Arab Journal of Gastroenterology xxx (xxxx) xxx

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Arab Journal of Gastroenterology

journal homepage: www.elsevier.com/locate/ajg

Original article

Short-term orlistat therapy improves fatty infiltration indices and liver

fibrosis scores in patients with non-alcoholic fatty liver disease and
metabolic syndrome
Vian Ahmed Wasta Esmail a, Mohammed Omer Mohammed b, Marwan S.M. Al-Nimer c,⇑
a
Department of Clinical Pharmacy, College of Pharmacy, University of Sulaimani, Sulaimani, Iraq
b
Department of Medicine, Department of Pharmacology, College of Medicine, University of Sulaimani, Sulaimani, Iraq
c
Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University, Erbil, Iraq

a r t i c l e i n f o a b s t r a c t

Article history: Background and study aims: Patients with non-alcoholic fatty liver disease (NAFLD) exhibit features of
Received 18 July 2018 metabolic syndrome, including a high body mass index, central obesity, high blood pressure, and abnor-
Accepted 28 December 2020 mal lipid profile values. Orlistat, an intestinal lipase enzyme inhibitor, improves insulin resistance. We
Available online xxxx
aimed to investigate the effects of short-term therapy with orlistat on the components of metabolic syn-
drome associated with NAFLD and explore its effect on liver fibrosis scores.
Keywords: Patients and methods: An open-label placebo-controlled clinical study using orlistat for 12 weeks was car-
Non-alcoholic fatty liver disease
ried out on 50 patients with NAFLD. They were divided into a placebo group (Group I) and an orlistat
Metabolic syndrome
Lipid indices
treatment group (120 mg per day, Group II). The diagnosis of NAFLD was made by ultrasonography
Liver fibrosis scores and laboratory investigations. Anthropometric and blood pressure measurements and hepatic liver
enzymes, fasting lipids, and blood glucose levels were determined before and after treatment. Lipid
indices including cholesterol (Chol-I), triglyceride (TG-I), triglyceride-glucose (TYG-I), and the scores
for lipid fibrosis using the NAFLD fibrosis score (NFS) and Fibrosis-4 score (Fib-4) were also determined.
Results: Orlistat significantly improved the anthropometric and metabolic indices (TG-I, TYG-I) and liver
enzymes. Orlistat demonstrated a favorable impact on the NAS and Fib-4 scores for liver fibrosis.
Conclusion: Orlistat improves the components of metabolic syndrome, leading to the improvement of
insulin resistance and thereby improves fatty infiltration of the liver. To a lesser extent, orlistat improved
the liver fibrosis scores.
Ó 2020 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.

Introduction
Non-alcoholic fatty liver disease (NAFLD) is a chronic multi-
system disease commonly associated with insulin resistance [1].
The relationship between insulin resistance and NAFLD is due to
the stimulatory effect of accumulated triglycerides (TG) in the liver
that induce hepatic insulin resistance [2]. NAFLD is considered a
component of metabolic syndrome because patients with NAFLD
exhibit a high body mass index (BMI), central obesity, high blood
pressure, and abnormal lipid profile values [3–5]. Various pharma-
cological interventions have been used to treat NAFLD. Statins
improve dyslipidemia, but they cause adverse reactions [6,7].
Fibrates correct the dyslipidemia of NAFLD by reducing serum TG
levels, increasing serum high-density lipoprotein-cholesterol
⇑ Corresponding author.
E-mail address: alnimermarwan@ymail.com (M.S.M. Al-Nimer).
(HDL-c), and improving insulin sensitivity and liver function [8].
A literature review showed a wide range of medicines used in
NAFLD management, including insulin sensitizers, antioxidants,
vitamin E, pentoxifylline, angiotensin receptor blockers, and n-3
polyunsaturated fatty acids [9]. Orlistat is a lipase enzyme inhibi-
tor that prevents fat absorption from the intestines and is approved
as an anti-obesity agent [10]. Orlistat improves glycemic control in
obese type 2-diabetic (T2D) patients [11]. Long-term orlistat ther-
apy (120 mg thrice daily for 24 weeks) improved liver enzymes
and ultrasonography findings in patients with NAFLD presenting
with obesity and dyslipidemia [12]. We hypothesized that the
pleiotropic effect of orlistat might correct the metabolic syndrome
components in NAFLD patients. This study aimed to investigate the
effects of short-term (12 weeks) orlistat treatment on the compo-
nents of metabolic syndrome associated with NAFLD and explore
its impact on liver fibrosis scoring.

https://doi.org/10.1016/j.ajg.2020.12.005
1687-1979/Ó 2020 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.

Please cite this article as: Vian Ahmed Wasta Esmail, Mohammed Omer Mohammed and Marwan S.M. Al-Nimer, Short-term orlistat therapy improves
fatty infiltration indices and liver fibrosis scores in patients with non-alcoholic fatty liver disease and metabolic syndrome, Arab Journal of Gastroenter-
ology, https://doi.org/10.1016/j.ajg.2020.12.005
Vian Ahmed Wasta Esmail, Mohammed Omer Mohammed and Marwan S.M. Al-Nimer
Patients and methods
This open-label placebo-controlled clinical study was con-
ducted by the Department of Clinical Pharmacy in cooperation
with the Department of Medicine of our institution, from August
2017 to April 2018.
The study was conducted according to the ethical guidelines of
the Scientific Committee of our Institution. Each patient signed a
consent form before admission to the study.
The authors recruited the patients from referrals to the internal
medicine consultants of our institution. The eligible patients were
of either sex, aged <60 years old, with symptoms suggestive of
NAFLD. The diagnosis of NAFLD was confirmed by ultrasonography
and laboratory studies. Patients with T2D were included because
they are at risk of developing NAFLD. Next, we excluded patients
with chronic liver disease (including alcoholic fatty liver disease),
viral hepatitis, chronic active hepatitis, connective tissue and
autoimmune diseases, and chronic kidney diseases. Pregnant
women and lactating or nursing mothers were also excluded.
A total of 50 patients (15 men and 35 women) diagnosed with
NAFLD were included in the study. The authors examined and
interviewed each patient, noting the characteristics of the partici-
pants and the profile of the metabolic syndrome criteria as
described by the National Cholesterol Education Program (NCEP)
Panel (III) [13].
Anthropometric measurements
These included the height (m), weight (kg), and waist circum-
ference (cm). A waist circumference of
88 cm (women)
and
102 cm (men) indicated central obesity. The BMI was calcu-
lated according to Quetelet’s equation:

 2
BMI kg=m2 ¼ WeightðkgÞ=Height ðmÞ
The waist-height ratio was calculated by dividing the waist
(cm) by height (cm), with a value of
0.5 indicating subjects at
risk of cardiovascular events. The conicity index (an obesity index
that predicts cardiovascular events), adult body surface area index
(ABSI), adult body fat (ABF), and lipid accumulation products were
determined as described in the literature [14,15].
Blood pressure measurements
The blood pressure (mmHg) was measured in the sitting posi-
tion, and the mean of three readings was taken. The difference
between systolic and diastolic blood pressure represented the
pulse pressure, and the mean arterial pressure was calculated as
diastolic blood pressure + 13 pulse pressure.
Biochemical measurements
A fasting peripheral venous blood sample was taken from each
patient on admission. The blood was centrifuged at 2,500 rpm for
10 min, and the serum was separated for laboratory analysis. The
serum glucose and lipid profile were measured using enzymatic
reaction kits. The absorbance of the serum-reagent reaction was
detected by a visible spectrophotometer at the specific wavelength
for each test according to the manufacturer’s instructions. The lipid
profile included fasting serum total cholesterol (TC), TG, and HDL-
c. The serum non-HDL-c level was determined by subtracting the
HDL-c from the TC. The cholesterol index (Chol-I), TG index (TG-
I), and TG-glucose index (TYG-I) (as a marker of insulin resistance)
were calculated as described elsewhere [15–17]. Liver enzymes
including alanine aminotransferase (ALT), aspartate transaminase
(AST), and alkaline phosphatase enzymes were determined. The
2
Arab Journal of Gastroenterology xxx (xxxx) xxx
ALT/AST and AST/ALT ratios were calculated as markers of insulin
resistance and prognostic markers of liver fibrosis [18–20].
Ultrasonography study
Each patient received an ultrasonography investigation. The
examination was done using a 2–5 MHz convex transducer. Next,
this investigation is based on the liver echogenicity exceeding that
of the renal cortex and spleen due to fatty infiltration [21]. The
grading of ultrasonography images is described in the literature
[22,23]:
Grade I (mild): the liver echogenicity is slightly increased.
Grade II (moderate): the echogenic liver masks the echogenic
walls of the portal vein branches.
Grade III (severe): the echogenicity of the liver obscures the
diaphragmatic outlines.
Assessment of liver fibrosis by using the NAFLD fibrosis score
(NFS) and fibrosis-4-score (Fib-4)
The NFS is composed of 6 variables, including age, hyper-
glycemia, BMI, platelet count, albumin, and AST/ALT ratio.
NFS = –1.675 + 0.037  age (year) + 0.094  BMI (kg/m2) + 1.13
 IFG/diabetes (yes = 1, no = 0) + 0.99  AST/ALT ratio  0.013 
platelet count (109/L)  0.66  albumin (g/dL). In this study,
we used a modification of this formula by omitting the albumin.
The fibrosis-4-score was calculated using the following
equation:
Ageðyear ÞASTlev elðU=LÞ
Fib  4 ¼ pffiffiffiffiffiffiffiffiffiffiffiffiffi
Plateletcountð109 =LÞ ALTðU=LÞ
A cutoff value of<1.45 indicates a negative predictive value for
advanced fibrosis [24].
Treatment and follow-up
The patients were randomly assigned to receive a placebo (car-
boxymethylcellulose tablets) or orlistat (120 mg/d) as a single
daily dose for 12 weeks. Each patient was clinically assessed and
had laboratory investigations done after treatment
Statistical analysis
The sample size was calculated using margins of error (a = 0.05,
b = 0.2), a two-tailed test, and a 95% confidence interval.
Statistical analyses were performed using SPSS version 20.0 and
Excel 2003 program for Windows. Next, the results were expressed
as number, percentage, and as mean ± standard deviation (SD). The
two-tailed, paired student’s t-test was used to assess the therapeu-
tic intervention. The differences were considered statistically sig-
nificant when p < 0.05. The multi-variable linear regression test
was used to assess any association between the ATL/AST ratio,
AST/ALT ratio, NFS and Fib-4 score, and the metabolic indices.
Results
The mean age ± SD of patients was 43.2 ± 9.1 years with a
female to male ratio of 1: 2.3 (Table 1). Concomitant illness, includ-
ing diabetes mellitus, thyroid gland disease, and dyslipidemia, was
observed in 32%, 22%, and 12% of participants, respectively. Radio-
logical and laboratory studies demonstrated variable degrees of
liver fatty infiltration. Ultrasonography findings showed that 52%
of patients exhibited moderate fatty infiltration, and the status of
liver fibrosis assessed by laboratory investigations showed that
the mean ± SD of AST/ALT ratio, Fib-4, and NAS scores were 0.70
8 ± 0.250, 0.038 ± 0.033, and  3118.9 ± 894.1 respectively. A sig-
nificant positive correlation was found between the score of Fib-4
Vian Ahmed Wasta Esmail, Mohammed Omer Mohammed and Marwan S.M. Al-Nimer Arab Journal of Gastroenterology xxx (xxxx) xxx

Table 1
Characteristics of participants with non-alcoholic fatty liver disease.

Characteristics Placebo Orlistat Total

Gender (male:female ratio) 07:18 08:17 15:35
Age (years) 44.0 ± 9.7 42.8 ± 8.4 43.2 ± 9.1
Residency
Rural 3 (12) 2(8) 5(10)
Urban 22 (88) 23(92) 45(90)
Smoking
Current 2 (8) 1(4) 3(6)
Ex-smokers 3 (12) 2(8) 5(10)
Coffee intake
No 12 (48) 10(40) 22(44)
Regular intake 1 (4) 4(16) 5(10)
Others (occasional) 12 (48) 11(44) 23(46)
Concomitant illness
Diabetes mellitus 7 (28) 9(36) 16(32)
Hypothyroidism 3 (12) 6(24) 9(18) Fig. 2. . Effect of orlistat therapy compared with placebo treatment on the fibrosis-
Hyperthyroidism 0 (0) 2(8) 2(4) 4-score in non-alcoholic fatty liver disease.
Hypertension 13 (52) 8(32) 21(42)
Migraine 0 (0) 2(8) 2(4)
Dyslipidemia 1 (4) 5(20) 6(12)
Irritable bowel syndrome 1 (4) 0(0) 1(2)
No concomitant illness 9 (36) 5(20) 14(28)

The results expressed as number (%).

with NFS (r = 0.469, p < 0.001) and with the AST/ALT ratio (0.550,
p < 0.001) (Fig. 1). The laboratory tests for insulin resistance
showed the mean ± SD of TYG and ALT/AST was 9.1 ± 0.61 and
1.59 ± 0.57, respectively. No significant difference was found

Fig. 3. Effect of orlistat therapy compared with placebo treatment on the non-
alcoholic fatty liver disease score in non-alcoholic fatty liver disease.

between Group I (placebo treatment) and Group II in patients’

characteristics or radiological and laboratory testing. The Fib-4
score was not significantly reduced after 12 weeks’ treatment with
placebo (p = 0.959) or orlistat (p = 0.510) (Fig. 2). Fig. 3 shows the
significant (p = 0.025) increase of NAS in Group I (placebo-treated
group) compared with a non-significant (p = 0.715) decrease of
NAS in Group II (orlistat-treated group).
Orlistat significantly reduced the BMI, waist circumferences,
waist to height ratio, conicity index, ABSI, and ABF (Table 2). It
did not produce significant changes in the value of the lipid accu-
mulation product. Orlistat treatment resulted in a non-significant
reduction of the fasting lipid profile and serum glucose (Table 3).
Next, Orlistat therapy significantly reduced the triglyceride index
and triglyceride-glucose index by 6.4% and 52.5%, respectively
(Table 3). Orlistat-treated patients did not show significant
changes in blood pressure (Table 4).

Discussion

This study showed the beneficial effects of short-term orlistat

Fig. 1. Correlation of Fibrosis-4 score with non-alcoholic fatty liver disease score
(A), and with AST/ALT ratio (B). AST: aspartate aminotransferase, ALT: alanine
aminotransferase.
3
therapy in patients with NAFLD. Orlistat improves the metabolic
syndrome and the scores of liver fibrosis, which is a late complica-
tion of NAFLD. Diabetes mellitus as a concomitant disease was
observed in 32% of our patients, which agrees with other studies
showing that 64.7% of patients with T2D demonstrate ultrasono-
graphic evidence of NAFLD [25]. The other common disease associ-
ated with NAFLD is hypertension, which was observed in 42% of
Vian Ahmed Wasta Esmail, Mohammed Omer Mohammed and Marwan S.M. Al-Nimer Arab Journal of Gastroenterology xxx (xxxx) xxx

Table 2
Effect of orlistat on the anthropometric measurements as a component of metabolic syndrome.

Placebo Orlistat
Before treatment After treatment P value Before treatment After treatment P value
Body weight (kg) 90.4 ± 20.4 90.1 ± 20.0 0.431 93.4 ± 10.5 91.5 ± 10.5 0.001
Body mass index (kg/m2) 33.9 ± 7.4 33.9 ± 7.2 0.447 35.4 ± 4.8 34.7 ± 4.7 0.002
Waist circumference (cm) 107.7 ± 12.7 106.8 ± 13.2 0.349 109.1 ± 7.6 106.4 ± 7.2 0.001
Waist to height ratio 0.661 ± 0.084 0.656 ± 0.086 0.355 0.672 ± 0.063 0.659 ± 0.059 0.002
Conicity index 1.334 ± 0.065 1.324 ± 0.074 0.353 1.324 ± 0.079 1.305 ± 0.080 0.015
Adult body surface area index 0.081 ± 0.004 0.131 ± 0.009 <0.001 0.080 ± 0.005 0.129 ± 0.013 <0.001
Adult body fat 45.1 ± 11.5 45.0 ± 11.2 0.398 43.48 ± 9.78 42.17 ± 10.04 0.012
Lipid accumulation product 100.1 ± 56.6 88.0 ± 54.0 0.055 93.19 ± 38.02 84.41 ± 40.12 0.24

The results are expressed as mean ± SD. P value calculated by using two-tailed paired t-test.

Table 3
Effect of orlistat on the fasting serum lipid profile and glucose.

Placebo Orlistat
Before treatment After treatment P value Before treatment After treatment P value
Fasting serum profile (mg/dl)
Total cholesterol 185.4 ± 31.8 172.9 ± 31.5 0.003 182.8 ± 36.2 171.3 ± 34.5 0.14
Triglyceride 173.6 ± 90.2 153.5 ± 80.1 0.077 165.3 ± 71.1 155.0 ± 71.4 0.49
HDL-c 42.4 ± 11.3 43.2 ± 10.2 0.535 39.6 ± 6.6 42.4 ± 17.2 0.44
Non-HDL-c 143.0 ± 27.7 129.7 ± 29.8 0.001 143.2 ± 36.0 128.9 ± 32.6 0.105
Cholesterol index 0.927 ± 0.159 0.865 ± 0.158 0.003 0.914 ± 0.181 0.857 ± 0.162 0.14
Triglyceride index 1.085 ± 0.564 0.960 ± 0.501 0.077 1.033 ± 0.445 0.969 ± 0.446 <0.001
Triglyceride Glucose Index 9.09 ± 0.67 7.97 ± 0.35 <0.001 9.104 ± 0.485 4.820 ± 0.280 <0.001
Atherogenic index 0.570 ± 0.285 0.607 ± 0.104 0.452 0.592 ± 0.202 0.610 ± 0.215 0.642
Fasting serum glucose (mg/dl) 120.9 ± 36.4 118.1 ± 39.3 0.265 123.4 ± 37.0 112.4 ± 24.7 0.103

The results are expressed as mean ± SD. P value calculated by using two-tailed paired t-test. HDL-c: High density lipoprotein-cholesterol

Table 4
Effect of orlistat on the arterial blood pressure.

Placebo Orlistat
Before treatment After treatment P value Before treatment After treatment P value
Blood pressure (mmHg)
Systolic 134.4 ± 20.0 131.3 ± 19.5 0.203 133.5 ± 20.5 134.720.5 0.763
Diastolic 83.9 ± 13.3 80.5 ± 11.3 0.073 84.8 ± 11.3 84.8 ± 1 9.0 0.364
Mean arterial 100.7 ± 15.0 97.4 ± 13.3 0.085 101.0 ± 13.7 99.9 ± 13.0 0.7

The results are expressed as mean ± SD. P value calculated by using two-tailed paired t-test.

our patients. This is in line with other studies that showed a sim-
ilarity between NAFLD and primary hypertension [26]. According
to the laboratory and radiological investigations, our patients
demonstrate insulin resistance and liver fatty infiltration without
clear evidence of liver fibrosis. Previous reports confirmed evi-
dence of insulin resistance in NAFLD and suggested that fatty liver
infiltration and insulin resistance run in parallel, as liver enzymes
significantly correlated with the homeostatic model assessment of
insulin resistance [27]. The significant correlation between the Fib-
4-score and AST/ALT ratio or NAS indicates that any of these mark-
ers may be useful in assessing liver fibrosis in patients with NAFLD.
Short-term orlistat therapy significantly improved obesity and
body fat accumulation measures. This finding is associated with a
non-significant effect on the lipid profile, indicating that orlistat
did not correct the dyslipidemia [28]. The significant effect of orlis-
tat in reducing the TG-I and TYG-I indicates that orlistat effectively
ameliorates insulin resistance [29]. Short-term orlistat therapy did
not significantly improve fasting serum glucose, while long-term
treatment can improve fasting serum glucose and insulin levels
[30]. The most exciting result of this study is that orlistat therapy
significantly improves liver fibrosis markers indicating the possi-
bility of orlistat’s action on fat deposits in the liver. Ali Khan
et al. [31] found that 16 weeks of treatment with orlistat improved
the ultrasound grades of fatty liver and was associated with sup-
pression of inflammatory markers. Our results showed that the
effect of orlistat on insulin resistance, fatty infiltration, and liver
fibrosis did not run in parallel. Therefore, the most reliable expla-
nation of these results is that orlistat significantly improves the
components of metabolic syndrome leading to improved insulin
resistance and thereby reducing fatty infiltration of the liver. A
liver biopsy as a diagnostic test of fatty liver infiltration and liver
fibrosis was not done because the ethical committee did not allow
it. We consider this a limitation of the study.
Lastly, we conclude that orlistat improves the components of
metabolic syndrome, leading to improvement of insulin resistance,
thereby improving fatty infiltration and, to a lesser extent, the
scoring of liver fibrosis.
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