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

States it is estimated to be between 10% and 46%, with most biopsy-
According to the American Association for the Study of Liver based studies reporting a prevalence of NASH of 3%e5% [2,3].
Diseases (AASLD) nonalcoholic fatty liver disease (NAFLD) is Most NAFLD patients do not mention any symptoms, while
defined as the presence of 5% hepatic steatosis without a sec- serum aminotransferases levels may be raised or within the upper
ondary cause of hepatic fat deposition like excessive alcohol use, normal limit [1]. Nevertheless, patients with histologically proved
chronic use of steatogenic medication, or genetic causes of hepatic NASH, particularly those with some degree of fibrosis, are at
fat accumulation [1]. NAFLD is subdivided into nonalcoholic fatty increased risk of developing cirrhosis, hepatocellular carcinoma
liver (NAFL) which is not associated with hepatocellular damage (HCC), or even liver failure leading to liver transplantation.
and nonalcoholic steatohepatitis (NASH) which is related with NAFLD is the most common liver disorder in Western world,
inflammation, ballooning of hepatocyte, and fibrosis. Global 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
* Corresponding author. cardiovascular morbidity and mortality has been suggested [5,6].
** Corresponding author. Brookline Ave, Slosberg-Landay SL-419, Boston, MA
Despite the extensive knowledge of the epidemiology, pathogen-
02215, USA.
E-mail addresses: [email protected] (C. Boutari), [email protected]. esis, and natural history of NAFLD, there is currently no approved
edu (C.S. Mantzoros). 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. Clinical Nutrition 41 (2022) 2195e2206

Abbreviations CT Computed Tomography

SMD Standardized Mean Difference
AASLD American Association for the Study of Liver Diseases CHOL Total cholesterol
NAFLD Nonalcoholic Fatty Liver Disease AST aspartate aminotransferase
NAFL Nonalcoholic Fatty Liver ALT alanine transaminase
NASH Nonalcoholic Steatohepatitis GGT Gamma-Glutamyl Transferase
HCC Hepatocellular Carcinoma NAS NAFLD activity score
T2DM Diabetes Mellitus Type 2 CV Cardiovascular
HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A reductase PPAR Peroxisome Proliferator-Activated Receptor
LDL low-density lipoprotein LFTs Liver Function Tests
CC Cochrane Collaboration CVD Cardiovascular disease
PRISMA Preferred Reporting Items for Systematic Reviews
and Meta-Analysis

changes are recommended, including diet and exercise for weight instance, the last and the biggest study included no more than 5
reduction, modification of cardiometabolic risk factors and pre- studies with totally 91 participants [21]. In this systematic review
vention of hepatic and extra-hepatic complications. Moreover, and meta-analysis, we tried to comprehensively ascertain the ef-
vitamin E and pioglitazone are currently used for non-diabetic and ficacy of statins in all treated patients with NAFLD or NASH and we
diabetic adults with histologically proven NASH respectively [1]. present the following biochemical and histological changes.
Particularly, current guidelines do only recommend pioglitazone
for patients with NASH and type 2 diabetes mellitus [1,7]. 2. Material & methods
The aetiology and the natural history of NAFLD/NASH is multi-
factorial. As it has been mentioned above, obesity and insulin This meta-analysis is based on previously conducted, published
resistance are often associated with the disease and are linked to studies in humans. Its framework was designed based on the rec-
abnormal lipid metabolism causing hepatic accumulation of tri- ommendations proposed by the Cochrane Collaboration (CC) and
acylglycerol [8]. These abnormalities are related to dysregulation of all results were summarized in accordance with the framework
different cellular functions and signaling pathways, such as insulin issued by the Preferred Reporting Items for Systematic Reviews and
signaling, de novo lipogenesis, mitochondrial dysfunction, oxida- Meta-Analysis (PRISMA) statement [22].
tive stress, and endoplasmic reticulum stress [9,10]. The liver me- The protocol of this systematic review was registered with the
tabolizes glucose and fatty acids and stores a considerable amount International Prospective Register of Systematic Reviews (PROS-
of lipid in the form of triacylglycerol when plasma levels are PERO, number CRD42022308571).
increased as it happens in hepatic steatosis [11]. In accordance with
the current knowledge of NASH pathogenesis, statins may be 2.1. Search strategy
beneficial in this condition [12]. Particularly, impaired lipid meta-
bolism results in biochemical, histological, and clinical changes Queries of studies were conducted in PubMed, Web of Science,
associated with NAFLD [13]. and SCOPUS up to November 2021. The following search terms
Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reduc- were used in various combinations: “non-alcoholic fatty liver dis-
tase (HMG-CoA), which is a key enzyme implicated in cholesterol ease,” “non-alcoholic steatohepatitis,” “Hydroxymethylglutaryl-
synthesis. They reduce hepatic free fatty acids and cholesteryl ester CoA reductase Inhibitors,” “HMG-CoA reductase inhibitors,” “sta-
availability, derived from newly synthesized cholesterol, that re- tins,” “atorvastatin,” “fluvastatin,” “lovastatin,” “pitavastatin,”
stricts the secretion of very low-density lipoprotein (LDL). Also, “pravastatin,” “rosuvastatin,” “simvastatin,” “biopsy,” “histology,”
they decrease triglycerides secretion from the liver without an “histopathology,” “transaminases,” “aminotranferases,” “liver en-
intrahepatic triglycerides accumulation [14]. In addition to their zymes,” “ultrasound,” “sonogram,” “imaging”.
lipid-lowering activity, they also exert pleiotropic properties,
including antioxidative, anti-inflammatory and antithrombotic ef- 2.2. Study selection
fects, and improve endothelial function [15]. Statins may also
modify the pathways involved in the impaired intrahepatic resis- We limited our search to studies in humans published in the
tance and vascular tone, leading to portal hypertension [16]. Thus, English language. All references of the selected literature were
statins seem to be an important weapon in the treatment of NAFLD, searched for additional relevant trials. Studies included in this
able not only to benefit abnormal lipid metabolism and subse- systematic review were randomized controlled trials, observational
quently reduce intrahepatic cholesterol [17], but also to regulate studies, and nonrandomized clinical trials that investigated the
the dynamic and the structural elements of hepatic fibrosis [16]. effect of any type and dose of statin use on biochemical, histolog-
Although primary treatment of NASH by statins are not rec- ical, and imaging findings (ultrasound, computed tomography [CT],
ommended by the current clinical practice AASLD guidelines [18], MRI) in NAFLD/NASH patients. There were no restrictions on
there have been studies in humans which have investigated the sample size or treatment duration. Two review authors screened
effects and the histological efficacy of several statins. However, the titles and abstracts of all potentially relevant trials. Studies were
although these studies reported results in the right direction, they eligible if the definition of NAFLD was in accordance to the practice
did not manage to depict a significant benefit of statins probably guidelines from the AASLD [18] or the EASL/EASD/EASO [7]. Diag-
due to their small sample size, the various types of statins admin- nostic criteria should have included biopsy or non-invasive imaging
istered and the different duration of follow-up. As for the system- techniques (ultrasound, CT, MRI). Also, studies were included if only
atic reviews and meta-analyses been conducted so far [19e21], the treatment arm received a statin. Studies were finally included if
they included a limited number of participants and studies. For they reported at least one of the primary or secondary outcomes.
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2.3. Data extraction and quality assessment 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
The titles and abstracts of identified articles were independently HDL (0.30, 95%CI [0.19, 0.40]; p < 0.00001; I2 ¼ 45%) (Figs. 1e4). The
screened by two members of the research team and the full text of main findings and outcomes extracted from each study are shown
articles that were not rejected was reviewed according to the in Table 3.
eligibility criteria. Disagreements were resolved by consensus. Data
were extracted into an Excel form. For each article data extracted 3.3. Statins reduce liver enzymes
included participants number, study characteristics, and findings of
interest (baseline and post-intervention values, between-group A significant decrease in liver enzyme levels was reported with a
changes in outcomes). standardized mean difference of
0.96 (95% CI -1.07 to
0.85;
The methodological quality of observational studies was p < 0.00001; I2 ¼ 92%) in aspartate aminotransferase (AST)
assessed with the Cochrane assessment of bias for non-randomized and
1.42 (95% CI -1.53 to
1.30; p < 0.00001; I2 ¼ 96%) in alanine
studies tool (ROBINS-I) [23]. For the RCTs, the Cochrane Collabo- transaminase (ALT). The standardized mean difference for gamma-
ration's tool for assessing risk of bias was utilized [24]. 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).
2.4. Statistical analysis
3.4. Statins decrease steatosis and NAS
Statistical analysis was performed using Review Manager
(RevMan) version 5.4. The Cochrane Collaboration, 2020. The There was a significant reduction in steatosis grade (Fig. 3) with
random-effects model was performed to pool continuous out- a standardized mean difference of
1.73 (95% CI -2.11 to
1.35;
comes from the studies assessing the effect of statins on NAFLD- p < 0.00001; I2 ¼ 98%) and NAFLD activity score (NAS) (Fig. 4) with
associated parameters to derive standardized mean differences a standardized mean difference of
1.09 (95% CI -1.39 to
0.79;
(SMDs) and corresponding 95% confidence intervals (CIs). Finally, p < 0.00001; I2 ¼ 93%) (Table 4). We did not include the study of
pooled results were derived for the total NAFL/NASH cohorts. Sfikas et al. in the analysis of NAS as outcome, due to the ambigu-
Statistical heterogeneity was evaluated using the I2 index and Q- ities in the methodology followed to estimate the changes in the
test P value. Either I2 > 50% or c2 test P < 0.1 indicates substantial NAFLD/NASH stage. Given the relatively large size of the Sfikas
heterogeneity [25]. In every instance, a p-value <0.05 was study, we also analyzed the other studies in the context of a
considered significant. sensitivity analysis, without that of Sfikas et al., and report that the
changes in all outcomes studied were still statistically significant
3. Results (See Supplementary Material) (see Fig. 9).

The initial search identified 791 articles from the electronic 3.5. Statins do not impair fibrosis stage significantly
databases (MEDLINE, n ¼ 128; SCOPUS, n ¼ 59; EMBASE, n ¼ 586;
CENTRAL, n ¼ 18). Following removal of duplicates and screening As it has been reported by the previous systematic review and
on the basis of titles and abstracts, 735 articles were further meta-analysis [20], statins do not change fibrosis stage significantly
excluded. After thorough assessment of 56 trials, 13 trials were (standardized mean difference 0.22 [95% CI -0.08 to 0.51; p ¼ 0.15;
included in the quantitative analysis. Figure 1 depicts the study I2 ¼ 59%]) (Table 4, Fig. 10) (see Fig. 11).
identification and selection of eligible trials.
3.6. Results after excluding studies without biopsy proven NAFLD
3.1. Details of characteristics of eligible trials
Even when the study (by Rana et al.) [28] without a biopsy-
The detailed characteristics of all eligible trials are presented in based diagnosis of NAFLD was removed the meta-analysis results
Table 1. All studies included in the analysis were reported between continued to suggest that statin use decreases significantly stea-
2007 and 2020 and the sample size of the treatment arm of each tosis grade (standardized mean difference was
1.19, 95% CI -1.66
trial varied from 10 to 453. The duration of follow-up ranged from to
0.72; p < 0.00001; I2 ¼ 98%).
30 weeks to 15.9 years. All studies used statins to treat dyslipidemia
in patients with NAFLD. Three trials used rosuvastatin [26e28], five 4. Discussion
used atorvastatin [29e33], one trial evaluated simvastatin [34], one
pitavastatin [35], and three trials used multiple statin types This is the most comprehensive study which assesses the results
[36e38]. The protocols of the included studies were very dissimilar. of statin use on NAFLD progression regardless of the method of
Our review considered change in the level of liver enzymes and diagnosis. A previous meta-analysis included only studies with
histological hepatic characteristics as inclusion criteria for primary histological diagnosis of the disease and did not systematically
outcome measures. The methods of diagnosis and measuring evaluate the alterations in serum lipid levels and liver function tests
change in NAFLD varied markedly (steatosis grading, NAS, [20]. Another recent meta-analysis [21] did not include some
necroeinflammatory activity grade, fibrosis stage, imaging findings studies that we finally took into account [26,30,36,38].
[CT or ultrasound findings]). Serum liver enzymes are moderately increased in patients with
NAFLD and for this reason, most of the non-invasive scoring sys-
3.2. Statins decrease cholesterol and triglycerides levels tems for the exclusion of advanced fibrosis, based mainly on labo-
ratory tests, take into account the aminotransferases [39e41]. It has
All studies reported the change in total cholesterol (CHOL) and been suggested that statins can decrease their levels, improving in
triglycerides. Ekstedt et al. [36], Kiyici et al. [31] and Georgescu et al. parallel hepatic injury in that patient group. A significant reduction
[32] did not display data regarding LDL and HDL changes. Also, of the level of ALT, AST and GGT was reported by all studies, except
Nelson et al. [34] did not provide data on HDL levels. The meta- two, one which reported an increasing trend of liver enzymes with
analysis results suggested that statin treatment decreased CHOL the use of rosuvastatin for 24 weeks [28], and another which pre-
(
2.56, 95% CI [
2.70,
2.42]; p < 0.00001; I2 ¼ 92%), LDL (
2.08, sented increases in all liver enzymes, probably due to its
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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 follow-up duration (up to 15.9 years) and we found similar results
[37]. Moreover, two studies [34,35], reported significant reduction indicating that duration of the study did not materially influence
in ALT levels but did not report similar results for the other two our results. None of the studies had more than three times eleva-
enzymes. This is likely due to the different types and dosages of tion of liver enzymes. Therefore, statins seem to exert favorable
statins used in the studies and the variable follow-up duration. effects in alleviating liver injury. Thus, the improvement of liver
Nevertheless, it is worth mentioning that we also run the analysis enzymes reinforces the long-validated concept that statins do not
without the Ekstedt et al. study, which had the most extended 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- been proven hepato-safe even in patients with increased amino-
transferases which is generally asymptomatic, occurs within the transferases and chronic liver diseases. Chalasani et al. first showed
first year of treatment, and often resolves spontaneously [42]. High that patients with elevated levels of liver enzymes were not
doses of statins caused considerable liver injury in animals possibly exposed to an increased risk of hepatotoxicity from using statins
due to the depletion of mevalonate or its downstream metabolite [46].
[43]. It has also been shown that higher doses and higher intensity The safety of statins in patients with elevated liver enzymes has
statin therapy are associated with an increased incidence of ami- been debated for several years and many health practitioners are
notransferases elevation [44,45]. Nevertheless, their hepatotoxicity still skeptical concerning their administration in this setting. A
in humans is scarce and unforeseeable [42]. Of note, statins have 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- However, given the fact that patients with NASH are at high CV
aminases and only 4 in 10 would utilize statins in the presence of an risk and that statins are the cornerstone of the treatment of dysli-
underlying liver disease [47]. These findings were confirmed also in pidemia and the prevention of cardiovascular events [50,51], the
subsequent studies revealing an under-prescription of statins in use of these pharmaceutical agents in NAFLD patients should not be
NAFLD patients even if they presented dyslipidemia or a high car- avoided or under-estimated. NAFLD patients are exposed to a great
diovascular (CV) risk [48,49]. cardio-metabolic risk [52]. Interestingly, cardiovascular disease

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C. Boutari, P.D. Pappas, D. Anastasilakis et al. Clinical Nutrition 41 (2022) 2195e2206

Fig. 11. Statins effect on fibrosis forest plot.

(CVD) is the predominant cause of death in these patients [53]. A indicates that statins can alleviate liver damage caused by NAFLD.
large body of evidence suggests that NAFLD is linked with a more Similarly, the results by previous meta-analyses [19e21] suggested
atherothrombotic risk profile beyond overweight/obesity and other the beneficial effect of statins on hepatic steatosis and NAS,
cardio-metabolic risk factors [54]. A meta-analysis of 16 observa- although Eslami et al. [19] and Rattanchaisit et al. [20] did not
tional studies including 34,043 patients concluded that patients manage to support this finding with statistical significance.
with NAFLD had a 64% higher risk of developing fatal or non-fatal Statins are believed to mitigate oxidative stress, prevent in-
cardiovascular events as compared to patients without NAFLD flammatory cell activation and hepatic stellate cell senescence,
(odds ratio [OR] 1.64; 95% confidence interval [CI] 1.26e2.13) [55]. reduce collagen synthesis and improve endothelial function [69]. A
Moreover, a meta-analysis of 34 studies suggested that NAFLD is recent meta-analysis confirmed that statins benefit the parameters
associated with an increased risk for incident CVD (HR 1.37; 95% CI of hepatic portal vessel pressure and consequently, the prognosis of
1.10e1.72) and that NAFLD patients are more likely to be diagnosed liver cirrhosis in long-term follow-up [70]. However, our meta-
with coronary heart disease (HR 2.31; 95% CI 1.46e3.65) [56]. analysis could not ascertain these actions on fibrosis stage. This is
Notably, NAFLD is related not only with a greater prevalence of probably due to the short follow-up time of the included studies. It
clinically established CVD, but also with indices of subclinical has been suggested that the average rate of fibrosis progression is
atherosclerosis such as increased arterial stiffness, carotid-artery longer than 7.5 years in NASH patients and more than 14 years in
intimal media thickness or coronary-artery calcium [57,58]. NAFLD patients and thus longer and larger studies are needed [71].
It is noteworthy that current guidelines concerning NAFLD/ Moreover, the results of the meta-analysis on influence of statins in
NASH report that statins can be safely used to treat dyslipidemia survival rate, decompensation events of liver cirrhosis, and hepa-
and subsequently to prevent CVD [7,59]. It is also important to note tocellular carcinoma derived from a 14-year follow-up [70]. A dose-
that, recently, an Expert Panel concluded that, according to five dependent effect of statins on these parameters has also been
post-hoc analyses of prospective long-term survival studies and described [70] and the various types and dosages of statins been
five smaller biopsy-proven NASH studies [26,30,60e65], statins led utilized in the studies of our meta-analysis are probably the reasons
to noticeable reductions in CVD events in comparison to those also for this non-significant decrease in fibrosis stage. A multicenter
on statins and healthy liver and suggested statin use either alone or European study concluded that statins were independently asso-
combined with a peroxisome proliferator-activated receptor (PPAR) ciated with protection from steatosis, NASH and significant fibrosis
g agonist or ezetimibe for the primary or secondary prevention of in 1201 subjects at high risk for NASH and a dose-dependent
CVD, and the avoidance of liver-related complications in patients relationship between the intensity of statin treatment and the
with NAFLD/NASH at high CVD or HCC risk [50]. Despite the notion reduced risk of liver damage was demonstrated [64]. Additionally,
of their harmful effect and toxicity, and the poor prescription and neither the meta-analysis by Rattanachaisit et al. [20], nor that by
adherence rates to statin treatment as well in patients with Fatima et al. [21], which however included less studies, confirmed a
elevated liver function tests (LFTs) in the past [66], it is now clear significant effect of statins on fibrosis stage.
that statins are efficacious and cost-saving both for primary and The present systematic review and meta-analysis is not without
secondary prevention of CVD [67]. limitations. The first and foremost is the inclusion of limited
Histological improvement was also accomplished after treat- number of eligible studies and the small sample size of each indi-
ment with statins. Our meta-analysis suggests a reduction in the vidual study. Furthermore, most of the studies had a different
steatosis grade mean as well as in NAS mean. NAS is a histologic follow-up period and used different types and dosages of statins.
evaluation system that includes the full spectrum of nonalcohol- Another point that should be mentioned is that a high percentage
associated fatty liver disease histologic changes and can assess of participants had comorbidities such as T2DM or metabolic syn-
changes following therapy in NAFLD patients. It is the sum of the drome. Last, many studies did not report data concerning the BMI of
separate scores for steatosis, hepatocellular ballooning and lobular the participants and its changes at the follow-up, although it is an
inflammation [68]. Of note, even without the studies not providing important factor impairing central obesity, insulin resistance and
hepatic biopsies [28,38], the beneficial effect of statins on steatosis NAFLD. Subgroup analysis to control for these factors could not be
grade and NAS remain significant. Growing body of evidence performed because of the small number of studies. These points

2203
C. Boutari, P.D. Pappas, D. Anastasilakis et al. Clinical Nutrition 41 (2022) 2195e2206

may affect the reliability and the robustness of our findings and Appendix A. Supplementary data
consequently, our results should be cautiously interpreted.
Supplementary data to this article can be found online at
5. Conclusion https://doi.org/10.1016/j.clnu.2022.08.001.

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