What Is Cotadutide? Definition and What Research Reports

Definition

Cotadutide is a synthetic, lipidated peptide designed to activate two receptors at once: the glucagon-like peptide-1 (GLP-1) receptor and the glucagon receptor. Because it engages both targets in a single molecule, the literature describes it as a dual receptor agonist or incretin co-agonist rather than a single-target GLP-1 analogue. It is an investigational compound that has been studied in adults with type 2 diabetes, overweight or obesity, metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) and diabetic kidney disease, and it also appears in publications under its development code MEDI0382. This page is for educational purposes only and is not medical advice; consult a licensed physician for any question about diagnosis, treatment or medication.

Molecular Class and Origin

Cotadutide belongs to the peptide class of GLP-1 receptor/glucagon receptor (GLP-1R/GcgR) dual agonists, a design strategy inspired by oxyntomodulin, a naturally occurring gut peptide that weakly activates both receptors. Laboratory synthesis and lipid modification are used to extend the circulating half-life of such peptides so they can be given less frequently than native hormones. In human studies the molecule has been administered subcutaneously; a population pharmacokinetic analysis in people with type 2 diabetes characterised how cotadutide exposure behaved across subjects and supported once-daily subcutaneous dosing in that programme (PMID 35235191).

The rationale behind the dual design is described in mechanistic terms across the literature: GLP-1 receptor activation is associated with glucose-dependent insulin secretion, slowed gastric emptying and reduced food intake, while glucagon receptor activation is associated with hepatic effects and energy expenditure. Researchers have used cotadutide as a tool to test whether combining the two signals produces metabolic and hepatic effects that differ from GLP-1 receptor agonism alone.

How the Term Is Used in Peptide Research

In the published literature, "cotadutide" appears in several distinct contexts:

• As a named investigational agent in randomised clinical trials of glycaemic, body-weight, hepatic and kidney endpoints.
• As a mechanistic probe in human physiology studies, where its glucagon receptor activity is used to interrogate hepatic glycogen handling.
• As a comparator concept in discussions of dual and triple agonist peptide design, alongside single-target GLP-1 receptor agonists.
• As a subject of clinical pharmacology modelling, including population pharmacokinetics, special-population bridging studies and exposure-response modelling of tolerability.
• As an intervention in rodent models of obesity and steatohepatitis.

What the Published Literature Reports

Glycaemic and body-weight endpoints

A 54-week randomised phase 2b study in adults with overweight or obesity and type 2 diabetes assigned participants to double-blind cotadutide at 100 µg, 200 µg or 300 µg, to placebo, or to open-label liraglutide 1.8 mg, and the study reported changes in metabolic and hepatic parameters across those arms (PMID 34016612). Earlier work describing efficacy, safety and mechanistic insights for the dual GLP-1 and glucagon receptor agonist reported effects on glucose control and body weight in people with type 2 diabetes together with mechanistic observations such as effects on gastric emptying (PMID 31608926). A phase I randomised, double-blind, placebo-controlled study in Japanese patients with type 2 diabetes and a body mass index of 25 kg/m² or higher evaluated the safety/tolerability, efficacy and pharmacokinetics of 600 µg cotadutide (PMID 37337366).

Liver endpoints

Hepatic outcomes have been a recurring focus. The 54-week phase 2b study reported hepatic as well as metabolic parameters in adults with overweight or obesity and type 2 diabetes (PMID 34016612), and a later trial assessed the safety and efficacy of the incretin co-agonist in participants with biopsy-proven non-cirrhotic MASH with fibrosis (PMID 38729399). In preclinical models, researchers reported resolution of NASH and hepatic fibrosis with the GLP-1R/GcgR dual agonist and linked the effect to modulation of mitochondrial function and lipogenesis (PMID 32478287).

Kidney endpoints

A randomised phase 2b trial examined the effects of the GLP-1 and glucagon receptor agonist on kidney outcomes in patients with diabetic kidney disease (PMID 39218393). Separately, a single-dose phase I bridging study characterised the pharmacokinetics and safety of cotadutide in individuals with renal impairment (PMID 37140727).

Mechanistic and animal studies

Human mechanistic work reported that cotadutide promoted glycogenolysis in people with overweight or obesity diagnosed with type 2 diabetes, an observation consistent with engagement of the glucagon receptor in the liver (PMID 38066113). In rodents, researchers reported that cotadutide improved brown adipose tissue thermogenesis in obese mice (PMID 37832793) and that it modulated hypothalamic orexigenic and anorexigenic neuropeptides in obese mice (PMID 38147963). These findings are model-specific and are not human outcome data.

Pharmacokinetics

Clinical pharmacology publications include a population pharmacokinetic analysis in subjects with type 2 diabetes (PMID 35235191) and the renal-impairment bridging study noted above, which reported single-dose pharmacokinetics and safety across renal function categories (PMID 37140727). Such analyses are used by researchers to describe exposure, variability and covariates rather than to establish clinical benefit.

Tolerability and Adverse Events: What Studies Report

Gastrointestinal symptoms are the most frequently discussed tolerability issue for this molecule class. An exposure-response analysis applied a Markov modelling approach to nausea incidence for cotadutide, quantifying how the probability of nausea related to drug exposure over time (PMID 39044369). Safety and tolerability were also primary or co-primary considerations in the phase I study of 600 µg cotadutide in Japanese patients with type 2 diabetes and a body mass index of 25 kg/m² or higher (PMID 37337366), in the trial in biopsy-proven non-cirrhotic MASH with fibrosis (PMID 38729399) and in the single-dose study in individuals with renal impairment (PMID 37140727). Readers comparing these reports should note that adverse-event profiles are reported per trial, per dose level and per population, and cannot be generalised beyond the settings studied.

Regulatory and Availability Status

Cotadutide is an investigational peptide. It has not been approved by the U.S. Food and Drug Administration or, to the best of the published record summarised here, by other major regulators for any indication, and every human dataset described above comes from a clinical trial setting with medical supervision, monitoring and ethics oversight. Peptides in this category are sometimes labelled "research use only" when sold as chemicals, which is a regulatory and labelling statement about the material, not an indication of safety or suitability for people. PeptideU does not sell peptides and does not provide instructions for using them.

Limits of the Evidence

The published cotadutide literature consists largely of phase 1 and phase 2 trials, clinical pharmacology analyses and animal experiments. Phase 2 studies are typically sized to examine biomarkers, surrogate endpoints and tolerability rather than long-term clinical outcomes such as cardiovascular events, liver decompensation or kidney failure. Results in obese mice — including the thermogenesis and hypothalamic neuropeptide findings — describe biology in that model and are not evidence of the same effects in humans. Anyone reading a single trial abstract should also check the comparator arm, the duration and the population, because a 54-week diabetes trial (PMID 34016612) and a single-dose pharmacokinetic study (PMID 37140727) answer very different questions.

Related Glossary Terms

• GLP-1 receptor agonist — a molecule activating only the GLP-1 receptor.
• Glucagon receptor agonist — a molecule activating the glucagon receptor.
• Dual agonist / co-agonist — one peptide engineered to activate two receptors, as with cotadutide.
• Oxyntomodulin — the endogenous peptide whose dual receptor activity inspired this design class.
• MASH / NASH — metabolic liver disease terminology used across the hepatic studies cited above.

References

• Effects of Cotadutide on Metabolic and Hepatic Parameters in Adults With Overweight or Obesity and Type 2 Diabetes: A 54-Week Randomized Phase 2b Study (Diabetes Care, 2021)
• Safety and Efficacy of Novel Incretin Co-agonist Cotadutide in Biopsy-proven Noncirrhotic MASH With Fibrosis (Clinical Gastroenterology and Hepatology, 2024)
• Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis (Nature Metabolism, 2020)
• Cotadutide promotes glycogenolysis in people with overweight or obesity diagnosed with type 2 diabetes (Nature Metabolism, 2023)
• Cotadutide improves brown adipose tissue thermogenesis in obese mice (Biochemical Pharmacology, 2023)
• Exposure-response modeling for nausea incidence for cotadutide using a Markov modeling approach (CPT: Pharmacometrics & Systems Pharmacology, 2024)
• Population Pharmacokinetics of Cotadutide in Subjects with Type 2 Diabetes (Clinical Pharmacokinetics, 2022)
• Pharmacokinetics and Safety of Cotadutide, a GLP-1 and Glucagon Receptor Dual Agonist, in Individuals with Renal Impairment: A Single-Dose, Phase I, Bridging Study (Clinical Pharmacokinetics, 2023)
• Efficacy, Safety, and Mechanistic Insights of Cotadutide, a Dual Receptor Glucagon-Like Peptide-1 and Glucagon Agonist (The Journal of Clinical Endocrinology and Metabolism, 2020)
• A randomized phase 2b trial examined the effects of the glucagon-like peptide-1 and glucagon receptor agonist cotadutide on kidney outcomes in patients with diabetic kidney disease (Kidney International, 2024)
• Cotadutide (GLP-1/Glucagon dual receptor agonist) modulates hypothalamic orexigenic and anorexigenic neuropeptides in obese mice (Peptides, 2024)
• Safety/tolerability, efficacy and pharmacokinetics of 600-μg cotadutide in Japanese type 2 diabetes patients with a body mass index of 25 kg/m² or higher: A phase I, randomized, double-blind, placebo-controlled study (Diabetes, Obesity & Metabolism, 2023)