Cotadutide (MEDI0382): Research & Studies

Research Overview#

Cotadutide (MEDI0382) was evaluated in a clinical program that included phase 1 safety studies, a phase 2a dose-escalation trial, and a phase 2b efficacy trial. The program generated promising data on metabolic and hepatic endpoints before being discontinued for strategic (not safety or efficacy) reasons.

The evidence level is classified as moderate because the data include a well-designed phase 2b trial with an active comparator, but the program was terminated before phase 3 confirmation.

Phase 2b: Metabolic and Hepatic Outcomes#

The pivotal phase 2b study (Nahra et al., 2021; PMID 34016612) was the most informative trial in the cotadutide program. This 54-week study randomized 834 adults with BMI of 25 or higher and type 2 diabetes on metformin to cotadutide 100, 200, or 300 mcg daily, placebo, or open-label liraglutide 1.8 mg daily.

Key metabolic results:

• All cotadutide doses significantly reduced HbA1c and body weight versus placebo (P<0.001)
• Weight loss with cotadutide 200 mcg was comparable to liraglutide 1.8 mg
• Weight loss with cotadutide 300 mcg exceeded liraglutide 1.8 mg

Key hepatic results:

• Cotadutide 300 mcg significantly improved ALT, AST, propeptide of type III collagen, fibrosis-4 index, and NAFLD fibrosis score versus placebo
• These hepatic improvements were not observed with liraglutide, suggesting they were driven by the glucagon receptor agonism component
• The hepatic data were the strongest differentiator of cotadutide from GLP-1-only agonists

Phase 2a: Dose-Escalation#

The phase 2a study (Ambery et al., 2018; PMID 29945727) was published in The Lancet and established the safety and preliminary efficacy of cotadutide in a dose-ascending design. The study demonstrated clinically meaningful reductions in blood glucose and body weight, supporting advancement to the larger phase 2b program.

Program Discontinuation#

AstraZeneca discontinued cotadutide development in April 2023. The decision was strategic rather than safety- or efficacy-driven:

1. Competitive landscape: The once-daily dosing frequency was increasingly disadvantageous as weekly GLP-1 agonists became the standard
2. Next-generation compound: AstraZeneca advanced AZD9550, a weekly GLP-1/glucagon dual agonist designed to address the dosing frequency limitation
3. Resource allocation: Focusing resources on the more competitive weekly molecule was considered strategically optimal

Evidence Quality Assessment#

Research Evidence Context#

Cotadutide (MEDI0382) belongs to the Metabolic category of research peptides. The research evidence for Cotadutide (MEDI0382) spans multiple study types and endpoints. Researchers should evaluate the strength of evidence based on study design, sample size, and publication status when drawing conclusions about efficacy and safety.

Key Clinical Studies#

The following studies provide the clinical evidence base for Cotadutide (MEDI0382):

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#

Authors: Nahra R, Wang T, Gadde KM, et al. (2021) — Diabetes Care

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.

Key Findings:

• 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
• Cotadutide 300 mcg improved ALT, AST, fibrosis-4 index, and NAFLD fibrosis score versus placebo
• Hepatic biomarker improvements were not observed with liraglutide, suggesting glucagon-mediated effect
• Most common adverse events: nausea (35%) and vomiting (17%), decreasing over time

Limitations: Liraglutide comparator was open-label, not blinded. Phase 2b sample sizes per arm were moderate. No liver biopsy endpoints were included. Program was discontinued before phase 3 confirmation.

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#

Authors: Ambery P, Parker VE, Stumvoll M, et al. (2018) — The Lancet

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.

Key Findings:

• Clinically meaningful reductions in blood glucose and body weight
• Dose-dependent efficacy across the dose range
• Acceptable safety and tolerability profile
• Supported advancement to the phase 2b program

Limitations: Small sample size and short treatment duration typical of phase 2a design. Did not include liver-specific endpoints that would later become central to the cotadutide program.

Evidence Quality Assessment#

The overall evidence level for Cotadutide (MEDI0382) is classified as moderate. There is meaningful clinical evidence from Phase 2 or similar trials, though larger confirmatory studies may be needed.

Research Gaps and Future Directions#

The following gaps in the current evidence base for Cotadutide (MEDI0382) have been identified:

• Phase 3 confirmatory trials were never conducted due to program discontinuation
• Long-term safety and efficacy data beyond 54 weeks were not obtained
• Liver biopsy-confirmed NASH endpoints were not assessed in any completed trial
• Head-to-head comparison with tirzepatide or semaglutide was never conducted
• Whether the hepatic benefits of dual GLP-1/glucagon agonism translate to clinical NASH outcomes remains unproven

Addressing these research gaps will be important for establishing a more complete understanding of Cotadutide (MEDI0382)'s therapeutic potential and safety profile.

Related Reading#

• Cotadutide (MEDI0382) overview and research guide
• Cotadutide (MEDI0382) dosing protocols
• Cotadutide (MEDI0382) molecular structure