Nature metabolismJun 2, 2020

Cotadutide may improve fatty liver disease and liver scarring by affecting energy use and fat production in liver cells

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 29, 2026

Abstract

Cotadutide significantly reduced liver fibrosis in preclinical mouse models of non-alcoholic steatohepatitis (NASH) compared to Liraglutide or Obeticholic acid.

Cotadutide reduces body weight, food intake, and improves glucose control primarily through GLP-1 signaling.
The reduction of liver lipid content and enhancement of mitochondrial function is directly mediated by Gcg signaling.
Key enzymes involved in lipid and glucose metabolism in the liver show specific phosphorylation changes in response to Cotadutide treatment.
Metabolomic and transcriptomic analyses indicate involvement of lipogenic, fibrotic, and inflammatory pathways associated with Gcg receptor activation.
The therapeutic effects of Cotadutide suggest a multi-faceted approach to improve liver function in steatohepatitis.

Simplified

Non-alcoholic fatty liver disease and steatohepatitis are highly associated with obesity and type 2 diabetes mellitus. Cotadutide, a GLP-1R/GcgR agonist, was shown to reduce blood glycemia, body weight and hepatic steatosis in patients with T2DM. Here, we demonstrate that the effects of Cotadutide to reduce body weight, food intake and improve glucose control are predominantly mediated through the GLP-1 signaling, while, its action on the liver to reduce lipid content, drive glycogen flux and improve mitochondrial turnover and function are directly mediated through Gcg signaling. This was confirmed by the identification of phosphorylation sites on key lipogenic and glucose metabolism enzymes in liver of mice treated with Cotadutide. Complementary metabolomic and transcriptomic analyses implicated lipogenic, fibrotic and inflammatory pathways, which are consistent with a unique therapeutic contribution of GcgR agonism by Cotadutide. Significantly, Cotadutide also alleviated fibrosis to a greater extent than Liraglutide or Obeticholic acid (OCA), despite adjusting dose to achieve similar weight loss in 2 preclinical mouse models of NASH. Thus Cotadutide, via direct hepatic (GcgR) and extra-hepatic (GLP-1R) effects, exerts multi-factorial improvement in liver function and is a promising therapeutic option for the treatment of steatohepatitis. in vivo

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COMPETING INTERESTS STATEMENT The authors declare competing interests as defined by Nature Research. Employee of AstraZeneca (R.C.L., K.M., S.O., J.C., J.N., J.G., L.J., C.J.R.). Owns stock in AstraZeneca (K.M., S.O., J.C., J.N., J.G., L.J., C.M.R., J.L.T., C.J.R.).

PubMed

Cotadutide may improve fatty liver disease and liver scarring by affecting energy use and fat production in liver cells

Abstract

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Abstract

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