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Metformin superior to low‑fat diet for the treatment of patients with nonalcoholic
fatty liver disease and/or steatohepatitis
Bashkim Resuli, Vigjilenca Demiraj, Adriana Babameto, Klara Sema, Valdete Malaj
University Service of Gastroenterology and Hepatology, Mother Theresa Hospital, Tirana, Albania
Nonalcoholic fatty liver disease
process: 1) the development of steatosis caused
(NAFLD) constitutes a worldwide health chal‑
by insulin resistance in the muscle, adipose tissue,
lenge. Cases of fatty liver diseases with inflam‑
and liver and 2) cytokine‑mediated inflammation,
mation that resemble alcoholic steatohepatitis
lipid peroxidation, and apoptosis.17‑19
but occur in nondrinkers were first described 30
Assessing liver injury in insulin resistant states
years ago.1,2 In the last decade, the disorder has
has become a major concern and no less of a chal‑
aroused a real interest. NAFLD is believed to ac‑
lenge given the current diagnostic tools. Liver bio‑
count for up to 90% of the cases of elevated liv‑
psy is regarded as the gold standard for the as‑
er function tests in patients without an identifi‑
sessment of fatty liver disease; however, its inva‑
able cause of liver disease.3 Recent studies have
siveness limits its use, especially in outpatients
made it clear that a subset of patients who devel‑
and research. On the other hand, sonography has
op nonalcoholic steatohepatitis (NASH), most‑
shown significantly high specificity and relative‑
ly those with alanine transaminase (ALT) levels
ly high sensitivity for the diagnostic occurrence
higher than twice the upper limit of normal, are
at increased risk of progression to liver disease
The search for the therapy of NASH is ongoing.
and may experience all complications of cirrho‑
Based on the concept of insulin resistance, a num‑
sis, such as end‑stage liver disease and hepatocel‑
ber of pilot studies have shown that reduction of
lular carcinoma.4‑8 Indeed, it can be argued that
body weight and improvement of insulin sensitiv‑
most cases of cryptogenic cirrhosis, which ranks
ity by metformin or thiazolidinediones provide
as the third leading indication for liver transplan‑
positive bio chemical and histo logical results.22‑29
tation after alcohol and hepatitis C, are due to
Metformin hydrochloride (N,N‑dimethylimidodi‑
carbonimidic diamide hydrochloride) is an anti‑
The rising prevalence of obesity, diabetes,
hyperglycemic drug of the biguanide class, which
and meta bolic syndrome evidently results in
decreases hepatic glucose production, decreases
an increasing prevalence of NAFLD. This trend
intestinal glucose absorption, and improves in‑
is of particular concern in the pediatric popu‑
sulin sensitivity by increasing peripheral glucose
lation, in which the reported increase in obesi‑
uptake and utilization. Despite that, it is known
ty will undoubtedly result in a higher evidence
that metformin therapy can lead to body weight
and prevalence of pediatric and adult NAFLD in
the future.10,11 In Albania, excess weight and obe‑
The objective of this study was to evalu‑
sity is becoming the major public health problem,
ate the efficacy of metformin compared with
primarily in middle‑aged women.12 NAFLD and
low‑fat diet (LFD) in patients with NAFLD and/
NASH are frequently observed in conjunction
with other components of the meta bolic syn‑
drome, such as arterial hypertension, diabetes,
Patients and methods Study population
obesity, and elevated lipids, which are considered
was a 24‑week prospective controlled trial com‑
Conflict of inter est: none declared.
the hepatic manifestations of the syndrome.13‑16
paring metformin plus LFD with LFD alone in 61
Why insulin resistance leads to fatty liver injury
outpatients with NAFLD and/or NASH, 46 men
is not completely clear. The most widely accept‑
(75%) and 15 women (25%), who presented at our
Copyright by Medycyna Praktyczna, Kraków 2012
ed patophysio logical model of NAFLD is a two‑hit
university department of gastroenterology and
POLSKIE ARCHIWUM MEDYCYNY WEWNĘTRZNEJ 2012; 122 (Suppl 1)
hepatology during 2008–2009. All patients ful‑
was more than 3.6 and body mass index more
filled the following criteria: 1) insulin resistance
than 27.5 kg/m2. Pre‑ and post‑treatment body
(Homeostasis Model Assessment Insulin Resi‑
mass, bio chemical data, and insulin resistance
stance – HOMA‑IR) value above 3.6; 2) elevation
were compared. The efficacy endpoints at 24 we‑
in the levels of ALT and aspartate transaminase
eks of the treatment were the normalization of
(AST); and 3) ultrasound evidence of fatty liver.
ALT and decreased insulin resistance.
The exclusion criteria were as follows: 1) presen‑
ce of hepatitis B and C virus infection markers
Continuous variables are pre‑
(HBsAg and anti‑HCV); 2) evidence of alcoho‑
sented as mean ± standard deviation. Group com‑
lic liver disease (less than 20 g ethanol per day);
parisons were conducted using the t
3) evidence of auto immune liver disease; 4) use
rences were considered significant at the P
of insulin‑sensitizing and hepatotoxic drugs in
the previous 6 months; 5) presence of diabetes or a severe systemic disease; 6) evidence of meta‑
Baseline body weight, bio chemical data,
bolic liver disease (α‑1‑antitrypsin deficiency, Wil‑
and insulin resistance (HOMA‑IR) of the patients
son disease, or hemo chromatosis); 7) active sub‑
are presented in TABLE 1
. Both groups were simi‑
lar in terms of age, sex, body weight, bio chemical
The study was approved by the National Eth‑
ics Committee. Informed consent was obtained
Significantly more patients treated with met‑
formin plus LFD (group A) achieved normal se‑rum ALT and AST levels and improvement of in‑
Patients were divided into 2 gro‑
sulin resistance compared with patients treated
ups. Group A included 35 patients (26 men and
with LFD alone (group B; P
<0.05; TABLE 2
9 women; mean age, 41.8 ±8.1 years) receiving
There was no significant difference in body
metformin 850 mg/daily plus low‑fat dietary
weight loss, fasting and postprandial blood glu‑
regime that aimed to reduce fat to 30% or lower
cose, total cholesterol, triglyceride and HDL
as generally recommended for 24 weeks. Group
cholesterol between the 2 groups (P
B included 26 patients (20 men and 6 women;
mean age, 42.6 ±7.3 years) receiving the same
No serious adverse events of metformin were
dietary counseling for the same period of time.
observed and treatment was not discontinued in
No vitamins or other nutritional supplements
were prescribed. Blood samples were obtained before and after the treatment (0 and 24 weeks)
There is currently no proven and
to determine serum levels of bilirubin, ALT and
approved treatment for patients with NAFLD
AST, fasting and postprandial blood glucose, fa‑
and/or NASH. Although body weight loss and
sting insulin, total cholesterol, triglycerides, and
life‑style modifications have been shown to be
high‑density lipoprotein (HDL) cholesterol.
effective,31,32 only a minority of patients are able
HOMA‑IR was calculated using the formula:
to adhere to sustained and intensive dietary inter‑
HOMA‑IR = fasting plasma insulin (microU/ml)
vention.33‑35 In the present study, we observed
× FPG (mg/dl)/405. We assumed IR when HOMA
that body mass loss (4–6 kg) at the end of treat‑ment with LFD alone was associated with nor‑malization of ALT in 21 of 26 patients (82%) and
Baseline characteristics of body weight, bio chemical data and insulin
attenuation of insulin resistance only in 20% of
the patients (TABLE 2
On the other hand, we found that a 24‑week
treatment with metformin at doses of 850 mg/dai‑
ly plus LFD was associated with a significantly higher rate of the normalization of ALT levels
and improvement of insulin resistance when com‑
pared with LFD alone. These data clearly indicate
the beneficial effect of metformin on insulin ac‑
tion. In fact, the role of hyperinsulinemia and in‑
creased insulin resistance as major pathogenic fac‑tors in the development of NAFLD and/or NASH,
and in this manner the therapeutic value of in‑
sulin‑sensitizing agents including thiazolidine‑
diones or biguanides, has been demonstrated in
several trials.28,36‑39 Moreover, it has been shown
that bio chemical response to treatment with metformin continued during a 6‑ to 12‑month
Data are presented as mean ± standard deviation.
follow‑up period, suggesting the sustained ef‑fect of the drug.40
Abbreviations: ALT – alanine transaminase, AST – aspartate transaminase,
HDL – high-density lipoprotein, HOMA-IR – Homeostasis Model Assessment Insulin
The meta bolic effect of metformin is thought to
Resistance, LFD – low-fat diet, MET – metformin
be mediated through the activation of adenosine
Metformin superior to low‑fat diet for the treatment.
Body weight, bio chemical data, and insulin resistance at 24 weeks
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