Cotadutide
Cotadutide (MEDI0382), GLP-1 and glucagon receptor dual agonist
Written by Aaron CuhaReviewed Sep 2026
Also known as: MEDI0382
A once-daily GLP-1 and glucagon dual agonist that AstraZeneca stopped developing in 2023 for what its own registry entries call strategic pipeline considerations, not safety. It leaves a randomised human record of more than a thousand people across phase 2 trials in type 2 diabetes, kidney disease and biopsy-proven MASH, and it never reached phase 3.
Overview
Cotadutide is a synthetic peptide with balanced agonist activity at the GLP-1 receptor and the glucagon receptor, given as a daily subcutaneous injection. It was developed by MedImmune and then AstraZeneca as MEDI0382 for type 2 diabetes with obesity, for diabetic kidney disease and for non-alcoholic steatohepatitis (now called MASH). Its place in the history of this drug class is that it was among the first dual agonists to show in people that adding glucagon receptor activity to a GLP-1 drug changes what happens in the liver, the idea that survodutide, mazdutide, pemvidutide and retatrutide now carry forward.
The human record is substantial for a drug that never reached phase 3. The largest trial, a 54 week phase 2b published in Diabetes Care in 2021, randomised 834 adults with type 2 diabetes and a BMI of 25 or more to cotadutide 100, 200 or 300 mcg daily, placebo, or open-label liraglutide 1.8 mg. Cotadutide lowered HbA1c and body weight against placebo at weeks 14 and 54 (P below 0.001 for all), weight loss at 300 mcg exceeded liraglutide 1.8 mg, and liver enzymes, propeptide of type III collagen and fibrosis scores improved with 300 mcg but not with liraglutide. Nausea affected 35 percent and vomiting 17 percent. In diabetic kidney disease (248 people, 26 weeks, Kidney International 2024), albuminuria fell 43.9 percent at 300 mcg and 49.9 percent at 600 mcg against placebo, with open-label semaglutide 1 mg as a reference arm and tolerability of the 600 mcg dose described as comparable to semaglutide. In PROXYMO (74 people with biopsy-proven non-cirrhotic MASH with fibrosis, 19 weeks), the 600 mcg dose reduced liver fat fraction by an absolute 5.0 percentage points against placebo and lowered ALT and AST, at the cost of adverse events in 91.7 percent against 37.5 percent and treatment discontinuation in 16.7 percent against 4.2 percent. Smaller mechanistic trials showed that weight loss was driven by a 41 percent fall in energy intake rather than a rise in energy expenditure, and that cotadutide depletes liver glycogen in a way liraglutide does not, evidence that the glucagon receptor is engaged in the human liver.
The programme ended in early 2023. Two AstraZeneca phase 1 trials, a thorough QT study (31 participants) and a hepatic impairment study (24 participants), were terminated and the sponsor entered the same text in the ClinicalTrials.gov why-stopped field for both: that discontinuing development of cotadutide was based on strategic pipeline considerations and that the premature closure was not due to any newly observed safety signals or a change in the risk benefit profile. That is the sponsor's own primary record and it is the only stated reason. Cotadutide was never approved anywhere and no phase 3 was ever registered.
Mechanism of action
In people, cotadutide's GLP-1 receptor action produces the familiar effects of the class: enhanced insulin secretion after meals, slower gastric emptying and reduced food intake. A 65 person phase 2a trial found postprandial glucose area under the curve fell 21.5 percent against a 6.3 percent rise on placebo, postprandial insulin rose, and gastric emptying half-time lengthened by about two hours. A 19 person energy balance study found weight loss was accounted for by a 41.3 percent reduction in energy intake with no meaningful change in energy expenditure by doubly labelled water. The glucagon receptor component is what distinguished it. In a randomised phase 2a with magnetic resonance spectroscopy, cotadutide reduced postprandial and fasting liver glycogen and liver fat more than both placebo and liraglutide, which the investigators interpreted as direct glucagon receptor action on the human liver promoting glycogenolysis. Glucagon receptor agonism also raises energy expenditure and hepatic fat oxidation in animals, and the mouse study most cited for cotadutide's liver effects (Nature Metabolism, 2020) found that its weight and glucose effects were mediated mainly through GLP-1 signalling while its effects on liver lipid, glycogen flux and mitochondrial turnover ran through the glucagon receptor, with greater fibrosis reduction than liraglutide or obeticholic acid at matched weight loss. That paper is animal work in mouse models of steatohepatitis and has been miscited as a human trial; it is not one.
Human evidence
A large phase 2 record and no phase 3. Randomised, placebo-controlled trials in 834 people with type 2 diabetes over 54 weeks, 248 with diabetic kidney disease over 26 weeks, 74 with biopsy-proven MASH over 19 weeks, and several smaller mechanistic studies, all funded by AstraZeneca. ClinicalTrials.gov lists 23 cotadutide or MEDI0382 studies, 21 completed and 2 terminated at programme closure.
- 54 week phase 2b, 834 people: HbA1c and weight lower than placebo at 14 and 54 weeks (P below 0.001); 300 mcg beat open-label liraglutide 1.8 mg on weight; liver enzymes and fibrosis scores improved on 300 mcg and not on liraglutide. Nausea 35 percent, vomiting 17 percent.
- Diabetic kidney disease phase 2b, 248 people, 26 weeks: albuminuria down 43.9 percent (300 mcg) and 49.9 percent (600 mcg) against placebo; kidney function (eGFR) not reported as improved; semaglutide 1 mg run open-label as a reference.
- PROXYMO, 74 people with biopsy-proven MASH, 19 weeks: liver fat down 5.0 absolute percentage points at 600 mcg; ALT and AST down; adverse events in 92 percent and discontinuation in 17 percent on that dose. No biopsy endpoint.
- Phase 2a, 65 people, 49 days: postprandial glucose down 21.5 percent, weight down 3.4 percent, gastric emptying slowed.
- Energy balance study, 19 completers: weight loss explained by a 41 percent fall in energy intake; no increase in energy expenditure detected.
- Liver glycogen study: fasting and postprandial liver glycogen reduced more than with liraglutide, taken as evidence of glucagon receptor action in the human liver.
- Chronic kidney disease phase 2a, 41 people, 32 days: postprandial glucose down 26.7 percent against a 3.7 percent rise, weight down 3.41 kg against 0.13 kg.
- Programme closure: two phase 1 trials terminated in early 2023 with the sponsor's registry statement that the reason was strategic and not safety.
What this does not tell you: No trial ran longer than 54 weeks and none measured a clinical outcome: no cardiovascular events, no kidney failure, no liver histology, no mortality. The MASH trial measured fat fraction and enzymes, not biopsy change. Comparator arms (liraglutide, semaglutide) were open-label, so those comparisons are unblinded. The programme was stopped by its sponsor before any confirmatory trial, so the phase 2 signals were never tested at scale, and the sponsor's stated reason is the only reason on record. None of this is evidence that cotadutide does not work; it is evidence that the question was never taken to phase 3.
Reading the research record
Cotadutide is the clearest example in the GLP-1 class of a compound with a positive phase 2 record that was abandoned for reasons unrelated to what the trials found. AstraZeneca's own registry entries say so in plain words: strategic pipeline considerations, not a safety signal, not a change in the risk benefit profile. Trade press at the time connected the decision to the company's later-generation candidates and to the once-weekly dosing that competitors had already achieved, but no primary source states that, and this profile reports only what the sponsor recorded. A daily injection entering phase 3 in 2023 against weekly semaglutide and tirzepatide, and against weekly dual agonists like survodutide, would have faced a commercial case that had little to do with its pharmacology.
The scientific legacy is real and it is mostly about the liver. The human glycogen and liver fat data, and the 54 week fibrosis marker data that separated cotadutide from liraglutide, were early evidence in people that glucagon receptor agonism adds something to GLP-1 agonism in the liver, the hypothesis that survodutide, pemvidutide and retatrutide are now testing in MASH at phase 3 scale. That is where the cotadutide record belongs: as the human proof of concept for a mechanism, not as a drug anyone can take. One correction worth recording: the 2020 Nature Metabolism paper often cited for cotadutide's effect on steatohepatitis is a mouse study, and the human randomised data are in Diabetes Care 2021 and Clinical Gastroenterology and Hepatology 2024.
The evidence, charted
Fig. 1 · evidence composition
8of 10 citations (80%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 4 distinct years, 2020 to 2024, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Not approved
UK
Approved
AU
Approved
CA
Not approved
Approved in 2 of 4, prescription route in 0, not approved in 2. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Key studies & citations
- Human2021
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
834 adults with type 2 diabetes and BMI 25 or more on metformin, randomised to cotadutide 100 mcg (100), 200 mcg (256) or 300 mcg (256), placebo (110) or open-label liraglutide 1.8 mg (110) for 54 weeks. HbA1c and weight fell against placebo at weeks 14 and 54 (all P below 0.001). Weight loss at 300 mcg exceeded liraglutide; liver enzymes and fibrosis scores improved at 300 mcg but not with liraglutide. Nausea 35 percent, vomiting 17 percent. Funded by AstraZeneca (registry NCT03235050, results posted 2020).
Diabetes Care - Human2024
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
248 people with type 2 diabetes and chronic kidney disease (mean eGFR 55, 47 percent on SGLT2 inhibitors), 26 weeks, randomised to cotadutide 100, 300 or 600 mcg, placebo, or open-label semaglutide 1 mg weekly. Urine albumin to creatinine ratio fell 43.9 percent at 300 mcg (95 percent CI 30.6 to 54.7) and 49.9 percent at 600 mcg (38.4 to 59.3) against placebo at week 14, sustained to week 26. Serious adverse events balanced; tolerability at 600 mcg described as comparable to semaglutide. Sponsor funded (NCT04515849, results posted January 2025).
Kidney International - Human2024
Safety and Efficacy of Novel Incretin Co-agonist Cotadutide in Biopsy-proven Noncirrhotic MASH With Fibrosis
PROXYMO: 74 people with biopsy-proven non-cirrhotic MASH with fibrosis, randomised to cotadutide 600 mcg, 300 mcg or placebo for 19 weeks. At 600 mcg, absolute liver fat fraction fell 5.0 percentage points against placebo (95 percent CI 1.5 to 8.5), ALT fell 23.5 U per L and AST 16.8 U per L. Any adverse event in 91.7, 76.9 and 37.5 percent; discontinuation for adverse events 16.7, 7.7 and 4.2 percent. No histological endpoint. Sponsor funded.
Clinical Gastroenterology and Hepatology - Human2020
Efficacy, Safety, and Mechanistic Insights of Cotadutide, a Dual Receptor Glucagon-Like Peptide-1 and Glucagon Agonist
Phase 2a, 65 adults with type 2 diabetes and overweight or obesity, 49 days of daily cotadutide (50 to 300 mcg) or placebo. Postprandial glucose area under the curve fell 21.5 percent against a 6.3 percent rise on placebo (P below 0.001); weight fell 3.41 percent against 0.08 percent (P equals 0.002); postprandial insulin rose and gastric emptying half-time lengthened by about two hours. Sponsor funded.
Journal of Clinical Endocrinology and Metabolism - Human2024
Dual glucagon-like peptide-1 and glucagon receptor agonism reduces energy intake in type 2 diabetes with obesity
Phase 2a energy balance study; 12 cotadutide and 7 placebo completers over 42 days. Weight change minus 4.0 percent against minus 1.4 percent (P equals 0.011); energy intake fell 41.3 percent against placebo; energy expenditure by doubly labelled water did not differ (1.0 percent, P equals 0.784). Weight loss was driven by eating less, not by burning more. Funded by AstraZeneca.
Diabetes, Obesity and Metabolism - Human2023
Cotadutide promotes glycogenolysis in people with overweight or obesity diagnosed with type 2 diabetes
Two-part randomised phase 2a using magnetic resonance spectroscopy. Cotadutide reduced postprandial (day 28) and fasting (day 35) liver glycogen against placebo, the primary endpoints, and reduced liver glycogen and fat more than liraglutide, which the authors interpret as glucagon receptor engagement in the human liver. Funded by AstraZeneca; several authors are AstraZeneca employees (NCT03555994).
Nature Metabolism - Review2024
Safety and efficacy of GLP-1 and glucagon receptor dual agonist for the treatment of type 2 diabetes and obesity: a systematic review and meta-analysis of randomized controlled trials
Pooled analysis of mazdutide and cotadutide placebo-controlled trials (11 published, 4 unpublished): HbA1c minus 0.63 percentage points (95 percent CI minus 0.82 to minus 0.44), body weight minus 4.16 percent (minus 5.41 to minus 2.92); no difference in serious adverse events (OR 1.03) but treatment-emergent adverse events OR 2.52 and vomiting OR 6.05. Funded by Chinese national science foundations, not by either manufacturer. Pools two different molecules.
Endocrine - Animal2020
Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis
Mouse models of steatohepatitis. Weight, food intake and glucose effects ran mainly through GLP-1 signalling; liver lipid, glycogen flux and mitochondrial effects through the glucagon receptor. Cotadutide reduced fibrosis more than liraglutide or obeticholic acid at matched weight loss. This is animal and mechanistic work with AstraZeneca employee authors; it has been miscited elsewhere as a human randomised trial and is not one.
Nature Metabolism - Human2023
A Thorough QTC Study to Assess the Effect of Cotadutide on Cardiac Repolarization in Healthy Participants
Phase 1, 31 participants, TERMINATED. Sponsor's why-stopped text: discontinuing the development of cotadutide, a daily injectable GLP-1/glucagon co-agonist, is based on strategic pipeline considerations; the premature closure is not due to any newly observed safety signals or a change in the risk/benefit profile.
ClinicalTrials.gov - Human2023
Pharmacokinetics of Cotadutide in Participants With Hepatic Impairment
Phase 1, 24 participants, TERMINATED March 2023 with the same sponsor statement: development discontinued for strategic pipeline considerations, not for safety signals or a change in the risk benefit profile.
ClinicalTrials.gov
Frequently asked questions
Is cotadutide still in development?
No. AstraZeneca stopped development in early 2023. The sponsor's own entries on ClinicalTrials.gov for two terminated phase 1 trials state that the decision was based on strategic pipeline considerations and was not due to any newly observed safety signal or change in the risk benefit profile. No phase 3 was ever registered and it was never approved anywhere.
What did the human trials show?
In 834 people with type 2 diabetes over 54 weeks, cotadutide lowered HbA1c and weight against placebo, and the 300 mcg dose produced more weight loss than liraglutide 1.8 mg along with improvements in liver enzymes and fibrosis scores that liraglutide did not produce. In 248 people with diabetic kidney disease it cut albuminuria by 44 to 50 percent. In 74 people with biopsy-proven MASH it reduced liver fat by 5 absolute percentage points but 92 percent on the top dose had adverse events. No trial measured a clinical outcome such as heart attacks, kidney failure or liver histology.
Why does a discontinued drug matter?
Because its human data were early evidence that adding glucagon receptor activity to a GLP-1 drug changes what happens in the liver, reducing glycogen and fat in ways liraglutide did not. That is the mechanism survodutide, pemvidutide and retatrutide now carry into phase 3. Cotadutide is the proof of concept, not a treatment option.
Was it stopped for safety reasons?
Not according to the only primary source. The sponsor wrote in the trial registry that closure was not due to newly observed safety signals or a change in the risk benefit profile. Its adverse event profile in trials was that of the GLP-1 class: nausea in about a third of people, vomiting in about one in six, and higher discontinuation at the highest doses.