cotadutide (MEDI0382) / AstraZeneca - LARVOL DELTA

Comparative Analysis of Glucagon Receptor Agonists vs Resmetirom in MASLD and MASH:Network Meta-Analysis of Clinical Trials (ENDO 2025) - "Resmetirom, a thyroid hormone receptor-β agonist, and glucagon receptor agonists (GRAs), such as Cotadutide, Retatrutide, and Survodutide, have demonstrated potential efficacy in recent clinical trials. SAE risk was not significantly elevated for Resmetirom (RR: 1.11, 95% CI: [0.77; 1.59], p = 0.58), but GRAs showed a trend toward higher SAE rates (RR: 2.38, 95% CI: [0.98; 5.82], p = 0.056).ConclusionsBoth Resmetirom and GRAs effectively reduce liver fat and ALT levels in MASLD/MASH patients, with Resmetirom offering a favorable safety profile and GRAs demonstrating superior ALT reductions but a potential increase in SAE risk. These findings underscore the promise of both therapeutic classes and highlight the need for further comparative trials to inform treatment decisions."

Retrospective data • Fibrosis • Genetic Disorders • Hepatocellular Cancer • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Oncology • Solid Tumor

Comparative Efficacy and Safety of Glucagon Receptor Agonists in Metabolic Outcomes: A Network Meta-Analysis of Randomized Controlled Trials (ENDO 2025) - "Retatrutide and survodutide demonstrate superior efficacy in weight loss and glycemic control among glucagon receptor agonists, though at the cost of higher adverse event-related discontinuation."

Retrospective data • Cardiovascular • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Comparative Analysis of Glucagon Receptor Agonists vs Resmetirom in MASLD and MASH:Network Meta-Analysis of Clinical Trials (ENDO 2025) - "Resmetirom, a thyroid hormone receptor-β agonist, and glucagon receptor agonists (GRAs), such as Cotadutide, Retatrutide, and Survodutide, have demonstrated potential efficacy in recent clinical trials. SAE risk was not significantly elevated for Resmetirom (RR: 1.11, 95% CI: [0.77; 1.59], p = 0.58), but GRAs showed a trend toward higher SAE rates (RR: 2.38, 95% CI: [0.98; 5.82], p = 0.056).ConclusionsBoth Resmetirom and GRAs effectively reduce liver fat and ALT levels in MASLD/MASH patients, with Resmetirom offering a favorable safety profile and GRAs demonstrating superior ALT reductions but a potential increase in SAE risk. These findings underscore the promise of both therapeutic classes and highlight the need for further comparative trials to inform treatment decisions."

Retrospective data • Fibrosis • Genetic Disorders • Hepatocellular Cancer • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Oncology • Solid Tumor

Beyond GLP-1: efficacy and safety of dual and triple incretin agonists in personalized type 2 diabetes care-a systematic review and network meta-analysis. (PubMed, Acta Diabetol) - "Receptor-specific targeting optimizes T2DM treatment, with Semaglutide supporting glycemic control, Tirzepatide enhancing weight loss and glucose regulation, and Retatrutide potentially offering broader metabolic benefits, advancing receptor-targeted, personalized therapy."

Journal • Retrospective data • Review • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese male mice. (PubMed, Nat Commun) - "Here, we utilize cotadutide, a well characterized GLP-1R/GCGR dual-agonist, and demonstrate improvement of insulin sensitivity during hyperinsulinemic euglycemic clamp following sub-chronic dosing in male, diet-induced obese (DIO) mice...Here we show, GLP-1R/GCGR dual agonism provides multimodal efficacy to decrease hepatic steatosis and consequently improve insulin sensitivity, in concert with recovery of endogenous β-cell function and reduced insulin demand. This substantiates GLP-1R/GCGR dual-agonism as a potentially effective T2D treatment."

Journal • Preclinical • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Pharmacokinetic-pharmacodynamic (PK/PD) modelling of cotadutide effect in patients with chronic kidney disease and type 2 diabetes mellitus. (PubMed, Br J Clin Pharmacol) - P2 | "This modelling assessment was successfully applied for cotadutide to understand the relationship between cotadutide dosing regimen and the response in UACR, UALB and body weight. These models have general application in analysing and interpreting data from CKD/diabetic kidney disease (DKD) studies."

Journal • PK/PD data • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Comparative Effectiveness of Semaglutide, Liraglutide, Orlistat, and Phentermine for Weight Loss in Obese Individuals: A Systematic Review. (PubMed, Cureus) - "This literature review evaluates and compares the effectiveness of four pharmacological agents semaglutide, liraglutide, orlistat, phentermine, and emerging agents like setmelanotide, amycretin, retatrutide, cagrilintide, and cotadutide in managing weight loss among obese. A detailed analysis was conducted on their mechanisms of action, dosing regimens, efficacy in weight loss, safety profiles, and their impact on obesity-related comorbidities. Although all agents presented distinct benefits, side effects such as gastrointestinal discomfort with orlistat and GLP-1 receptor agonists, and potential dependency with phentermine, necessitate tailored treatment approaches. This review highlights the importance of integrating pharmacotherapy with lifestyle interventions to achieve sustainable weight management and identifies areas for future research to optimize therapeutic outcomes for individuals with obesity."

HEOR • Journal • Review • Cardiovascular • Gastrointestinal Disorder • Genetic Disorders • Obesity

Potential New Treatments for Chronic Kidney Diseases: A Concise Review. (PubMed, Curr Pharm Des) - "This concise review will shed light on the clinical trials of runcaciguat, cotadutide, osocimab, and Endothelin Receptor Antagonists (ERAs) in patients with CKD and/or ESKD. These drugs were retrieved following surveying the Clinical Trial database as well as the Pubmed database, both maintained by the US National Library of Medicine."

Journal • Cardiovascular • Chronic Kidney Disease • Diabetes • Hypertension • Metabolic Disorders • Nephrology • Renal Disease • Transplantation

Cotadutide reversible self-assembly based long-acting injectable depot for sustained delivery of GLP-1 glucagon receptor agonists with controlled burst release. (PubMed, J Control Release) - "This extended-release formulation also maintains smaller peak and trough fluctuation within therapeutic window, and PK modelling of repeated dose indicates this formulation could enable a possible dose frequency of 14 days in rat with assumed therapeutic concentration (ratios of the maximum concentration and the trough concentration) Cmax/Ctrough window. This new long-acting injectable (LAI) method could open the door to transforming short-life peptides with sub-optimal half-life into candidates for weekly or even monthly dosing regimens, potentially leading to novel drug products which and increased patient comfort."

Journal • Metabolic Disorders

A Study of Cotadutide in Participants Who Have Chronic Kidney Disease With Type 2 Diabetes Mellitus (clinicaltrials.gov) - P2 | N=248 | Completed | Sponsor: AstraZeneca | Phase classification: P2b ➔ P2

Phase classification • Chronic Kidney Disease • Diabetes • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Glucagon-like Peptide-1 Receptor Agonists for Adult Obesity: Where Next? (ISPOR-EU 2024) - "The most commonly assessed GLP-1 RAs were liraglutide and semaglutide (48%), followed by exenatide (24%) and dulaglutide (21%). Other less commonly identified agents included danuglipron, cotadutide, taspoglutide and mazdutide (2% each)... This research highlights growing interest and evidence in GLP-1 RAs for obesity management. Further research is needed to continue evaluating the long-term efficacy and safety of these interventions."

Clinical • Cardiovascular • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Polycystic Ovary Syndrome • Type 2 Diabetes Mellitus

Safety and Pharmacokinetics of AZD9550, a GLP-1R/GCGR Dual Agonist, in a First-in-Human Study (OBESITY WEEK 2024) - "Background: Cotadutide was a synthetic once-daily GLP-1R/GCGR dual peptide agonist with a relative potency ratio of approximately 5:1... AZD9550 led to dose-dependent reductions in body weight in obese mice. In healthy participants, there were no safety or tolerability concerns with a pharmacokinetic profile supporting once-weekly dosing. AZD9550 is a novel, investigational drug for obesity with an optimized ratio of glucagon and GLP-1R agonism that is being studied further as a treatment to maximize weight loss and end-organ protection."

Clinical • P1 data • PK/PD data • Genetic Disorders • Obesity • Pain

Glucagon and glucagon-like peptide-1 dual agonist therapy: A possible future towards fatty kidney disease. (PubMed, Eur J Clin Invest) - "Glucagon-like peptide-1 agonists and sodium-glucose cotransporter-2 inhibitors are two novel classes of glucose-lowering medications with potential implications and beneficiary effects on renal outcomes, including estimated glomerular filtration rate, albuminuria and chronic kidney disease progression. Recently, dual agonist therapies targeting glucagon-like peptide-1 and glucagon receptors, namely survodutide and cotadutide, have been evaluated in managing metabolically associated fatty liver disease, a well-established example of visceral obesity. Fatty kidney is another novel concept implicated in the pathophysiology of chronic kidney disease among patients with visceral obesity."

Journal • Review • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • CNS Disorders • Diabetes • Dyslipidemia • Genetic Disorders • Hepatology • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Vascular Neurology

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. (PubMed, Kidney Int) - "Safety and tolerability of cotadutide 600 μg were comparable to semaglutide. Thus, our study shows that in patients with T2Dand CKD, cotadutide significantly reduced UACR on top of standard of care with an acceptable tolerability profile, suggesting kidney protective benefits that need confirmation in a larger study."

Journal • P2b data • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Exposure-response modeling for nausea incidence for cotadutide using a Markov modeling approach. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "The simulations indicated that the biweekly titration with twofold dose escalation is superior to other titration schemes with a relatively low predicted nausea event rate at 600 μg (25%) and a shorter titration interval (8 weeks) to reach the therapeutic dose. The model can be utilized to optimize starting dose and titration schemes for other therapeutics in clinical trials to achieve an optimal risk-benefit balance and reach the therapeutic dose with minimal titration steps."

Journal • Gastrointestinal Disorder • Genetic Disorders • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis • Obesity

CD9 Counteracts Liver Steatosis and Mediates GCGR Agonist Hepatic Effects. (PubMed, Adv Sci (Weinh)) - "Moreover, CD9 reinforcement in the liver alleviated hepatic steatosis, and blockage of CD9 abolished the remission of hepatic steatosis induced by cotadutide treatment. Thus, CD9 medicates the hepatic beneficial effects of GCGR signaling, and may server as a promising therapeutic target for hepatic steatosis."

Journal • Metabolic Disorders • Targeted Protein Degradation • CD9 • CFD • FLI1

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. (PubMed, Endocrine) - "These results suggest that mazdutide and cotadutide are effective for glycaemic control and weight reduction in individuals with T2DM, obesity, or both."

Journal • Retrospective data • Review • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

PROXYMO-ADV: A Study to Evaluate the Safety and Efficacy of Cotadutide Given by Subcutaneous Injection in Adult Participants With Non-cirrhotic Non-alcoholic Steatohepatitis With Fibrosis (clinicaltrials.gov) - P2 | N=54 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Trial completion • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis

Safety and Efficacy of Novel Incretin Co-agonist Cotadutide in Biopsy-proven Non-cirrhotic MASH with Fibrosis. (PubMed, Clin Gastroenterol Hepatol) - "PROXYMO provides preliminary evidence for the safety and efficacy of GLP-1/GCG receptor co-agonism in biopsy-proven non-cirrhotic MASH with fibrosis, supporting further evaluation of this mechanism in MASH."

Biopsy • Journal • Diabetes • Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • Type 2 Diabetes Mellitus • GCG

Advancing Diabetes Care: Novel Drug Interventions in the Management and Control of Type 2 Diabetes Mellitus (ISPOR 2024) - " The study examines ongoing clinical trials evaluating the efficacy and safety of drugs like Cotadutide, Enavogliflozin, Retatrutide, ORMD-0801, and Imeglimin for T2DM, and reported data for at least 1 outcome of interest...Cotadutide, an insulinotropic drug, has shown promising results in improving glycemic control and weight loss in T2DM patients through delayed gastric emptying. Enavogliflozin had a slightly larger reduction in HbA1c levels (-0.99%) than Bexagliflozin...As monotherapy or adjunctive therapy (with metformin), it is found to be effective, has low risk of hypoglycemia, and enhances insulin action and sensitivity. Over the past decade, numerous glucose-lowering medications have been approved, requiring careful consideration of their risks and benefits. It is critical to establish the strongest evidence for improving glycemic control and reducing the risk of complications ."

Diabetes • Gastroenterology • Gastrointestinal Disorder • Hypoglycemia • Metabolic Disorders • Type 2 Diabetes Mellitus

Dual glucagon-like peptide-1 and glucagon receptor agonism reduces energy intake in type 2 diabetes with obesity. (PubMed, Diabetes Obes Metab) - "Weight loss with cotadutide is primarily driven by reduced EI, with relatively small compensatory changes in EE."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Characterisation of cotadutide's dual GLP-1/glucagon receptor agonistic effects on glycaemic control using an in vivo human glucose regulation quantitative systems pharmacology model. (PubMed, Br J Pharmacol) - P1/2 | "The 4GI quantitative systems pharmacology model was able to predict the clinical effects of cotadutide on glucose, insulin, GLP-1, glucagon and GIP given known in vitro potency. The analyses demonstrated that the quantitative systems pharmacology model, and its successive refinements, will be a valuable tool to support the clinical development of cotadutide and related compounds."

Journal • Preclinical • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Population Pharmacokinetic Modeling of Cotadutide: A Dual Agonist Peptide of Glucagon-Like Peptide and Glucagon Receptors Administered to Participants with Type II Diabetes Mellitus, Chronic Kidney Disease, Obesity and Non-Alcoholic Steatohepatitis. (PubMed, Clin Pharmacokinet) - "A popPK model was developed for cotadutide with cotadutide clinical data, and the impact of the statistically significant covariates identified was not considered clinically meaningful. The popPK model will be used to evaluate exposure-response relationships for cotadutide clinical data."

Journal • PK/PD data • Chronic Kidney Disease • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus • GCG

Polyagonists in Type 2 Diabetes Management. (PubMed, Curr Diab Rep) - "Tirzepatide, cotadutide, BI456906, ritatrutide, and CagriSema have entered phase 3 clinical trials...Polyagonism has become a key strategy to address the complex pathogenesis of type 2 diabetes and co-morbidities and increasing number of agents are moving through clinical trials. Heterogeneity in efficacy-safety profiles calls for application of precision medicine and need for judicious personalization of care."

Journal • Review • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Cotadutide (GLP-1/Glucagon dual receptor agonist) modulates hypothalamic orexigenic and anorexigenic neuropeptides in obese mice. (PubMed, Peptides) - "The hypothalamic arcuate neurons were labeled by immunofluorescence, and protein expressions (Western blotting) for neuropeptide Y (NPY), proopiomelanocortin (POMC), agouti-related protein (AgRP), and cocaine- and amphetamine-regulated transcript (CART). Cotadutide modulates energy balance through the gut-brain axis and its associated signaling pathways. The study provides insights into the mechanisms underlying cotadutide's anti-obesity effects and its possible implications for obesity treatment."

Journal • Preclinical • Genetic Disorders • Obesity • POMC-null Obesity • CALCR • LEP • LEPR • SOCS3