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Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 21, 2022; 28(35): 5129-5140
Published online Sep 21, 2022. doi: 10.3748/wjg.v28.i35.5129
Combination strategies for pharmacologic treatment of non-alcoholic steatohepatitis
Jaspreet Suri, Sebastian Borja, Joseph K Lim
Jaspreet Suri, Department of Gastroenterology, Norwalk Hospital, Norwalk, CT 06856, United States
Sebastian Borja, Department of Internal Medicine, Norwalk Hospital, Norwalk, CT 06850, United States
Joseph K Lim, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, United States
ORCID number: Jaspreet Suri (0000-0002-3897-7234); Joseph K Lim (0000-0003-1037-5773).
Author contributions: Suri J was responsible for background data review, writing, editing and final review of the manuscript; Borja S was responsible for background data review and writing of the manuscript; Lim JK was responsible for writing, editing and final review of the manuscript.
Conflict-of-interest statement: Suri J, None; Borja S, None; Lim JK, research contract (to Yale University) from Allergan, Celgene, Genfit, Intercept, Pfizer, Viking.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Joseph K Lim, MD, Professor, Section of Digestive Diseases, Yale University School of Medicine, Yale Liver Center, 333 Cedar Street, LMP 1080, New Haven, CT 06520, United States.
Received: June 24, 2022
Peer-review started: June 24, 2022
First decision: July 11, 2022
Revised: July 26, 2022
Accepted: August 25, 2022
Article in press: August 25, 2022
Published online: September 21, 2022


Non-alcoholic steatohepatitis (NASH) is defined as hepatic steatosis, inflammation, and hepatocyte injury with or without fibrosis. It has emerged as the second leading indication for liver transplantation with a rising death rate in the non-transplantable population. While there are many drugs in evaluation, currently no approved therapies are on the market for this condition. Given this importance, the Food and Drug Administration has provided formal guidance regarding drug development for stopping or reversing NASH or NASH associated fibrosis. The complex pathogenesis of NASH and its bidirectional relationship with metabolic syndrome has highlighted multiple drugs of interest that address metabolic, inflammatory, and fibrotic factors. A few promising liver specific targets include farnesoid X receptor agonists and peroxisome proliferator-activated receptor agonists. Previously studied drug classes such as glucagon-like peptide-1 analogs or sodium/glucose transport protein 2 inhibitors have also demonstrated ability to improve hepatic steatosis. Here we discuss current rationale, scientific work, and preliminary data in combining multiple drugs for the purposes of a multimodal attack on the pathogenesis of NASH. We highlight multiple Phase 2 and Phase 3 studies that demonstrate the potential to achieve a response rate higher than previously assessed monotherapies for this condition. Ultimately, one of these combination strategies may rise above in its safety and efficacy to become a part of a standardized approach to NASH.

Key Words: Non-alcoholic steatohepatitis, Fatty liver, Combination treatment, Drug therapy, Pharmacologic treatment, Clinical trials

Core Tip: Multimodal combination approaches targeting two or more molecular pathways contributing to steatohepatitis and liver fibrosis are needed to augment efficacy of novel investigational drug regimens to achieve non-alcoholic steatohepatitis (NASH) resolution and NASH fibrosis improvement.


Non-alcoholic steatohepatitis (NASH) is defined as the presence of ≥ 5% hepatic steatosis and inflammation with hepatocyte injury with or without fibrosis. Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of pathology encompassing hepatic steatosis, steatohepatitis (NASH), and liver fibrosis, and poses a significant challenge to the medical community as there are currently no Food and Drug Administration (FDA) approved therapies available on the market. The definition of NAFLD includes the lack of secondary causes of hepatic steatosis such as alcohol consumption, steatogenic medication or hereditary liver disease. With NAFLD-associated death rates on the rise and NASH emerging as the second most common indication for liver transplantation, there has been heightened urgency to target various disease pathways in NASH development with the hopes of controlling the global impact of this disease[1,2]. With this rising importance, the FDA has published formal guidance regarding drug development aimed at stopping or reversing NASH and NASH fibrosis. The current drug development pipeline contains many mono-therapeutic options which address a wide range of metabolic, inflammatory, and fibrosis target pathways associated with NASH pathogenesis.

The pathophysiology of NASH is based on a bidirectional relationship between type 2 diabetes mellitus (T2DM), hypertension, obesity and dyslipidemia–or metabolic syndrome. This relationship contributes to excess free fatty acids generated from lipolysis and de novo lipogenesis in the liver, which creates lipotoxic species which induce oxidative stress, inflammasome activation, and fibrinogenesis[3] . Liver specific targets aimed at decreasing histologic inflammation or fibrosis such as farnesoid X receptor (FXR) agonists or peroxisome proliferator-activated receptor (PPAR) agonists are currently being evaluated for the treatment of NASH. These are in addition to drug classes such as glucagon-like peptide-1 (GLP-1) agonists and sodium/glucose transport protein 2 inhibitors that were initially approved for treatment of diabetes but have demonstrated the ability to decrease liver fat content[4,5]. While individually these agents have shown promise in early trials, there has been growing interest in pursuing a multimodal combination approach targeting two or more molecular targets/pathways responsible for NASH and NASH-associated liver fibrosis, particularly in context of modest effects of single agent strategies on histologic endpoints, with fewer than 50% of patients achieving either NASH resolution of fibrosis improvement of one stage or greater[6]. Therefore, this mini review will succinctly summarize the current efforts to examine combination strategies of drugs which may further augment therapeutic response in patients with NASH.


The FDA generally has two pathways for drug approval. The traditional pathway focuses on clinical benefit endpoints (i.e., morbidity and mortality) and requires long term data. A brief review is provided in Figure 1. The accelerated approval pathway is intended to expedite the process for serious medical conditions with unmet needs. This pathway relies on short term surrogate markers that would reliably predict long term clinical outcomes to support drug approval. To inform clinical trial design for investigational drugs under evaluation for NASH, industry guidance was issued by the FDA in 2018 with a focus on patients with non-cirrhotic NASH with stage 2-3 liver fibrosis[7]. Although histologic endpoints were reinforced as required for assessment of surrogate endpoints for NASH and liver fibrosis, the agency encouraged the development and validation of noninvasive biomarkers in clinical trials to accelerate drug development. NASH was defined as a NAFLD activity score (NAS) greater than or equal to 4 with at least 1 point each in inflammation and ballooning degeneration, plus a NASH Clinical Research Network fibrosis score greater than stage 1 fibrosis but less than stage 4 for enrollment in these trials. Lastly, the primary regulatory endpoints required to support accelerated approval include: (1) NASH resolution on histology (NAS less than 4 with individual components scores of 0 for ballooning degeneration and 0-1 for inflammation) without worsening fibrosis; (2) Improvement in liver fibrosis greater than or equal to one stage without worsening NASH; or (3) NASH resolution and improvement in fibrosis by one stage or greater. Clinical benefit for these drugs was defined as superiority to placebo in delayed disease progression measured by a composite endpoint including progression to cirrhosis, hepatic decompensation, change in MELD score, liver transplantation, or all-cause mortality.

Figure 1
Figure 1 Flow diagram of standard Food and Drug Administration drug approval process.

Key phase 2 trials for NASH therapeutics are summarized in Table 1. In brief, one major class being pursued is fibroblast growth factor 21 (FGF21) agonists such as pegbelfermin. FGF21 is endogenously produced by the liver and has a pleiotropic effect on metabolism that may benefit patients with NASH. Endogenous FGF21 concentrations are elevated as much as 10-fold in patients with obesity, NAFLD or NASH, leading to the hypothesis that these may represent an FGF21-resistant state which may benefit from exogenous stimulation to improve insulin sensitivity and lipid metabolism[8] . GLP-1 is an incretin hormone made by intestinal cells post prandially for which receptors are predominantly in the pancreas, adipose tissue and brain. It regulates plasma glucose by stimulating glucose release and inhibiting glucagon secretion. GLP-1 agonists have previously shown to improve hepatic steatosis, decrease liver inflammation, and ameliorate insulin resistance in murine models of fatty liver disease. Semaglutide and liraglutide have shown promising results with statistically significant NASH improvement or resolution compared to placebo[9,10]. Norursodeoxycholic acid is an orally administered side chain-shortened homologue of ursodeoxycholic acid that undergoes hepatic enrichment with hepatoprotective, anti-inflammatory, and antifibrotic activity. It has shown significant reduction of serum alanine aminotransferase (ALT) within 12 wk of treatment when compared with placebo, encouraging further investigation[11]. Aldafermin is an analogue of fibroblast growth factor 19 (FGF19) which regulates bile acid metabolism and fat storage in the liver. FGF19 levels are lower in patients with NAFLD and insulin resistance. Activation of the FGF19 pathway has been shown to improve insulin sensitivity and liver steatosis. In a 24-wk placebo-controlled trial, the aldafermin group experienced a significant reduction in absolute liver fat content compared with placebo (P = 0.002) and fibrosis improvement of at least 1 stage (38% vs 18%, P = 0.10)[12]. The currently ongoing phase 2b ALPINE 4 study is designed to assess the efficacy, safety and tolerability of this agent (NCT04210245).

Table 1 Phase 2 trials in non-alcoholic steatohepatitis.
Trial name/NCT number
Mechanism of action
Enrollment (targeted)
Study arms
Primary or relevant end point(s)
NCT03976401Akero TherapeuticsAKR-001FGF 21 receptor agonist80(1) AKR-001 50 mg QD; and (2) Placebo112Change in liver fat fraction measured by MRI-PDFFOngoing
NCT0454118689bioBIO89-100FGF 21 receptor agonist90(1) BIO89-100 (QW or every 2 wk); and (2) Placebo112Change in various lab parameters TG, LDL, HDL, fasting glucose. Change in liver fat fraction measured by MRI-PDFFOngoing
NCT02097277Bristol-Myers SquibbPegbelfermin (BMS-986036)FGF 21 receptor agonist120(1) Pegbelfermin 1 mg QD; (2) Pegbelfermin 5 mg QD; (3) Pegbelfermin 20 mg QD; (4) Pegbelfermin 20 mg weekly; and (5) Placebo84Safety, tolerability, and change in HbA1c. Change in insulin sensitivity, lipids, adiponectin, and disease progression biomarkersNo significant effects of pegbelfermin versus placebo on HbA1c. Pegbelfermin 20 mg/d significantly improved high-density lipoprotein cholesterol and triglycerides. Most frequent adverse events were injection-site bruising and diarrhea
NCT01237119Novo NordiskLiraglutideGLP-1analogue52(1) Liraglutide 1.8 mg SC QD; and (2) Placebo336Resolution of NASH without worsening fibrosis 39% who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with 9% in placebo (P = 0·019). Side efffects diarrhea and loss of appetite
NCT02970942Novo Nordisk SemaglutideGLP-1 analogue320(1) Semaglutide 0.1 mg SC QD; (2) Semaglutide 0.2 mg SC QD; (3) Semaglutide 0.4 mg SC QD; and (4) Placebo504Resolution of NASH without worsening fibrosis. Improvement in fibrosis, LFTs, A1c levelNASH resolution was achieved in 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P < 0.001 for semaglutide 0.4 mg vs placebo). Side effects including nausea, constipation, and vomiting which was higher in the 0.4-mg group
2013-004605-38Dr Falk Pharma GmbHNorursodeoxycholic acidhomologue of ursodeoxycholic acid, undergoes hepatic enrichment with hepatoprotective, anti-inflammatory, and antifibrotic activity198(1) 500 mg norursodeoxycholic acid QD; (2) 1500 mg norursodeoxycholic acid QD; and (3) Placebo112Change in ALT levelsDose-dependent reduction in ALT with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (P < 0.0001). Side effects included headache, gastrointestinal disorders, and infections
COHORT 4/NCT02443116 NGM BiopharmaceuticalsAldaferminAnalog of fibroblast growth factor 19, inhibits bile acid synthesis and regulates metabolic homeostasis78(1) aldafermin 1 mg QD; and (2) Placebo168Improvement in liver fibrosis of greater or equal to one stage with no worsening of NASHAldafermin group with higher rate of liver fat content reduction compared to placebo (7.7% vs 2.7%, P = 0.02). Aldafermin produced significantly greater decrease in bile acids, liver enzymes. Fibrosis improvement without worsening NASH higher in aldafermin group (38% vs 18%, P = 0.10). NASH resolution without worsening fibrosis higher in aldafermin group (24% vs 9%, P = 0.20). Side effects include diarrhea, headache, abdominal distation and peripheral edema
ALPINE 4/NCT04210245NGM BiopharmaceuticalsAldaferminAnalog of fibroblast growth factor 19, inhibits bile acid synthesis and regulates metabolic homeostasis72(1) Aldafermin 0.3 mg QD; (2) Aldafermin 1 mg QD; (3) Aldafermin 3 mg; and (4) Placebo168Improvement in liver fibrosis of greater or equal to one stage with no worsening of NASHOngoing
FLIGHT-FXR/NCT02855164Novartis Pharmaceutical TropifexorFXR agonist152(1) TXR 140 g QD; (2) TXR 200gr QD; and (3) Placebo 84Changes in liver fat fraction, liver enzymes, body weightEnd point achieved in TXR 800 mg vs 1200 mg vs Placebo (51% vs 55% vs 34%, P = 0.001). Side effects include mild pruritus and increase in LDL
NATIVE/NCT03008070InventivaLanifibranorPPAR agonist247(1) Lanifibranor 800 mg QD; (2) Lanifibranor 1200 mg QD; and (3) Placebo168Responder analysis based on the improvement of the SAF activity scoreL800 mg vs 1200 mg vs Placebo (51% vs 55% vs 34%) P = 0.0015. SE weight gain, peripheral edema
FASCINATE-1/NCT03938246Sagimet Biosciences IncTVB-2640FASN inhibitor99(1) TVB2640 25 mg QD; (2) TVB2640 50 mg; and (3) Placebo84Change in hepatic fat fraction from baseline in subjects with NASH by proton-density fat fraction by magnetic resonance imagingDose-dependent relative changes in liver fat by MRI-PDFF were -28.2% with 50 mg (P < 0.005 vs placebo), -9.6% with 25 mg, and +4.5% with placebo. 30% relative reduction in liver fat at week 12 were 61% (P < 0.001 vs placebo)
NCT02856555Gilead SciencesFirsocostatAcetyl-coenzyme A carboxylase Inhibitor126(1) Firsocostat 20 mg QD; (2) Firsocostat 5 mg QD; and (3) Placebo84Safety and tolerability. Secondary end point efficacy (NASH improvement without fibrosis)Decrease of at least 30% from baseline in MRI-PDFF occurred in 48% of patients with 20 mg (P = 0.004), 23% given 5 mg (P = 0.43), and 15% given placebo. SE cause, abdominal pain, diarrhea
VOYAG/LBP20Viking therapeutics VK2809Thyroid beta receptor agonist, selectively cleaved in hepatic tissue45(1) VK2809 5 mg QD; (2) VK2809 10 mg QOD; (3) VK280910 mg QD; and (4) Placebo84Safety, tolerability and efficacy in reducing liver fat content and LDL < Liver fat content was 8.7% for 5 mg QD (P = 0.0014) vs 8.9% 10 mg QOD (P = 0.013) vs 10.6% for 10 mg QD (P = 0.0030), vs 1.1% for placebo. 70% in VK2809 therapy showed a ≥ 50%. Reduction in MRI-PDFF (P = 0.014)
NCT02912260Madrigal PharmaceuticalsResmetirom (MGL-3196)Selective thyroid hormone receptor-β agonist 125(1) Resmetirom 80 mg QD; and (2) Placebo252Change in liver fat fraction measured by MRI-PDFF80 mg vs placebo reduction of hepatic fat at week 12 (-32.9% vs -10.4%; P < 0·0001) and week 36 (-37.3% vs -8.5%; P < 0·0001)
NCT02784444Cirius TherapeuticsMSDC-0602KInsulin sensitizer designed to preferentially target the mitochondrial pyruvate carrier with direct binding to the transcriptional factor PPARγ392(1) MSDC-0602K 62.5 mg QD; (2) MSDC-0602K 125 mg QD; (3) MSDC-0602K 250 mg QD; and (4) Placebo364Hepatic histological and activity score improvement in either ballooning or lobular inflammationNo increase in fibrosis stage at 12 moPrimary end point placebo 29.7%, vs 62.5 mg 29.8%, vs 125 mg 32.9% vs 250 mg 39.5% (95%CI: 0.44–1.81) (95%CI: 0.60–2.48), (95%CI: 0.83–3.27)

FXR agonists, which bind to the transcription factor FXR to help regulate bile acid metabolism are in multiple phases of clinical trial investigation. The FXR agonist tropifexor has demonstrated a robust and dose-dependent decrease in ALT, hepatic fat fractionation, and body weight with good safety and tolerability after 12 wk of treatment in a phase 2 trial[13]. The PPARα, β/δ and γ, play a central role in the regulation of glucose and lipid metabolism and of the inflammatory and fibrogenic pathways which contribute to NASH pathogenesis. Lanifibranor (IVA337), a pan-PPAR agonist, combines pharmacological effects that could improve fatty acid oxidation, dyslipidemia, and insulin sensitivity, and has demonstrated anti-inflammatory, antifibrotic and hepatoprotective effects in preclinical models and phase 1/2 trials. TVB-2640 is an orally bioavailable, first-in-class fatty acid synthase (FASN) inhibitor. FASN is a key enzyme in the de novo lipogenesis pathway that is responsible for the synthesis of excess fat and activation of fibrogenic and inflammatory mechanisms in the liver of patients with NASH. TVB-2640 demonstrated significant improvement in several NASH endpoints in the FASCINATE-1 trial as summarized in Table 1[14]. Firsocostat (GS-0976) is an inhibitor of ACC (acetyl-coenzyme A carboxylase) which catalyzes de novo lipogenesis in the liver. In a randomized placebo-controlled trial, firsocostat 20 mg decreased hepatic steatosis and surrogate markers of fibrosis[15]. VK2809 is a small molecule prodrug of a potent thyroid beta receptor agonist which has demonstrated favorable effects on lipid metabolism and biomarkers of hepatic steatosis and steatohepatitis in a phase 2 trial, supporting its potential role in patients with NASH[16]. MSDC-0602K is a novel insulin sensitizer designed to preferentially target the mitochondrial pyruvate carrier while minimizing direct binding to the transcriptional factor PPARγ. MSDC-0602K did not demonstrate statistically significant effects on primary and secondary histologic endpoints in a phase 2 trial, but favorable effects on liver cell injury and glucose metabolism support further investigation for in patients with type 2 diabetes[17].


Novel investigational agents which have completed are undergoing evaluation in phase 3 trials are summarized in Table 2. Obeticholic acid, an FXR agonist, has been shown to improve the histological features of NASH, with fibrosis improvement in 23% of patients treated with Obeticholic acid compared with 12% in placebo group[18]. Elafibranor, a PPAR agonist, improves liver enzymes, lipids, glucose levels, and markers of systemic inflammation and is being tested in a phase 3 study (NCT02704403)[19]. Aramchol inhibits steroyl-CoA desaturase 1, a key enzyme in hepatic lipogenesis that converts saturated fatty acids into monounsaturated fatty acid. In the phase 2b ARREST trial, aramchol demonstrated liver fat reduction, biochemical improvement, NASH resolution and fibrosis reduction in a dose response pattern[20]. It has since been included in an ongoing phase 3 trial to test its safety and efficacy (NCT04104321). Cenicriviroc is an oral, dual antagonist of C-C motif chemokine receptor (CCR) types 2 and 5. It has shown anti-inflammatory and anti-fibrotic properties, which are mediated by CCR types 2 and 5 (CCR2/CCR5) blockade. In a randomized double-blind phase 2b study of 289 subjects, cenicriviroc was associated with a statistically significant improvement in NASH fibrosis of one stage or greater vs placebo (20% vs 10%; P = 0.02)[21]. A phase 3 randomized, double-blind, placebo-controlled trial (AURORA) is currently ongoing with evaluation of 2000 adults with NASH who are treated with cenicriviroc or placebo for 52 wk[22]. Resmetirom is a liver-directed, orally active, selective thyroid hormone receptor-β agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity. In a phase 2b study, resmetirom treated patients showed a relative reduction of hepatic fat compared with placebo with statistically significant NASH resolution vs placebo[23], and is currently under evaluation in a phase 3 registration trial (NCT03900429). GR-MD-02 (belapectin), is an inhibitor of galectin 3 that reduces liver fibrosis and portal hypertension. In a phase 2 trial, belapectin was safe but not associated with significant reduction in hepatic venous pressure gradient (HVPG) or fibrosis. However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin reduced HVPG and development of varices, suggesting a possible benefit in patients with NASH cirrhosis without esophageal varices[24] . In the phase 3 NAVIGATE trial, the safety and efficacy of belapectin is under evaluation with primary clinical endpoints of development of varices and event-free survival (NCT04365868).

Table 2 Phase 3 trials in non-alcoholic steatohepatitis.
Trial name/NCT number
Mechanism of action
Enrollment (targeted)
Study arms
Duration (weeks)
Primary or relevant end point(s)
REGENERATE/NCT02548351 Intercept PharmaceuticalsObeticholic acidFarnesoid X receptor agonist2480(1) Obeticholic acid 10 mg QD; (2) Obeticholic acid 25 mg QD; and (3) Placebo72-378Fibrosis improvement (≥ 1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis Fibrosis improvement endpoint-(12%) placebo, (18%) obeticholic acid 10 mg, (23%) obeticholic acid group 25 mg. Safety most common adverse event was pruritus
RESOLVE-IT/NCT02704403GenfitElafibranorPPAR agonist2157(1) Elafibranor 120 mg QD; and (2) Placebo72-216Change in fibrosis. Change in histologic score of NASH ongoing
ARMOR/NCT0410432Galmed pharmaceuticalsAramcholSCD-1 inhibitor247(1) Aramchol 600 mg QD; (2) Aramchol 400 mg qd; and (3) Placebo364(1) Evaluate the safety and efficacy as measured with % change in the liver triglycerides concentration; and (2) SafetyOngoing
AURORA/NCT03028740Tobira TherapeuticsCenicrivirocDual antagonist of CCR types 2 and 52000(1) Cenicriviroc 150 mg; and (2) Placebo364(1) Proportion of subjects with ≥ 1-stage improvement in liver fibrosis and no worsening of steatohepatitis at month 12 relative to screening; and (2) Safety Ongoing
MAESTRO-NASH/ NCT03900429Madrigal PharmaceuticalsResmetiromSelective thyroid hormone receptor-β agonist2000(1) resmetirom 80 mg QD; (2) resmetirom 100 mg QD; and (3) Placebo364NASH resolution, with at least a 2-point reduction in NAS (NASH Activity Score-biopsy), and with no worsening of fibrosis. Secondary end p. (1) Liver fibrosis improvement of at least one stage, with no worsening of NASH; and (2) Lowering of LDL-cholesterolOngoing
NAVIGATE/NCT04365868Galectin TherapeuticsGR-MD-02 (belapectin)Inhibitor of galectin 31010(1) Belapectin 2 mg/kg intravenously (IV) every other week; (2) Belapectin 4 mg/kg intravenously (IV) every other week; and (3) Placebo504Development of new esophageal varices at 78 weeks in the belapectin group Cumulative incidence rate of decompensations and event-free survival by time to first cirrhosis related clinical eventOngoing

The rationale of combining two or more strategies for NASH therapy aims to augment rates of NASH resolution and NASH fibrosis improvement. By targeting the development of steatohepatitis, liver fibrosis as well as controlling metabolic syndrome, we may achieve response rates higher than 32% as seen currently via trials of drugs as monotherapy[6]. Table 3 is a collection of studies currently underway, and some completed, that evaluate multidrug regimens for the treatment of NASH. FXR agonists, which regulate bile acid metabolism, are one major class of drugs incorporated in many of these trials. Obeticholic acid, a promising drug in this class, has demonstrated the dose-dependent ability to improve liver fibrosis and steatohepatitis in NASH patients with stage F2/F3 fibrosis based on initial and secondary analysis of the REGENERATE trials[18,25]. Cilofexor, another FXR agonist, has been tested in combination with firsocostat, an ACC inhibitor and selonsertib, an ASK1 inhibitor, in the phase 2b ATLAS study that demonstrated improvements in liver enzymes, fibrosis, NAS score on histology and improvements in liver elastography in the cilofexor/firsocostat group compared to placebo[26]. Ongoing studies with tropifexor include combinations with cenicriviroc and LYS0006 with early results still pending and waiting to be reviewed.

Table 3 Multidrug regimens for the treatment of non-alcoholic steatohepatitis.
Trial name/NCT number
Mechanism of action
Enrollment (targeted)
Study arms
Duration (weeks)
Primary or relevant end point(s)
NCT02781584 (Proof of Concept)1Gilead SciencesSelonsertib, firsocostat, cilofexor, fenofibrate, icosapent ethyl(1) Selonsertib-selective ASK1 inhibitor; (2) Firsocostat-ACC inhibitor; (3) Cilofexor-FXR agonist; (4) Fenofibrate-PPAR agonist; and (5) Icosapent ethyl-under investigation220(1) Selonsertib; (2) Firsocostat; (3) Cilofexor; (4) Selonsertib + cilofexor; (5) Selonsertib + firsocostat; (6) Firsocostat + cilofexor; (7) Firsocostat (cirrhotic patients); (8) Cilofexor (cirrhotic patients); (9) Selonsertib + firsocostat + cilofexor; (10) Firsocostat + fenofibrate 48 mg; (11) Firsocostat + fenofibrate 145 mg; and (12) Icosapent ethyl + firsocostat + cilofexor 12(1) Adverse events; (2) Serious adverse events; and (3) Lab abnormalities
ATLAS/NCT034494462Gilead SciencesSelonsertib, firsocostat, cilofexor(1) Selonsertib-selective ASK1 inhibitor; (2) Firsocostat-ACC inhibitor; and (3) Cilofexor-FXR agonist 395(1) Selonsertib + firsocostat + placebo; (2) Selonsertib + cilofexor + placebo; (3) Firsocostat + cilofexor + placebo; (4) Selonsertib + placebo + placebo; (5) Firsocostat + placebo + placebo; (6) Cilofexor + placebo + placebo; and (7) 3 placebos48(1) Adverse events; (2) Lab abnormalities; and (3) Improvement of ≥ 1-stage in fibrosis without worsening of NASH
NCT039870742Gilead Sciences, Novo NordiskCilofexor, semaglutide, firsocostat(1) Semaglutide-GLP-1 agonist; (2) Firsocostat-ACC inhibitor; and (3) Cilofexor-FXR agonist109(1) Semaglutide; (2) Firsocostat + semaglutide; (3) Semaglutide + cilofexor 30 mg; (4) Semaglutide + cilofexor 100 mg; and (5) Semaglutide + firsocostat + cilofexor 24(1) Adverse events; (2) Serious adverse events; and (3) Lab abnormalities
ELIVATE/NCT040658412NovartisTropifexor, licogliflozin(1) Tropifexor-FXR agonist; and (2) Licogliflozin-SGLT1/2 inhibitor380(1) Tropifexor + licogliflozin; (2) Tropifexor + placebo; (3) Licogliflozin + placebo; and (4) 2 placebos48(1) Improvement of ≥ 1-stage in fibrosis without worsening of NASH; and (2) Resolution of NASH without worsening fibrosis
NCT037761752APfizerPF-05221304, PF-06865571(1) PF-05221304-ACC inhibitor; and (2) PF-06865571 - DGAT 2 inhibitor99(1) ACC inhibitor + placebo; (2) DGAT2 inhibitor + placebo; (3) ACC inhibitor + DGAT2 inhibitor; and (4) 2 placebos6Improvement in fat fraction
TANDEM/NCT035175402Novartis, AllerganTropifexor, cenicriviroc(1) Tropifexor-FXR agonist; and (2) Cenicriviroc-CCR2/CCR5 inhibitor193(1) Tropifexor; (2) Cenicriviroc; (3) Tropifexor dose 1 + cenicriviroc; and (4) Tropifexor dose 2 + cenicriviroc 48(1) improvement in fibrosis; and (2) Resolution of steatohepatitis
CONTROL/NCT026339562Intercept PharmaceuticalsObeticholic acid, atorvastatin(1) Obeticholic acid-FXR agonist; and (2) Atorvastatin-HMG-CoA reductase inhibitor 84(1) Obeticholic acid 5 mg/10 mg/25 mg + atorvastatin 10 mg/20 mg; and (2) Placebo + atorvastatin 10 mg/20 mg16(1) Change in LDL concentration; (2) Change in LDL particle size; and (3) Change in LDL particle concentration
NCT042352052Albireo PharmaElobixibat, cholestyramine(1) Elobixibat-IBAT inhibitor; and (2) Cholestyramine-bile acid binding resin 100(1) Elobixibat + cholestyramine; (2) Elobixibat + placebo; (3) Placebo + cholestyramine; and (4) 2 placebos16(1) Change in liver fat fraction measured by MRI-PDFF; and (2) Change in fibrosis measured by MRE
PUVENAFLD/NCT041988052DSM Nutritional ProductsVitamin E, omega-3 fatty acid(1) Vitamin E-scavenging reactive oxidation species; and (2) Omega 3 FA-competing with omega 6 for cyclooxgenase and lipoxygenase-mediated inflammatory eicosanoid production, forming anti-inflammatory compounds200(1) Vitamin E + placebo; (2) Omega-3 fatty acid + placebo; (3) Omega 3-fatty acid + vitamin E; and (4) 2 placebos24(1) Change in liver fat fraction measured by MRI-PDFF; (2) Change in liver enzymes; and (3) FIB-4 scores
NEXSCOT/NCT041471952NovartisLYS006, tropifexor (1) Tropifexor-FXR agonist; and (2) LYS006-leukotriene A4 hydrolase inhibitor250(1) LYS006; and (2) LYS006 + tropifexor21(1) Change in ELF score; and (2) Change in liver fat fraction measured by MRI-PDFF
NCT024665162Gilead SciencesSelonsertib, simtuzumab(1) Selonsertib-selective ASK1 inhibitor; and (2) Simtuzumab-lysyl oxidase-like 2 inhibitor 72(1) Selonsertib 6 mg; (2) Selonsertib 18 mg; (3) Selonsertib 6 mg + simtuzumab; (4) Selonsertib 18 mg + simtuzumab; and (5) Simtuzumab 24(1) Adverse events; (2) Serious adverse events; (3) Lab abnormalities; and (4) Number of participants who prematurely discontinued study due to adverse events
NCT017032602AstraZenecaRoflumilast, pioglitazone(1) Roflumilast-phosphodiesterase 4 inhibitor; and (2) Pioglitazone-PPAR agonist16(1) Roflumilast + pioglitazone; (2) Roflumilast + placebo; and (3) Pioglitazone + placebo20(1) Change in liver enzymes; and (2) Change in liver fat fraction measured by MRI-PDFF

By now it is well known that features of metabolic syndrome increase the risk of developing NAFLD. Type 2 diabetes, specifically, is a risk factor for NASH and its presence increases the risk of progression of NASH fibrosis[27,28]. Therefore, some of the ongoing trials in combination therapy for NASH include semaglutide, pioglitazone or licogliflozin; from drug classes that traditionally have been utilized for the management of T2DM. In one randomized, placebo controlled trial in patients with biopsy proven NASH, a GLP-1 analog, liraglutide, was associated with greater improvement in steatohepatitis and lower progression of fibrosis[9]. A proof-of-concept trial is currently underway including semaglutide along with cilofexor and firsocostat. Licogliflozin, which has shown benefit in lowering liver fat content, is being studied as part of a combination trial with tropifexor in the ELIVATE trial. Numerous trials have already established the benefit of pioglitazone in improving inflammation and fibrosis in patients with biopsy proven NASH and therefore it is included as recommended management for a select group of patients according to the most recent American Association for the Study of Liver Diseases guidelines on NAFLD[29].

Aside from the ability to decrease inflammation and fibrosis in NASH, allowing treatment with lower doses of various drugs in combination or improvement the side effect profile are two alternate motives for pursuing combination therapy. In Wister rat models for NASH, one group was able to demonstrate a synergistic therapeutic effect on inflammation and oxidative stress from combining elafibranor and obeticholic acid at lower doses than with each drug in monotherapy[30]. FXR agonists have been shown to increase low density lipoprotein (LDL) cholesterol concentrations. In the CONTROL study, the authors were able to lower the LDL concentration below baseline with the addition of atorvastatin[31]. In a separate phase 2, proof-of-concept trial, fenofibrate was tested in combination with the ACC inhibitor, firsocostat, to help lower triglyceride levels[32].


In this concise review, we have discussed numerous possible therapeutic options for cessation or reversal of NASH and associated fibrosis. It is clear that NASH and particularly NASH fibrosis or cirrhosis is a leading topic garnering much interest in the study of liver diseases today, which would be appropriate considering the clinical impact. Although some of the above targets may seem promising, there are still a few concerns regarding study of this particular topic. Firstly, it is evident by reviewing the endpoints of each of the studies listed above that there is much heterogeneity. This is partly because the gold standard of liver biopsy to prove effectiveness in this endeavor is cumbersome, costly, and generally not favored by patients. The use of surrogates for liver fibrosis and resolution including markers of turnover, inflammation, or non-invasive assessments of liver scarring have not universally been agreed upon in the use of clinical trials. Secondly, for those studies that have utilized liver biopsies are part of their endpoint assessment, there can be considerable inter-observer variability in interpretation of liver biopsy specimens, assuming they are of adequate quality. Additionally, it is apparent that many of the study developers use magnetic resonance imaging with proton density fat fraction for assessment of liver fat content while there are additional tools such as the controlled attenuation parameter of transient elastography systems which might be more acceptable as a point of care test. Lastly, endoscopic and surgical bariatrics represent an emerging area of therapeutic development for the management of obesity in context of NASH. In one prospective study of 180 patients, bariatric surgery was associated with NASH resolution in 84% of patients with improvement in fibrosis in 70% of patients at the 5 year mark after surgery[33]. Separately, in a 6 mo multi-center study of 85 patients with T2DM undergoing duodenal mucosal resurfacing, not only did their A1c improve, but so did their ALT levels and FIB-4 scores hinting at the possible insulin sensitizing, lipid lowering, anti-inflammatory and antioxidant effects of this procedure[34]. In conclusion, more effective treatments for NASH are urgently needed, and combination pharmacotherapy represents among the most promising approaches in develpoment.


Provenance and peer review: Invited article; Externally peer reviewed.

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Specialty type: Gastroenterology and hepatology

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P-Reviewer: Ji G, China; Radford-Smith DE, Australia S-Editor: Fan JR L-Editor: A P-Editor: Fan JR

1.  Paik JM, Henry L, De Avila L, Younossi E, Racila A, Younossi ZM. Mortality Related to Nonalcoholic Fatty Liver Disease Is Increasing in the United States. Hepatol Commun. 2019;3:1459-1471.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 81]  [Cited by in F6Publishing: 86]  [Article Influence: 20.3]  [Reference Citation Analysis (0)]
2.  Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, Ahmed A. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148:547-555.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1191]  [Cited by in F6Publishing: 1231]  [Article Influence: 148.9]  [Reference Citation Analysis (0)]
3.  Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24:908-922.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1376]  [Cited by in F6Publishing: 1444]  [Article Influence: 275.2]  [Reference Citation Analysis (0)]
4.  Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, Bansal B, Kaur P, Jevalikar G, Gill HK, Choudhary NS, Mithal A. Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial). Diabetes Care. 2018;41:1801-1808.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 267]  [Cited by in F6Publishing: 286]  [Article Influence: 53.4]  [Reference Citation Analysis (0)]
5.  Petit JM, Cercueil JP, Loffroy R, Denimal D, Bouillet B, Fourmont C, Chevallier O, Duvillard L, Vergès B. Effect of Liraglutide Therapy on Liver Fat Content in Patients With Inadequately Controlled Type 2 Diabetes: The Lira-NAFLD Study. J Clin Endocrinol Metab. 2017;102:407-415.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 70]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
6.  Dufour JF, Caussy C, Loomba R. Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges. Gut. 2020;69:1877-1884.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 72]  [Article Influence: 26.3]  [Reference Citation Analysis (0)]
7.  Services USD of H and H. Noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: developing drugs for treatment. Guid Ind. 2018;.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 1]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
8.  Kaufman A, Abuqayyas L, Denney WS, Tillman EJ, Rolph T. AKR-001, an Fc-FGF21 Analog, Showed Sustained Pharmacodynamic Effects on Insulin Sensitivity and Lipid Metabolism in Type 2 Diabetes Patients. Cell Rep Med. 2020;1:100057.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 40]  [Cited by in F6Publishing: 42]  [Article Influence: 13.3]  [Reference Citation Analysis (0)]
9.  Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, Hazlehurst JM, Guo K; LEAN trial team, Abouda G, Aldersley MA, Stocken D, Gough SC, Tomlinson JW, Brown RM, Hübscher SG, Newsome PN. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387:679-690.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 991]  [Cited by in F6Publishing: 846]  [Article Influence: 141.6]  [Reference Citation Analysis (0)]
10.  Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, Sanyal AJ, Sejling AS, Harrison SA; NN9931-4296 Investigators. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med. 2021;384:1113-1124.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 349]  [Cited by in F6Publishing: 389]  [Article Influence: 116.3]  [Reference Citation Analysis (0)]
11.  Traussnigg S, Schattenberg JM, Demir M, Wiegand J, Geier A, Teuber G, Hofmann WP, Kremer AE, Spreda F, Kluwe J, Petersen J, Boettler T, Rainer F, Halilbasic E, Greinwald R, Pröls M, Manns MP, Fickert P, Trauner M; Austrian/German NAFLD-norUDCA study group. Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial. Lancet Gastroenterol Hepatol. 2019;4:781-793.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 35]  [Cited by in F6Publishing: 31]  [Article Influence: 8.8]  [Reference Citation Analysis (0)]
12.  Harrison SA, Neff G, Guy CD, Bashir MR, Paredes AH, Frias JP, Younes Z, Trotter JF, Gunn NT, Moussa SE, Kohli A, Nelson K, Gottwald M, Chang WCG, Yan AZ, DePaoli AM, Ling L, Lieu HD. Efficacy and Safety of Aldafermin, an Engineered FGF19 Analog, in a Randomized, Double-Blind, Placebo-Controlled Trial of Patients With Nonalcoholic Steatohepatitis. Gastroenterology. 2021;160:219-231.e1.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 103]  [Cited by in F6Publishing: 102]  [Article Influence: 51.5]  [Reference Citation Analysis (0)]
13.  Tropifexor SA. A highly potent FXR agonist, produces robust and dose-dependent reductions in hepatic fat and serum alanine aminotransferase in patients with fibrotic NASH after 12 wk of therapy: FLIGH-FXR part C interim results. Hepatology. 2019;70.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Loomba R, Rinella M, Harrison S, Wong VW-S, Ratziu V, Mohseni R, Lucas KJ, Perry RG, Rahmini R, Trotter JF. Novel first-in-class, fatty acid synthase inhibitor, TVB-2640 vs. placebo demonstrates clinically significant reduction in liver fat by MRI-PDFF in NASH: a phase 2 randomised controlled trial (FASCINATE-1). J Hepatol. 2020;73:S53-S54.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 2]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
15.  Loomba R, Kayali Z, Noureddin M, Ruane P, Lawitz EJ, Bennett M, Wang L, Harting E, Tarrant JM, McColgan BJ, Chung C, Ray AS, Subramanian GM, Myers RP, Middleton MS, Lai M, Charlton M, Harrison SA. GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2018;155:1463-1473.e6.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 178]  [Cited by in F6Publishing: 183]  [Article Influence: 35.6]  [Reference Citation Analysis (0)]
16.  Loomba R, Neutel J, Mohseni R, Bernard D, Severance R, Dao M, Saini S, Margaritescu C, Homer K, Tran B, Mancini M, Masamune H, Lian B. LBP-20-VK2809, a Novel Liver-Directed Thyroid Receptor Beta Agonist, Significantly Reduces Liver Fat with Both Low and High Doses in Patients with Non-Alcoholic Fatty Liver Disease: A Phase 2 Randomized, Placebo-Controlled Trial. J Hepatol. 2019;70:e150-1.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 30]  [Article Influence: 7.8]  [Reference Citation Analysis (0)]
17.  Harrison SA, Alkhouri N, Davison BA, Sanyal A, Edwards C, Colca JR, Lee BH, Loomba R, Cusi K, Kolterman O, Cotter G, Dittrich HC. Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase IIb study. J Hepatol. 2020;72:613-626.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 107]  [Cited by in F6Publishing: 101]  [Article Influence: 35.7]  [Reference Citation Analysis (0)]
18.  Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, Bedossa P, Geier A, Beckebaum S, Newsome PN, Sheridan D, Sheikh MY, Trotter J, Knapple W, Lawitz E, Abdelmalek MF, Kowdley KV, Montano-Loza AJ, Boursier J, Mathurin P, Bugianesi E, Mazzella G, Olveira A, Cortez-Pinto H, Graupera I, Orr D, Gluud LL, Dufour JF, Shapiro D, Campagna J, Zaru L, MacConell L, Shringarpure R, Harrison S, Sanyal AJ; REGENERATE Study Investigators. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019;394:2184-2196.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 493]  [Cited by in F6Publishing: 430]  [Article Influence: 123.3]  [Reference Citation Analysis (0)]
19.  Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, Romero-Gomez M, Boursier J, Abdelmalek M, Caldwell S, Drenth J, Anstee QM, Hum D, Hanf R, Roudot A, Megnien S, Staels B, Sanyal A; GOLDEN-505 Investigator Study Group. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 2016;150:1147-1159.e5.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 665]  [Cited by in F6Publishing: 685]  [Article Influence: 95.0]  [Reference Citation Analysis (0)]
20.  Ratziu V, Ladron-De-Guevara L, Safadi R, Poordad F, Fuster F, Flores-Figueroa J, Harrison SA, Arrese M, Fargion S, Ben-Bashat D.   One-year results of the global phase 2b randomized placebo-controlled arrest trial of aramchol, a stearoyl CoA desaturase inhibitor, in patients with NASH. In: Hepatology. WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ United States, 2018: 1448A-1449A.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Friedman SL, Ratziu V, Harrison SA, Abdelmalek MF, Aithal GP, Caballeria J, Francque S, Farrell G, Kowdley KV, Craxi A, Simon K, Fischer L, Melchor-Khan L, Vest J, Wiens BL, Vig P, Seyedkazemi S, Goodman Z, Wong VW, Loomba R, Tacke F, Sanyal A, Lefebvre E. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. 2018;67:1754-1767.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 410]  [Cited by in F6Publishing: 389]  [Article Influence: 82.0]  [Reference Citation Analysis (0)]
22.  Anstee QM, Neuschwander-Tetri BA, Wong VW, Abdelmalek MF, Younossi ZM, Yuan J, Pecoraro ML, Seyedkazemi S, Fischer L, Bedossa P, Goodman Z, Alkhouri N, Tacke F, Sanyal A. Cenicriviroc for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis: AURORA Phase 3 study design. Contemp Clin Trials. 2020;89:105922.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 64]  [Article Influence: 14.5]  [Reference Citation Analysis (0)]
23.  Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, Alkhouri N, Bansal MB, Baum S, Neuschwander-Tetri BA, Taub R, Moussa SE. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019;394:2012-2024.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 226]  [Cited by in F6Publishing: 235]  [Article Influence: 56.5]  [Reference Citation Analysis (0)]
24.  Chalasani N, Abdelmalek MF, Garcia-Tsao G, Vuppalanchi R, Alkhouri N, Rinella M, Noureddin M, Pyko M, Shiffman M, Sanyal A, Allgood A, Shlevin H, Horton R, Zomer E, Irish W, Goodman Z, Harrison SA, Traber PG; Belapectin (GR-MD-02) Study Investigators. Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension. Gastroenterology. 2020;158:1334-1345.e5.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 128]  [Cited by in F6Publishing: 127]  [Article Influence: 42.7]  [Reference Citation Analysis (0)]
25.  Sanyal AJ, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, Bedossa P, Khalili M, Boursier J, Stinton L.   Obeticholic acid treatment in patients with non-alcoholic steatohepatitis: a secondary analysis in the regenerate study across fibrosis stages. In: AISF Annual Meeting 2020, 2020: 46–7.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Loomba R, Noureddin M, Kowdley KV, Kohli A, Sheikh A, Neff G, Bhandari BR, Gunn N, Caldwell SH, Goodman Z, Wapinski I, Resnick M, Beck AH, Ding D, Jia C, Chuang JC, Huss RS, Chung C, Subramanian GM, Myers RP, Patel K, Borg BB, Ghalib R, Kabler H, Poulos J, Younes Z, Elkhashab M, Hassanein T, Iyer R, Ruane P, Shiffman ML, Strasser S, Wong VW, Alkhouri N; ATLAS Investigators. Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH. Hepatology. 2021;73:625-643.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 82]  [Cited by in F6Publishing: 72]  [Article Influence: 41.0]  [Reference Citation Analysis (0)]
27.  Neuschwander-Tetri BA, Clark JM, Bass NM, Van Natta ML, Unalp-Arida A, Tonascia J, Zein CO, Brunt EM, Kleiner DE, McCullough AJ, Sanyal AJ, Diehl AM, Lavine JE, Chalasani N, Kowdley KV; NASH Clinical Research Network. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology. 2010;52:913-924.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 319]  [Cited by in F6Publishing: 279]  [Article Influence: 24.5]  [Reference Citation Analysis (0)]
28.  Younossi ZM, Gramlich T, Matteoni CA, Boparai N, McCullough AJ. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol. 2004;2:262-265.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67:328-357.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3228]  [Cited by in F6Publishing: 2973]  [Article Influence: 645.6]  [Reference Citation Analysis (1)]
30.  Noel B, Ratziu V, Harrison S, Rigou G, degallaix nathalie, texier frederic, Brozek J, Daix V, Belanger C, roudot alice, megnien sophie, hum dean, staels bart, Walczak R, sanyal arun.   Combination drug therapy allows synergistic therapeutic dosereduction in NASH: A case study of ELAFIBRANOR (GFT505) and an FXR agonist combination in a model of severe NASH. 2017. [cited 10 January 2022]. Available from:  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Pockros PJ, Fuchs M, Freilich B, Schiff E, Kohli A, Lawitz EJ, Hellstern PA, Owens-Grillo J, Van Biene C, Shringarpure R, MacConell L, Shapiro D, Cohen DE. CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients. Liver Int. 2019;39:2082-2093.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 75]  [Article Influence: 19.8]  [Reference Citation Analysis (0)]
32.  Lawitz EJ, Neff G, Ruane PJ, Younes Z, Zhang J, Jia C, Chuang J, Huss R, Chung C, Subramanian M.   Fenofibrate mitigates increases in serum triglycerides due to the ACC inhibitor firsocostat in patients with advanced fibrosis due to NASH: a phase 2 randomized trial. In: Hepatology. WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ United States, 2019: 1489A-1490A.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Lassailly G, Caiazzo R, Ntandja-Wandji LC, Gnemmi V, Baud G, Verkindt H, Ningarhari M, Louvet A, Leteurtre E, Raverdy V, Dharancy S, Pattou F, Mathurin P. Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis. Gastroenterology. 2020;159:1290-1301.e5.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 179]  [Cited by in F6Publishing: 173]  [Article Influence: 59.7]  [Reference Citation Analysis (0)]
34.  van Baar ACG, Beuers U, Wong K, Haidry R, Costamagna G, Hafedi A, Deviere J, Ghosh SS, Lopez-Talavera JC, Rodriguez L, Galvao Neto MP, Sanyal A, Bergman JJGHM. Endoscopic duodenal mucosal resurfacing improves glycaemic and hepatic indices in type 2 diabetes: 6-month multicentre results. JHEP Rep. 2019;1:429-437.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 25]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]