Cotadutide research findings - The Echo Compendium

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

Cotadutide MARKETED

heart-rate-chronotropy Increase

Low evidence

In a single-dose phase 1 study (36 on drug, 12 placebo), the balanced GLP-1/glucagon dual agonist cotadutide (MEDI0382) showed a dose-dependent increase in heart rate;...

Ambery PD et al., Br J Clin Pharmacol 2018;84(10):2325-2335 Source

Full findingIn a single-dose phase 1 study (36 on drug, 12 placebo), the balanced GLP-1/glucagon dual agonist cotadutide (MEDI0382) showed a dose-dependent increase in heart rate; treatment-emergent adverse events were mild/moderate (commonest vomiting, nausea, dizziness).

Populationsingle-dose phase 1 study, 36 on drug / 12 placebo

Fundingindustry - AstraZeneca/MedImmune (trial sponsor; inferred from registration trial)

Scope limitssmall sample (N~48); short duration

Comparatorsplacebo

Cotadutide MARKETED

heart-rate-chronotropy Increase

Low evidence

Increased pulse rate with cotadutide vs placebo, consistent with GLP-1 monoagonists

Asano M et al. Diabetes Obes Metab 2021;23:1859-1867 Source

PopulationOverweight Japanese T2D, phase 1/2a (n=61), up to 48 days, RCT

Fundingindustry - AstraZeneca (trial sponsor; inferred from registration trial)

Scope limitsidentifier not fully verified; small sample (N~61)

Comparatorsplacebo

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

Cotadutide MARKETED

renal Decrease

Moderate evidence

A PK/PD model from the same phase 2b CKD/T2D study predicted ~-45.6% UACR and ~-47.2% urinary-albumin change versus placebo at 26 weeks with 600 ug cotadutide,...

Yu et al., Br J Clin Pharmacol 2025;91(9):2672-2683 Source

Full findingA PK/PD model from the same phase 2b CKD/T2D study predicted ~-45.6% UACR and ~-47.2% urinary-albumin change versus placebo at 26 weeks with 600 ug cotadutide, corroborating the dose-dependent antialbuminuric effect.

PopulationSecondary PK/PD modelling analysis of the phase 2 randomised controlled trial NCT04515849 (247 participants); cotadutide 100/300/600 ug vs semaglutide 1 mg vs placebo.

Fundingindustry - AstraZeneca (cotadutide PK/PD analysis; disclosed)

Scope limitsmodel-predicted (PK/PD) surrogate endpoint; same trial programme NCT04515849 as PMID39218393

Comparatorsplacebo; semaglutide 1 mg

Cotadutide MARKETED

renal Decrease

Moderate evidence

In a phase 2b trial in T2D + CKD, cotadutide (GLP-1/glucagon dual agonist) dose-dependently reduced urinary albumin-to-creatinine ratio versus placebo, reaching...

Selvarajah V et al., Kidney Int 2024;106(6):1170-1180 Source

Full findingIn a phase 2b trial in T2D + CKD, cotadutide (GLP-1/glucagon dual agonist) dose-dependently reduced urinary albumin-to-creatinine ratio versus placebo, reaching significance at 300 ug (-43.9%) and 600 ug (-49.9%) at week 14, sustained to week 26, on top of standard of care.

PopulationPhase 2 double-blind randomised controlled trial (NCT04515849): 248 randomised; T2D + CKD (eGFR 20 to <90, UACR >50 mg/g); cotadutide 100/300/600 ug daily vs placebo, vs open-label semaglutide 1 mg.

Fundingindustry - AstraZeneca (cotadutide phase 2b sponsor; disclosed)

Scope limitsphase 2b surrogate (UACR) endpoint; ~47% on background SGLT2i

Comparatorsplacebo; semaglutide 1 mg

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

Cotadutide MARKETED

Pharmacology and mechanism Decrease

Moderate evidence

Cotadutide (MEDI0382) is a balanced GLP-1/glucagon receptor dual agonist (oxyntomodulin-like) reported to activate GLP-1 and glucagon receptors at approximately 5:1,...

Nahra et al., Diabetes Care 2021;44(6):1433-1442 (phase 2b); Ambery et al., Lancet 2018 (... Source

Full findingCotadutide (MEDI0382) is a balanced GLP-1/glucagon receptor dual agonist (oxyntomodulin-like) reported to activate GLP-1 and glucagon receptors at approximately 5:1, GLP-1 activity counterbalancing glucagon-driven hepatic glucose output while glucagon adds energy expenditure and hepatic-fat-lowering. In a 54-week phase 2b study in overweight/obesity + T2D it reduced body weight, HbA1c and liver fat vs placebo and vs liraglutide; AstraZeneca reportedly deprioritised it.

PopulationAdults with overweight/obesity and T2D; phase 2a (n~65) and phase 2b 54-week study (n~834), double-blind, placebo- and liraglutide-controlled

Fundingindustry-AstraZeneca

Scope limitsMechanism: balanced GLP-1/GCGR co-agonist, OXM-analogue. Glucagon arm framed as driving hepatic glycogenolysis/fat reduction and energy expenditure. Receptor ratio (~5:1) from review/company sources, not regulatory. Development status as reported (deprioritised), not a verdict.

Comparatorsplacebo; liraglutide

Cotadutide MARKETED

Pharmacology and mechanism Not directional

Low evidence

GLP-1R/GcgR dual agonist with GcgR-biased lipid engagement; lipid C18 moiety gives stronger GcgR engagement vs SAR425899; once-daily s.c.

Li Y et al. PNAS 2023;120:e2303696120 Source

PopulationIn-vitro/structural (cryo-EM) and PK

Fundingindustry - AstraZeneca (trial sponsor; inferred from registration trial)

ComparatorsSAR425899; peptide 15

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

Cotadutide MARKETED

hepatic-mash Decrease

Moderate evidence

Cotadutide 300 µg improved AST, ALT, PRO-C3, FIB-4, NAFLD fibrosis score vs placebo (not seen with liraglutide); promotes hepatic glycogenolysis and liver fat...

Nahra R et al. Diabetes Care 2021;44:1433-1442 Source

Full findingCotadutide 300 µg improved AST, ALT, PRO-C3, FIB-4, NAFLD fibrosis score vs placebo (not seen with liraglutide); promotes hepatic glycogenolysis and liver fat reduction via GcgR

PopulationOverweight/obese T2D, phase 2b ad hoc (n=834, 54 wk) and phase 2a glycogen study (NCT03555994)

Fundingindustry-AstraZeneca

Scope limitsconference/abstract-level; identifier not fully verified; open-label (unblinded)

Comparatorsplacebo; liraglutide 1.8 mg

Cotadutide MARKETED

hepatic-mash Decrease

Very low evidence

Cotadutide resolved NASH/fibrosis in preclinical models more than liraglutide or OCA at matched weight loss; GcgR drives hepatic lipid/mitochondrial effects

Boland ML et al. Nat Metab 2020;2:413-431 Source

PopulationMouse NASH models + GLP-1R KO mice (preclinical mechanism)

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsanimal data; human relevance uncertain

Comparatorsliraglutide; obeticholic acid

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

Cotadutide MARKETED

Weight change Decrease

Moderate evidence

Once-daily cotadutide reduced body weight vs placebo in overweight/obese T2D

Ambery P et al. Lancet 2018;391:2607-2618 Source

PopulationOverweight/obese T2D adults, phase 2a (n=51 randomised, 22 cotadutide analysed), 41 days, RCT, double-blind, placebo-controlled, up to 200 µg s.c.

Fundingindustry-AstraZeneca

Scope limitsshort duration; small sample (N~51)

Comparatorsplacebo

Cotadutide MARKETED

Weight change Decrease

Moderate evidence

54-week cotadutide reduced weight vs placebo; 200 µg similar to liraglutide 1.8 mg, 300 µg greater than liraglutide

Nahra R et al. Diabetes Care 2021;44:1433-1442 Source

PopulationOverweight/obesity + T2D on metformin (n=834), phase 2b, 54 wk, RCT double-blind, comparator open-label liraglutide 1.8 mg

Fundingindustry-AstraZeneca

Scope limitsconference/abstract-level; identifier not fully verified; open-label (unblinded)

Comparatorsplacebo; liraglutide 1.8 mg

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

Cotadutide MARKETED

Glycaemic control Decrease

Moderate evidence

Cotadutide reduced post-MMTT glucose AUC vs placebo in overweight/obese T2D (phase 2a, 41 days).

Ambery P et al. Lancet 2018;391:2607-2618 Source

PopulationOverweight/obese T2D, phase 2a (n=51) and phase 2b (n=834), up to 54 wk, RCT

Fundingindustry-AstraZeneca

Scope limitsshort duration; small sample (N~51)

Comparatorsplacebo; liraglutide 1.8 mg

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

Cotadutide MARKETED

Insulin and beta-cell function Mixed

Moderate evidence

The GLP-1/glucagon dual cotadutide reduced fasting hepatic glycogen ~38% vs placebo and ~41% vs liraglutide (13C-MRS), confirming GCGR engagement promoting...

Parker VER et al., Nat Metab 2023;5(12):2086-2093 Source

Full findingThe GLP-1/glucagon dual cotadutide reduced fasting hepatic glycogen ~38% vs placebo and ~41% vs liraglutide (13C-MRS), confirming GCGR engagement promoting glycogenolysis (glycogen not fully depleted); mouse receptor dissection shows cotadutide's glucose control and weight loss are predominantly GLP-1-mediated while liver lipid/glycogen-flux effects are glucagon-mediated.

PopulationOverweight/obese T2D (human glycogen MRS) + mouse dissection

Fundingindustry-AstraZeneca

Scope limitsReused from corpus T3-008/L2-028 (+ Boland 2020 mouse PMID:32478287). cotadutide-minus-liraglutide isolates GCGR on the liver. Glycogen readout, NOT a formal EGP tracer.

Comparatorsplacebo; liraglutide

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

Cotadutide MARKETED

Lipids and lipoproteins Decrease

Moderate evidence

Improvements in lipid profile with cotadutide 300 µg vs placebo

Nahra R et al. Diabetes Care 2021;44:1433-1442 Source

PopulationOverweight/obese T2D, phase 2b (n=834), 54 wk, RCT

Fundingindustry-AstraZeneca

Scope limitsconference/abstract-level; identifier not fully verified; open-label (unblinded)

Comparatorsplacebo; liraglutide 1.8 mg

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

Cotadutide MARKETED

Gastrointestinal tolerability Increase

Moderate evidence

GI adverse events (nausea, vomiting) most common; decreased over time

Nahra R et al. Diabetes Care 2021;44:1433-1442 Source

PopulationOverweight/obese T2D, phase 2a & 2b

Fundingindustry-AstraZeneca

Scope limitsconference/abstract-level; identifier not fully verified; open-label (unblinded)

Comparatorsplacebo; liraglutide 1.8 mg