Insulin sensitisers in the treatment of non-alcoholic fatty liver disease

132 Pages·2011·0.97 MB·English

by  Shyangdan D

Health Technology Assessment 2011; Vol. 15: No.381
Current trials
Health Technology Assessment 2011; Vol. 15: No. 38 ISSCNo n1c3l6u6si-o5n2s78
ISSN 1366-5278
AAcbksntorwacletdgements
Contribution of authors
List of abbreviations
References
Executive summary
ABpapcekngdriox u1n d
SMeaertchho dstsrategy 79
LRiteersautultsre search strategy
CDliniaicganlo esfifsectiveness search strategy
Insulin sensitisers in the treatment of DIimagpnliocasttiicosn ss efoarr crehs setararctehgy
CFousnt deifnfegctiveness search strategy
non-alcoholic fatty liver disease:
ChAapppteern 1d ix 2
a systematic review CIhnatrraocdtuercistitoicns of included studies 83
What is non-alcoholic fatty liver disease?
AWppheant dciax u3s e s non-alcoholic fatty liver disease and its progression?
Quality of included studies 99
Other conditions associated with non-alcoholic fatty liver disease
Prevalence and natural history of non-alcoholic fatty liver disease
D Shyangdan, C Clar, N Ghouri, R Henderson, Appendix 4
Clinical features of non-alcoholic fatty liver disease
Protocol 105
Diagnosis of non-alcoholic fatty liver disease
T Gurung, D Preiss, N Sattar, A Fraser Technology Assessment Report commissioned by the NIHR HTA programme on behalf of
Biochemical picture associated with non-alcoholic fatty liver disease
the National Institute for Health and Clinical Excellence
and N Waugh Predicting non-alcoholic fatty liver disease
Project 09/16
Treatment of non-alcoholic fatty liver disease
Final protocol 23 February 2010
Conclusion
Decision problems
Health Technology Assessment programme
Chapter 2
Clinical effectiveness
Methodology
Results
Discussion
Conclusions
Chapter 3
Diagnosis of non-alcoholic fatty liver disease and its stages
Introduction
Methods
Diagnosis of non-alcoholic fatty liver disease
Diagnosis of non-alcoholic steatohepatitis
Other considerations
Conclusions
Implications for trials and diagnostic research needs
Chapter 4
Review of economics studies
Chapter 5
November 2011
Discussion
10.3310/hta15380
Statement of principal findings
Some issues
A trial in non-alcoholic fatty liver disease/steatosis
A trial in non-alcoholic steatohepatitis
Health Technology Assessment A Health Technology Assessment trial?
NIHR HTA programme
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Insulin sensitisers in the treatment of
non-alcoholic fatty liver disease:
a systematic review
D Shyangdan,1 C Clar,2 N Ghouri,3 R Henderson,4
T Gurung,1 D Preiss,3 N Sattar,3 A Fraser5 and N Waugh1*
1Warwick Evidence, Health Sciences Research Institute, Warwick Medical School,
University of Warwick, Coventry, UK
2Hasenheide 67, Berlin, Germany
3University of Glasgow, Glasgow, UK
4NHS Highland, Inverness, UK
5Aberdeen Royal Infirmary, Aberdeen, UK
*Corresponding author
Declared competing interests of authors: none
Published November 2011
DOI: 10.3310/hta15380
This report should be referenced as follows:
Shyangdan D, Clar C, Ghouri N, Henderson R, Gurung T, Preiss D, et al. Insulin sensitisers in the
treatment of non-alcoholic fatty liver disease: a systematic review. Health Technol Assess 2011;15(38).
Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta
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Clinical Medicine.
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ii
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DOI: 10.3310/hta15380 Health Technology Assessment 2011; Vol. 15: No. 38 iii
Abstract
Insulin sensitisers in the treatment of non-alcoholic fatty liver
disease: a systematic review
D Shyangdan,1 C Clar,2 N Ghouri,3 R Henderson,4 T Gurung,1 D Preiss,3
N Sattar,3 A Fraser5 and N Waugh1*
1Warwick Evidence, Health Sciences Research Unit, Warwick Medical School, University of Warwick,
Coventry, UK
2Hasenheide 67, Berlin, Germany
3University of Glasgow, Glasgow, UK
4NHS Highland, Inverness, UK
5Aberdeen Royal Infirmary, Aberdeen, UK
*Corresponding author
Background: Non-alcoholic fatty liver disease (NAFLD) is closely linked with obesity and
the prevalence of NAFLD is about 17% to 33% in the Western world. There is a strong
association of NAFLD with insulin resistance and, hence, insulin sensitisers have been
tried. This systematic review examined the clinical effectiveness of insulin sensitisers in
patients with NAFLD, to help decide whether or not a trial or trials of the insulin sensitisers
was necessary and also to explore whether or not non-invasive alternatives to liver biopsy
were available that could be used in a large trial of the insulin sensitisers.
Objective: To review the use of insulin sensitisers in the treatment of NAFLD.
Review methods: A systematic review of the clinical effectiveness of metformin,
rosiglitazone and pioglitazone was carried out, including reviews and randomised
controlled trials (RCTs). Databases searched were MEDLINE, 1950 to June 2010; EMBASE,
1980 to June 2010; Science Citation Index Expanded, June 2010; Conference Proceedings
Citation Index – Science June 2010; The Cochrane Library 2005–10. Abstracts were
screened independently by two researchers. A narrative review of diagnostic methods
was conducted.
Results: Clinical effectiveness. We identified 15 RCTs (one available as abstract). Four
papers explored efficacy of pioglitazone, one rosiglitazone, eight metformin; two compared
metformin and rosiglitazone, although one used both metformin and rosiglitazone. The
duration of most trials was between 6 and 12 months. Many trials had a small number of
participants and the quality of the studies was mixed. Pioglitazone improved all parameters
of liver histology. Metformin showed mixed results, with ultrasound changes in two studies
showing some improvement in steatosis, whereas there were no changes in the other two.
Metformin, however, showed no improvement in non-alcoholic steatohepatitis (NASH)
stages. Metformin showed greater reduction in glycosylated haemoglobin (–0.23% to
–1.2% vs –0.2% to –0.7%) and fasting plasma glucose (+0.05 to –3.19 mmol/l vs –0.17
to –1.11 mmol/l) compared with pioglitazone. Metformin led to weight reduction (–4.3 to
–6.7 kg), whereas participants on pioglitazone gained weight (+2.5 to +4.7 kg). Alanine
aminotransferase levels were reduced with both metformin and pioglitazone; however, the
reduction in levels with pioglitazone was not different to that caused by vitamin E. Most
studies suggested that metformin led to a significant reduction in insulin resistance.
© Queen’s Printer and Controller of HMSO 2011. This work was produced by Shyangdan et al. under the terms of a commissioning contract issued by
the Secretary of State for Health.
iv Abstract
Diagnosis. Non-invasive methods of diagnosing NAFLD without liver biopsy, using
combinations of clinical history, laboratory tests and ultrasound, have been explored, but
so far liver biopsy is the only proven method of distinguishing simple steatosis from NASH.
Transient elastography appears useful, but less so in obese individuals. Magnetic
resonance spectroscopy shows promise, but is expensive and not readily available.
Limitations: Mixed quality of trials, with lack of detail as to how some trials were
conducted. Many trials had small numbers of patients.
Conclusions: The main need for drug trials is at the NASH stage. However, at present, any
trial in the more advanced forms of NAFLD would have to use liver biopsy. The highest
priority for research may, therefore, be in the diagnosis of NAFLD, and the differentiation
between steatosis and NASH. The newer agents, the glucagon-like peptide-1 analogues
such as liraglutide, may be more worthy of a trial.
Funding: The National Institute for Health Research Health Technology
Assessment programme.
DOI: 10.3310/hta15380 Health Technology Assessment 2011; Vol. 15: No. 38 v
Contents
List of abbreviations vii
Executive summary ix
1. Introduction 1
What is non-alcoholic fatty liver disease? 1
What causes non-alcoholic fatty liver disease and its progression? 2
Other conditions associated with non-alcoholic fatty liver disease 5
Prevalence and natural history of non-alcoholic fatty liver disease 5
Clinical features of non-alcoholic fatty liver disease 8
Diagnosis of non-alcoholic fatty liver disease 8
Biochemical picture associated with non-alcoholic fatty liver disease 9
Predicting non-alcoholic fatty liver disease 9
Treatment of non-alcoholic fatty liver disease 9
Conclusion 12
Decision problems 12
2. Clinical effectiveness 13
Methodology 13
Results 15
Discussion 48
Conclusions 50
3. Diagnosis of non-alcoholic fatty liver disease and its stages 51
Introduction 51
Methods 51
Diagnosis of non-alcoholic fatty liver disease 52
Diagnosis of non-alcoholic steatohepatitis 53
Other considerations 57
Conclusions 58
Implications for trials and diagnostic research needs 58
4. Review of economics studies 59
5. Discussion 61
Statement of principal findings 61
Some issues 62
A trial in non-alcoholic fatty liver disease/steatosis 62
A trial in non-alcoholic steatohepatitis 63
A Health Technology Assessment trial? 63
Current trials 63
Conclusions 66
Acknowledgements 67
References 69
© Queen’s Printer and Controller of HMSO 2011. This work was produced by Shyangdan et al. under the terms of a commissioning contract issued by
the Secretary of State for Health.
vi Contents
Appendix 1 Search strategy 79
Appendix 2 Characteristics of included studies 83
Appendix 3 Quality of included studies 99
Appendix 4 Protocol 105
Health Technology Assessment programme 111
DOI: 10.3310/hta15380 Health Technology Assessment 2011; Vol. 15: No. 38 vii
List of abbreviations
AISF Italian Association for the Study of the Liver
ALD alcohol-related fatty liver disease
ALT alanine aminotransferase
AST aspartate aminotransferase
AUROC area under receiver operating characteristic curve
BAAT BMI, age, ALT, TG
BAD BMI, age, T2DM
BARD BMI, AST/ALT ratio, T2DM
BARG BMI, age, AST/ALT ratio, HbA or glucose
1c
b.i.d. twice a day
BMI body mass index
CASP Critical Appraisal Skills Programme
CK-18 cytokeratin-18
CRN Clinical Research Network
CT computerised tomography
DBP diastolic blood pressure
DCC Data Coordinating Centre
DURATION Diabetes therapy Utilization: Researching changes in A , weight and other factors
1c
Through Intervention with Exenatide ONce weekly
FBC full blood count
FLD fatty liver disease
FLIRT Fatty Liver Improvement with Rosiglitazone Therapy
FPG fasting plasma glucose
GGT gamma-glutamyl transferase
GLP-1 glucagon-like peptide-1
HAIR hypertension, ALT, insulin resistance
HbA glycosylated haemoglobin
1c
HBV hepatitis B virus
HCC hepatocellular carcinoma
HCV hepatitis C virus
HDL high-density lipoprotein
HOMA–IR homeostatic model assessment–insulin resistance
HTA Health Technology Assessment
IQR interquartile range
ITT intention to treat
IU international unit
LDL low-density lipoprotein
LEAD Liraglutide Effect and Action in Diabetes
LFT liver function test
MRE magnetic resonance elastography
MRI magnetic resonance imaging
MRS magnetic resonance spectroscopy
NAFL non-alcoholic fatty liver
NAFLD non-alcoholic fatty liver disease
NAS NAFLD activity score
NASH non-alcoholic steatohepatitis
NEFA non-esterified fatty acid
NFS NAFLD Fibrosis Score
© Queen’s Printer and Controller of HMSO 2011. This work was produced by Shyangdan et al. under the terms of a commissioning contract issued by
the Secretary of State for Health.
viii List of abbreviations
NGT normal glucose tolerance
NICE National Institute for Health and Clinical Excellence
NIHR National Institute for Health Research
PedsQL Pediatric Quality of Life Inventory
PPAR peroxisome proliferators-activated receptor
QoL quality of life
RCT randomised controlled trial
SBP systolic blood pressure
SD standard deviation
SE standard error
SF-36 Short Form questionnaire-36 items
SIGN Scottish Intercollegiate Guidelines Network
T2DM type 2 diabetes mellitus
TC total cholesterol
TE transient elastography
TG triglyceride
TONIC Treatment of Non-alcoholic Fatty Liver Disease in Children
TZD thiazolidinedione
USG ultrasonography
UDCA ursodeoxycholic acid
All abbreviations that have been used in this report are listed here unless the abbreviation is well
known (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only
in figures/tables/appendices, in which case the abbreviation is defined in the figure legend or in
the notes at the end of the table.