Annals of Hepatology 6(4) 2007: 222-226
Annals of Hepatology 2007; 6(4): October-December: 222-226
Metformin is effective in achieving biochemical
response in patients with nonalcoholic fatty liver disease
(NAFLD) not responding to lifestyle interventions*
Ajay Duseja;1 Ashim Das;2 Radha Krishan Dhiman;1 Yogesh Kumar Chawla;1 Kiran K. Thumburu;1 Sanjay Bhadada;3 Anil
*This work was presented at the Asian Pacific Digestive Week at
Cebu City, Philippines in November 2006 (J Gastroenterol
Hepatol 2006; 21 (suppl 6): A457).
1Departments of Hepatology.
Postgraduate Institute of Medical Education & Research,
Nonalcoholic fatty liver disease - NAFLD, nonalcoholic
steatohepatitis - NASH, , insulin resistance -IR, ursodeoxycholic
acid - UDCA, alanine transaminase - ALT, hepatitis B surface
antigen -HBsAg, anti hepatitis C virus antbodies - anti HCV,
anti-nuclear antibody - ANA, anti-smooth muscle antibody -
ASMA, anti-liver kidney microsomal antibody - LKM, anti-
mitochondrial antibody - AMA, body mass index -BMI, world
health organization – WHO, fasting plasma glucose - FPG, high
density lipoprotein –HDL, low density lipoprotein - LDL,
triglycerides - TG, tumor necrosis factor alpha - TNF-α,
homeostasis model assessment for insulin resistance - HOMA- IR.
Address for correspondence:
Dr. Ajay Duseja MD, DM, MNAMS, FACG
Department of Hepatology
PGIMER Chandigarh, India
Manuscript received and accepted: 10 and 17 October 2007
Background: Insulin resistance plays an important
role in the pathogenesis of NAFLD. Pharmacological
treatment of patients with NAFLD is still evolving. In-
sulin sensitizing drugs like metformin may be effec-
tive in these patients. Twenty five adult patients with
NAFLD who did not achieve normalization of alanine
transaminases (ALT) after 6 months of lifestyle inter-
ventions and UDCA were treated with metformin
500mg tid for 6 months. Insulin resistance was deter-
mined by HOMA- IR. Liver function tests were done
monthly and patients were defined having no re-
sponse, partial response or complete biochemical re-
sponse depending on the change in ALT. Results were
compared with 25 patients with NAFLD from the
same cohort treated only with lifestyle interventions
(disease controls). Results: Thirteen (52%) patients
had class III (n = 5) or class IV (n = 8) disease amount-
ing to histological NASH. Of these 13 patients none
had severe inflammation and none had stage 4 fibro-
sis (cirrhosis). All 25 patients with NAFLD had insulin
resistance in comparison to healthy controls. In com-
parison to disease controls (127.5 ± 41.8 vs. 118 ±
21.6 p = NS), all patients treated with metformin had
partial biochemical response (mean ALT 122.2 ± 26.8
vs 74.3 ± 4.2 p < 0.01) and 14 (56%) of them achieved
complete normalization of ALT. Conclusions: Met-
formin is effective to achieve biochemical response in
patients with NAFLD who do not respond to lifestyle
interventions and UDCA.
Key words: Nonalcoholic steatohepatitis, NASH, insu-
lin resistance, diabetes mellitus, metabolic syndrome,
Nonalcoholic fatty liver disease (NAFLD) includes
patients with simple steatosis and nonalcoholic steato-
hepatitis (NASH), which can even progress to cirrhosis
and hepatocellular carcinoma.1,2 Pharmacological treat-
ment of patients with NAFLD is still evolving and since
insulin resistance (IR) plays a key role in the pathogene-
sis of nonalcoholic fatty liver disease (NAFLD), insulin
sensitizing drugs like metformin may have role in the
treatment of patients with NAFLD.3-9
Objective of this study was to determine the role of met-
formin in achieving biochemical response in patients with
nonalcoholic fatty liver disease who did not respond to life-
style interventions and ursodeoxycholic acid (UDCA).
Patients and methods
In a prospective analysis (April 2001 – March 2007), 25
patients with NAFLD who did not have complete biochemi-
cal response after 6 months of lifestyle interventions and
Ajay Duseja et al. Metformin is effective in achieving biochemical response in patients with (NAFLD)
UDCA were included in the study after an informed consent.
The project had the approval of institute’s ethical committee.
Life style interventions included moderate sustained exercise
like brisk walking, jogging, swimming, cycling etc at least for
30-45 minutes per day, low fat and low calorie diet and slow
weight reduction (10% of base line in 6 months, not more
than 1.6 Kg/week) in those with overweight and obesity.
UDCA was given in a dosage of 300 mg twice daily. Inclu-
sion criteria were adult (> 16 yrs.) nonalcoholic individuals
(total abstinence or intake less than 20 g/day, confirmed by
two family members) with raised serum alanine aminotrans-
ferase (ALT) (> 1.5 x ULN x at least 6 months), ultrasound
showing hyperechoic liver or other features of steatosis, nega-
tive viral markers (HBsAg, anti HCV - 3rd generation), nega-
tive autoimmune markers [anti-nuclear antibody (ANA), anti-
smooth muscle antibody (ASMA), anti-liver kidney microso-
mal antibody (LKM), anti-mitochondrial antibody (AMA)],
normal serum ceruloplasmin & absent Keyser Fleisher rings
on slit lamp examination, normal iron parameters and a liver bi-
opsy consistent with NAFLD. Pregnant females and patients
with diabetes mellitus were excluded from the study.
Twenty five patients with NAFLD from the same cohort
with comparable age, gender, BMI, waist, baseline ALT,
insulin resistance and metabolic syndrome were included
as disease controls. These patients were also non respond-
er to lifestyle interventions and UDCA and were contin-
ued on only lifestyle interventions without metformin
All patients underwent a detailed physical examina-
tion including anthropometry. Overweight (BMI ≥ 23
but < 25 kg/m2), obesity (BMI ≥ 25 kg/m2) and abnor-
mal waist circumference [> 90 cm (males), > 80 cm (fe-
males)] were defined as per the Asia Pacific criteria.10,11
Diabetes mellitus was defined as per the WHO criteria
with fasting plasma glucose (FPG) ≥ 126 mg/dL or plas-
ma glucose ≥ 200 mg/dL in a symptomatic patient or a 2-
hour plasma glucose on glucose tolerance test ≥ 200 mg/
dL12 and patients qualifying these criteria were excluded
from the study. Lipid profile was taken as abnormal when
serum cholesterol was > 200 mg/dL, serum high-density
lipoprotein (HDL) < 40 mg/dL in males & < 50 mg/dL in
females, serum low-density lipoprotein (LDL) > 130 mg/
dL and serum triglycerides were > 150 mg/dL.13
In addition to measurement of fasting serum insulin
levels (radioimmunoassay), fasting C-peptide (ELISA)
and serum TNF- α (ELISA) levels were also determined
in these patients.
Metabolic syndrome was defined by the presence of at
least ≥ 3 out of five modified adult treatment panel III
criteria including modified abnormal waist as per the
Asia Pacific criteria, FPG >110 mg/dL, hypertension
(blood pressure ≥ 130/85 mmHg or on anti-hypertensive
drugs), serum triglycerides > 150 mg/dL, and serum high
density lipoprotein (HDL) < 40 mg/dL (males) & < 50
Histologically patients were classified into four
classes as per Matteoni et al (Class – 1 = Simple ste-
atosis, Class – 2 = Steatosis + lobular inflammation,
Class – 3 = + Ballooned hepatocytes, Class – 4 = +
Mallory hyaline or fibrosis) and those patients with
class 3 or 4 were defined as having NASH.14 Further
patients with NASH were graded and staged according
to Brunt et al.15
Insulin resistance was determined by homeostasis
model assessment for insulin resistance ( HOMA- IR) cal-
culated as the product of fasting insulin (µU/L) and fast-
ing plasma glucose (mmol/L) divided by 22.5. An abso-
lute value of HOMA-IR > 1.64 was taken as abnormal.3,16
Treatment and follow up
Patients were treated with tablet metformin 500 mg/tid
for 6 months in addition to the life style interventions.
Disease controls were continued on only lifestyle inter-
ventions without metformin. Liver function tests were
done monthly and patients were defined as having no re-
sponse, partial response or complete biochemical re-
sponse depending on the change in ALT.
All data is expressed in mean ± SD until otherwise
specified. Students‘t’ test, chi square test and Mann-
Whitney U test were used to determine the differences be-
tween different groups. A p value of < 0.05 was taken as
There were 25 patients (males 17 mean age 36.4 ± 9.2
years). Other clinical and biochemical details including
metabolic syndrome are shown in Table I.
Annals of Hepatology 6(4) 2007: 222-226224
Details of the histopathology are shown in Table II.
Thirteen (52%) patients had class III (n = 5) or class IV
(n = 8) disease amounting to histological NASH. Of these
13 patients none had severe inflammation and none had
stage 4 fibrosis (cirrhosis).
Patients with NAFLD had significantly higher HOMA-
IR in comparison to the historical healthy controls.
(Mean HOMA – IR = 7.6 ± 2.9 vs 1.4 ± 1.2) (p = < 0.01).
Though BMI did not change significantly in both the
groups, in comparison to disease controls (127.5 ± 41.8
vs 118 ± 21.6 p = NS), all patients treated with metformin
had partial biochemical response (mean ALT 122.2 ±
26.8 vs 74.3 ± 4.2 p < 0.01) and 14 (56%) of them
achieved complete normalization of ALT and continue to
do so on follow up for 3 months (Figure 1). No patient
experienced any side effect and there were no dropouts.
Insulin resistance, which is responsible for increased
lipolysis from adipose tissue and hepatic steatosis, is
very common in patients with NAFLD.3,17 Increased fatty
acid oxidation, oxidative stress and cytokines may lead
on to steatohepatitis and its consequences in some of
these patients.18 All our patients with NAFLD had IR as
demonstrated by significantly higher HOMA-IR in com-
parison to healthy controls. High C-peptide to insulin ra-
tio (Table I) in our patients with NAFLD is indicative of
primary insulin resistance in these patients rather than
the hyperinsulinemia occurring due to decreased hepatic
extraction of insulin due to any liver disease.1
First line of treatment in patients with NAFLD is al-
ways weight reduction by life style interventions and
control of other risk factors. Pharmacological treatment
for NAFLD is still evolving and there is no single agent,
which is effective in achieving the complete response.19
Earlier studies did show UDCA to be an effective mode
of treatment in these patients20 but a recent randomized
placebo controlled trial showed that UDCA is no better
than placebo in the treatment of patients with NASH.21
The options in patients like ours who do not respond to
above measures are limited. Since insulin resistance is
the major pathogenetic mechanism, insulin-sensitizing
drugs have a role in the treatment.22-24 Thiazolidinediones
group of drugs including troglitazone, rosiglitazone and
Table II. Liver histology in 25 patients with NAFLD.
NASH (class III+ IV) on histology (n =13)
Grade- 16 (46%)
Table I. Baseline characteristics of 25 patients with NAFLD.
Mean age (yrs.)
Mean BMI (kg/m2)
Mean waist (cm)
Mean ALT (IU/L)
C- peptide (pmol/L)
Mean insulin (pmol/L)
Mean TNF-α (pg/mL)
Mean Cholesterol (mg/dL)
Mean HDL (mg/dL)
Mean LDL (mg/dL)
Mean TG (mg/dL)
17 : 8
36.4 ± 9.2
26.8 ± 3.6
96.8 ± 10.0
122.2 ± 26.8
422 ± 1255
212.1 ± 164.3
26.7 ± 17.5
192 ± 46
37 ± 9.5 mg/dL
112 ± 38.5 mg/dL
202 ± 98.4 mg/dL
BMI – Body mass index
ALT – Alanine aminotransferase
TNF – Tumor necrosis factor
HDL – High-density lipoprotein
LDL – Low-density lipoprotein
TG – Triglycerides
Figure 1. Shows significant change in ALT in the patients who
got metformin (patients) in comparison to those continued on
only lifestyle modifications (disease controls). There was no
change in BMI in both groups.
Ajay Duseja et al. Metformin is effective in achieving biochemical response in patients with (NAFLD)
ESTE DOCUMENTO ES ELABORADO POR MEDI-
(56%) of them. We also found it to be safe with no patient
experiencing any side effect and there were no dropouts.
Our study has certain drawbacks. Number of patients
is small and results may change with large number of pa-
tients. We evaluated patients only for biochemical re-
sponse and since ALT may not have good correlation
with histology in patients with NAFLD, improvement in
ALT in our patients may not signify histological re-
In conclusion, our study shows that insulin resistance
is common in patients with NAFLD.
Metformin is an alternative option to achieve bio-
chemical response in patients with NAFLD who do not
respond to lifestyle interventions and UDCA. Results
need to be reproduced in larger number of patients in a
randomized placebo controlled trial with histological
pioglitazone have been used in the treatment of NAFLD.
Troglitazone has been withdrawn from the market due to
its potential hepatotoxicity, which has been described
even with rosiglitazone and pioglitazone.22-24
Metformin through its anti- TNF and insulin sensitiz-
ing actions is an effective drug for achieving biochemi-
cal response in patients with NAFLD, and data on its use
both experimental25 and in patients4-9 with NAFLD is
evolving. Most of the studies on metformin are open la-
bel studies.4,8 One randomized trial using metformin
found it to be better than vitamin E and lifestyle inter-
ventions in improving the liver biochemistry and histo-
logical activity including steatosis, inflammation and fi-
brosis and none of the patients had any side effects.9 In
another study 36 patients with NASH were randomized
to lipid and calorie-restricted dietary treatment alone and
metformin 850 mg b.d. plus dietary treatment for 6
months. The mean serum alanine/aspartate aminotrans-
ferase, insulin and C-peptide levels decreased and the in-
dex of insulin resistance improved significantly from
baseline in the group given metformin, significantly
greater than those in the group given dietary treatment
alone. Though not significant, more patients in the met-
formin group showed improvement in the necro-inflam-
matory activity, compared with the group given dietary
Though we did not evaluate them for histological im-
provement, our patients had significant biochemical re-
sponse in comparison to patients continued only on life-
style interventions with normalization of ALT in 14
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