Clinical Nutrition 41 (2022) 2195e2206

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Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Meta-analyses

Statins’ efficacy in non-alcoholic fatty liver disease: A systematic

review and meta-analysis
Chrysoula Boutari a, *, Panagiotis D. Pappas b, Dimitrios Anastasilakis a,
Christos S. Mantzoros c, **
a
Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
b
First Department of Obstetrics and Gynaecology, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki 56429, Greece
c
Department of Medicine, Boston VA Healthcare System and Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Slosberg-
Landay SL-419, Boston, MA 02215, USA

a r t i c l e i n f o s u m m a r y

Article history: Background & aims: Non-alcoholic fatty liver disease (NAFLD) is closely related with the metabolic
Received 13 May 2022 syndrome and cardiovascular disease. Currently there is no approved medication for NAFLD. Although it
Accepted 1 August 2022 has been suggested that statins can be safely used by patients with elevated liver enzymes, their effect on
NAFLD has not been clearly defined. The aim of this study is to evaluate the effectiveness of statins on
Keywords: biochemical and histological parameters in patients with NAFLD.
Fibrosis
Methods: We searched PubMed, Web of Science, and SCOPUS for clinical trials and observational studies
Non-alcoholic fatty liver
concerning the effects of statins on the development and treatment of NAFLD, regardless of the type or
Statins
Steatohepatitis
dosage of statin, the duration of treatment or the methods used for the diagnosis of NAFLD (biopsy or
imaging technique) up to November 2021.
Results: We identified 13 studies. Liver function tests and lipid profile were significantly improved. There
was a significant decrease in steatosis grade (standardized mean difference, SMD -1.73, 95% CI -2.11
to
1.35; p < 0.00001; I2 ¼ 98%) and in NAFLD activity score (NAS) (SMD -1.09 (95% CI -1.39 to
0.79;
p < 0.00001; I2 ¼ 93%)).
Conclusions: Statins effectively decrease liver enzymes and beneficially affect liver histology in NAFLD
patients.
© 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

1. Introduction prevalence of NAFLD is 6%e35% (median 20%), while in the United

According to the American Association for the Study of Liver
Diseases (AASLD) nonalcoholic fatty liver disease (NAFLD) is
defined as the presence of 5% hepatic steatosis without a sec-
ondary cause of hepatic fat deposition like excessive alcohol use,
chronic use of steatogenic medication, or genetic causes of hepatic
fat accumulation [1]. NAFLD is subdivided into nonalcoholic fatty
liver (NAFL) which is not associated with hepatocellular damage
and nonalcoholic steatohepatitis (NASH) which is related with
inflammation, ballooning of hepatocyte, and fibrosis. Global
* Corresponding author.
** Corresponding author. Brookline Ave, Slosberg-Landay SL-419, Boston, MA
02215, USA.
E-mail addresses: chrisoulabgr@yahoo.gr (C. Boutari), cmantzor@bidmc.harvard.
edu (C.S. Mantzoros).
States it is estimated to be between 10% and 46%, with most biopsy-
based studies reporting a prevalence of NASH of 3%e5% [2,3].
Most NAFLD patients do not mention any symptoms, while
serum aminotransferases levels may be raised or within the upper
normal limit [1]. Nevertheless, patients with histologically proved
NASH, particularly those with some degree of fibrosis, are at
increased risk of developing cirrhosis, hepatocellular carcinoma
(HCC), or even liver failure leading to liver transplantation.
NAFLD is the most common liver disorder in Western world,
where the major risk factors for NAFLD, such as central obesity,
diabetes mellitus type 2 (T2DM), hyperlipidemia, and metabolic
syndrome are at high prevalence [4]. In parallel, a strong relation-
ship between NAFLD and metabolic syndrome as well as increased
cardiovascular morbidity and mortality has been suggested [5,6].
Despite the extensive knowledge of the epidemiology, pathogen-
esis, and natural history of NAFLD, there is currently no approved
medication for its prevention and/or treatment and lifestyle

https://doi.org/10.1016/j.clnu.2022.08.001
0261-5614/© 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
C. Boutari, P.D. Pappas, D. Anastasilakis et al.
Abbreviations
AASLD American Association for the Study of Liver Diseases
NAFLD Nonalcoholic Fatty Liver Disease
NAFL Nonalcoholic Fatty Liver
NASH Nonalcoholic Steatohepatitis
HCC Hepatocellular Carcinoma
T2DM Diabetes Mellitus Type 2
HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A reductase
LDL low-density lipoprotein
CC Cochrane Collaboration
PRISMA Preferred Reporting Items for Systematic Reviews
and Meta-Analysis
changes are recommended, including diet and exercise for weight
reduction, modification of cardiometabolic risk factors and pre-
vention of hepatic and extra-hepatic complications. Moreover,
vitamin E and pioglitazone are currently used for non-diabetic and
diabetic adults with histologically proven NASH respectively [1].
Particularly, current guidelines do only recommend pioglitazone
for patients with NASH and type 2 diabetes mellitus [1,7].
The aetiology and the natural history of NAFLD/NASH is multi-
factorial. As it has been mentioned above, obesity and insulin
resistance are often associated with the disease and are linked to
abnormal lipid metabolism causing hepatic accumulation of tri-
acylglycerol [8]. These abnormalities are related to dysregulation of
different cellular functions and signaling pathways, such as insulin
signaling, de novo lipogenesis, mitochondrial dysfunction, oxida-
tive stress, and endoplasmic reticulum stress [9,10]. The liver me-
tabolizes glucose and fatty acids and stores a considerable amount
of lipid in the form of triacylglycerol when plasma levels are
increased as it happens in hepatic steatosis [11]. In accordance with
the current knowledge of NASH pathogenesis, statins may be
beneficial in this condition [12]. Particularly, impaired lipid meta-
bolism results in biochemical, histological, and clinical changes
associated with NAFLD [13].
Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reduc-
tase (HMG-CoA), which is a key enzyme implicated in cholesterol
synthesis. They reduce hepatic free fatty acids and cholesteryl ester
availability, derived from newly synthesized cholesterol, that re-
stricts the secretion of very low-density lipoprotein (LDL). Also,
they decrease triglycerides secretion from the liver without an
intrahepatic triglycerides accumulation [14]. In addition to their
lipid-lowering activity, they also exert pleiotropic properties,
including antioxidative, anti-inflammatory and antithrombotic ef-
fects, and improve endothelial function [15]. Statins may also
modify the pathways involved in the impaired intrahepatic resis-
tance and vascular tone, leading to portal hypertension [16]. Thus,
statins seem to be an important weapon in the treatment of NAFLD,
able not only to benefit abnormal lipid metabolism and subse-
quently reduce intrahepatic cholesterol [17], but also to regulate
the dynamic and the structural elements of hepatic fibrosis [16].
Although primary treatment of NASH by statins are not rec-
ommended by the current clinical practice AASLD guidelines [18],
there have been studies in humans which have investigated the
effects and the histological efficacy of several statins. However,
although these studies reported results in the right direction, they
did not manage to depict a significant benefit of statins probably
due to their small sample size, the various types of statins admin-
istered and the different duration of follow-up. As for the system-
atic reviews and meta-analyses been conducted so far [19e21],
they included a limited number of participants and studies. For
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Clinical Nutrition 41 (2022) 2195e2206
CT Computed Tomography
SMD Standardized Mean Difference
CHOL Total cholesterol
AST aspartate aminotransferase
ALT alanine transaminase
GGT Gamma-Glutamyl Transferase
NAS NAFLD activity score
CV Cardiovascular
PPAR Peroxisome Proliferator-Activated Receptor
LFTs Liver Function Tests
CVD Cardiovascular disease
instance, the last and the biggest study included no more than 5
studies with totally 91 participants [21]. In this systematic review
and meta-analysis, we tried to comprehensively ascertain the ef-
ficacy of statins in all treated patients with NAFLD or NASH and we
present the following biochemical and histological changes.
2. Material & methods
This meta-analysis is based on previously conducted, published
studies in humans. Its framework was designed based on the rec-
ommendations proposed by the Cochrane Collaboration (CC) and
all results were summarized in accordance with the framework
issued by the Preferred Reporting Items for Systematic Reviews and
Meta-Analysis (PRISMA) statement [22].
The protocol of this systematic review was registered with the
International Prospective Register of Systematic Reviews (PROS-
PERO, number CRD42022308571).
2.1. Search strategy
Queries of studies were conducted in PubMed, Web of Science,
and SCOPUS up to November 2021. The following search terms
were used in various combinations: “non-alcoholic fatty liver dis-
ease,” “non-alcoholic steatohepatitis,” “Hydroxymethylglutaryl-
CoA reductase Inhibitors,” “HMG-CoA reductase inhibitors,” “sta-
tins,” “atorvastatin,” “fluvastatin,” “lovastatin,” “pitavastatin,”
“pravastatin,” “rosuvastatin,” “simvastatin,” “biopsy,” “histology,”
“histopathology,” “transaminases,” “aminotranferases,” “liver en-
zymes,” “ultrasound,” “sonogram,” “imaging”.
2.2. Study selection
We limited our search to studies in humans published in the
English language. All references of the selected literature were
searched for additional relevant trials. Studies included in this
systematic review were randomized controlled trials, observational
studies, and nonrandomized clinical trials that investigated the
effect of any type and dose of statin use on biochemical, histolog-
ical, and imaging findings (ultrasound, computed tomography [CT],
MRI) in NAFLD/NASH patients. There were no restrictions on
sample size or treatment duration. Two review authors screened
the titles and abstracts of all potentially relevant trials. Studies were
eligible if the definition of NAFLD was in accordance to the practice
guidelines from the AASLD [18] or the EASL/EASD/EASO [7]. Diag-
nostic criteria should have included biopsy or non-invasive imaging
techniques (ultrasound, CT, MRI). Also, studies were included if only
the treatment arm received a statin. Studies were finally included if
they reported at least one of the primary or secondary outcomes.
C. Boutari, P.D. Pappas, D. Anastasilakis et al.
2.3. Data extraction and quality assessment
The titles and abstracts of identified articles were independently
screened by two members of the research team and the full text of
articles that were not rejected was reviewed according to the
eligibility criteria. Disagreements were resolved by consensus. Data
were extracted into an Excel form. For each article data extracted
included participants number, study characteristics, and findings of
interest (baseline and post-intervention values, between-group
changes in outcomes).
The methodological quality of observational studies was
assessed with the Cochrane assessment of bias for non-randomized
studies tool (ROBINS-I) [23]. For the RCTs, the Cochrane Collabo-
ration's tool for assessing risk of bias was utilized [24].
2.4. Statistical analysis
Statistical analysis was performed using Review Manager
(RevMan) version 5.4. The Cochrane Collaboration, 2020. The
random-effects model was performed to pool continuous out-
comes from the studies assessing the effect of statins on NAFLD-
associated parameters to derive standardized mean differences
(SMDs) and corresponding 95% confidence intervals (CIs). Finally,
pooled results were derived for the total NAFL/NASH cohorts.
Statistical heterogeneity was evaluated using the I2 index and Q-
test P value. Either I2 > 50% or c2 test P < 0.1 indicates substantial
heterogeneity [25]. In every instance, a p-value <0.05 was
considered significant.
3. Results
The initial search identified 791 articles from the electronic
databases (MEDLINE, n ¼ 128; SCOPUS, n ¼ 59; EMBASE, n ¼ 586;
CENTRAL, n ¼ 18). Following removal of duplicates and screening
on the basis of titles and abstracts, 735 articles were further
excluded. After thorough assessment of 56 trials, 13 trials were
included in the quantitative analysis. Figure 1 depicts the study
identification and selection of eligible trials.
3.1. Details of characteristics of eligible trials
The detailed characteristics of all eligible trials are presented in
Table 1. All studies included in the analysis were reported between
2007 and 2020 and the sample size of the treatment arm of each
trial varied from 10 to 453. The duration of follow-up ranged from
30 weeks to 15.9 years. All studies used statins to treat dyslipidemia
in patients with NAFLD. Three trials used rosuvastatin [26e28], five
used atorvastatin [29e33], one trial evaluated simvastatin [34], one
pitavastatin [35], and three trials used multiple statin types
[36e38]. The protocols of the included studies were very dissimilar.
Our review considered change in the level of liver enzymes and
histological hepatic characteristics as inclusion criteria for primary
outcome measures. The methods of diagnosis and measuring
change in NAFLD varied markedly (steatosis grading, NAS,
necroeinflammatory activity grade, fibrosis stage, imaging findings
[CT or ultrasound findings]).
3.2. Statins decrease cholesterol and triglycerides levels
All studies reported the change in total cholesterol (CHOL) and
triglycerides. Ekstedt et al. [36], Kiyici et al. [31] and Georgescu et al.
[32] did not display data regarding LDL and HDL changes. Also,
Nelson et al. [34] did not provide data on HDL levels. The meta-
analysis results suggested that statin treatment decreased CHOL
(
2.56, 95% CI [
2.70,
2.42]; p < 0.00001; I2 ¼ 92%), LDL (
2.08,
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Clinical Nutrition 41 (2022) 2195e2206
95%CI [
2.20,
1.95]; p < 0.00001; I2 ¼ 64%) and triglycerides
(
0.72, 95%CI [
0.83,
0.62]; p < 0.00001; I2 ¼ 75%) and increased
HDL (0.30, 95%CI [0.19, 0.40]; p < 0.00001; I2 ¼ 45%) (Figs. 1e4). The
main findings and outcomes extracted from each study are shown
in Table 3.
3.3. Statins reduce liver enzymes
A significant decrease in liver enzyme levels was reported with a
standardized mean difference of
0.96 (95% CI -1.07 to
0.85;
p < 0.00001; I2 ¼ 92%) in aspartate aminotransferase (AST)
and
1.42 (95% CI -1.53 to
1.30; p < 0.00001; I2 ¼ 96%) in alanine
transaminase (ALT). The standardized mean difference for gamma-
glutamyl transferase (GGT) was
0.83 (95% CI -0.94 to
0.72;
p < 0.00001; I2 ¼ 89%) (Table 2, Figs. 5e7) (see Fig. 8).
3.4. Statins decrease steatosis and NAS
There was a significant reduction in steatosis grade (Fig. 3) with
a standardized mean difference of
1.73 (95% CI -2.11 to
1.35;
p < 0.00001; I2 ¼ 98%) and NAFLD activity score (NAS) (Fig. 4) with
a standardized mean difference of
1.09 (95% CI -1.39 to
0.79;
p < 0.00001; I2 ¼ 93%) (Table 4). We did not include the study of
Sfikas et al. in the analysis of NAS as outcome, due to the ambigu-
ities in the methodology followed to estimate the changes in the
NAFLD/NASH stage. Given the relatively large size of the Sfikas
study, we also analyzed the other studies in the context of a
sensitivity analysis, without that of Sfikas et al., and report that the
changes in all outcomes studied were still statistically significant
(See Supplementary Material) (see Fig. 9).
3.5. Statins do not impair fibrosis stage significantly
As it has been reported by the previous systematic review and
meta-analysis [20], statins do not change fibrosis stage significantly
(standardized mean difference 0.22 [95% CI -0.08 to 0.51; p ¼ 0.15;
I2 ¼ 59%]) (Table 4, Fig. 10) (see Fig. 11).
3.6. Results after excluding studies without biopsy proven NAFLD
Even when the study (by Rana et al.) [28] without a biopsy-
based diagnosis of NAFLD was removed the meta-analysis results
continued to suggest that statin use decreases significantly stea-
tosis grade (standardized mean difference was
1.19, 95% CI -1.66
to
0.72; p < 0.00001; I2 ¼ 98%).
4. Discussion
This is the most comprehensive study which assesses the results
of statin use on NAFLD progression regardless of the method of
diagnosis. A previous meta-analysis included only studies with
histological diagnosis of the disease and did not systematically
evaluate the alterations in serum lipid levels and liver function tests
[20]. Another recent meta-analysis [21] did not include some
studies that we finally took into account [26,30,36,38].
Serum liver enzymes are moderately increased in patients with
NAFLD and for this reason, most of the non-invasive scoring sys-
tems for the exclusion of advanced fibrosis, based mainly on labo-
ratory tests, take into account the aminotransferases [39e41]. It has
been suggested that statins can decrease their levels, improving in
parallel hepatic injury in that patient group. A significant reduction
of the level of ALT, AST and GGT was reported by all studies, except
two, one which reported an increasing trend of liver enzymes with
the use of rosuvastatin for 24 weeks [28], and another which pre-
sented increases in all liver enzymes, probably due to its
C. Boutari, P.D. Pappas, D. Anastasilakis et al. Clinical Nutrition 41 (2022) 2195e2206

Fig. 1. Study selection flow diagram.

Table 1
Characteristics of eligible trials and demographics of patients in statin treatment arm.

Study Country Design N Mean age Duration Type of statins and Diagnostic
(years) (years) dosage (mg/day) Method

Kiyici et al. (2003) Turkey Prospective cohort 27 50.2 ± 1.4 0.5 Atorvastatin 10 mg/day Liver biopsy
Athyros et al. (2006) Greece Randomized controlled trial 63 60 ± 11.0 1 Atorvastatin 20 mg/day Liver ultrasonography
Ekstedt et al. (2007) Sweden Retrospective cohort 17 48.7 ± 9.1 1.0e15.9 Simvastatin, Liver biopsy
Atorvastatin,
Pravastatin
Georgescu et al. (2007) Romania Prospective cohort 10 55.0 ± 7.5 0.6 Atorvastatin 20 mg/day Liver biopsy
Hyogo et al. (2008) Japan Prospective cohort 31 52.5 2 Atorvastatin 10 mg/day Liver biopsy
Nelson et al. (2009) USA Randomized controlled trial 10 52.6 ± 8.6 1 Simvastatin 20 mg/day Liver biopsy
Hyogo et al. (2011) Japan Prospective cohort 20 50.6 1 Pitavastatin 2 mg/day Liver biopsy
Maroni et al. (2011) Italy Retrospective cohort 43 54.5 ± 9.6 1 Atorvastatin, Liver ultrasonography
Simvastatin, Lovastatin,
Rosuvastatin,
Fluvastatin
Nakahara et al. (2012) Japan Prospective cohort 19 46.3 2 Rosuvastatin 2.5 mg/ Liver biopsy
day
Hyogo et al. (2012) Japan Prospective cohort 42 50.0 ± 12.7 1 Atorvastatin 10 mg/day Liver biopsy
Kargiotis et al. (2015) Greece Prospective cohort 20 40.5 ± 5.6 1 Rosuvastatin 10 mg/ Liver biopsy
day
Rana et al. (2016) India Randomized controlled trial 34 N/A 0.5 Rosuvastatin Liver ultrasonography
Sfikas et al. (2020) Greece Randomized controlled trial 453 43.6 ± 6.0a 1 Atorvastatin 31 mg/ NAFLD activity score,
day, Rosuvastatin FIB-4 score, Liver
24 mg/day, Pitavastatin ultrasonography
3.2 mg/day
a
Calculated values.

retrospective design and the information bias that results from that
[37]. Moreover, two studies [34,35], reported significant reduction
in ALT levels but did not report similar results for the other two
enzymes. This is likely due to the different types and dosages of
statins used in the studies and the variable follow-up duration.
Nevertheless, it is worth mentioning that we also run the analysis
without the Ekstedt et al. study, which had the most extended
follow-up duration (up to 15.9 years) and we found similar results
indicating that duration of the study did not materially influence
our results. None of the studies had more than three times eleva-
tion of liver enzymes. Therefore, statins seem to exert favorable
effects in alleviating liver injury. Thus, the improvement of liver
enzymes reinforces the long-validated concept that statins do not
increase the risk of liver injury also in NAFLD.

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Fig. 2. Statins effect on total cholesterol (CHOL) forest plot.

Fig. 3. Statins effect on LDL forest plot.

Fig. 4. Statins effect on HDL forest plot.

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Table 2
Statins effect on liver enzymes in statin treatment arm (values pre- and post-treatment with statin).

Study ALT (pre) ALT (post) AST (pre) AST (post) GGT (pre) GGT (post)
(IU/L) (IU/L) (IU/L) (IU/L) (IU/L) (IU/L)

Kiyici et al. (2003) 81.8 ± 8.9 44.8 ± 5.7 45.4 ± 4 32.1 ± 3 64.2 ± 9.5 37.2 ± 4.2
Athyros et al. (2006) 54 ± 23 32 ± 9 38 ± 11 25 ± 8 52 ± 28 33 ± 8
Ekstedt et al. (2007) 80 ± 48 63 ± 40 41 ± 15 36 ± 13 N/A N/A
Georgescu et al. (2007) 66.7 ± 16.4 34.8 ± 15.7 N/A N/A 40.6 ± 27 27.5 ± 13.9
Hyogo et al. (2008) 89.4 ± 46.3 35.9 ± 13.5 51.1 ± 23.3 25.8 ± 7.3 87 ± 74 51 ± 16
Nelson et al. (2009) 70.4 ± 29.6 49.5 ± 15.6 43.3 ± 14.8 36.5 ± 11.5 N/A N/A
Hyogo et al. (2011) 102.1 ± 60.1 68.2 ± 48.3 62.6 ± 48.9 41.8 ± 18.2 94.5 ± 82.7 59.6 ± 21.1
Maroni et al. (2011) 37.6 ± 14.2 44.7 ± 30.4 26.3 ± 8.2 34.3 ± 31.6 76.4 ± 59 86.5 ± 93.3
Nakahara et al. (2012) 68.7 ± 52.5 50.3 ± 27.8 40.1 ± 22.8 33.8 ± 15.2 78.7 ± 83.6 61.4 ± 51.2
Hyogo et al. (2012) 89 ± 61.9 56.6 ± 52.3 48 ± 26.7 33 ± 18.4 90.4 ± 89.9 65.1 ± 49.9
Kargiotis et al. (2015) 66.6 27.6 56.9 18.3 76.4 42.4
Rana et al. (2016) 51.9 ± 17.5 59.9 ± 30.6 44.6 ± 17.8 52.9 ± 27.3 N/A N/A
Sfikas et al. (2020) 61.2 ± 14.3 36 ± 9.1 46.4 ± 12.3 33.8 ± 9 46.4 ± 15.3 33.9 ± 10.5

Table 3
Statins effect on lipid profile in statin treatment arm (values pre- and post-treatment with statin).

Study CHOL (pro) CHOL (post) LDL (pro) LDL (post) HDL (pro) HDL (post) trigl (pro) trigl (post)
(mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL)

Kiyici et al. (2003) 238.2 ± 6.6 183.7 ± 7 N/A N/A N/A N/A 82 ± 5.4 71.9 ± 8.9
Athyros et al. (2006) 235.9 ± 42.5 162.4 ± 30.9 154.7 ± 38.7 100.5 ± 23.2 38.7 ± 15.5 42.5 ± 19.3 88.9 ± 46.4 61.9 ± 27.1
Ekstedt et al. (2007) 264 ± 86 176 ± 39 N/A 101 ± 35 N/A 45 ± 9.5 184 ± 99 159 ± 60
Georgescu et al. (2007) 325.9 ± 49.2 208.6 ± 13.8 N/A N/A N/A N/A 223.3 ± 80 145.9 ± 44.4
Hyogo et al. (2008) 237 ± 39 163 ± 32 147 ± 31 81 ± 27 50 ± 12 55 ± 12 199 ± 90 132 ± 44
Nelson et al. (2009) 230.5 ± 72.5 209.1 ± 114.7 138.5 102.7 N/A N/A 388.7 ± 507.9 490 ± 890.5
Hyogo et al. (2011) 252.8 ± 53 184 ± 41.9 160.7 ± 45.4 100.3 ± 32.1 50.1 ± 15.6 52.6 ± 11.4 216.9 ± 113.1 169.4 ± 94.8
Maroni et al. (2011) 289.8 ± 46.0 192.3 ± 33.8 194.4 ± 41.3 110.9 ± 25.9 56.1 ± 16.4 54.3 ± 15.4 212 ± 146.2 146.2 ± 105.8
Nakahara et al. (2012) 245.3 ± 30.8 170.8 ± 22.3 170.5 ± 32.3 90.5 ± 22.4 58.2 ± 15.8 55.1 ± 14.5 172.9 ± 63.6 151.5 ± 55
Hyogo et al. (2012) 233.9 ± 35 177 ± 35.5 144.5 ± 29.2 92.9 ± 30.8 48 ± 12.5 54.1 ± 11.9 206.8 ± 114.8 150.1 ± 73.1
Kargiotis et al. (2015) 251 ± 22 179 ± 9 180 ± 23 110 ± 11 38 ± 5 44 ± 5 187 ± 19 117 ± 18
Rana et al. (2016) 205.1 ± 29.3 146.8 ± 19.0 113.2 ± 38.3 59.4 ± 12.5 37.9 ± 5.1 40.4 ± 4.6 260.7 ± 21.4 138.1 ± 14.2
Sfikas et al. (2020) 237 ± 39 163 ± 32 147 ± 31 81 ± 27 50 ± 12 55 ± 12 199 ± 90 132 ± 44

Fig. 5. Statins effect on triglycerides forest plot.

The most typical side effect of statins is elevation in amino-
transferases which is generally asymptomatic, occurs within the
first year of treatment, and often resolves spontaneously [42]. High
doses of statins caused considerable liver injury in animals possibly
due to the depletion of mevalonate or its downstream metabolite
[43]. It has also been shown that higher doses and higher intensity
statin therapy are associated with an increased incidence of ami-
notransferases elevation [44,45]. Nevertheless, their hepatotoxicity
in humans is scarce and unforeseeable [42]. Of note, statins have
been proven hepato-safe even in patients with increased amino-
transferases and chronic liver diseases. Chalasani et al. first showed
that patients with elevated levels of liver enzymes were not
exposed to an increased risk of hepatotoxicity from using statins
[46].
The safety of statins in patients with elevated liver enzymes has
been debated for several years and many health practitioners are
still skeptical concerning their administration in this setting. A
survey of more than nine hundred physicians showed that only half

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Fig. 6. Statins effect on ALT forest plot.

Fig. 7. Statins effect on AST forest plot.

Fig. 8. Statins effect on GGT forest plot.

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Table 4
Statins effect on histological findings (steatosis grade, NAS, fibrosis stage) in statin treatment arm (values pre- and post-treatment with statin).

Study Steatosis grade (pro) (%) Steatosis grade (post) (%) NAS (pro) NAS (post) Fibrosis stage (pro) Fibrosis stage (post)

Kiyici et al. (2003) N/A N/A N/A N/A N/A N/A

Athyros et al. (2006) N/A N/A N/A N/A N/A N/A
Ekstedt et al. (2007) N/A N/A N/A N/A N/A N/A
Georgescu et al. (2007) N/A N/A 6.7 ± 1.3 5 ± 1.6 N/A N/A
Hyogo et al. (2008) 1.6 ± 0.1 0.8 ± 0.1 4.1 ± 0.3 2.9 ± 0.2 1.8 ± 0.2 1.9 ± 0.2
Nelson et al. (2009) N/A N/A N/A N/A 1.3 ± 0.7 1.5 ± 0.9
Hyogo et al. (2011) 2.8 ± 0.6 2.5 ± 0.7 6.7 ± 1.3 6.3 ± 1.2 2.3 ± 0.7 2.1 ± 0.6
Maroni et al. (2011) N/A N/A N/A N/A N/A N/A
Nakahara et al. (2012) 1.4 ± 0.8 1.1 ± 0.3 3.9 ± 1.5 3.4 ± 1.0 2.3 ± 0.7 2 ± 0.7
Hyogo et al. (2012) N/A N/A 3.9 ± 1 3 ± 0.9 N/A N/A
Kargiotis et al. (2015) 3±0 0.05 ± 0.1 8±0 0.2 ± 0.4 N/A N/A
Rana et al. (2016) 2.6 ± 0.5 1.3 ± 0.5 N/A N/A N/A N/A
Sfikas et al. (2020) N/A N/A N/A N/A N/A N/A

Fig. 9. Statins effect on steatosis grade forest plot.

Fig. 10. Statins effect on NAFLD activity score (NAS) forest plot.

of them would prescribe statins in case of high baseline trans-
aminases and only 4 in 10 would utilize statins in the presence of an
underlying liver disease [47]. These findings were confirmed also in
subsequent studies revealing an under-prescription of statins in
NAFLD patients even if they presented dyslipidemia or a high car-
diovascular (CV) risk [48,49].
However, given the fact that patients with NASH are at high CV
risk and that statins are the cornerstone of the treatment of dysli-
pidemia and the prevention of cardiovascular events [50,51], the
use of these pharmaceutical agents in NAFLD patients should not be
avoided or under-estimated. NAFLD patients are exposed to a great
cardio-metabolic risk [52]. Interestingly, cardiovascular disease

2202
C. Boutari, P.D. Pappas, D. Anastasilakis et al.
Fig. 11. Statins effect on fibrosis forest plot.
(CVD) is the predominant cause of death in these patients [53]. A
large body of evidence suggests that NAFLD is linked with a more
atherothrombotic risk profile beyond overweight/obesity and other
cardio-metabolic risk factors [54]. A meta-analysis of 16 observa-
tional studies including 34,043 patients concluded that patients
with NAFLD had a 64% higher risk of developing fatal or non-fatal
cardiovascular events as compared to patients without NAFLD
(odds ratio [OR] 1.64; 95% confidence interval [CI] 1.26e2.13) [55].
Moreover, a meta-analysis of 34 studies suggested that NAFLD is
associated with an increased risk for incident CVD (HR 1.37; 95% CI
1.10e1.72) and that NAFLD patients are more likely to be diagnosed
with coronary heart disease (HR 2.31; 95% CI 1.46e3.65) [56].
Notably, NAFLD is related not only with a greater prevalence of
clinically established CVD, but also with indices of subclinical
atherosclerosis such as increased arterial stiffness, carotid-artery
intimal media thickness or coronary-artery calcium [57,58].
It is noteworthy that current guidelines concerning NAFLD/
NASH report that statins can be safely used to treat dyslipidemia
and subsequently to prevent CVD [7,59]. It is also important to note
that, recently, an Expert Panel concluded that, according to five
post-hoc analyses of prospective long-term survival studies and
five smaller biopsy-proven NASH studies [26,30,60e65], statins led
to noticeable reductions in CVD events in comparison to those also
on statins and healthy liver and suggested statin use either alone or
combined with a peroxisome proliferator-activated receptor (PPAR)
g agonist or ezetimibe for the primary or secondary prevention of
CVD, and the avoidance of liver-related complications in patients
with NAFLD/NASH at high CVD or HCC risk [50]. Despite the notion
of their harmful effect and toxicity, and the poor prescription and
adherence rates to statin treatment as well in patients with
elevated liver function tests (LFTs) in the past [66], it is now clear
that statins are efficacious and cost-saving both for primary and
secondary prevention of CVD [67].
Histological improvement was also accomplished after treat-
ment with statins. Our meta-analysis suggests a reduction in the
steatosis grade mean as well as in NAS mean. NAS is a histologic
evaluation system that includes the full spectrum of nonalcohol-
associated fatty liver disease histologic changes and can assess
changes following therapy in NAFLD patients. It is the sum of the
separate scores for steatosis, hepatocellular ballooning and lobular
inflammation [68]. Of note, even without the studies not providing
hepatic biopsies [28,38], the beneficial effect of statins on steatosis
grade and NAS remain significant. Growing body of evidence
2203
Clinical Nutrition 41 (2022) 2195e2206
indicates that statins can alleviate liver damage caused by NAFLD.
Similarly, the results by previous meta-analyses [19e21] suggested
the beneficial effect of statins on hepatic steatosis and NAS,
although Eslami et al. [19] and Rattanchaisit et al. [20] did not
manage to support this finding with statistical significance.
Statins are believed to mitigate oxidative stress, prevent in-
flammatory cell activation and hepatic stellate cell senescence,
reduce collagen synthesis and improve endothelial function [69]. A
recent meta-analysis confirmed that statins benefit the parameters
of hepatic portal vessel pressure and consequently, the prognosis of
liver cirrhosis in long-term follow-up [70]. However, our meta-
analysis could not ascertain these actions on fibrosis stage. This is
probably due to the short follow-up time of the included studies. It
has been suggested that the average rate of fibrosis progression is
longer than 7.5 years in NASH patients and more than 14 years in
NAFLD patients and thus longer and larger studies are needed [71].
Moreover, the results of the meta-analysis on influence of statins in
survival rate, decompensation events of liver cirrhosis, and hepa-
tocellular carcinoma derived from a 14-year follow-up [70]. A dose-
dependent effect of statins on these parameters has also been
described [70] and the various types and dosages of statins been
utilized in the studies of our meta-analysis are probably the reasons
for this non-significant decrease in fibrosis stage. A multicenter
European study concluded that statins were independently asso-
ciated with protection from steatosis, NASH and significant fibrosis
in 1201 subjects at high risk for NASH and a dose-dependent
relationship between the intensity of statin treatment and the
reduced risk of liver damage was demonstrated [64]. Additionally,
neither the meta-analysis by Rattanachaisit et al. [20], nor that by
Fatima et al. [21], which however included less studies, confirmed a
significant effect of statins on fibrosis stage.
The present systematic review and meta-analysis is not without
limitations. The first and foremost is the inclusion of limited
number of eligible studies and the small sample size of each indi-
vidual study. Furthermore, most of the studies had a different
follow-up period and used different types and dosages of statins.
Another point that should be mentioned is that a high percentage
of participants had comorbidities such as T2DM or metabolic syn-
drome. Last, many studies did not report data concerning the BMI of
the participants and its changes at the follow-up, although it is an
important factor impairing central obesity, insulin resistance and
NAFLD. Subgroup analysis to control for these factors could not be
performed because of the small number of studies. These points
C. Boutari, P.D. Pappas, D. Anastasilakis et al.
may affect the reliability and the robustness of our findings and
consequently, our results should be cautiously interpreted.
5. Conclusion
Based on still limited, but yet more extensive evidence
compared to previous systematic reviews and meta-analyses, sta-
tins efficiently reduce liver enzymes and improve liver histology in
NAFLD patients. Thus, physicians should not hesitate to prescribe
statins in NAFLD patients and especially those at high CVD risk,
except possibly in very advanced stages of NASH, since this class of
pharmaceutical agents apparently has the potential for deceler-
ating the progression of NAFLD. Future large-scale randomized
trials, with rigorous methodology and extended study length are
required to further establish the role of statins in the management
of NAFLD. However, since statins are now generic drugs, the in-
terest of pharmaceutical companies in conducting more random-
ized controlled clinical trials may be limited.
Data availability
All data generated or analysed during this study are included in
this published article (and its supplementary information files).
Funding statement
This research received no specific grant from any funding
agency in the public, commercial or not-for-profit sectors.
Authors’ relationships and activities
The authors declare that there are no relationships or activities
that might bias, or be perceived to bias, their work.
Authors contribution
CSM conceived the study; CSM, CB, DA and PDP developed the
search strategy; CB, and PDP conducted the searches; CB and PDP
conducted the screening of studies; CB and DA conducted the data
extraction and quality assessment; CB conducted the qualitative
synthesis of the findings with input from PDP; CB, DA and PDP led
the drafting of the manuscript. All authors provided critical input,
reviewed the manuscript for important content, take responsibility
for the contents of this article and approved the final version sub-
mitted for publication.
Conflicts of interest
Over the past 3 years, CSM has been a shareholder of and reports
grants through his Institution and personal consulting fees from
Coherus Inc and AltrixBio, he reports grants through his institution
from Merck, he reports grants through his institution and personal
consulting fees from Novo Nordisk, reports personal consulting fees
and support with research reagents from Ansh Inc, reports personal
consulting fees from Genfit, Lumos, Amgen, Corcept, Intercept,
Astra Zeneca and Regeneron, reports support (educational activity
meals at and through his institution) from Amarin, Novo Nordisk
and travel support and fees from TMIOA, Elsevier, College Inter-
nationale Researche Servier and the Cardio Metabolic Health Con-
ference. None is related to the work presented herein. C.S.M. also
reports that he was member of the California Walnut Commission
Scientific Advisory Board and has received travel and grant support
by the California Walnut Commission, outside the submitted work.
The remaining authors declare no conflicts of interest. The
remaining authors declare no conflicts of interest.
2204
Clinical Nutrition 41 (2022) 2195e2206
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.clnu.2022.08.001.
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