<a><b>Objective: </b></a>Cotadutide, a <a>dual GLP-1 and glucagon receptor agonist</a>,
is under development for nonalcoholic steatohepatitis (NASH) and type 2
diabetes. The effects of cotadutide on hepatic and metabolic parameters were
evaluated in participants with overweight/obesity and type 2 diabetes.
<p><b>Research Design and Methods:</b> In this phase 2b
study, 834 adults with BMI ≥25kg/m<sup>2</sup> and type 2 diabetes inadequately
controlled with metformin (glycated hemoglobin A1c [HbA1c] of 7.0%─10.5% [53─91
mmol/mol]) were randomized to double-blind cotadutide 100µg (n=100), 200µg
(n=256), or 300µg (n=256), placebo (n=110), or open-label liraglutide 1.8mg
(n=110), all administered subcutaneously (NCT03235050). Coprimary endpoints
were changes in HbA1c and body weight at week 14.<b> </b>The originally randomized
interventions were continued to week 54.<b> </b>Liver damage biomarkers and liver fibrosis algorithms were
assessed.</p>
<p><b>Results</b>: Cotadutide significantly decreased HbA1c and body weight at weeks 14 and
54 versus placebo (all <i>P</i><0.001). Improvements in lipid profile,
aspartate aminotransferase and alanine aminotransferase levels, <a>PRO-C3 level, fibrosis-4 index</a>, and <a>nonalcoholic fatty
liver disease fibrosis score</a> were observed with cotadutide 300µg versus
placebo, but not with liraglutide. Weight loss with cotadutide 200µg was
similar to liraglutide 1.8mg, and greater with cotadutide 300µg versus
liraglutide 1.8mg. <a>The most common adverse events with cotadutide
(nausea, 35%; vomiting, 17%) decreased over time. </a></p>
<p><b>Conclusions: </b>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. </p>
Antisense Inhibition of Glucagon Receptor by IONIS-GCGRRx Improves Type 2 Diabetes Without Increase in Hepatic Glycogen Content in Patients With Type 2 Diabetes on Stable Metformin Therapy
