Cotadutide: Mechanism, Dosing & Research Data

Cotadutide (MEDI0382) is a once-daily subcutaneous dual agonist of GLP-1 and glucagon receptors, developed by AstraZeneca/MedImmune. The glucagon receptor component adds hepatic fat mobilization and energy expenditure to GLP-1-mediated satiety, making cotadutide particularly suited for non-alcoholic steatohepatitis (NASH) and obesity with significant hepatic fat content.

Mechanism of Action

GLP-1R agonism: reduces food intake, slows gastric emptying, stimulates glucose-dependent insulin secretion, reduces HbA1c
GCGR agonism: increases hepatic glucose output at low glucagon doses is minimal (insulin-dominated by GLP-1 effect), but drives hepatic fat oxidation and bile acid production
Combined GLP-1/glucagon: greater weight loss than GLP-1 alone; glucagon-driven thermogenesis (brown adipose tissue activation) amplifies energy expenditure
Hepatic fat reduction: GCGR agonism accelerates beta-oxidation of fatty acids in liver, reducing hepatic steatosis and NASH
Once-daily delivery via C18 fatty acid albumin-binding modification extends half-life analogous to semaglutide approach

Research Findings

MEDI0382 Phase IIa (obese T2D): 54% reduction in liver fat content by MRI-PDFF vs 14% placebo over 26 weeks; greater than seen with liraglutide
Body weight reduction of 5-8% in 26-week Phase IIa in T2D patients, comparable to GLP-1 monotherapy
NASH histology improvement: Phase II data showed reduction in NAS (NAFLD activity score) and fibrosis markers vs baseline
GI tolerability: nausea/vomiting rates similar to GLP-1 monotherapy; glucagon component does not worsen GI side effects
AstraZeneca paused cotadutide development in 2021 to focus on other metabolic assets; data remain valuable for dual GLP-1/GCGR pharmacology

Research Protocols

Clinical Phase II: 100-300 mcg SC once daily with weekly dose escalation for T2D/NASH patients over 26 weeks
Rodent NASH model (STAM/MCD diet): 10-30 nmol/kg SC daily for 4-8 weeks; liver histology as primary endpoint
Energy expenditure: indirect calorimetry in lean/DIO mice dosed with 3-10 nmol/kg cotadutide to quantify thermogenic effect
GLP-1R/GCGR functional assay: cAMP accumulation at 0.01-100 nM; assess selectivity ratio

Interactions

Semaglutide/tirzepatide: mechanistic comparison; cotadutide adds glucagon hepatic fat benefit vs pure GLP-1 agonism
Insulin: GLP-1R agonism of cotadutide is glucose-dependent; low hypoglycemia risk with basal insulin co-administration
Statin/fibrate: complementary for metabolic liver disease; cotadutide addresses hepatic steatosis via different mechanism

Safety Profile

Phase II safety: nausea 30-40%, vomiting 10-20% at therapeutic doses (titration reduces incidence). No hypoglycemia when used without secretagogues. No cardiac signals identified. Development paused by AstraZeneca in 2021; not currently advancing.