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Weight loss, insulin resistance, and study design confound results in a meta-analysis of animal models of fatty liver

Hunter, Harriet1; de Gracia Hahn, Dana1; Duret, Amedine1; Im, Yu Ri1; Cheah, Qinrong1; Dong, Jiawen1; Fairey, Madison1; Hjalmarsson, Clarissa1; Li, Alice1; Lim, Hong Kai1; McKeown, Lorcan1; Mitrofan, Claudia-Gabriela1; Rao, Raunak1; Utukuri, Mrudula1; Rowe, Ian A2; Mann, Jake3

Published Oct 16, 2020 on Dryad. https://doi.org/10.5061/dryad.pzgmsbcgc

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Oct 16, 2020 version files 581.57 KB

Abstract

The classical drug development pipeline necessitates studies using animal models of human disease to gauge future efficacy in humans, however there is a low conversion rate from success in animals to humans. Non-alcoholic fatty liver disease (NAFLD) is a complex chronic disease without any established therapies and a major field of animal research. We performed a meta-analysis with meta-regression of 603 interventional rodent studies (10,364 animals) in NAFLD to assess which variables influenced treatment response. Weight loss and alleviation of insulin resistance were consistently associated with improvement in NAFLD. Multiple drug classes that do not affect weight in humans caused weight loss in animals. Other study design variables, such as age of animals and dietary composition, influenced the magnitude of treatment effect. Publication bias may have increased effect estimates by 37-79%. These findings help to explain the challenge of reproducibility and translation within the field of metabolism.