DTIC ADA535258: The Effect of Metformin and Standard Therapy Versus Standard Therapy Alone in Nondiabetic Patients with Insulin Resistance and Nonalcoholic Steatohepatitis (NASH): A Pilot Trial

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Therapeutic Advances in Gastroenterology Original Research
The effect of metformin and standard TherapeuticAdvancesin
Gastroenterology
(2009)2(3)157–163
therapy versus standard therapy alone
DOI:10.1177/
1756283X09105462
in nondiabetic patients with insulin
(cid:2)TheAuthor(s),2009.
Reprintsandpermissions:
http://www.sagepub.co.uk/
resistance and nonalcoholic steatohepatitis journalsPermissions.nav
(NASH): a pilot trial
William W. Shields, K.E. Thompson, G.A. Grice, S.A. Harrison and W.J. Coyle
Abstract: Nonalcoholic steatohepatitis (NASH) is increasing in prevalence and is related to
underlying insulin resistance. The aim of this study was to assess the efficacy of metformin
on the characteristic histopathologic lesions of NASH. This was a 12-month prospective,
randomized, placebo-controlled trial comparing diet and exercise alone to diet, exercise
and metformin in nondiabetic patients with insulin resistance and NASH. Patients were
randomized to either group A or B. Group A received placebo, dietary counseling, recom-
mendations for weight loss and exercise four times per week. Group B received long-acting
metformin 500mg daily (titrated to 1000mg daily) plus dietary counseling, recommendations
for weight loss and exercise four times per week. Histopathology was assessed at 12 months
and biopsies were scored by two pathologists who were blinded to all data. Twenty-three
subjects were screened and 19 were randomized to either group A (n¼10) or group B (n¼9).
Seven of the 10 subjects in group Acompleted the study including repeat liver biopsy while all
patientsingroupBcompletedthestudy.Bodymassindeximprovedinbothgroupsdecreasing
by 1.7kg/m2 in group A and 0.9kg/m2 in group B (not significant, control versus treatment).
Homeostasis model assessment of insulin resistance scores improved in both groups
decreasing by 1.14 in group A and 1.58 in group B (not significant, control versus treatment).
No significant difference in histopathology was seen between groups on follow-up liver
biopsy. Metformin appeared to have little effect in improvement in liver function tests or
liver histology in nondiabetic patients with insulin resistance and NASH. Decrease in BMI Correspondenceto:
through diet and exercise significantly improved HOMA-IR scores, serum WilliamW.Shields
Departmentof
aminotransferases and liver histology. Gastroenterology,Naval
MedicalCenterSanDiego,
SanDiego,CA,USA
Keywords: NASH, insulin resistance, metformin, histopathology william.shields@
med.navy.mil
K.E.Thompson
G.A.Grice
DepartmentofPathology,
NavalMedicalCenter
SanDiego,SanDiego,CA,
Introduction NAFLDthatmayprogresstoend-stageliverdis-
USA
Nonalcoholic fatty liver disease (NAFLD) is an ease,liver-relateddeathandhepatocellularcarci-
S.A.Harrison
increasingly recognized condition of excess fat noma [Sanyal, 2003; Bugianesi et al. 2002; Divisionof
Gastroenterologyand
deposition within the liver [Angulo, 2002]. McCullough, 2002]. The pathologic criteria are
Hepatology,BrookeArmy
NAFLD includes a spectrum of liver pathology now well established and the diagnosis can only MedicalCenter,FortSam
Houston,TX,USA
ranging from bland hepatic steatosis to steato- be made once the absence or limited use of
W.J.Coyle
hepatitis and cirrhosis [Sanyal, 2002]. alcohol is confirmed. The estimated prevalence
Divisionof
Nonalcoholic steatohepatitis (NASH) is an of NAFLD may be as high as one third in the Gastroenterologyand
Hepatology,ScrippsClinic
inflammatory and fibrosing condition of the general population [Browning et al. 2004].
TorreyPines,LaJolla,CA,
liver thought to be an intermediate stage of Bland hepatic steatosis seems to have a relatively USA
http://tag.sagepub.com 157
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4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER
The effect of metformin and standard therapy versus standard therapy
5b. GRANT NUMBER
alone in nondiabetic patients with insulin resistance and nonalcoholic
steatohepatitis (NASH): a pilot trial 5c. PROGRAM ELEMENT NUMBER
6. AUTHOR(S) 5d. PROJECT NUMBER
5e. TASK NUMBER
5f. WORK UNIT NUMBER
7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION
Naval Medical Center,Department of Gastroenterology,San REPORT NUMBER
Diego,CA,92134
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Approved for public release; distribution unlimited
13. SUPPLEMENTARY NOTES
14. ABSTRACT
Nonalcoholic steatohepatitis (NASH) is increasing in prevalence and is related to underlying insulin
resistance. The aim of this study was to assess the efficacy of metformin on the characteristic
histopathologic lesions of NASH. This was a 12-month prospective randomized, placebo-controlled trial
comparing diet and exercise alone to diet, exercise and metformin in nondiabetic patients with insulin
resistance and NASH. Patients were randomized to either group A or B. Group A received placebo, dietary
counseling, recommendations for weight loss and exercise four times per week. Group B received
long-acting metformin 500mg daily (titrated to 1000mg daily) plus dietary counseling, recommendations
for weight loss and exercise four times per week. Histopathology was assessed at 12 months and biopsies
were scored by two pathologists who were blinded to all data. Twenty-three subjects were screened and 19
were randomized to either group A (n?10) or group B (n?9). Seven of the 10 subjects in group A completed
the study including repeat liver biopsy while all patients in group B completed the study. Body mass index
improved in both groups decreasing by 1.7 kg/m2 in group A and 0.9 kg/m2 in group B (not significant,
control versus treatment). Homeostasis model assessment of insulin resistance scores improved in both
groups decreasing by 1.14 in group A and 1.58 in group B (not significant, control versus treatment). No
significant difference in histopathology was seen between groups on follow-up liver biopsy. Metformin
appeared to have little effect in improvement in liver function tests or liver histology in nondiabetic
patients with insulin resistance and NASH. Decrease in BMI through diet and exercise significantly
improved HOMA-IR scores, serum aminotransferases and liver histology.
15. SUBJECT TERMS
16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF 18. NUMBER 19a. NAME OF
ABSTRACT OF PAGES RESPONSIBLE PERSON
a. REPORT b. ABSTRACT c. THIS PAGE Same as 8
unclassified unclassified unclassified Report (SAR)
Standard Form 298 (Rev. 8-98)
Prescribed by ANSI Std Z39-18
Therapeutic Advances in Gastroenterology 2 (3)
benign clinical course whereas up to 20% of Additional inclusion criteria included agegreater
NASH individuals may develop cirrhosis than17years,geographicstabilityfor1yearfrom
[McCullough, 2002]. The metabolic syndrome, study inclusion and an unremarkable serologic
characterized by increased waist circumference, evaluation for chronic liver diseases including
hypertriglyceridemia, reduced high density lipo- viral hepatitis studies, autoimmune studies, anti-
protein (HDL) levels, elevated blood pressure, mitochondrialantibodies,ironindicesand,when
and/or fasting hyperglycemia, is a strong risk deemed appropriate, alpha-1 antitrypsin studies
factor for NAFLD and insulin resistance plays a and ceruloplasmin levels. Patients were excluded
pivotal role in the pathophysiology of the disease iftheyhadknowndiabetesmellitus(type1or2),
[Hamaguchietal.2005;Choudhuryetal.2004]. afastingbloodsugar4125mg/dl,priorhistoryof
The optimal therapy for NAFLD has not been alcoholic liver disease, any other known chronic
established. Current recommendations are for liver disease, renal insufficiency (defined in this
dietary modifications, aerobic exercise, and study as a serum creatinine 41.2), a known
moderateweight lossin order todecrease insulin allergic reaction to metformin, prior use of an
resistance. Other recommendations would insulin-sensitizing agent such as metformin or a
includeavoidingoffendingagentssuchasalcohol thiazolidinedione, gastric bypass within 2 years,
andcontrollingassociatedmedicaldisorderssuch untreated thyroid disease, coagulopathy, chronic
as diabetes mellitus and hyperlipidemia [Reid, thrombocytopenia, or significant alcohol use
2006]. Pharmacotherapy focusing on improving defined as consumption of 420g/day or
or reversing insulin resistance is a target of 80g/weekduringthe2yearspriortostudyenroll-
research. Metformin received approval by the ment. All subjects signed an informed consent
FDA for clinical use in the United States in for participation in the study. The study was
1995 and revolutionized the treatment of dia- approved by our Department of Clinical
betes mellitus type 2 and insulin resistance. InvestigationandInstitutionalReviewBoard.
Rather than increase insulin levels it works to
improveinsulinsensitivityandthereforedecrease Study design
insulin requirements [Bailey and Turner, 1996]. Subjects who met eligibility requirements were
Previous studies of metformin have shown bio- randomized to group A or B by the pharmacy
chemical improvement in NAFLD patients and using a computer-generated program. Patients
suggest histologic improvement [Loomba et al. randomized to group A (control group) received
2009; Buglianesi et al. 2005; Uygun et al. 2004; placebo. Group B (treatment group) received
CoyleandDelaney,1999],buthavebeenlimited long-acting metformin 500mgdaily.In addition,
to uncontrolled trials. We hypothesized that 12 bothgroupswerereferredtoadieticianforcoun-
months of metformin therapy would improve selingregardingaDASH(DietaryApproachesto
liver histology compared to diet and exercise in Stop Hypertension) diet emphasizing fruit, vege-
nondiabetic,insulin-resistantpatientswithbiopsy tablesandloweringsaturatedfatandcholesterol.
proven NASH. Bothgroupswerealsoadvisedtoattempttocom-
plete 30 minutes of aerobic exercise four times
per week. Study participants were seen 2 weeks
Materials and methods after enrollment and at 6-week intervals there-
after where BMI was measured and compliance
Patients with exercise regimen was assessed. At the
The study subjects were obtained as consecutive 3-month follow-up visit, if serum aminotrans-
patients referred to the adult gastroenterology ferases did not show improvement then the
clinic at the Naval Medical Center, San Diego placebo or metformin dose was doubled (to a
with a histologic diagnosis of NASH defined by maximum dose of metformin of 1000mg/d).
the presence of cytologic ballooning and inflam- Thetreatmentperiodwas12monthsinduration
mation in addition to steatosis. Study subjects andrepeatliverbiopsywasperformedaftercom-
must have had a liver biopsy within 18 months pletion of the therapy.
of enrollment to be eligible for the study. Subjects
were included if they had biopsy-confirmed Methods
NASH and one of the following: a body mass All subjects had a complete clinical, anthropo-
index (BMI) 427kg/m2; a fasting blood sugar metric and laboratory evaluation at the time of
between 110 and 125mg/dl; a diagnosis of poly- enrollment. The clinical data included age, race,
cysticovariansyndrome;orthemetabolicsyndrome. sex, blood pressure, height, weight and BMI.
158 http://tag.sagepub.com
WW Shields, KE Thompson et al.
Baseline laboratory measurements included fast- Endpoints
inginsulinandglucosemeasurement,fastinglipid The primary objective of this pilot study was
profile with total cholesterol, triglycerides and improvement in histopathology in metformin-
HDL levels and liver enzymes including alanine treated patients compared with placebo.
aminotransferase (ALT), aspartate aminotrans- Secondary endpoints included overall improve-
ferase (AST) and alkaline phosphatase. A home- ment in BMI, HOMA-IR and serum amino-
ostasis model assessment of insulin resistance transferases.
(or HOMA-IR) score was calculated using the
formula: fasting insulin (mIU/ml) (cid:2) fasting glu- Statistical analysis
cose (mg/dl)/405 [Matthews et al. 1985]. A liver The scores were compared across study arms at
biopsywasperformedasentryrequirementforthe entry and at end of study using a Wilcoxon
studyandrepeatedin12monthsatstudyconclu- signed-rank test. The scores were compared
sion. All biopsies were evaluated separately in a between the two study groups using the two-
blinded fashion by two study pathologists who sample Wilcoxon rank-sum test. The analysis
scoredthehistologyusingthescoringsystempro- was carried out on an intention-to-treat basis.
posed by Brunt et al. [1999] (Box 1). At study A p value of 50.05 was considered significant.
conclusion,scoreswereassessed.Scoresdiffering All data in the text and tables are given as
by 1 or less between the two pathologists were means (cid:3) standard deviation.
averaged. Scores differing by more than 1 were
than re-evaluated by both pathologists and a
final score was given. In addition, all biopsies Results
were given a NAFLD activity score as proposed Twenty-three consecutive patients were assessed
byKleineretal.[2005]. and fulfilled entry criteria for eligibility in the
study. Four patients declined to participate.
Box 1. Nonalcoholic steatohepatitis histopathologic Nineteen patients were randomly assigned to
scoringsystem [Brunt et al.1999]. either group A (n¼10) or group B (n¼9). All
patients in group B completed the study includ-
Necroinflammatory Grade:
ing repeat liver biopsy at 12 months. All liver
1-Mild
2-Moderate biopsies were deemed adequate for interpreta-
3-Severe tion.ThreepatientsingroupAdidnotcomplete
Steatosis (%ofhepatocytes inspecimen): the study (two were lost to follow up and
1-one one declined further participation in the
2-upto 33%
study).Theirdataareincludedinthefinalinten-
3-33–66%
tion-to-treat analysis. Four of nine patients in
4-466%
group B (treatment group) were titrated up to
Hepatocellular Ballooning and Disarry:
metformin 1000mg/day. Figure 1 illustrates the
1-minimal, focallyinvolving
2-mild,obvious ballooning study flow.
3-marked, obvious ballooningand disarry
Intra-acinar (lobular) inflammation (inflammatory Baseline data
fociper20x): Thebaselineclinicalanddemographicdatafrom
0-none
the two groups are shown in Table 1. The two
1-1–2/20x
groups were similar regarding their laboratory
2-3–4/20x
3-44/20x and anthropometric data. The treatment group
wasolderandpredominantlymale.Themajority
PortalTract Inflammation:
0-none ofpatientsinbothgroupswereCaucasian,obese
1-mild (BMI430) and had laboratory evidence of insu-
2-moderate lin resistance and hyperlipidemia. Most showed
3-severe
mild abnormalities in ALTand AST.
Fibrosis Stage:
0-none
Clinical outcomes
1-zone 3perisinusoidal/pericellular fibrosis
2-zone 3 perisinusoidal/pericellular fibrosis with BMI improved in both treatment arms.In group
periportal fibrosis A, the BMI decreased by 1.7kg/m2 whereas in
3-zone 3 perisinusoidal/pericellular fibrosis with group B the BMI decreased by 0.9kg/m2. The
periportal fibrosis withbridging
difference between control group and treatment
4-cirrhosis
groupwasnotsignificant(p¼0.514).Inallstudy
http://tag.sagepub.com 159
Therapeutic Advances in Gastroenterology 2 (3)
Assessed for eligibility
(n=23)
Declined to participate
(n=4)
Randomly assigned
(n=19)
Allocated to control group Allocated to treatment
(n=10) Group(n=9)
Lost to follow-up (n=2)
Analyzed (n=9)
Discontinued intervention (n=1)
Analyzed (n=7)
Figure 1. Study flow.
Table1. Baseline clinicaland demographic data. NS
Characteristic Group A: GroupB: PValue p=0.007
Control Treatment 33
(n¼10) (n¼9)
32.5
Age 44.4 (þ/(cid:4)12) 50.2(þ/(cid:4)9.1) 0.252
Sex(M:F) 5:5 8:1 0.091
Race 32
Hispanic 1 1
Caucasian 5 6 31.5
Asian 4 1
AfricanAmerican 0 1 31
BMI(kg/m2) 32.8(þ/(cid:4)4.9) 32.2(þ/(cid:4)4.9) 0.775
HOMA-IR 4.02(þ/(cid:4)3.99) 6.14(þ/(cid:4)4.5) 0.124
30.5
FastingInsulin(mIU/mL) 14.9(þ/(cid:4)8.4) 31.4(þ/(cid:4)32.9) 0.177
Total Cholestero(mg/dl) 196.2(þ/(cid:4)55.4) 213.3(þ/(cid:4)49.8) 0.624
30
Triglycerides (mg/dL) 163.2(þ/(cid:4)85.2) 209.8(þ/(cid:4)114.2) 0.513
ALT (IU/L) 97.5(þ/(cid:4)45.6) 79.4(þ/(cid:4)26.1) 0.513 Group A Group B Overall
AST(IU/L) 62(þ/(cid:4)21.4) 52.8(þ/(cid:4)12.6) 0.595
AlkPhos (IU/L) 84.5(þ/(cid:4)20.3) 80.4(þ/(cid:4)25.5) 0.414 Figure 2. Body mass index (kg/m2) between study
subjects at baseline (blue bars) and end of
treatment (red bars).
subjects, the BMI decreased by 1.3kg/m2.
Thiswas significant (p¼0.007) and is illustrated 20.1IU/l in group A, 5.7IU/l in group B and
in Figure 2. 13.2IU/l overall. The differences between the
two groups were not significant for ALT, AST
Insulin resistance was improved in all study sub- or alkaline phosphatase. The overall improve-
jects. HOMA-IR decreased by 1.14 in group A ments were significant for ALT (p¼0.014) and
andby1.58ingroupB.Therewasnosignificant AST(p¼0.04)andapproachedsignificancewith
difference between the two groups (p¼0.886). alkaline phosphatase (p¼0.056).
Overall, HOMA-IR decreased by 1.18. This
was significant (p¼0.002) and is illustrated in HistologicoutcomesareshowninTable2.There
Figure 3. were no statistically significant differences
between the two groups in regards to overall
Liver enzymes improved in both treatment NAFLDactivityscore(NAS),individualcompo-
groups (Figures 4 and 5). ALT levels decreased nents of NAS or fibrosis. There was, however, a
by40.7IU/lingroupA,21.5IU/lingroupBand significant improvement in steatosis and NAS
31.6IU/l overall. AST levels decreased by across all study subjects (p¼0.021).
160 http://tag.sagepub.com
WW Shields, KE Thompson et al.
NS NS
p=0.002
7 p=0.04
70
6 60
5 50
4 40
3 30
2 20
1 10
0 0
Group A Group B Overall Group A Group B Overall
Figure 3. Insulin resistance (HOMA-IR) between Figure 5. Aspartate aminotransferase between
groups at baseline (blue bars) and end of treatment groups at baseline (blue bars) and end of treatment
(red bars). (red bars).
NS [Sanyal et al. 2004], pentoxifylline [Adams et al.
p=0.014 2004] and ursodeoxycholic acid [Lindor et al.
120 2004]. Small randomized, controlled trials have
suggested a benefit using the thiazolidinedione,
100 pioglitazone. Belfort et al. [2006] demonstrated
bothmetabolicandhistologicimprovementin55
80 patients with NASH treated for 6 months with
pioglitazone [Belfort et al. 2006]. This has been
60 supportedbyamorerecentstudyofpioglitazone
in 74 NASH patients treatedfor 1 year with pio-
40 glitazone [Aithal et al. 2008]. However, this type
of insulin sensitizer is associated with side effects
20
such as weight gain and increased fracture risk
that raise questions as to the utility of using this
0
drug long term. Furthermore, not every NASH
Group A Group B Overall
patient appears to have a favorable histopatholo-
gic response. Therefore, it would seem appropri-
Figure 4. Alanine aminotransferase between groups
ate to assess the utility of other medications that
at baseline (blue bars) and end of treatment (red
bars). improve insulin sensitivity such as metformin.
Metformin is indicated for the treatment of dia-
betesmellitusandassuchwouldbeconsidereda
Discussion candidate drug to treat NASH given the under-
Insulin resistance and the metabolic syndrome lying association. Improvement in insulin sensi-
play a central role in the pathogenesis of tivity is thought to occur via upregulation of
NAFLDandNASH[Choudhury,2004].Atpre- AMP-activated protein kinase (AMPK), an inte-
sent, the standard of care is aimed at weight loss gral component of glucose and lipid metabolism
through aerobic exercise and dietary changes. that results in decreased hepatic glucose and
However, large, randomized controlled trials triacylglycerol production as well as increased
evaluating the efficacy of weight loss on histo- peripheral glucose utilization via skeletal
pathology in NASH are lacking [Clark, 2006]. muscle. A recent Cochrane Review suggested a
Subsequently, multiple pharmacotherapies have favorable response with metformin in two small,
been investigated with variable results including randomized trials in improving aminotrans-
lipid lowering agents [Gomez-Dominguez et al. ferases [Angelico et al. 2007]. Data is limited
2006; Basaranoglu et al. 1998], vitamin E with regards to changes in histology and trials
http://tag.sagepub.com 161
Therapeutic Advances in Gastroenterology 2 (3)
Table 2. Baseline and endoftreatment histology.
Variable Control Treatment Overall pvalue pvalue
(controlvs (overall)
treatment)
Baseline End of Baseline Endof Baseline End of
treatment treatment treatment
Grade 1.9 1.55 1.5 1.39 1.71 1.47 0.67 0.064
Steatosis 2.23 1.58 2 1.91 2.12 1.74 0.23 0.019
Ballooning 1.78 1.5 1.69 1.47 1.74 1.49 0.967 0.09
Intra-acinar inflammation 1.4 1.28 1.25 1.36 1.33 1.32 0.478 0.951
Portaltract inflammation 1.38 1.3 0.78 0.56 1.09 0.95 0.523 0.22
Fibrosis 1.7 1.9 1.61 1.56 1.66 1.74 0.447 0.933
NAS(NAFLD activity score) 4.6 3.4 3.9 3.8 4.3 3.6 0.108 0.021
reviewing metformin lack double-blinding con- with the statistical results. Second, the potential
trols and/or control biopsy data. Our study is benefitmaybemaskedbyarelativelylowdoseof
the first reported prospective, randomized, metformin (maximum 1000mg/d). It is impor-
double blinded, placebo-controlled trial of 12 tant to note, however, that our study specifically
months of therapy with metformin in the treat- excluded patients with a diagnosis of diabetes
ment of NASH in nondiabetic patients with mellitus type 2. Finally, although our study has
primary histologic endpoints. There was no sig- histologicendpointsat12months,thebenefitsof
nificant difference between patients treated with inflammationimprovementandpotentialfibrosis
metformin compared to those randomized to reversal may require longer-term histologic data.
placebowithregardstochangesinserumamino- Clearly, in the field of NASH large-scale trials
transferases, insulin resistance or in liver with long-term histologic endpoints are
histology. necessary.
All patients met with a dietician and were given
instructions for a DASH diet. In addition, they Conclusion
were asked to comply with an aerobic exercise Metforminappearstohavelittleeffectcompared
regimen of 30 minutes at least four times a with placebo in improving liver chemistries or
week.Lifestylemodifications havebeenthestan- liver histology in nondiabetic, insulin-resistant
dard of care in the treatment of NAFLD despite patients with NASH. Weight loss utilizing the
limited supportive data. Our patients signifi- DASH diet and regular aerobic exercise signifi-
cantly improved their BMI throughout the cantly improves insulin resistance, serum amino-
12-month study. This improvement in BMI was transferases and liver histology in NASH.
associated with an improvement in insulin resis-
tance as HOMA-IR scores were significantly
lower at the end of the study in both groups.
Conflict of interest statement
In addition, there was significant improvement
The opinion or assertions contained herein are
in serum aminotransferase levels and more
the private views of the authors and are not to
importantly in liver histology with a significant
be construed as official or reflecting the view of
improvement in steatosis and NAFLD activity
the Department of the Army, Navy or the
scores. There were also trends toward signifi-
Department of Defense.
canceinimprovementinballooningdegeneration
and overall inflammatory grade. Our study pro-
vides needed support for continued recommen-
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