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Effect of pharmacological interventions and placebo on liver Histology in nonalcoholic steatohepatitis: A network meta-analysis

  • Author Footnotes
    1 These authors equally contributed to the study.
    Grazia Pennisi
    Footnotes
    1 These authors equally contributed to the study.
    Affiliations
    Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE), University of Palermo, Italy
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  • Author Footnotes
    1 These authors equally contributed to the study.
    Ciro Celsa
    Footnotes
    1 These authors equally contributed to the study.
    Affiliations
    Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE), University of Palermo, Italy
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  • Author Footnotes
    1 These authors equally contributed to the study.
    Marco Enea
    Footnotes
    1 These authors equally contributed to the study.
    Affiliations
    Dipartimento di Scienze Economiche, Aziendali e Statistiche, University of Palermo, 90133 Palermo, Italy
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  • Marco Vaccaro
    Affiliations
    Dipartimento di Scienze Economiche, Aziendali e Statistiche, University of Palermo, 90133 Palermo, Italy
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  • Vito Di Marco
    Affiliations
    Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE), University of Palermo, Italy
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  • Carlo Ciccioli
    Affiliations
    Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE), University of Palermo, Italy
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  • Giuseppe Infantino
    Affiliations
    Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE), University of Palermo, Italy
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  • Claudia La Mantia
    Affiliations
    Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE), University of Palermo, Italy
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  • Stefanie Parisi
    Affiliations
    Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE), University of Palermo, Italy
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  • Federica Vernuccio
    Affiliations
    Dipartimento di Biomedicina, Neuroscienze e Diagnostica avanzata (BIND), University of Palermo, Italy
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  • Antonio Craxì
    Affiliations
    Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE), University of Palermo, Italy
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  • Author Footnotes
    2 These authors equally contributed to the study.
    Calogero Cammà
    Footnotes
    2 These authors equally contributed to the study.
    Affiliations
    Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE), University of Palermo, Italy
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  • Author Footnotes
    2 These authors equally contributed to the study.
    Salvatore Petta
    Correspondence
    Corresponding author. Section of Gastroenterology and Hepatology, PROMISE, Policlinico Universitario Paolo Giaccone, Piazza delle Cliniche, 2, 90127 Palermo, Italy.
    Footnotes
    2 These authors equally contributed to the study.
    Affiliations
    Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE), University of Palermo, Italy
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  • Author Footnotes
    1 These authors equally contributed to the study.
    2 These authors equally contributed to the study.

      Highlights

      • By meta-analysis, the pooled rate of spontaneous NASH resolution without fibrosis worsening was 17%.
      • By meta-analysis, the pooled rate of spontaneous ≥1 stage reduction of fibrosis without worsening of NASH was 21%.
      • Meta-regression analysis showed that phase 3 vs phase 2 trials, older age and higher baseline AST levels were risk factors for more rapid histological progression.
      • By network meta-analysis Semaglutide and pioglitazone with/without Vitamin E had the highest probability of being the most effective therapeutic regimens for achieving NASH resolution without worsening of fibrosis.
      • By network meta-analysis aldafermin, lanifibranor and obethicolic acid had the highest probability of achieving ≥1 stage reduction of fibrosis without worsening of NASH.

      Abstract

      Background

      The aims of this study were to quantify the histological improvement and its risk factors in patients with NASH enrolled in the placebo arms of randomized controlled trials (RCTs), and to indirectly compare the effect of several investigational drugs for NASH on validated histological outcomes.

      Data synthesis

      A comprehensive search was conducted to detect phase 2 and 3 RCTs comparing pharmacological interventions in patients with NASH. According to Food and Drug Administration (FDA) recommendations, primary outcomes included: 1) NASH resolution without worsening of fibrosis; 2) At least 1-point reduction in fibrosis without worsening of NASH. Meta-analysis and meta-regressions were conducted on placebo arms, while network meta-analysis was performed on intervention arms.
      A total of 15 RCTs met the eligibility criteria. The meta-analysis on placebo arms showed a pooled estimate rate of 17% (95%C.I. 12%–23%;I2 = 86%; p < 0.01) for NASH resolution without worsening of fibrosis and of 21% (95%C.I. 13%–31%;I2 = 84%; p < 0.01) for ≥1stage improvement of fibrosis without worsening of NASH. Phase 3 (vs Phase 2)RCTs, older age and higher AST levels were significantly associated with progression of liver disease by univariate meta-regression. At network meta-analysis, Semaglutide (P-score 0.906), Pioglitazione alone (score 0.890) and plus Vitamin E (0.826) had the highest probability of being ranked the most effective intervention for NASH resolution without worsening of fibrosis, while Aldafermin (0.776), Lanifibranor (0.773) and Obeticholic acid (0.771) had the highest probability to achieve ≥1 stage of fibrosis improvement without worsening of NASH.

      Conclusion

      This study confirms the heterogeneity of histological progression of untreated patients with NASH and provides evidence to stratify patients according to identified risk factors in future RCTs of combination therapies. PROSPERO CRD42021287205.

      Keywords

      Abbreviations:

      NAFLD (nonalcoholic fatty liver disease), NASH (nonalcoholic steatohepatitis), HCC (hepatocellular carcinoma), LD (liver decompensation), RCTs (randomized controlled trials), BMI (Body Mass Index), AST (aspartate aminotrasferase), ALT (alanine aminotrasferase), FDA (Food and Drug Administration), LRE (liver-related events), HDL (high-density lipoprotein), LDL (low-density lipoprotein)

      1. Introduction

      The prevalence of nonalcoholic fatty liver disease (NAFLD), because of the increasing spread of obesity and diabetes, is dramatically growing, and NAFLD has become the main cause of chronic liver disease worldwide in the last decade [
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
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      Global epidemiology of non-alcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence and outcomes.
      ]. This picture is of great clinical and economic [
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      • Degli Esposti L.
      • Shreay S.
      • Petroni M.L.
      • Marchesini G.
      a LHUs group
      Healthcare resource utilization and costs of nonalcoholic steatohepatitis patients with advanced liver disease in Italy.
      ] impact because NAFLD patients, and especially those with nonalcoholic steatohepatitis (NASH) and liver fibrosis, are at high risk of developing liver-related events (LRE) – such as liver decompensation (LD) and hepatocellular carcinoma (HCC)- and extrahepatic complications – such as cardiovascular diseases and extrahepatic cancers [
      • Taylor R.S.
      • Taylor R.J.
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      • Bhala N.
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      • Anstee Q.M.
      • McPherson S.
      • Newsome P.N.
      Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.
      ,
      • Kanwal F.
      • Kramer J.R.
      • Mapakshi S.
      • Natarajan Y.
      • Chayanupatkul M.
      • Richardson P.A.
      • et al.
      Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.
      ,
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      • Li A.A.
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      • Cholankeril G.
      • Glenn J.S.
      • Ahmed A.
      Trends in mortality from extrahepatic complications in patients with chronic liver disease, from 2007 through 2017.
      ].
      Lifestyle modification, including dietary caloric restriction and increasing physical activity, with the goal of leading to weight loss of at least 5%–7% of baseline weight is the current backbone of NAFLD and NASH treatment because able to promote both NASH resolution and fibrosis improvement [
      • Vilar-Gomez E.
      • Martinez-Perez Y.
      • Calzadilla-Bertot L.
      • Torres-Gonzalez A.
      • Gra-Oramas B.
      • Gonzalez-Fabian L.
      • Friedman S.L.
      • Diago M.
      • Romero-Gomez M.
      Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis.
      ]. Unfortunately, structured and multidisciplinary programs are necessary to facilitate maintained weight loss achievement [
      • Mazzotti A.
      • Caletti M.T.
      • Brodosi L.
      • Di Domizio S.
      • Forchielli M.L.
      • Petta S.
      • Bugianesi E.
      • Bianchi G.
      • Marchesini G.
      An internet-based approach for lifestyle changes in patients with NAFLD: two-year effects on weight loss and surrogate markers.
      ] and in real-life only a minority of patients can obtain weight loss. Therefore, the development of safe and effective pharmacological treatments for patients with NASH and fibrosis is a relevant unmet need.
      In the last years, several drugs for the treatment of patients with NASH, tested against placebo and focused on different mechanisms of actions are under investigation in randomized controlled trials (RCTs) in various phases of development [
      • Do A.
      • Ilagan-Ying Y.C.
      • Mehal W.Z.
      • Lim J.K.
      Drug development of nonalcoholic fatty liver disease: challenges in research, regulatory pathways, and study endpoints.
      ,
      • Tang J.T.
      • Mao Y.M.
      Development of new drugs for the treatment of nonalcoholic steatohepatitis.
      ,
      • Mantovani A.
      • Byrne C.D.
      • Targher G.
      Efficacy of peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors for treatment of non-alcoholic fatty liver disease: a systematic review.
      ]. The Food and Drug Administration (FDA) defined the outcomes needed for drugs approval [
      ,
      • Loomba R.
      • Ratziu V.
      • Harrison S.A.
      NASH clinical trial design international working group. Expert panel review to compare FDA and EMA guidance on drug development and endpoints in nonalcoholic steatohepatitis.
      ]. Specifically, in patients with non-cirrhotic NASH, ≥1 stage reduction in fibrosis stage without worsening of NASH and/or NASH resolution without worsening of fibrosis were the established surrogate histological endpoints of phase 3 RCTs necessary for the conditional approval of tested drugs, waiting for demonstrating the long-term effects on hard clinical outcomes like cirrhosis progression and development of LD and/or HCC [
      • Rinella M.E.
      • Tacke F.
      • Sanyal A.J.
      Anstee QM; participants of the AASLD/EASL Workshop. Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD.
      ,
      • Cheung A.
      • Neuschwander-Tetri B.A.
      • Kleiner D.E.
      • Schabel E.
      • Rinella M.
      • Harrison S.
      • Ratziu V.
      • Sanyal A.J.
      • Loomba R.
      • Jeannin Megnien S.
      • Torstenson R.
      • Miller V.
      Liver forum case definitions working group. Defining improvement in nonalcoholic steatohepatitis for treatment trial endpoints: recommendations from the liver forum.
      ,
      • Adams L.A.
      End-points for drug treatment in NASH.
      ,
      • Ratziu V.
      A critical review of endpoints for non-cirrhotic NASH therapeutic trials.
      ,
      • Caussy C.
      • Reeder S.B.
      • Sirlin C.B.
      • Loomba R.
      Noninvasive, quantitative assessment of liver fat by MRI-PDFF as an endpoint in NASH trials.
      ]. However, the impact of FDA-defined histological outcomes on the natural history of NASH patients has been poorly studied to date.
      Results from many RCTs in NASH patients reported a high variability in the response rate of placebo-treated arms, this relevant issue potentially affecting the overall meaning of the studies and sometimes leading to contrasting results from phase 2 to phase 3 trials [
      • Ratziu V.
      • Harrison S.A.
      • Francque S.
      • et al.
      Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening.
      ,
      • Friedman S.L.
      • Ratziu V.
      • Harrison S.A.
      • Abdelmalek M.F.
      • Aithal G.P.
      • Caballeria J.
      • Francque S.
      • Farrell G.
      • Kowdley K.V.
      • Craxi A.
      • Simon K.
      • Fischer L.
      • Melchor-Khan L.
      • Vest J.
      • Wiens B.L.
      • Vig P.
      • Seyedkazemi S.
      • Goodman Z.
      • Wong V.W.
      • Loomba R.
      • Tacke F.
      • Sanyal A.
      • Lefebvre E.
      A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis.
      ,
      • Ratziu V.
      • Friedman S.L.
      Why do so many NASH trials fail?.
      ]. Consistently, the identification of variables affecting the response rate in placebo-treated arms could lead to a better stratification of patients in placebo and active treatment arms. Furthermore, the lack of head-to-head comparison between the drugs in development, together with the before described high heterogeneity in placebo response, make it difficult to establish what drug could be preferred.
      Therefore, by using FDA surrogate histological endpoints for clinical trials in non-cirrhotic NASH, the aims of the present study were 1) to provide an updated meta-analysis to quantify histological improvement in patients with NASH treated with placebo also identifying its predictors, and 2) to perform a comparative network meta-analysis to indirectly assess the benefit of drugs under investigation for NASH.

      2. Methods

      The reporting of this systematic review follows the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement [
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elabo- ration.
      ]. Institutional review board approval and informed consent was waived as this was not an individual patient–data meta-analysis.

      2.1 Search strategy and study selection

      A systematic search of MEDLINE, EMBASE, and SCOPUS databases was performed including the following terms: “non-alcoholic steatohepatitis” OR “NASH” OR “non-alcoholic fatty liver” OR “NAFLD” combined with “randomized controlled trial”. The search included reports published until October 2021. The computer search was supplemented with manual searches of the reference lists of all review articles and primary studies retrieved to identify additional studies. When the results of a single study were reported in more than one publication, only the most recent and complete data were included in the meta-analysis. When the same intervention was evaluated in both phase 2 and 3 RCTs, only the phase 3 RCT was included for that intervention. Moreover, we performed a search for abstracts presented at main relevant hepatological conference proceedings (EASL, European Association for the Study of the Liver and AASLD, American Association for the Study of Liver Diseases) from 2017 to 2021. Abstracts that had been published subsequently as a full-text study were excluded if a full-text study already was included in the meta-analysis. Two independent investigators (GP, CiC) reviewed the titles and abstracts of all papers identified by the search. Full-text manuscripts were retrieved for the included abstracts and were subsequently screened for eligibility by two independent investigators (GP, CiC). Discrepancies among reviewers were not frequent (interobserver variation <10%) and were resolved by discussion.

      2.2 Eligibility criteria

      Studies were included in the meta-analysis if they met the following criteria: 1) they were randomized phase 2 or phase 3 trials evaluating pharmacological agents for NASH; 2) they enrolled patients with biopsy-proven NASH; 3) they compared one or more pharmacological agent with placebo or with each other; 4) they reported at least one of the two FDA-based endpoints, [
      ] that are a) resolution of NASH without worsening of fibrosis or b) one or more stage reduction of fibrosis without worsening of NASH); 5) they had a minimum follow-up of 24 weeks.
      Studies were excluded if: 1) they were observational studies; 2) they evaluated only lifestyle modifications; 3) they did not report histological results of follow-up liver biopsy after treatment; 4) they included less than 30 patients.

      2.3 Data extraction

      Study-level variables included the last name of the first author, the publication year, the trial phase, the number of centers (single versus multiple), the duration of follow-up, the names of intervention(s) and their dosing, the number of patients receiving intervention(s) and placebo and the definition of placebo. When different dosing of the same intervention or different combinations of interventions were evaluated in the same RCT, only data on the most effective arm were extracted.
      Patient-level variables included age, gender, diabetes, body weight, body mass index (BMI), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and NAS score.
      Risk of bias was assessed using the Cochrane risk of bias assessment tool in which studies were deemed to be at low, high, or unclear risk [
      • Higgins J.P.
      • Altman D.G.
      • Gotzsche P.C.
      • et al.
      The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
      ]. This tool includes the following domains: random sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting. Only full-text papers were evaluated for the risk of bias.

      2.4 Outcomes

      The number of patients who achieved NASH resolution without worsening of fibrosis and the number of patients who achieved the improvement of one or more stage of fibrosis without worsening of NASH were extracted as main histological outcome measures for intervention and placebo arms of each included trial. The proportion of patients achieving these endpoints was calculated after the exclusion of patients with no follow-up biopsy.

      2.5 Statistical analysis

      First, we performed a conventional meta-analysis of placebo arms of included RCTs. The pooled estimates of the achievement of the two main histological outcomes were obtained using a random-effects model with the generic inverse variance method. The method of moments estimator, proposed by DerSimonian and Laird, was used to assess between-study variance [
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      ]. Heterogeneity was assessed with the Pearson chi-square test and the I2 statistic. Univariate logistic meta-regression analysis was used to examine associations between patient- or study-level covariates and main histological outcomes and to explore and explain the heterogeneity in the placebo rate. Variables with a P value less than 0.10 was considered statistically significant. The amount of heterogeneity in the outcomes explained by risk factors was evaluated with the R2 index.
      Next, we performed a frequentist network meta-analysis of intervention arms. For the two main histological outcomes, odds ratios (OR) and 95% confidence intervals (95% C.I.) were meta-analysed using the DerSimonian and Laird random-effects model [
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      ]. The frequentist approach provides a point estimate from the network along with 95% Confidence Interval (95% C.I.) from the frequency distribution of the estimate. We calculated the relative ranking of the interventions for achieving the main histological outcomes as their P-scores [
      • Rücker G.
      • Schwarzer G.
      Ranking treatments in frequentist network meta-analysis works without resampling methods.
      ]. P-score ranges between 0 when a treatment is certainly the worst, and 1 when a treatment is certainly the best. Univariate logistic meta-regression analysis was used to examine associations between patient- or study-level covariates and main histological outcomes. Finally, P-scores of treatments for the two main histological outcomes were added together to identify the most effective drugs overall. Sensitivity analyses included Bayesian network meta-analysis with relative ranking of interventions calculated as their surface under the cumulative ranking (SUCRA) [
      • Salanti G.
      • Ades A.E.
      • Ioannidis J.P.
      Graphical methods and numerical summaries for presenting results from multiple-treatment meta- analysis: an overview and tutorial.
      ] and Bayesian meta-regression analysis. The Egger regression test was performed to evaluate the asymmetry of the Begg funnel plot and potential publication bias. All analyses were performed with R (R Core Team, 2020).

      2.6 Certainty of evidence

      The GRADE approach was used to rate the certainty of evidence of estimates derived from direct meta-analysis [
      • Guyatt G.H.
      • Oxman A.D.
      • Montori V.
      • Vist G.
      • Kunz R.
      • Brozek J.
      • et al.
      GRADE guidelines: 5. Rating the quality of evidence--publication bias.
      ,
      • Puhan M.A.
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      • Murad M.H.
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      • Singh J.A.
      • Kessels A.G.
      • Guyatt G.H.
      GRADE Working Group
      A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis.
      ]. According to the GRADE approach, direct evidence from RCTs starts at high certainty and can be rated down, based on risk of bias, indirectness, imprecision, inconsistency (or heterogeneity) and/or publication bias, to levels of moderate, low and very low.
      The certainty of evidence (ie, certainty in the estimates) was evaluated using the Confidence in Network Meta-Analysis (CINeMA) approach [
      • Nikolakopoulou A.
      • Higgins J.P.T.
      • Papakonstantinou T.
      • et al.
      CINeMA: an approach for assessing confidence in the results of a network meta-analysis.
      ]. CINeMA approach includes the following six domains: within-study bias (i.e. the impact of risk of bias in the included studies), reporting bias (i.e. publication and other reporting bias), indirectness, imprecision, heterogeneity and incoherence. The reviewer's input is required at the study level for within-study bias and indirectness. After the application of the user-defined rules, judgments for each domain are made as: no concerns, some concerns, or major concerns. Judgments across domains are summarised to obtain four levels of certainty for each relative treatment effect: very low, low, moderate or high certainty of evidence [
      • Nikolakopoulou A.
      • Higgins J.P.T.
      • Papakonstantinou T.
      • et al.
      CINeMA: an approach for assessing confidence in the results of a network meta-analysis.
      ].

      3. Results

      3.1 Literature search and study characteristics

      The flow-chart of the study selection process is showed in Fig. S1. Our primary search identified 5108 titles and abstracts. After review of the studies, 15 RCTs (14 full-papers and 1 abstract) [
      • Ratziu V.
      • Sanyal A.
      • Harrison S.A.
      • Wong V.W.
      • Francque S.
      • Goodman Z.
      • Aithal G.P.
      • Kowdley K.V.
      • Seyedkazemi S.
      • Fischer L.
      • Loomba R.
      • Abdelmalek M.F.
      • Tacke F.
      Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study.
      ,
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ,
      • Sanyal A.J.
      • Abdelmalek M.F.
      • Suzuki A.
      • et al.
      No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial.
      ,
      • Loomba R.
      • Sirlin C.B.
      • Ang B.
      • et al.
      Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).
      ,
      • Cusi K.
      • Orsak B.
      • Bril F.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      ,
      • Younossi Z.M.
      • Ratziu V.
      • Loomba R.
      • et al.
      Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.
      ,
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      Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial.
      ,
      • Harrison S.A.
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      Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
      ,
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      A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis.
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      STELLAR-3 and STELLAR-4 Investigators. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials.
      ,
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      • Harrison S.A.
      NN9931-4296 investigators. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      ,
      • Harrison S.A.
      • Neff G.
      • Guy C.D.
      • Bashir M.R.
      • Paredes A.H.
      • Frias J.P.
      • Younes Z.
      • Trotter J.F.
      • Gunn N.T.
      • Moussa S.E.
      • Kohli A.
      • Nelson K.
      • Gottwald M.
      • Chang W.C.G.
      • Yan A.Z.
      • DePaoli A.M.
      • Ling L.
      • Lieu H.D.
      Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis.
      ,
      • Ratziu V.
      • de Guevara L.
      • Safadi R.
      • et al.
      Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.
      ,
      • Francque S.M.
      • Bedossa P.
      • Ratziu V.
      • Anstee Q.M.
      • Bugianesi E.
      • Sanyal A.J.
      • Loomba R.
      • Harrison S.A.
      • Balabanska R.
      • Mateva L.
      • Lanthier N.
      • Alkhouri N.
      • Moreno C.
      • Schattenberg J.M.
      • Stefanova-Petrova D.
      • Vonghia L.
      • Rouzier R.
      • Guillaume M.
      • Hodge A.
      • Romero-Gómez M.
      • Huot-Marchand P.
      • Baudin M.
      • Richard M.P.
      • Abitbol J.L.
      • Broqua P.
      • Junien J.L.
      • Abdelmalek M.F.
      NATIVE study group. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH.
      , ] enrolling 4.499 patients (2.714 patients receiving interventions and 1.785 receiving placebo) fulfilled the inclusion criteria and were selected for meta-analysis. Study-level characteristics of included RCTs are shown in Table S1. Eleven studies [
      • Ratziu V.
      • Sanyal A.
      • Harrison S.A.
      • Wong V.W.
      • Francque S.
      • Goodman Z.
      • Aithal G.P.
      • Kowdley K.V.
      • Seyedkazemi S.
      • Fischer L.
      • Loomba R.
      • Abdelmalek M.F.
      • Tacke F.
      Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study.
      ,
      • Sanyal A.J.
      • Abdelmalek M.F.
      • Suzuki A.
      • et al.
      No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial.
      ,
      • Loomba R.
      • Sirlin C.B.
      • Ang B.
      • et al.
      Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).
      ,
      • Cusi K.
      • Orsak B.
      • Bril F.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      ,
      • Bril F.
      • Biernacki D.M.
      • Kalavalapalli S.
      • Lomonaco R.
      • Subbarayan S.K.
      • Lai J.
      • Tio F.
      • Suman A.
      • Orsak B.K.
      • Hecht J.
      • Cusi K.
      Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial.
      ,
      • Harrison S.A.
      • Bashir M.R.
      • Guy C.D.
      • Zhou R.
      • Moylan C.A.
      • Frias J.P.
      • Alkhouri N.
      • Bansal M.B.
      • Baum S.
      • Neuschwander-Tetri B.A.
      • Taub R.
      • Moussa S.E.
      Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
      ,
      • Harrison S.A.
      • Goodman Z.
      • Jabbar A.
      • Vemulapalli R.
      • Younes Z.H.
      • Freilich B.
      • Sheikh M.Y.
      • Schattenberg J.M.
      • Kayali Z.
      • Zivony A.
      • Sheikh A.
      • Garcia-Samaniego J.
      • Satapathy S.K.
      • Therapondos G.
      • Mena E.
      • Schuppan D.
      • Robinson J.
      • Chan J.L.
      • Hagerty D.T.
      • Sanyal A.J.
      A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis.
      ,
      • Newsome P.N.
      • Buchholtz K.
      • Cusi K.
      • Linder M.
      • Okanoue T.
      • Ratziu V.
      • Sanyal A.J.
      • Sejling A.S.
      • Harrison S.A.
      NN9931-4296 investigators. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      ,
      • Harrison S.A.
      • Neff G.
      • Guy C.D.
      • Bashir M.R.
      • Paredes A.H.
      • Frias J.P.
      • Younes Z.
      • Trotter J.F.
      • Gunn N.T.
      • Moussa S.E.
      • Kohli A.
      • Nelson K.
      • Gottwald M.
      • Chang W.C.G.
      • Yan A.Z.
      • DePaoli A.M.
      • Ling L.
      • Lieu H.D.
      Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis.
      ,
      • Ratziu V.
      • de Guevara L.
      • Safadi R.
      • et al.
      Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.
      ,
      • Francque S.M.
      • Bedossa P.
      • Ratziu V.
      • Anstee Q.M.
      • Bugianesi E.
      • Sanyal A.J.
      • Loomba R.
      • Harrison S.A.
      • Balabanska R.
      • Mateva L.
      • Lanthier N.
      • Alkhouri N.
      • Moreno C.
      • Schattenberg J.M.
      • Stefanova-Petrova D.
      • Vonghia L.
      • Rouzier R.
      • Guillaume M.
      • Hodge A.
      • Romero-Gómez M.
      • Huot-Marchand P.
      • Baudin M.
      • Richard M.P.
      • Abitbol J.L.
      • Broqua P.
      • Junien J.L.
      • Abdelmalek M.F.
      NATIVE study group. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH.
      ] were phase 2 RCTs and all but one [
      • Cusi K.
      • Orsak B.
      • Bril F.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      ] were multicenter RCTs. Only one RCT [
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ] had two active arms (Pioglitazone and Vitamin E). Follow-up duration ranged from 24 [
      • Loomba R.
      • Sirlin C.B.
      • Ang B.
      • et al.
      Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).
      ,
      • Francque S.M.
      • Bedossa P.
      • Ratziu V.
      • Anstee Q.M.
      • Bugianesi E.
      • Sanyal A.J.
      • Loomba R.
      • Harrison S.A.
      • Balabanska R.
      • Mateva L.
      • Lanthier N.
      • Alkhouri N.
      • Moreno C.
      • Schattenberg J.M.
      • Stefanova-Petrova D.
      • Vonghia L.
      • Rouzier R.
      • Guillaume M.
      • Hodge A.
      • Romero-Gómez M.
      • Huot-Marchand P.
      • Baudin M.
      • Richard M.P.
      • Abitbol J.L.
      • Broqua P.
      • Junien J.L.
      • Abdelmalek M.F.
      NATIVE study group. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH.
      ] to 96 weeks [
      • Ratziu V.
      • Sanyal A.
      • Harrison S.A.
      • Wong V.W.
      • Francque S.
      • Goodman Z.
      • Aithal G.P.
      • Kowdley K.V.
      • Seyedkazemi S.
      • Fischer L.
      • Loomba R.
      • Abdelmalek M.F.
      • Tacke F.
      Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study.
      ,
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ].
      Table S2 shows the patient-level characteristics of included RCTs. The mean age ranged from 46.6 [
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ] to 60 years [
      • Bril F.
      • Biernacki D.M.
      • Kalavalapalli S.
      • Lomonaco R.
      • Subbarayan S.K.
      • Lai J.
      • Tio F.
      • Suman A.
      • Orsak B.K.
      • Hecht J.
      • Cusi K.
      Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial.
      ] and from 45.4 [
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ] to 61 years [
      • Harrison S.A.
      • Wong V.W.
      • Okanoue T.
      • Bzowej N.
      • Vuppalanchi R.
      • Younes Z.
      • Kohli A.
      • Sarin S.
      • Caldwell S.H.
      • Alkhouri N.
      • Shiffman M.L.
      • Camargo M.
      • Li G.
      • Kersey K.
      • Jia C.
      • Zhu Y.
      • Djedjos C.S.
      • Subramanian G.M.
      • Myers R.P.
      • Gunn N.
      • Sheikh A.
      • Anstee Q.M.
      • Romero-Gomez M.
      • Trauner M.
      • Goodman Z.
      • Lawitz E.J.
      • Younossi Z.
      STELLAR-3 and STELLAR-4 Investigators. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials.
      ] in the intervention group and placebo group, respectively. One study included only nondiabetic patients [
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ], while one study [
      • Bril F.
      • Biernacki D.M.
      • Kalavalapalli S.
      • Lomonaco R.
      • Subbarayan S.K.
      • Lai J.
      • Tio F.
      • Suman A.
      • Orsak B.K.
      • Hecht J.
      • Cusi K.
      Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial.
      ] included only diabetic patients; in the remaining studies, the percentage of patients with diabetes ranged from 28% [
      • Loomba R.
      • Sirlin C.B.
      • Ang B.
      • et al.
      Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).
      ] to 76% [
      • Harrison S.A.
      • Wong V.W.
      • Okanoue T.
      • Bzowej N.
      • Vuppalanchi R.
      • Younes Z.
      • Kohli A.
      • Sarin S.
      • Caldwell S.H.
      • Alkhouri N.
      • Shiffman M.L.
      • Camargo M.
      • Li G.
      • Kersey K.
      • Jia C.
      • Zhu Y.
      • Djedjos C.S.
      • Subramanian G.M.
      • Myers R.P.
      • Gunn N.
      • Sheikh A.
      • Anstee Q.M.
      • Romero-Gomez M.
      • Trauner M.
      • Goodman Z.
      • Lawitz E.J.
      • Younossi Z.
      STELLAR-3 and STELLAR-4 Investigators. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials.
      ] for interventions and from 28% [
      • Loomba R.
      • Sirlin C.B.
      • Ang B.
      • et al.
      Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).
      ] to 78% [
      • Harrison S.A.
      • Wong V.W.
      • Okanoue T.
      • Bzowej N.
      • Vuppalanchi R.
      • Younes Z.
      • Kohli A.
      • Sarin S.
      • Caldwell S.H.
      • Alkhouri N.
      • Shiffman M.L.
      • Camargo M.
      • Li G.
      • Kersey K.
      • Jia C.
      • Zhu Y.
      • Djedjos C.S.
      • Subramanian G.M.
      • Myers R.P.
      • Gunn N.
      • Sheikh A.
      • Anstee Q.M.
      • Romero-Gomez M.
      • Trauner M.
      • Goodman Z.
      • Lawitz E.J.
      • Younossi Z.
      STELLAR-3 and STELLAR-4 Investigators. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials.
      ] for placebo. Mean baseline BMI ranged from 29.5 [
      • Harrison S.A.
      • Bashir M.R.
      • Guy C.D.
      • Zhou R.
      • Moylan C.A.
      • Frias J.P.
      • Alkhouri N.
      • Bansal M.B.
      • Baum S.
      • Neuschwander-Tetri B.A.
      • Taub R.
      • Moussa S.E.
      Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
      ] to 35.8 kg/m2 [
      • Younossi Z.M.
      • Ratziu V.
      • Loomba R.
      • et al.
      Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.
      ,
      • Harrison S.A.
      • Wong V.W.
      • Okanoue T.
      • Bzowej N.
      • Vuppalanchi R.
      • Younes Z.
      • Kohli A.
      • Sarin S.
      • Caldwell S.H.
      • Alkhouri N.
      • Shiffman M.L.
      • Camargo M.
      • Li G.
      • Kersey K.
      • Jia C.
      • Zhu Y.
      • Djedjos C.S.
      • Subramanian G.M.
      • Myers R.P.
      • Gunn N.
      • Sheikh A.
      • Anstee Q.M.
      • Romero-Gomez M.
      • Trauner M.
      • Goodman Z.
      • Lawitz E.J.
      • Younossi Z.
      STELLAR-3 and STELLAR-4 Investigators. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials.
      ] for interventions and from 32.2 [
      • Harrison S.A.
      • Bashir M.R.
      • Guy C.D.
      • Zhou R.
      • Moylan C.A.
      • Frias J.P.
      • Alkhouri N.
      • Bansal M.B.
      • Baum S.
      • Neuschwander-Tetri B.A.
      • Taub R.
      • Moussa S.E.
      Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
      ] to 36.8 kg/m2 [
      • Harrison S.A.
      • Wong V.W.
      • Okanoue T.
      • Bzowej N.
      • Vuppalanchi R.
      • Younes Z.
      • Kohli A.
      • Sarin S.
      • Caldwell S.H.
      • Alkhouri N.
      • Shiffman M.L.
      • Camargo M.
      • Li G.
      • Kersey K.
      • Jia C.
      • Zhu Y.
      • Djedjos C.S.
      • Subramanian G.M.
      • Myers R.P.
      • Gunn N.
      • Sheikh A.
      • Anstee Q.M.
      • Romero-Gomez M.
      • Trauner M.
      • Goodman Z.
      • Lawitz E.J.
      • Younossi Z.
      STELLAR-3 and STELLAR-4 Investigators. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials.
      ] for placebo. Mean baseline ALT levels ranged from 40 [
      • Bril F.
      • Biernacki D.M.
      • Kalavalapalli S.
      • Lomonaco R.
      • Subbarayan S.K.
      • Lai J.
      • Tio F.
      • Suman A.
      • Orsak B.K.
      • Hecht J.
      • Cusi K.
      Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial.
      ] to 86 IU/mL [
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ] for interventions and from 44 [
      • Harrison S.A.
      • Wong V.W.
      • Okanoue T.
      • Bzowej N.
      • Vuppalanchi R.
      • Younes Z.
      • Kohli A.
      • Sarin S.
      • Caldwell S.H.
      • Alkhouri N.
      • Shiffman M.L.
      • Camargo M.
      • Li G.
      • Kersey K.
      • Jia C.
      • Zhu Y.
      • Djedjos C.S.
      • Subramanian G.M.
      • Myers R.P.
      • Gunn N.
      • Sheikh A.
      • Anstee Q.M.
      • Romero-Gomez M.
      • Trauner M.
      • Goodman Z.
      • Lawitz E.J.
      • Younossi Z.
      STELLAR-3 and STELLAR-4 Investigators. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials.
      ] to 81 IU/mL [
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ] for placebo. Mean baseline AST levels ranged from 32 [
      • Bril F.
      • Biernacki D.M.
      • Kalavalapalli S.
      • Lomonaco R.
      • Subbarayan S.K.
      • Lai J.
      • Tio F.
      • Suman A.
      • Orsak B.K.
      • Hecht J.
      • Cusi K.
      Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial.
      ] to 59 IU/mL [
      • Sanyal A.J.
      • Abdelmalek M.F.
      • Suzuki A.
      • et al.
      No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial.
      ] for interventions and from 32 [
      • Loomba R.
      • Sirlin C.B.
      • Ang B.
      • et al.
      Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).
      ] to 59 IU/mL [
      • Younossi Z.M.
      • Ratziu V.
      • Loomba R.
      • et al.
      Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.
      ] for placebo. The mean baseline NAS ranged from 3.7 [
      • Bril F.
      • Biernacki D.M.
      • Kalavalapalli S.
      • Lomonaco R.
      • Subbarayan S.K.
      • Lai J.
      • Tio F.
      • Suman A.
      • Orsak B.K.
      • Hecht J.
      • Cusi K.
      Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial.
      ] to 5.7 [
      • Harrison S.A.
      • Neff G.
      • Guy C.D.
      • Bashir M.R.
      • Paredes A.H.
      • Frias J.P.
      • Younes Z.
      • Trotter J.F.
      • Gunn N.T.
      • Moussa S.E.
      • Kohli A.
      • Nelson K.
      • Gottwald M.
      • Chang W.C.G.
      • Yan A.Z.
      • DePaoli A.M.
      • Ling L.
      • Lieu H.D.
      Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis.
      ] for interventions and from 4.2 [
      • Bril F.
      • Biernacki D.M.
      • Kalavalapalli S.
      • Lomonaco R.
      • Subbarayan S.K.
      • Lai J.
      • Tio F.
      • Suman A.
      • Orsak B.K.
      • Hecht J.
      • Cusi K.
      Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial.
      ] to 5.5 [
      • Harrison S.A.
      • Goodman Z.
      • Jabbar A.
      • Vemulapalli R.
      • Younes Z.H.
      • Freilich B.
      • Sheikh M.Y.
      • Schattenberg J.M.
      • Kayali Z.
      • Zivony A.
      • Sheikh A.
      • Garcia-Samaniego J.
      • Satapathy S.K.
      • Therapondos G.
      • Mena E.
      • Schuppan D.
      • Robinson J.
      • Chan J.L.
      • Hagerty D.T.
      • Sanyal A.J.
      A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis.
      ] for placebo.
      Table S3 reports the risk of bias assessment for the included studies, showing an overall low risk of bias.

      3.2 Meta-analysis of placebo arms, response rate in NASH patients

      The pooled estimate for the rate of NASH resolution without worsening of fibrosis (that was available in 15 RCTs [
      • Ratziu V.
      • Sanyal A.
      • Harrison S.A.
      • Wong V.W.
      • Francque S.
      • Goodman Z.
      • Aithal G.P.
      • Kowdley K.V.
      • Seyedkazemi S.
      • Fischer L.
      • Loomba R.
      • Abdelmalek M.F.
      • Tacke F.
      Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study.
      ,
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ,
      • Sanyal A.J.
      • Abdelmalek M.F.
      • Suzuki A.
      • et al.
      No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial.
      ,
      • Loomba R.
      • Sirlin C.B.
      • Ang B.
      • et al.
      Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).
      ,
      • Cusi K.
      • Orsak B.
      • Bril F.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      ,
      • Younossi Z.M.
      • Ratziu V.
      • Loomba R.
      • et al.
      Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.
      ,
      • Bril F.
      • Biernacki D.M.
      • Kalavalapalli S.
      • Lomonaco R.
      • Subbarayan S.K.
      • Lai J.
      • Tio F.
      • Suman A.
      • Orsak B.K.
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      Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial.
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      Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
      ,
      • Harrison S.A.
      • Goodman Z.
      • Jabbar A.
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      • Younes Z.H.
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      • Mena E.
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      • Robinson J.
      • Chan J.L.
      • Hagerty D.T.
      • Sanyal A.J.
      A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis.
      ,
      • Harrison S.A.
      • Wong V.W.
      • Okanoue T.
      • Bzowej N.
      • Vuppalanchi R.
      • Younes Z.
      • Kohli A.
      • Sarin S.
      • Caldwell S.H.
      • Alkhouri N.
      • Shiffman M.L.
      • Camargo M.
      • Li G.
      • Kersey K.
      • Jia C.
      • Zhu Y.
      • Djedjos C.S.
      • Subramanian G.M.
      • Myers R.P.
      • Gunn N.
      • Sheikh A.
      • Anstee Q.M.
      • Romero-Gomez M.
      • Trauner M.
      • Goodman Z.
      • Lawitz E.J.
      • Younossi Z.
      STELLAR-3 and STELLAR-4 Investigators. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials.
      ,
      • Newsome P.N.
      • Buchholtz K.
      • Cusi K.
      • Linder M.
      • Okanoue T.
      • Ratziu V.
      • Sanyal A.J.
      • Sejling A.S.
      • Harrison S.A.
      NN9931-4296 investigators. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      ,
      • Harrison S.A.
      • Neff G.
      • Guy C.D.
      • Bashir M.R.
      • Paredes A.H.
      • Frias J.P.
      • Younes Z.
      • Trotter J.F.
      • Gunn N.T.
      • Moussa S.E.
      • Kohli A.
      • Nelson K.
      • Gottwald M.
      • Chang W.C.G.
      • Yan A.Z.
      • DePaoli A.M.
      • Ling L.
      • Lieu H.D.
      Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis.
      ,
      • Ratziu V.
      • de Guevara L.
      • Safadi R.
      • et al.
      Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.
      ,
      • Francque S.M.
      • Bedossa P.
      • Ratziu V.
      • Anstee Q.M.
      • Bugianesi E.
      • Sanyal A.J.
      • Loomba R.
      • Harrison S.A.
      • Balabanska R.
      • Mateva L.
      • Lanthier N.
      • Alkhouri N.
      • Moreno C.
      • Schattenberg J.M.
      • Stefanova-Petrova D.
      • Vonghia L.
      • Rouzier R.
      • Guillaume M.
      • Hodge A.
      • Romero-Gómez M.
      • Huot-Marchand P.
      • Baudin M.
      • Richard M.P.
      • Abitbol J.L.
      • Broqua P.
      • Junien J.L.
      • Abdelmalek M.F.
      NATIVE study group. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH.
      , ] including 1610 patients) was 17% (95% C.I. 12%–23%, I2 = 86%, p < 0.01), ranging from 5% [
      • Ratziu V.
      • de Guevara L.
      • Safadi R.
      • et al.
      Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.
      ] to 36% [
      • Sanyal A.J.
      • Abdelmalek M.F.
      • Suzuki A.
      • et al.
      No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial.
      ] (Fig. 1A). Among the variables assessed by univariate meta-regression analysis, trial phase 3 and age were significantly associated with a lower placebo rate, accounting for 47% and 39% of the overall heterogeneity, respectively (Table 1).
      Fig. 1
      Figure 1(A) Pooled estimate of the rate of NASH resolution without worsening of fibrosis. (B) Pooled estimate of the rate of ≥1 stage reduction of fibrosis without worsening of NASH.
      Table 1Predictors of histological outcomes (NASH resolution without worsening of fibrosis and ≥1 stage reduction of fibrosis without worsening of NASH) in placebo arms by univariate meta-regression.
      Studies (n)Patients (n)β95% CIp-valueR2
      NASH resolution without worsening of fibrosis
      Study year (from oldest to most recent)151610−0.10−0.20; 0.010.06514.2%
      Phase 3 (vs phase 2)151610−1.06−1.81; −0.320.00846.7%
      Age151610−0.11−0.19; −0.030.01139.0%
      ≥1 stage reduction of fibrosis without worsening of NASH
      Phase 3 (vs phase 2)7941−0.74−1.47; −0.020.04658.6%
      AST levels7941−0.07−0.15; −0.010.04459.0%
      NASH, non-alcoholic steatohepatitis. 95% C.I., 95% Confidence interval.
      The pooled estimate for the rate of ≥1 stage reduction of fibrosis without worsening of NASH (that was available in 7 RCTs [
      • Younossi Z.M.
      • Ratziu V.
      • Loomba R.
      • et al.
      Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.
      ,
      • Harrison S.A.
      • Goodman Z.
      • Jabbar A.
      • Vemulapalli R.
      • Younes Z.H.
      • Freilich B.
      • Sheikh M.Y.
      • Schattenberg J.M.
      • Kayali Z.
      • Zivony A.
      • Sheikh A.
      • Garcia-Samaniego J.
      • Satapathy S.K.
      • Therapondos G.
      • Mena E.
      • Schuppan D.
      • Robinson J.
      • Chan J.L.
      • Hagerty D.T.
      • Sanyal A.J.
      A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis.
      ,
      • Harrison S.A.
      • Wong V.W.
      • Okanoue T.
      • Bzowej N.
      • Vuppalanchi R.
      • Younes Z.
      • Kohli A.
      • Sarin S.
      • Caldwell S.H.
      • Alkhouri N.
      • Shiffman M.L.
      • Camargo M.
      • Li G.
      • Kersey K.
      • Jia C.
      • Zhu Y.
      • Djedjos C.S.
      • Subramanian G.M.
      • Myers R.P.
      • Gunn N.
      • Sheikh A.
      • Anstee Q.M.
      • Romero-Gomez M.
      • Trauner M.
      • Goodman Z.
      • Lawitz E.J.
      • Younossi Z.
      STELLAR-3 and STELLAR-4 Investigators. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials.
      ,
      • Newsome P.N.
      • Buchholtz K.
      • Cusi K.
      • Linder M.
      • Okanoue T.
      • Ratziu V.
      • Sanyal A.J.
      • Sejling A.S.
      • Harrison S.A.
      NN9931-4296 investigators. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      ,
      • Harrison S.A.
      • Neff G.
      • Guy C.D.
      • Bashir M.R.
      • Paredes A.H.
      • Frias J.P.
      • Younes Z.
      • Trotter J.F.
      • Gunn N.T.
      • Moussa S.E.
      • Kohli A.
      • Nelson K.
      • Gottwald M.
      • Chang W.C.G.
      • Yan A.Z.
      • DePaoli A.M.
      • Ling L.
      • Lieu H.D.
      Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis.
      ,
      • Ratziu V.
      • de Guevara L.
      • Safadi R.
      • et al.
      Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.
      ,
      • Francque S.M.
      • Bedossa P.
      • Ratziu V.
      • Anstee Q.M.
      • Bugianesi E.
      • Sanyal A.J.
      • Loomba R.
      • Harrison S.A.
      • Balabanska R.
      • Mateva L.
      • Lanthier N.
      • Alkhouri N.
      • Moreno C.
      • Schattenberg J.M.
      • Stefanova-Petrova D.
      • Vonghia L.
      • Rouzier R.
      • Guillaume M.
      • Hodge A.
      • Romero-Gómez M.
      • Huot-Marchand P.
      • Baudin M.
      • Richard M.P.
      • Abitbol J.L.
      • Broqua P.
      • Junien J.L.
      • Abdelmalek M.F.
      NATIVE study group. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH.
      ] including 941 patients) was 21% (95% C.I. 13%–31%, I2 = 84%, p < 0.01), ranging from 12% [
      • Younossi Z.M.
      • Ratziu V.
      • Loomba R.
      • et al.
      Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.
      ] to 39% [
      • Francque S.M.
      • Bedossa P.
      • Ratziu V.
      • Anstee Q.M.
      • Bugianesi E.
      • Sanyal A.J.
      • Loomba R.
      • Harrison S.A.
      • Balabanska R.
      • Mateva L.
      • Lanthier N.
      • Alkhouri N.
      • Moreno C.
      • Schattenberg J.M.
      • Stefanova-Petrova D.
      • Vonghia L.
      • Rouzier R.
      • Guillaume M.
      • Hodge A.
      • Romero-Gómez M.
      • Huot-Marchand P.
      • Baudin M.
      • Richard M.P.
      • Abitbol J.L.
      • Broqua P.
      • Junien J.L.
      • Abdelmalek M.F.
      NATIVE study group. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH.
      ] (Fig. 1B). Univariate logistic meta-regression analysis was performed to identify potential sources of heterogeneity among studies. Among the variables assessed, trial phase 3 and AST levels was significantly associated with a lower placebo rate, accounting for 58% and 59% of the overall heterogeneity, respectively (Table 1).

      3.3 Network meta-analysis of NASH resolution without worsening of fibrosis

      Sixteen interventions from 15 RCTs were evaluated for this outcome (Fig. 2). Compared to placebo, Semaglutide (OR 6.89 42%, 95% C.I. 2.90–16.35), Pioglitazone 45 mg (OR 6.44, 95% C.I. 2.59–16.06), Pioglitazone plus Vitamin E (OR 5.10, 95% C.I. 1.70–15.29), Vitamin E (OR 3.24, 95% C.I. 1.64–6.42), Lanifibranor (OR 3.11, 95% C.I. 1.58–6.10) and Pioglitazone 30 mg (OR 2.63, 95% C.I. 1.30-5-32) were significantly better than placebo (Fig. 3). Other interventions did not show superiority against placebo. According to P-score, Semaglutide (P-score 0.906), Pioglitazone 45 mg (P-score 0.890) and Pioglitazone plus Vitamin E (P-score 0.826) had the highest probability of being ranked the most effective intervention. Conversely, EPA-E (P-score 0.186), Emricasan (P-score 0.119) and Selonsertib (P-score 0.071) had the lowest probability of being ranked the most effective intervention. Heterogeneity evaluated by I2 was 0% (p = 0.99). Univariate meta-regression analysis did not find any variables significantly associated with this outcome. In the sensitivity analysis, Bayesian network meta-analysis with SUCRA ranking and Bayesian meta-regression analysis showed similar results (Figs. S2 and S3).
      Fig. 2
      Figure 2Network meta-analysis of comparisons between interventions and placebo for NASH resolution without worsening of fibrosis. Width of the lines is proportional to the number of randomly assigned participants.
      Fig. 3
      Figure 3Forest plot of network meta-analysis of interventions compared to placebo ranking from best to worst based on P-score for NASH resolution without worsening of fibrosis.

      3.4 Network meta-analysis of ≥1 stage reduction of fibrosis without worsening of NASH

      Seven interventions were evaluated for this outcome (Fig. 4). Compared to placebo, Lanifibranor (OR 2.57, 95% C.I. 1.12–5.88) and Obeticholic Acid (OR 2.22, 95% C.I. 1.14–4.32) were significantly better than placebo (Fig. 5). Other interventions did not show superiority against placebo. According to P-score, Aldafermin (P-score 0.776), Lanifibranor (P-score 0.773) and Obeticholic Acid (P-score 0.711) had the highest probability of being ranked the most effective intervention, while Selonsertib (P-score 0.243) and Emricasan (P-score 0.066) had the lowest probability of being ranked the most effective intervention. Heterogeneity evaluated by I2 was 49.3% (p = 0.16). Univariate meta-regression analysis did not find any variables significantly associated with this outcome. In the sensitivity analysis, Bayesian network meta-analysis with SUCRA ranking and Bayesian meta-regression analysis showed similar results (Figs. S4 and S5).
      Fig. 4
      Figure 4Network meta-analysis of comparisons between interventions and placebo for ≥1 stage reduction of fibrosis without worsening of NASH. Width of the lines is proportional to the number of randomly assigned participants.
      Fig. 5
      Figure 5Forest plot of network meta-analysis of interventions compared to placebo ranking from best to worst based on P-score for ≥1 stage reduction of fibrosis without worsening of NASH.

      3.5 Publication bias and certainty of evidence

      Publication bias was not evaluable because only a single study was included for each drug comparison.
      For the outcome of NASH resolution without worsening of fibrosis, Pioglitazone (both 30 and 45 mg), Vitamin E, Pioglitazone plus Vitamin E, Semaglutide and Lanifibranor had a better outcome when compared to Placebo, Cenicriviroc, Emricasan, Selonsertib, which was supported by high certainty of evidence. Pioglitazone 45 mg, Vitamin E, Pioglitazone plus Vitamin E, Semaglutide and Lanifibranor had a better outcome when compared to Elafibranor, with high certainty of evidence. Pioglitazone 45 mg and Semaglutide had a better outcome when compared with Obeticholic acid, Ezetimibe and Resmetiron, with high certainty of evidence. Pioglitazone 30 mg and Vitamin E had a better outcome when compared to EPA-E, with high certainty of evidence. Aramchol had a better outcome when compared with Emricasan and Selonsertib, with high certainty of evidence. Aldafermin, Elafibranor and Obeticholic acid had a better outcome when compared with Selonsertib, with high certainty of evidence. Other comparisons were supported by moderate to very low certainty of evidence, because of major concerns for within-study bias and imprecision (Supplementary Table S4).
      For the outcome of ≥1 stage reduction of fibrosis without worsening of NASH, Obeticholic acid and Lanifibranor had a better outcome when compared to Placebo and Selonsertib, which was supported by high certainty of evidence. Obeticholic acid, Lanifibranor and Aldafermin had a better outcome when compared to Emricasan, with high certainty of evidence. Other comparisons were supported by low to very low certainty of evidence because of major concerns for imprecision (Supplementary Table S5).

      4. Discussion

      In this meta-analysis, collecting data of about 4500 patients enrolled in 15 placebo-RCTs on NASH drug treatment evaluating surrogate histological outcomes established by FDA for phase 3 trials, we found that the pooled rate of spontaneous NASH resolution without fibrosis worsening was 17% -ranging from 5% to 36%-, and the pooled rate of spontaneous ≥1 stage reduction of fibrosis without worsening of NASH was 21% -ranging from 12% to 39%. Meta-regression analysis showed older age and higher baseline AST levels were risk factors for more rapid histological progression, and that phase 2 vs phase 3 trials was an at lower risk setting. Moreover, network meta-analysis showed that Semaglutide and pioglitazone with/without Vitamin E had the highest probability of being the most effective therapeutic regimens for achieving NASH resolution without worsening of fibrosis, while aldafermin, lanifibranor and obethicolic acid had the highest probability of achieving ≥1 stage reduction of fibrosis without worsening of NASH.
      The overall novelty of our study lies in the evaluation of hard composite histological endpoints - NASH resolution without worsening of fibrosis or ≥1 stage reduction of fibrosis without worsening of NASH - designed by FDA for the conditional approval of drugs tested in phase 3 RCTs for the treatment of patients with noncirrhotic NASH. Although previous published meta-analyses [
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      The association between phase 3 RCTs and lower placebo-response compared to phase 2 RCTs could result from the higher sample size of phase 3 RCTs leading to lower heterogeneity. A recent meta-analysis reported lower sample size as a factor significantly affecting mean change in magnetic resonance spectroscopy-intrahepatic triglyceride content in NAFLD patients receiving placebo [
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      ], showing that normal AST or ALT levels do not exclude the presence of significant histological abnormalities, it should be underlined that all these studies had a cross-sectional design. By contrast, our meta-regression analysis showed that high baseline AST levels were significantly associated with a lower probability of achieving a histological improvement at a second follow-up biopsy. Indeed, the proven efficacy of diet and physical activity in the improvement of NASH and fibrosis [
      • Vilar-Gomez E.
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      ] may explain the response of placebo when lifestyle modifications were suggested. On the other side, the Hawthorne effect may also play a role to explain placebo rates in the absence of explicit lifestyle management in the trial design. The awareness of being observed may lead patients in placebo arms to modify their behavior with a progressive improvement of their histological features. From a clinical point of view, our meta-analysis can be helpful to better interpret the results of the effectiveness of pharmacological interventions and to properly design RCTs on NASH, better stratifying the baseline risk for liver disease progression.
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      ] may suggest that NASH treatment could require targeting multiple pathways with different mechanisms of action, these considerations shedding light on the potential utility of multitargeted combination drugs. In fact, single drug therapy, even if targeting multiple pathogenic pathways, seems not enough effective on clinical relevant improvement of histological liver injury. Consistently, preliminary small studies searched for comparison of combination versus monotherapy in patients with NASH and advanced liver fibrosis [
      • Loomba R.
      • et al.
      Safety and efficacy of combination therapies including cilofexor/firsocostat in patients with bridging fibrosis and cirrhosis due to NASH: results of the Phase 2b ATLAS trial [accepted for oral presentation].
      ]. All in all, we suggest that the design of future RCTs should explore the use of combination therapies for a successful treatment of NASH, for example a combination of GLP-1 agonists plus FXR/FGF19 agonists, or GLP-1 agonists in combination with panPPAR agonists. Semaglutide is a promising pharmacological intervention acting as GLP-1 receptor agonists given beneficial indirect effects on insulin resistance and body weight and given direct effects on lipotoxicity and liver inflammation [
      • Newsome P.N.
      • Buchholtz K.
      • Cusi K.
      • Linder M.
      • Okanoue T.
      • Ratziu V.
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      NN9931-4296 investigators. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      ,
      • Mantovani A.
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      • Beatrice G.
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      • Lonardo A.
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      Glucagon-like peptide-1 receptor agonists for treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: an updated meta-analysis of randomized controlled trials.
      ]. Although our analysis showed that semaglutide was the most effective drug to achieve NASH resolution, we did not confirm a similar results for fibrosis improvement. This could be related to the short follow-up of RCT that evaluated semaglutide. Further, larger scale RCTs with a longer follow-up are needed to substantiate the long-term efficacy of semaglutide on fibrosis improvement. Pioglitazone regulates insulin sensitivity by the activation of peroxisome proliferator-activated receptor (PPAR)-γ, that modulates the transcription of genes involved in lipid metabolism and inducing mitochondrial beta-oxidation [
      • Cusi K.
      • Orsak B.
      • Bril F.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      ,
      • Pennisi G.
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      • Spatola F.
      • Dallio M.
      • Federico A.
      • Petta S.
      Pharmacological therapy of non-alcoholic fatty liver disease: what drugs are available now and future perspectives.
      ]. The addition of Vitamin E enhances antioxidant effect from lipid peroxidation and oxygen-free radicals to prevent the cellular structure integrity [
      • Sanyal A.J.
      • Chalasani N.
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      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ,
      • Cusi K.
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      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      ]. Aldafermin is an engineered, non-tumorigenic analog of the human fibroblast growth factor 19 (FGF19) that leads to reduction in liver steatosis and improvement in insulin sensitivity [
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      ]. Lanifibranor acts as agonist in a well-balanced way on the three PPAR isoforms, better than single or dual agonism, resulting in simultaneous improvement of insulin sensitivity and inflammation; on the other hand, the multitargerted mechanism of action likely gives a protective effect on fibrogenesis [
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      ,
      • Pennisi G.
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      • Spatola F.
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      Pharmacological therapy of non-alcoholic fatty liver disease: what drugs are available now and future perspectives.
      ]. Obeticholic acid is a selective and potent agonist of farnesoid X receptor agonist, resulting in improvement of insulin sensitivity and decrease of hepatic lipid synthesis, as well as able it is able to modulate gut barrier integrity and to prompt an anti-inflammatory and antifibrotic effect [
      • Younossi Z.M.
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      • et al.
      Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.
      ].
      This meta-analysis has some limitations. First, it was performed using aggregate data, therefore our summary results describe only between-study, not between-patient differences because they reflect group averages rather than individual data. Only an individual patient data meta-analysis can provide a more detailed treatment comparison in order to overcome the disease heterogeneity, finally implementing a personalized approach in NAFLD patients. Second, histological endpoints recommended by FDA for conditional approval were assessed as primary outcomes of our analysis. However, the surrogacy of these histological endpoints with clinical outcomes remains to be established. Third, limitation concerns about the intrinsic heterogeneity in meta-analysis and meta-regression. Differences in study design among trials (number of subjects and duration of RCTs, evolving definition of NASH resolution) and in outcome assessment, demographic and clinical features of patients enrolled, and the type of pharmacological interventions may limit the comparability of trials. Looking at the network meta-analysis, number of studies per comparisons and the network meta-analysis configuration may affect estimates of ranking probabilities [
      • Kibret T.
      • Richer D.
      • Beyene J.
      Bias in identification of the best treat- ment in a Bayesian network meta-analysis for binary outcome: a simulation study.
      ]. However, our results were confirmed in a sensitivity analysis by using a Bayesian approach. Finally, small sample size of some of the evaluated trials like that on Aldafermin [
      • Harrison S.A.
      • Neff G.
      • Guy C.D.
      • Bashir M.R.
      • Paredes A.H.
      • Frias J.P.
      • Younes Z.
      • Trotter J.F.
      • Gunn N.T.
      • Moussa S.E.
      • Kohli A.
      • Nelson K.
      • Gottwald M.
      • Chang W.C.G.
      • Yan A.Z.
      • DePaoli A.M.
      • Ling L.
      • Lieu H.D.
      Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis.
      ], and the lack of evaluation of the impact of experimental drugs on extrahepatic outcomes, could further affect the interpretation of the results.
      In conclusion, our meta-analyses performed on phase 2 and 3 RCTs assessing the efficacy of pharmacological treatments of NASH, have confirmed the highly heterogeneous spontaneous improvement rate in placebo-treated patients, affected by more advanced phase of study, older age and higher AST level at baseline. Semaglutide and pioglitazone appeared to be more effective on NASH activity while aldafermin, lanifibranor and obeticholic acid performed better on the evolution of fibrosis. In order to increase the efficacy of pharmacological treatments reducing the time needed to reach clinically consistent histological improvements, combination of GLP-1 agonists plus FXR/FGF19 agonists, or GLP-1 agonists in combination with panPPAR agonists should be assessed prospectively.

      Founding

      None.

      Author Contributions

      Grazia Pennisi, Ciro Celsa, Marco Enea Marco Vaccaro, Vito Di Marco, Carlo Ciccioli, Giuseppe Infantino, Claudia La Mantia, Stefanie Parisi, Federica Vernuccio, Antonio Craxì, Calogero Cammà, Salvatore Petta had full control of the study design, data analysis and interpretation and preparation of article. All authors were involved in planning the analysis and drafting the article. The final draft article was approved by all the authors.

      Declaration of competing interest

      None.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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