cotadutide (MEDI0382) / AstraZeneca - LARVOL DELTA

Defining the efficacy and tolerability ceiling of pure incretin therapies in steatotic liver disease: a network meta-analysis of phase 2 and 3 trials (EASD 2026) - "(1) Liver Fat Clearance (MRI-PDFF): The tri-agonist retatrutide achieved the highest efficacy hierarchy (SUCRA 98%), yielding a -82.4% relative reduction in hepatic steatosis. GLP-1/glucagon dual-agonists (mazdutide, efinopegdutide) consistently outperformed both GLP-1/GIP agents and pure GLP-1 mono-agonists...While earlier dual-agonists (survodutide, cotadutide) exhibited high adverse event-related discontinuation rates (15.2-20.0%), next-generation agents (mazdutide, pemvidutide) maintained placebo-like tolerability (<1.0% discontinuation) alongside profound hepatic fat clearance. Multi-receptor incretin agonism yields a stepwise, dose-and-receptor dependent superiority in clearing hepatic steatosis compared to pure GLP-1 therapy. While the addition of glucagon drives unparalleled fat clearance, optimizing the tolerability profile remains the defining factor for the clinical viability of next-generation incretins."

P2 data • Retrospective data • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Effectiveness and Safety of GLP-1-Based Therapy for Weight Loss in Advanced Kidney Disease and ESKD: A Systematic Review and Meta-Analysis (KIDNEY WEEK 2026) - "Two studies investigated a range of GLP1RAs, 9 Semaglutide, 2 Tirzepatide, 1 Cotadutide and 6 Liraglutide...While their side effect profile is comparable, the withdrawal rate was high. GLP-1 based therapy could be an important therapeutic option to support weight loss in patients with ESKD under specialist monitoring."

Metastases • Retrospective data • Review • Diabetes • Gastroenterology • Genetic Disorders • Hepatology • Metabolic Disorders • Nephrology • Obesity • Pancreatitis • Renal Disease • Severe Hypoglycemia • Type 2 Diabetes Mellitus

Efficacy and Safety of Dual GLP-1/Glucagon Receptor Agonism in Overweight and Obesity: A Class-Specific Systematic Review and Meta-Analysis. (PubMed, Diabetes Obes Metab) - "Dual GLP-1/GCGR agonists produce meaningful weight loss and metabolic improvements with acceptable short-term safety, though longer head-to-head trials are needed to confirm durability and cardiovascular safety."

Journal • Retrospective data • Cardiovascular • Genetic Disorders • Obesity

Efficacy and Safety of Dual and Triple Glucagon-Like Peptide-1-Based Polyagonists in Metabolic Dysfunction-Associated Steatotic Liver Disease and Steatohepatitis: A Systematic Review and Meta-Analysis. (PubMed, Cureus) - "The included GLP-1-based polyagonists-tirzepatide, survodutide, pemvidutide, retatrutide, and cotadutide-significantly increased MASH resolution or histological improvement without worsening of fibrosis (RR 3.32, 95% CI 2.28-4.84; I² = 20%) and fibrosis improvement without worsening of MASH (RR 1.49, 95% CI 1.15-1.94; I² = 0%)...However, gastrointestinal intolerance, pharmacological heterogeneity, the small number of trials, and limited follow-up warrant cautious interpretation. Larger phase 3 trials are needed to clarify drug-specific efficacy, long-term safety, and effects on liver-related and cardiovascular outcomes."

Journal • Retrospective data • Review • Cardiovascular • Diabetes • Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus

Renoprotective effects of tubular glucagon receptor activation mediated by V-ATPase. (PubMed, Sci Adv) - "Recent clinical trials have shown that dual GLP-1R/GCGR agonists, including mazdutide and cotadutide, provide kidney benefits in patients with type 2 diabetes and CKD, suggesting a potential contribution of GCGR activation to these renal effects. Consistently, re-expression of tubular GCGR via AAV9 restores lysosomal function, reduces phospholipid accumulation, and mitigates renal injury in DKD. Together, these findings provide genetic evidence for the renoprotective role of tubular GCGR in DKD, delineate a kidney-intrinsic GCGR-ATP6V1A-lysosome axis that protects tubular integrity, and extend prior GCGR-in-kidney observations into a more concrete GCGR-lysosome mechanism."

Journal • Diabetes • Metabolic Disorders • Renal Disease • Type 2 Diabetes Mellitus

Metabolic Dysfunction-Associated Steatotic Liver Disease and Incretin Receptor Agonists: A Metabolic Approach to Halting Liver Disease Progression. (PubMed, Medicina (Kaunas)) - "Emerging agents like cotadutide (a GLP-1/glucagon receptor agonist) and retatrutide (a GLP-1/GIP/glucagon triagonist) represent a novel therapeutic frontier, with early clinical data indicating potent hepatoprotective effects and favorable metabolic remodeling. This narrative review examines the hepatoprotective potential of incretin-based therapies, highlighting how targeted intervention on the underlying metabolic dysfunction may lead to significant improvements in MASLD. These therapies may also exert beneficial effects on fibrosis progression; however, the currently available evidence remains limited."

Journal • Review • Diabetes • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus

Evolution of incretin-based therapies: From GLP-1 monotherapy to dual and triple agonists: A new era in metabolic therapy. (PubMed, Indian J Med Res) - "While DPP-4 inhibitors offer modest glycaemic benefits, GLP1RAs such as liraglutide and semaglutide have demonstrated significant weight loss and cardiometabolic protection. Dual GIP/GLP-1 agonist tirzepatide and triple agonist retatrutide have shown unprecedented efficacy, with up to 24% body weight reduction and improvement in hepatic and inflammatory markers. Agents like cotadutide and efinopegdutide further expand indications to MASLD and metabolic dysfunction associated steatohepatitis (MASH)...Incretin-based multi-agonists offer a transformative, multi-system approach to metabolic disease but require tailored implementation. This review provides an updated synthesis of therapeutic developments and outlines priorities for future research, regulatory policy, and equitable global integration as incretin-based therapies have evolved into a versatile class addressing glycaemic control, weight loss, and cardio-metabolic risk."

Journal • Monotherapy • Review • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus

Renal Outcomes of GLP-1 Receptor Agonists and Tirzepatide Across CKD Stages and Metabolic Phenotypes (Type 2 Diabetes and/or Overweight/Obesity): A Scoping Review. (PubMed, Diabetes Ther) - "GLP-1-based therapies demonstrate consistent renoprotective signals across CKD stages and metabolic phenotypes, particularly in type 2 diabetes. Evidence is strongest for semaglutide and dulaglutide, with emerging data for tirzepatide and other incretin-based agents. These findings provide a structured evidence map to inform future consensus and clinical decision-making."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Diabetes • Genetic Disorders • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus

Relative Efficacy of Next-Generation Incretin Therapies for Cardio-Renal Protection in Type 2 Diabetes: Evidence From a Network Meta-Analysis. (PubMed, Diabetes Obes Metab) - "Cardiovascular and renal benefits of GLP-1-based therapies are outcome-specific. Semaglutide favoured MACE/MI reduction, dulaglutide and tirzepatide supported stroke prevention, and albuminuria outcomes were more responsive than eGFR. Further long-term head-to-head trials are needed."

Journal • Retrospective data • Cardiovascular • Diabetes • Metabolic Disorders • Myocardial Infarction • Renal Disease • Type 2 Diabetes Mellitus

Comparative Efficacy and Safety of Glucagon Receptor Agonists on Metabolic Outcomes: A Network Meta-Analysis of Randomised Controlled Trials. (PubMed, Endocrinol Diabetes Metab) - "Retatrutide and survodutide exhibit the most favourable efficacy profiles for obesity and T2DM, with acceptable safety. These findings support their potential clinical use and highlight the need for future head-to-head trials."

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

Systemic Pharmacokinetic Principles of Therapeutic Peptides. (PubMed, Clin Pharmacokinet) - "In summary, our results underscore that the systemic pharmacokinetics of peptide drugs generally follow size-related physiological scaling patterns and provide quantitative tools to facilitate translational assessments in the drug discovery process."

Journal • PK/PD data

Glycemic control, weight-loss effects, and safety of cotadutide in individuals with type 2 diabetes: A systematic review and meta-analysis. (PubMed, World J Diabetes) - "Cotadutide demonstrated glycemic control and weight-loss benefits in short-term, small RCTs (mostly phase 2). However, small sample sizes, very low to low certainty of evidence, and the absence of data on long-term cardiovascular and renal outcomes highlight substantial uncertainties, warranting cautious interpretation and further investigation in larger, longer-term trials to establish its safety and efficacy profile."

Journal • Retrospective data • Cardiovascular • Constipation • Diabetes • Dyspepsia • Gastroenterology • Gastrointestinal Disorder • 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. (PubMed, Endocrinol Diabetes Metab) - "GRAs superiorly reduce ALT levels, MRI-PDFF, and ELF. Resmetirom significantly reduces AST, HDL, and LDL levels, increases MASH resolution without worsening of fibrosis, and offers a more favourable safety profile. Both GRAs and resmetirom significantly increase adiponectin."

Clinical • Journal • Retrospective data • Review • Fatigue • Fibrosis • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Co-Administration of GLP-1R/GCGR and Amylin Receptor Agonists Improves Body Weight in DIO Rats (OBESITY WEEK 2025) - "We aimed to evaluate the combination effects of AZD6234 and the GLP-1R/GCGR agonist cotadutide (cota) on BW gain in obese (DIO) rats, and acute effects on GE in chow fed rats. DIO rats treated with a combination of AZD6234 and cota displayed an additive effect on decreasing BW gain vs. monotherapy accompanied by a decrease in peri-renal fat pad and liver weights. Treatment with AZD6234 or cota showed an expected decrease in GE in dose-dependent manner, and an additional effect on GE was observed with combination treatment at sub-maximal doses as compared to monotherapy."

Preclinical • Genetic Disorders • Obesity

Weight Loss, Obesity Medication, and Risk of Obesity-Associated Cancer: A Meta-Analysis of Randomized Controlled Trials. (PubMed, Obesity (Silver Spring)) - "Weight reduction mediated by current AOMs was not associated with a reduced risk of overall or site-specific obesity-associated cancer in patients with overweight or obesity, while a decreased risk of overall obesity-associated cancer was observed in coagonist users."

Journal • Retrospective data • Review • Genetic Disorders • Obesity • Oncology

COMPARATIVE EVALUATION OF GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS AND THEIR ASSOCIATION WITH THE RISK OF ASTHMA INCIDENCE: A COMPREHENSIVE BAYESIAN NETWORK META-ANALYSIS (CHEST 2025) - "For the reduction of asthma incidence, Semaglutide ranked highest (RR: 0.20, 95% CrI: 0.01 to 2.08; SUCRA: 84.83%), compared to Control (SUCRA: 44.9%), with Liraglutide ranked second (RR: 0.55, 95% CrI: 0.08 to 4.07; SUCRA: 64.4%). Other interventions included Exenatide (RR: 0.56, 95% CrI: 0.07 to 4.57; SUCRA: 63.57%), Lixisenatide (RR: 0.56, 95% CrI: 0.06 to 5.00; SUCRA: 63.08%), Cotadutide (RR: 0.81, 95% CrI: 0.05 to 39.67; SUCRA: 50.67%), Efpeglenatide (RR: 1.08, 95% CrI: 0.09 to 16.37; SUCRA: 43.95%), Dulaglutide (RR: 1.52, 95% CrI: 0.20 to 11.46; SUCRA: 32.65%), Albiglutide (RR: 1.77, 95% CrI: 0.24 to 12.90; SUCRA: 28.16%) and Tirzepatide (RR: 2.81, 95% CrI: 0.18– 115.35; SUCRA: 23.77%)... In conclusion, our Bayesian network meta-analysis demonstrates that Semaglutide is the most effective GLP-1 receptor agonist in reducing asthma incidence in patients with type 2 diabetes. In contrast, Tirzepatide and Albiglutide were associated with an increased risk of asthma...."

Retrospective data • Asthma • Diabetes • Immunology • Inflammation • Metabolic Disorders • Respiratory Diseases • Type 2 Diabetes Mellitus

TURNING THE TIDE ON FATTY LIVER: EFFICACY AND SAFETY OF GLP-1 RECEPTOR AGONISTS IN THE TREATMENT OF METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE AND STEATOHEPATITIS – A SYSTEMATIC REVIEW (AASLD 2025) - "Cotadutide produced greater weight loss than liraglutide. GLP-1 receptor agonists, particularly semaglutide, offer significant benefits in reducing hepatic fat, resolving MASH, and improving cardiometabolic parameters in MASLD/MASH patients, especially those with early-stage fibrosis. Their safety profile is favorable, with manageable gastrointestinal side effects. While benefits in advanced fibrosis are limited, GLP-1 RAs are poised to become a cornerstone in the management of MASLD/MASH, especially for patients with metabolic comorbidities."

Clinical • Review • Cardiovascular • Diabetes • Fibrosis • Genetic Disorders • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus

SAFETY AND EFFICACY OF COTADUTIDE, A DUAL GLP-1 AND GLUCAGON RECEPTOR AGONIST IN ADULTS WITH NON-CIRRHOTIC METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS WITH FIBROSIS: FINAL RESULTS: FROM A PHASE IIB RANDOMIZED, PLACEBO-CONTROLLED, PROOF-OF CONCEPT STUDY (AASLD 2025) - "Cotadutide 300 μg and 600 μg showed safety and tolerability consistent with its known profile in adults with non-cirrhotic MASH with fibrosis. Numerical improvements in MASH resolution were observed without worsening of liver fibrosis. Compared to placebo, a higher proportion in the Cotadutide 600 μg group experienced liver fibrosis improvement without MASH deterioration."

Clinical • P2b data • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Efficacy of Dual Glucagon and Glucagon-like Peptide-1 Receptor Agonists Across the Cardiometabolic Continuum: A Review of Current Clinical Evidence. (PubMed, Rev Cardiovasc Med) - "Emerging clinical evidence on agents such as survodutide and cotadutide has revealed striking improvements in glycated hemoglobin (HbA1c) levels and body weight, consistently outperforming traditional GLP-1 receptor agonists. This review highlights the transformative potential of dual GLP-1/Gcg receptor agonists, providing a thorough examination of their mechanisms of action, clinical efficacy, and safety profiles across the cardio-metabolic continuum. As the limitations of existing therapies become increasingly evident, these next-generation agents are poised to redefine the standard of care across the cardiometabolic continuum, ushering in a new era of precision medicine for metabolic disease."

Journal • Review • Cardiovascular • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus • GCG

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 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

From In Vitro Efficacy to Long-Term HbA1c Response for GLP-1R/GlucagonR Agonism Using the 4GI-HbA1c Systems Model. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Retrospective analysis showed that the model adequately predicted the effect of cotadutide and liraglutide on fasting plasma glucose and HbA1c (Root Means Square Percent Error (RMSPE) 5.9% and 13%, respectively). This demonstrates the potential of the 4GI-HbA1c systems model as a valuable tool in supporting the clinical development of novel GLP-1 and/or glucagon agonists."

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

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