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

• Published in: Diabetes care Vol. 44; no. 6; pp. 1433 - 1442
• Main Authors: Nahra, Rajaa, Wang, Tao, Gadde, Kishore M, Oscarsson, Jan, Stumvoll, Michael, Jermutus, Lutz, Hirshberg, Boaz, Ambery, Philip
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01-06-2021
• Subjects: Adult; Adults; Algorithms; Biomarkers; Blood Glucose; Body weight; Body weight loss; Cardiovascular and Metabolic Risk; Collagen (type III); Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Double-Blind Method; Evaluation; Fatty liver; Fibrosis; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin A - analysis; Hemoglobin; Humans; Hypoglycemic Agents - therapeutic use; Kidney diseases; Lipids; Liraglutide - therapeutic use; Liver; Liver - chemistry; Liver diseases; Metabolism; Metformin; Nausea; Obesity; Obesity - complications; Obesity - drug therapy; Overweight; Overweight - complications; Overweight - drug therapy; Parameters; Peptides; Research design; Vomiting; Weight control; Weight loss
• ISSN: 0149-5992; 1935-5548
• DOI: 10.2337/dc20-2151

Cotadutide, a dual GLP-1 and glucagon receptor agonist, is under development for nonalcoholic steatohepatitis (NASH) and chronic kidney disease with type 2 diabetes. The effects of cotadutide on hepatic and metabolic parameters were evaluated in participants with overweight/obesity and type 2 diabetes.
In this phase 2b study, 834 adults with BMI ≥25 kg/m
and type 2 diabetes inadequately controlled with metformin (glycated hemoglobin A
[HbA
] of 7.0%-10.5% [53-91 mmol/mol]) were randomized to double-blind cotadutide 100 μg (
= 100), 200 μg (
= 256), or 300 μg (
= 256); placebo (
= 110); or open-label liraglutide 1.8 mg (
= 110)-all administered subcutaneously. Coprimary end points were changes in HbA
and body weight at week 14. The originally randomized interventions were continued to week 54. Liver damage biomarkers and liver fibrosis algorithms were assessed.
Cotadutide significantly decreased HbA
and body weight at weeks 14 and 54 versus placebo (all
< 0.001). Improvements in lipid profile, AST and ALT levels, propeptide of type III collagen level, fibrosis-4 index, and nonalcoholic fatty liver disease fibrosis score were observed with cotadutide 300 μg versus placebo, but not with liraglutide. Weight loss with cotadutide 200 μg was similar to that with liraglutide 1.8 mg and greater with cotadutide 300 μg versus liraglutide 1.8 mg. The most common adverse events with cotadutide (nausea, 35%; vomiting, 17%) decreased over time.
Cotadutide treatment for 54 weeks improved glycemic control and weight loss in participants with overweight/obesity and type 2 diabetes. Ad hoc analyses demonstrated improvements in hepatic parameters and support further evaluation of cotadutide in NASH.