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Efficacy, Safety, and Mechanistic Insights of Cotadutide, a Dual Receptor Glucagon-Like Peptide-1 and Glucagon Agonist
Open accessAbstract
Context: Cotadutide is a dual receptor agonist with balanced glucagon-like peptide-1 and glucagon activity. Objective: To evaluate different doses of cotadutide and investigate underlying mechanisms for its glucose-lowering effects. Design/setting: Randomized, double-blind, phase 2a study conducted in 2 cohorts at 5 clinical trial sites. Patients: Participants were 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs. Intervention: Once-daily subcutaneous cotadutide or placebo for 49 days. Doses (50–300 µg) were uptitrated weekly (cohort 1) or biweekly (cohort 2). Main outcome measures: Co-primary end points (cohort 1) were percentage changes from baseline to end of treatment in glucose (area under the curve from 0 to 4 hours [AUC0–4h]) post–mixed-meal tolerance test (MMTT) and weight. Exploratory measures included postprandial insulin and gastric emptying time (GET; cohort 2). Results: Patients received cotadutide (cohort 1, n = 26; cohort 2, n = 20) or placebo (cohort 1, n = 13; cohort 2, n = 6). Significant reductions were observed with cotadutide vs placebo in glucose AUC0–4h post MMTT (least squares mean [90% CI], −21.52% [−25.68, −17.37] vs 6.32% [0.45, 12.20]; P < 0.001) and body weight (−3.41% [−4.37, −2.44] vs −0.08% [−1.45, 1.28]; P = 0.002). A significant increase in insulin AUC0–4h post MMTT was observed with cotadutide (19.3 mU.h/L [5.9, 32.6]; P = 0.008) and GET was prolonged on day 43 with cotadutide vs placebo (t½: 117.2 minutes vs −42.9 minutes; P = 0.0392). Conclusion: These results suggest that the glucose-lowering effects of cotadutide are mediated by enhanced insulin secretion and delayed gastric emptying. Trial Registration: ClinicalTrials.gov, NCT03244800.
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“Clinical research on GLP-1/ glucagon receptor co-agonists also reveals clear decreases in amino acid levels (Parker et al, 2020;Simonsen et al, 2022).”
From Emerging pharmacotherapies for obesity: A systematic review (2025) · cites this paper as Parker et al, 2020
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“Clinical research on GLP-1/ glucagon receptor co-agonists also reveals clear decreases in amino acid levels (Parker et al, 2020;Simonsen et al, 2022).”
From Emerging pharmacotherapies for obesity: A systematic review (2025) · cites this paper as Parker et al, 2020
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“data from clinical trials of once-daily GLP-1R/GcgR co-agonists cotadutide (previously MEDI0382) [[21], [22], [23]] and SAR425899 [24,25] have generated guarded optimism over the modest effects on weight reduction (<10% after 4–6 weeks of treatment)”
From Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice (2022) · cites this paper as [22]
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“Cotadutide effectively lowered blood sugar levels and reduced weight in obese individuals and T2DM patients, increased insulin secretion, delayed gastric emptying, with the most common side effects being gastrointestinal symptoms (nausea and vomiting), which were dose-dependent [99,100].”
From New Developments in Pharmacological Treatment of Obesity and Type 2 Diabetes—Beyond and within GLP-1 Receptor Agonists (2024) · cites this paper as [100]
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“There were two further phase IIa studies evaluating cotadutide with the first one showing that it reduced glucose levels in those with obesity and T2DM with the mechanism being greater insulin secretion and delayed gastric emptying [46].”
From The Road towards Triple Agonists: Glucagon-Like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide and Glucagon Receptor - An Update. (2024) · cites this paper as [46]
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Metadata
- Authors
- Parker, V. E. R., Robertson, D., Wang, T., Hornigold, D. C., Petrone, M., Cooper, A. T., Posch, M. G., Heise, T., Plum-Moerschel, L., Schlichthaar, H., Klaus, B., Ambery, P. D., Meier, J. J., & Hirshberg, B.
- Affiliations
- AstraZeneca (United Kingdom) (GB)
- AstraZeneca (United States) (US)
- Charité – Universitätsmedizin Berlin (DE)
- Profil Institute for Metabolic Research (DE)
- Profil, Mainz, Germany
- SMO.MD, Magdeburg, Germany
- Nuvisan (Germany) (DE)
- AstraZeneca, Gothenburg, Sweden
- St. Josef-Hospital (DE)
- Corresponding author
- Parker, Victoria E R
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2019-10-14
- Volume
- 105
- Issue
- 3
- Pages
- 803-820
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2981305821
- Cited by
- 123
- References
- 37
- Citations by year
- 2026: 12 · 2025: 9 · 2024: 27 · 2023: 30 · 2022: 14 · 2021: 19 · 2020: 11
- FWCI
- 8.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AstraZeneca. V. Ruvini Jayasinghe
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Pharmacology (medical) › Pharmacology and Obesity Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- cotadutide, dual receptor agonist, glucagon-like peptide-1, glucagon, type 2 diabetes, obesity, glucose-lowering effect, postprandial insulin, gastric emptying, weight loss, mixed meal tolerance test, dose escalation, drug safety, adverse events, GLP-1 receptor, GIP receptor, incretin-based therapy, pharmacokinetics
- MeSH terms
- Glucagon-Like Peptide-1 Receptor Agonists, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Follow-Up Studies, Glucagon, Humans, Male, Middle Aged, Obesity, Peptides, Prognosis, Biomarkers, Receptors, Glucagon, Overweight, Glucagon-Like Peptide 1
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