proof-of-concept and surfaced the tolerability tradeoffs that shaped what came next.
References
- Nahra R, et al. Cotadutide vs Placebo and Open-label Liraglutide in Patients with Type 2 Diabetes (PROXYMO). Diabetes Care. 2021;44(6):1433-1442. https://pubmed.ncbi.nlm.nih.gov/33941684/
- Boland ML, et al. Cotadutide induces beneficial hepatometabolic effects in obese patients with type 2 diabetes. Cell Metab. 2020;31(4):812-822. https://pubmed.ncbi.nlm.nih.gov/32208296/