Lifestyle modifications for nonalcohol-related fatty liver disease: a network meta-analysis

Elena Buzzetti, Audrey Linden, Lawrence M.J. Best, Angela M. Madden, Danielle Roberts, Thomas J.G. Chase, Suzanne C. Freeman, Nicola J. Cooper, Alex J. Sutton, Dominic Fritche, Elisabeth Jane Milne, Kathy Wright, Chavdar S. Pavlov, Brian R. Davidson, Emmanuel Tsochatzis, Kurinchi Selvan Gurusamy

    Research output: Contribution to journalReview articlepeer-review

    1 Citation (Scopus)

    Abstract

    Background: The prevalence of nonalcohol-related fatty liver disease (NAFLD) varies between 19% and 33% in different populations. NAFLD decreases life expectancy and increases the risks of liver cirrhosis, hepatocellular carcinoma, and requirement for liver transplantation. There is uncertainty surrounding the relative benefits and harms of various lifestyle interventions for people with NAFLD. Objectives: To assess the comparative benefits and harms of different lifestyle interventions in the treatment of NAFLD through a network meta-analysis, and to generate rankings of the different lifestyle interventions according to their safety and efficacy. Search methods: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, World Health Organization International Clinical Trials Registry Platform, and trials registers until February 2021 to identify randomised clinical trials in people with NAFLD. Selection criteria: We included only randomised clinical trials (irrespective of language, blinding, or status) in people with NAFLD, whatever the method of diagnosis, age, and diabetic status of participants, or presence of non-alcoholic steatohepatitis (NASH). We excluded randomised clinical trials in which participants had previously undergone liver transplantation. Data collection and analysis: We planned to perform a network meta-analysis with OpenBUGS using Bayesian methods and to calculate the differences in treatments using hazard ratios (HRs), odds ratios (ORs), and rate ratios (RaRs) with 95% credible intervals (CrIs) based on an available-participant analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. However, the data were too sparse for the clinical outcomes. We therefore performed only direct comparisons (head-to-head comparisons) with OpenBUGS using Bayesian methods. Main results: We included a total of 59 randomised clinical trials (3631 participants) in the review. All but two trials were at high risk of bias. A total of 33 different interventions, ranging from advice to supervised exercise and special diets, or a combination of these and no additional intervention were compared in these trials. The reference treatment was no active intervention. Twenty-eight trials (1942 participants) were included in one or more comparisons. The follow-up ranged from 1 month to 24 months. The remaining trials did not report any of the outcomes of interest for this review. The follow-up period in the trials that reported clinical outcomes was 2 months to 24 months. During this short follow-up period, clinical events related to NAFLD such as mortality, liver cirrhosis, liver decompensation, liver transplantation, hepatocellular carcinoma, and liver-related mortality were sparse. This is probably because of the very short follow-up periods. It takes a follow-up of 8 years to 28 years to detect differences in mortality between people with NAFLD and the general population. It is therefore unlikely that differences by clinical outcomes will be noted in trials with less than 5 years to 10 years of follow-up. In one trial, one participant developed an adverse event. There were no adverse events in any of the remaining participants in this trial, or in any of the remaining trials, which seemed to be directly related to the intervention. Authors' conclusions: The evidence indicates considerable uncertainty about the effects of the lifestyle interventions compared with no additional intervention (to general public health advice) on any of the clinical outcomes after a short follow-up period of 2 months to 24 months in people with nonalcohol-related fatty liver disease. Accordingly, high-quality randomised clinical trials with adequate follow-up are needed. We propose registry-based randomised clinical trials or cohort multiple randomised clinical trials (a study design in which multiple interventions are trialed within large longitudinal cohorts of participants to gain efficiencies and align trials more closely to standard clinical practice), comparing aerobic exercise and dietary advice versus standard of care (exercise and dietary advice received as part of national health promotion). The reason for the choice of aerobic exercise and dietary advice is the impact of these interventions on indirect outcomes which may translate to clinical benefit. The outcomes in such trials should be mortality, health-related quality of life, decompensated liver cirrhosis, liver transplantation, and resource use measures including costs of intervention and decreased healthcare use after a minimum follow-up of eight years, to find meaningful differences in the clinically important outcomes.

    Original languageEnglish
    Article numberCD013156
    JournalCochrane Database of Systematic Reviews
    Volume2021
    Issue number6
    DOIs
    Publication statusPublished - 11 Jun 2021

    Bibliographical note

    Funding Information:
    Outcomes reported: resolution of fatty liver disease Follow-up (months): 8 Source of funding (quote): "Funding for this study was provided by the China State Sport General Administration (2013B040, 2015B039), the Chinese Nature Science Foundation (NSFC 31571219), and the Shanghai Jiao Tong University Zhiyuan Foundation (CP2014013). Funding to RB was provided by the Sigrid Juselius Foundation, the Instrumentation Research Foundation, the Finnish Medical Foundation, the Paulo Foundation and the Academy of Finland (130557, 270352)." Trial name/trial registry number: ISRCTN 42622771 We tried to contact the authors in December 2020

    Funding Information:
    Source of funding: "We thank the European Foundation for the Study of Diabetes (EFSD) for funding thisstudy [09/H1008/1]." Trial name/trial registry number: not stated We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "this study was funded by a research grant from the Italian Ministry of Health." Trial name/trial registry number: NCTO1798719 We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "Supported by Science and Technology Department of Zhejiang Province of China, No. 2005C24001, No. 2004C30064" Trial name/trial registry number: not stated We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "This work was supported by a grant from the Science and Technology Commission of Shanghai, China (No: 13DZ2260700), Shanghai New Hundred Talents Program (No: XBR2013091), and Shanghai Key Developing Disciplines Program (No: 2015ZB0501)" Trial name/trial registry number: ChiCTR-IOR-16008949 We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "This work was partially supported by Fundación IMSS, A.C." Trial name/trial registry number: not stated We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "This work was supported by RC 2012-2014, Linea 4, C. 32 (D.D.G. n. 110/2014) and “PO Puglia FESR 2007-2013, Asse I, Linea 1.2, Accordo di Programma Quadro in materia di Ricerca Scientifica, intervento “Reti di Laboratori Pubblici di Ricerca”, progetto L.A.I.F.F.—RETE DI LABORATORI PER L’INNOVAZIONE NEL CAMPO DEGLI ALIMENTI FUNZIONALI (codice n. 47)" Trial name/trial registry number: CT02347696 We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "This work was supported by the European Foundation for the Study of Diabetes." Trial name/trial registry number: NCT01834300 We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "This study was partly funded by H2020 under grant no. 634413 for the EPoS projects and by Yakult Europe." Trial name/trial registry number: NCT02366052, NUCES NASH We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no Health-F2-2009-241762, for the project FLIP; the Medical Research Council; the UK National Institute for Health Research Biomedical Research Centre on Ageing and Age-Related Diseases and Diabetes UK." Trial name/trial registry number: not stated We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "AFIP, FAPESP 2008/53069-0 and 2006/00684-3, FAPESP (CEPID/Sleep #9814303-3 S.T) CNPq, CAPES, CENESP, FADA, and UNIFESP-EPM, supported the CEPE-GEO Interdisciplinary Obesity Intervention Program." Trial name/trial registry number: NCT01358773 We tried to contact the authors in December 2020

    Funding Information:
    Outcomes reported: mortality at maximum follow-up, liver transplantation at maximum follow-up, decompensation (number of people), cirrhosis (number of people), resolution of fatty liver disease Follow-up (months): 12 Source of funding (quote): "This study was supported in part by the Nutritional Research Foundation of the United Kingdom, the direct grant of the Chinese University of Hong Kong (ref 2011.1.025) and a grant from the Research Grants Council of the Hong Kong SAR (Project No. SEG CUHK_02)." Trial name/trial registry number: NCT00868933 We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "This study was funded by a faculty development grant from the American College of Gastroenterology. Nina Parikh is affiliated with CareMessage, the text messaging software company that was used in this study." Trial name/trial registry number: NCT03082703 We tried to contact the authors in December 2020

    Funding Information:
    This project was funded by the National Institute for Health Research (NIHR) Systematic Reviews Programme (project number 16/114/17) and was supported by the Complex Reviews Support Unit, also funded by the National Institute for Health Research (project number 14/178/29).

    Funding Information:
    Source of funding (quote): "This study was supported by Food Security Research Center and School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran" Trial name/trial registry number: NCT01419912; IRCT201105282839 N2 We tried to contact the authors in December 2020.

    Funding Information:
    Outcomes reported: resolution of fatty liver disease Follow-up (months): 6 Source of funding (quote): "Funding/support: National Council of Technological and Scientific Development (CNPQ). We thank the Alves de Queiroz Family Fund for Research and CNPq for financial support." Trial name/trial registry number: NCT02427087 We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (No. 2604307, No. 15K15037, No. 14F04009, and No. 16H03255)." Trial name/trial registry number: UMIN000022901 We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "This work was supported by the Shanghai Shenkang Hospital Development Center Appropriate Technology Promotion Project: Promotion and Application of Nondrug Treatment Technology for Nonalcoholic Fatty Liver Disease under Grant [number SHDC12012207] and the Shanghai Health and Family Planning Commission Health Industry Clinical Research Project: “Research on the therapeutic effect of weight management based on wearable devices on nonalcoholic fatty liver disease” under Grant [number 201840164]" Trial name/trial registry number: not stated We tried to contact the authors in March 2021

    Funding Information:
    Source of funding: "This paper was supported by the Khoramshahr Oil Company. The authors would like to thank Javad Salimi, head of the oil factory of Ganjeh, Roudbar, and Aboozar Falahzadeh, head of the oil factory laboratory" Trial name/trial registry number: IRCT201111022709N20 We tried to contact the authors in March 2021

    Funding Information:
    Source of funding (quote): "This study was supported by grants from the Allen Foundation, the New Balance Foundation, and the National Institute of Diabetes and Digestive and Kidney Diseases (K24DK082730 and T32DK07699). Additional support was provided from the National Center for Research Resources (UL1 RR025758) to the Harvard Catalyst Clinical and Translational Science Center at Harvard University." Trial name/trial registry number: NCT00480922 We tried to contact the authors in December 2020

    Funding Information:
    We acknowledge the help of Adam Young, UK, who extracted some data from some studies.?We acknowledge the help and support of the Cochrane Hepato-Biliary Group, Cochrane Central Editorial Unit, and copy editors. The authors would also like to thank the peer reviewers listed below who provided comments to improve the review. We also thank Amanda Brand, researcher at the Centre for Evidence-based Health Care, Stellenbosch University, South Africa and co-ordinator at Cochrane Nutrition, for comments on the review. Peer reviewers of protocol: Somaya Albhaisi, USA; Mario Marasone, Italy; Ludovico Abenavoli, Italy?Peer reviewers of review: Amanda Brand, South Africa (Cochrane Nutrition); Takumi Kawaguchi, Japan; Ludovico Abenavoli, Italy; Mario Masarone, Italy; Theresa Moore (Cochrane Editorial and Methods Department), UK?Contact Editors: Christian Gluud (Co-ordinating Editor of the Hepato-Biliary), Denmark; Rachel Richardson (Associate Editor of the Abdomen and Endocrine Network), UK?Sign-off Editor: Cindy Farquhar (Senior Editor of the Abdomen and Endocrine Network), New Zealand Cochrane Review Group funding acknowledgement: the Danish State is the largest single funder of the Cochrane Hepato-Biliary Group through its investment in the Copenhagen Trial Unit, Centre for Clinical Intervention Research, the Capital Region of Denmark, Rigshospitalet, Copenhagen, Denmark. This project was funded by the National Institute for Health Research (NIHR) Systematic Reviews Programme (project number 16/114/17) and was supported by the Complex Reviews Support Unit, also funded by the National Institute for Health Research (project number 14/178/29). The views and opinions expressed therein are those of the review authors and do not necessarily reflect those of the 16/114/17 or 14/178/29 Programmes, the NIHR, the NHS, or the Department of Health. The views and opinions expressed in this review are those of the authors and do not necessarily reflect those of the Danish State or the Copenhagen Trial Unit.

    Funding Information:
    Source of funding (quote): "Research reported in this publication was supported by the Thrasher Research Fund (TRF13337), the National Institute of Diabetes and Digestive and Kidney Diseases (DK079626), the National Center for Advancing Translational Sciences (1TL1TR001418-01), and the National Institute of General Medical Sciences (NIH T32GM008361)" Trial name/trial registry number: NCT02787668 We tried to contact the authors in March 2021

    Funding Information:
    Source of funding (quote): "No financial support provided" Trial name/trial registry number: IRCT2016071211763N24 We tried to contact the authors in December 2020

    Funding Information:
    Outcomes reported: mortality at maximum follow-up, serious adverse events (number of people), any adverse events (number of people) Follow-up (months): 3 Source of funding (quote): "funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, under grant no. (49/142/1432)" Trial name/trial registry number: not stated We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "The study was sponsored in part by a grant from the Kamut Enterprise of Europe (KEE), Oudenaarde, Belgium" Trial name/trial registry number: not stated We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "this work was supported by the European Union Seventh Framework Programme [grant number F2-2009-241762]; the Medical Research Council [grant numbers G0700718 (to K.H.) and G1100160 (to K.G.H.)]; the National Institute for Health Research [grant numbers NIHR-SRF-2011-04-017 (to M.I.T.)] and Diabetes, U.K. [grant number 08/0003759 (to C.T.)]. Q.M.A. is the recipient of a Clinical Senior Lectureship Award from the Higher Education Funding Council for England (HEFCE). Q.M.A. and C.P.D. are members of the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Programme of the European Union under Grant Agreement 634413." Trial name/trial registry number: ISRCTN78698481 We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "This study was supported by the Isfahan University of Medical Sciences, Isfahan, Iran" Trial name/trial registry number: IRCT2014101811763N17 We tried to contact the authors in March 2021

    Funding Information:
    Outcomes reported: resolution of fatty liver disease Follow-up (months): 16 Source of funding (quote): "The project was funded by a grant from the Health and Medical Research Fund, Food and Health Bureau, Hong Kong SAR Government (Ref. no: 11122981) and the Direct Grant for Research (Ref. no: 2014.1.065)." Trial name/trial registry number: not stated We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "This research has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement Health-F22009-241762 for the Fatty Liver Inhibition of Progression project, The Medical Research Council, Diabetes UK, The Newcastle Centre for Ageing and Vitality, The UK National Institute for Health Research Biomedical Research Centre on Ageing and Age-Related Diseases, and was supported by a Senior Fellowship from the National Institute for Health Research (M.I.T.)." Trial name/trial registry number: ISRCTN16070927 We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "We thanked the following grants for funding the current study including USM short term grant (reference no: 304/PPSP/61313173) and Research University Individual (RUI) grant (reference no: 1001/PPSP/812151)" Trial name/trial registry number: not stated We tried to contact the authors in March 2021

    Funding Information:
    Source of funding (quote): "Fundació La Marató TV3 (Spain) project ref. 201630.10. Instituto de Salud Carlos III through the Fondo de Investigación para la Salud (Projects PI14/00636 and PI17/01827, and CIBEROBN CB12/03/30038, and Proyecto Intramural CIBER OBN18PI03), Health Department of the Government of Navarra (61/2015), and Grant of support to research groups no. 35/2011 and 23/2012 (Balearic Islands Government), which are co-funded by the European Regional Development Fund. Other funding received: EU-COST Action CA16112, and IDISBA Grants (FOLIUM, PRIMUS, SYNERGIA, and LIBERI). Catalina M. Mascaró received an FPU PhD Grant from the Spanish Ministry of Education". Trial name/trial registry number: NCT04442620 We tried to contact the authors in March 2021

    Funding Information:
    Source of funding (quote): "This publication was supported by the Deanship of Scientific Research at Prince Sattam bin Abdulaziz University" Trial name/trial registry number: NCT03774511 We tried to contact the authors in March 2021

    Funding Information:
    Outcomes reported: resolution of fatty liver disease Follow-up (months): 4 Source of funding (quote): "Supported in part by grants to Paolo Moghetti from the University ofVerona and from the Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy. The funding sources had no involvement in the design, execution or analysis of the study." Trial name/trial registry number: NCT01182948 - Subproject of RAED2 study We tried to contact the authors in December 2020

    Funding Information:
    Source of funding (quote): "The study was funded by the National Health and Medical Research Council of Australia and the Lions Medical Research Foundation." Trial name/trial registry number: not stated We tried to contact the authors in December 2020

    Publisher Copyright:
    Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

    ASJC Scopus subject areas

    • Pharmacology (medical)

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