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Review
. 2020 Oct;69(10):1877-1884.
doi: 10.1136/gutjnl-2019-319104. Epub 2020 May 7.

Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges

Jean-François Dufour  1   2 , Cyrielle Caussy  3   4 , Rohit Loomba  5
Affiliations
Review

Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges

Jean-François Dufour et al. Gut. 2020 Oct.

Abstract

Non-alcoholic steatohepatitis (NASH) is becoming a leading cause of cirrhosis with the burden of NASH-related complications projected to increase massively over the coming years. Several molecules with different mechanisms of action are currently in development to treat NASH, although reported efficacy to date has been limited. Given the complexity of the pathophysiology of NASH, it will take the engagement of several targets and pathways to improve the results of pharmacological intervention, which provides a rationale for combination therapies in the treatment of NASH. As the field is moving towards combination therapy, this article reviews the rationale for such combination therapies to treat NASH based on the current therapeutic landscape as well as the advantages and limitations of this approach.

Keywords: hepatobiliary disease; liver; nonalcoholic steatohepatitis.

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Conflict of interest statement

Competing interests: CC received consultant fees from NovoNordisk, AstraZeneca, Gilead. J-FD Advisory committees: Bayer, BMS, Falk, Genfit, Genkyotex, Gilead Science, HepaRegenix, Intercept, Eli Lilly, Merck, Novartis; Speaking and teaching: Bayer, BristolMyers Squibb, Intercept, Genfit, Gilead Science, Novartis. RL serves as a consultant or advisory board member for Arrowhead Pharmaceuticals, AstraZeneca, Bird Rock Bio, Boehringer Ingelheim, Bristol-Myer Squibb, Celgene, Cirius, CohBar, Conatus, Eli Lilly, Galmed, Gemphire, Gilead, Glympse bio, GNI, GRI Bio, Intercept, Ionis, Janssen, Merck, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prometheus, Sanofi, Siemens, and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Boehringer-Ingelheim, Bristol-Myers Squibb, Cirius, Eli Lilly and Company, Galectin Therapeutics, Galmed Pharmaceuticals, GE, Genfit, Gilead, Intercept, Grail, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, NuSirt, Pfizer, pH Pharma, Prometheus, and Siemens. He is also cofounder of Liponexus.

Figures

Figure 1
Figure 1
(A) Percentage of patients with resolution of non-alcoholic steatohepatitis (NASH) defined as ballooning 0 and inflammation 0–1, without worsening fibrosis in placebo and intervention arms of randomised clinical trials showing an effect. (B) Percentage of patients with more than one-stage improvement in fibrosis without worsening of NASH in placebo and intervention arms of randomised clinical trials showing an effect. The references are provided in the text, the data for the obeticholic acid phase 3 are based on study by Sanyal et al.
Figure 2
Figure 2
Rationale for combination therapy to treat non-alcoholic steatohepatitis (NASH). Drugs with different mechanisms of action targeting hepatic steatosis, inflammation and fibrosis could be combined. Ideally, such combinations should be safe and have positive effects beyond the liver such as weight loss, cardiovascular protection, insulin sensitisation and lipid reduction.
See this image and copyright information in PMC

References

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