Cotadutide (MEDI0382)

What is Cotadutide (MEDI0382)?#

Cotadutide (also known as MEDI0382) was a dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist developed by AstraZeneca for the treatment of type 2 diabetes, obesity, and non-alcoholic steatohepatitis (NASH). It was a 31-amino acid synthetic peptide with an N-terminal palmitic acid conjugation and an internal amide bridge (Glu1-Lys10) designed to provide balanced dual receptor agonism with a bias toward GLP-1 receptor activation.

Cotadutide represented an innovative approach to metabolic disease by combining GLP-1-mediated glycemic control and appetite suppression with glucagon-mediated enhancement of hepatic fat oxidation and energy expenditure. The dual agonism was intended to provide therapeutic benefits beyond what GLP-1-only agonists could achieve, particularly for liver-related metabolic conditions.

AstraZeneca discontinued cotadutide development in April 2023 as a strategic decision to advance AZD9550, a next-generation weekly dual agonist with potentially improved pharmacokinetic and competitive properties.

Mechanism of Action#

Cotadutide acts as a dual agonist at two related but functionally distinct receptors:

• GLP-1 receptor agonism (EC50 ~6.9 pM): Stimulates glucose-dependent insulin secretion, suppresses glucagon release, delays gastric emptying, and reduces appetite through central satiety pathways
• Glucagon receptor agonism (EC50 ~10.2 pM): Promotes hepatic glycogenolysis and gluconeogenesis, increases energy expenditure, enhances hepatic lipid oxidation, and reduces hepatic fat accumulation

The GLP-1-biased dual agonism was designed so that the glycemic benefits of GLP-1 receptor activation would counterbalance the hyperglycemic effects of glucagon, while the hepatic metabolic benefits of glucagon receptor activation would provide additive therapeutic value for NASH and fatty liver disease.

Research Overview#

Cotadutide was evaluated in multiple phase 1 and phase 2 clinical trials. The phase 2b study (Nahra et al., 2021; n=834) demonstrated significant improvements in HbA1c, weight loss, and hepatic parameters including ALT, AST, and fibrosis biomarkers. The hepatic effects were particularly noteworthy, as they suggested potential utility in NASH treatment beyond what GLP-1-only agonists had demonstrated.

Important Considerations#

• Reached phase 2b clinical trials but never advanced to phase 3
• Discontinued in April 2023 as a strategic decision, not due to safety concerns
• Replaced by AZD9550, a next-generation weekly dual agonist in AstraZeneca's pipeline
• Not available for clinical use or purchase through any channel
• Dual GLP-1/glucagon agonism is being actively pursued by multiple companies with other compounds

Key Research Findings#

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, published in Diabetes Care (Nahra R et al., 2021; PMID: 34016612):

Largest cotadutide clinical trial (n=834) comparing cotadutide 100, 200, and 300 mcg to placebo and open-label liraglutide 1.8 mg over 54 weeks. Demonstrated significant HbA1c reduction, weight loss, and improvements in hepatic biomarkers.

• HbA1c and body weight significantly decreased at weeks 14 and 54 versus placebo (all P<0.001)
• Weight loss with cotadutide 200 mcg was similar to liraglutide 1.8 mg
• Weight loss with cotadutide 300 mcg exceeded liraglutide 1.8 mg

MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study, published in The Lancet (Ambery P et al., 2018; PMID: 29945727):

Phase 2a dose-escalation study establishing safety, tolerability, and preliminary efficacy of cotadutide in patients with overweight/obesity and type 2 diabetes. Demonstrated clinically meaningful reductions in blood glucose and body weight.

• Clinically meaningful reductions in blood glucose and body weight
• Dose-dependent efficacy across the dose range
• Acceptable safety and tolerability profile

Related Reading#

• Cotadutide (MEDI0382) research studies and evidence
• Cotadutide (MEDI0382) dosing protocols
• Cotadutide (MEDI0382) side effects profile
• Mazdutide research guide
• Pemvidutide research guide