Liver Safety of Statins in Prediabetes or T2DM and Nonalcoholic Steatohepatitis

Liver Safety of Statins in Prediabetes or T2DM and Nonalcoholic
Steatohepatitis: Post-hoc Analysis of a Randomized Trial
Fernando Bril, MD; Paola Portillo Sanchez, MD; Romina Lomonaco, MD; Beverly Orsak,
RN; Joan Hecht, RN; Fermin Tio, MD; Kenneth Cusi, MD
ENDOCRINOLOGY & METABOLISM
The Journal of Clinical Endocrinology & Metabolism

Endocrine Society
THE JOURNAL OF CLINICAL
Submitted: April 12, 2017

Accepted: May 26, 2017
First Online: June 01, 2017
ADVANCE ARTICLE: JCEM
Advance Articles are PDF versions of manuscripts that have been peer reviewed and accepted but
not yet copyedited. The manuscripts are published online as soon as possible after acceptance and
before the copyedited, typeset articles are published. They are posted "as is" (i.e., as submitted by
the authors at the modification stage), and do not reflect editorial changes. No
corrections/changes to the PDF manuscripts are accepted. Accordingly, there likely will be
differences between the Advance Article manuscripts and the final, typeset articles. The
manuscripts remain listed on the Advance Article page until the final, typeset articles are posted.
At that point, the manuscripts are removed from the Advance Article page.
DISCLAIMER: These manuscripts are provided "as is" without warranty of any kind, either express
or particular purpose, or non-infringement. Changes will be made to these manuscripts before
publication. Review and/or use or reliance on these materials is at the discretion and risk of the
reader/user. In no event shall the Endocrine Society be liable for damages of any kind arising
references to, products or publications do not imply endorsement of that product or publication.
The Journal of Clinical Endocrinology & Metabolism; Copyright 2017 DOI: 10.1210/jc.2017-00867
Statins in NASH
Liver Safety of Statins in Prediabetes or T2DM and Nonalcoholic

Steatohepatitis: Post-hoc Analysis of a Randomized Trial
Fernando Bril, MD1,2; Paola Portillo Sanchez, MD1,2; Romina Lomonaco, MD1,2; Beverly Orsak,
RN3; Joan Hecht, RN4; Fermin Tio, MD5; Kenneth Cusi, MD1,2,3,4
1
Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL. 2Malcom Randall VA
LE
Medical Center, Gainesville, FL. 3Diabetes, University of Texas Health Science Center at San Antonio (UTHSCSA),
San Antonio, TX. 4Audie L. Murphy VA Medical Center, San Antonio, TX. 5Pathology, University of Texas Health
Science Center at San Antonio (UTHSCSA), San Antonio, TX.
Received 12 April 2017. Accepted 26 May 2017.
IC
Context
Patients with NAFLD have a high cardiovascular risk, but statins are rarely prescribed due to
fear of hepatotoxicity.
Objective
T
To perform a prospective assessment of the long-term safety of statins in patients with
prediabetes/T2DM and NASH.
Design
R
Post-hoc analysis of statin use during a randomized, controlled trial (RCT) assessing
A
pioglitazone vs. placebo in patients with NASH.
Patients
A total of 101 subjects (86 on statins) with biopsy-proven NASH and prediabetes/T2DM were
followed for up to 36 months.
E
Interventions
Oral glucose tolerance test and percutaneous liver biopsy (baseline, month 18, and 36). Liver 1H-
C
MRS and euglycemic insulin clamp with measurement of glucose turnover (baseline and month
18).
N
Main outcome measure

Histological (liver biopsy) and biochemical (plasma ALT) safety of statin use among patients
with NASH.
A
Results
Only 37% of patients were on statins at enrollment despite their high cardiovascular risk. Non-
V
statin users had higher plasma ALT levels, but similar histologic severity of liver disease at
baseline. In both statin users and non-users, the same number of subjects (n=4) had a ≥2-fold
D
increase in plasma aminotransferases during follow-up. One non-statin user was discontinued
because of this elevation. Values returned to normal without any active measure in all other
cases. No changes on liver histology or hepatic insulin resistance were observed in patients with
A
NASH newly started on a statin and receiving placebo during the main RCT.
Conclusions
Statin therapy is safe in patients with prediabetes/T2DM and biopsy-proven NASH. Given their
high cardiovascular risk, statin therapy should be encouraged in this population.
We prospectively assessed the histologic safety of statins in patients with prediabetes or T2DM and
NASH. We determined that statins can safely be used in this high-risk population.
1
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition that ranges from benign
liver fat accumulation to severe inflammation and necrosis (known as nonalcoholic
steatohepatitis [NASH]), in the absence of alcohol abuse and other causes of liver disease such as
viruses, autoimmunity or drug-induced hepatitis (1, 2). It is characterized by insulin resistance
and the coexistence of other components of the metabolic syndrome (MetS) like obesity,
prediabetes or type 2 diabetes (T2DM), hypertriglyceridemia with increased apolipoprotein B
secretion, low high-density lipoprotein cholesterol (HDL-C), and small, dense low-density
lipoprotein (LDL) (3, 4).
Patients with NAFLD are at increased risk of cardiovascular disease (CVD) (5). Many
LE
mechanisms have been postulated to explain this association (i.e. more severe insulin resistance,
subclinical inflammation, ectopic fat accumulation with potential cardiolipotoxicity, and worse
dyslipidemia) (6, 7). Due to their highly atherogenic profile, patients with NAFLD are strong
candidates for the use of statins (8).
IC
Unfortunately, concerns remain regarding their safety in patients with NASH, especially in
those with elevated plasma aminotransferases. There is a belief among clinicians that patients
with NASH are at a higher risk of hepatotoxicity when prescribed a statin (9), and it has even
T
been postulated that statins could increase hepatic fat accumulation in patients with NAFLD
(10). This perception has had serious implications, as many patients with NAFLD are denied
statins and other lipid-lowering therapies on a daily basis (11). For instance, only 9% of 638
R
patients with NAFLD were treated with a statin in a previous report, despite the vast majority of
them having dyslipidemia (12). The use of statins was also significantly low (45%) in a cohort of
A
346 patients with T2DM and NAFLD (13).

Some studies have suggested that statins may be safe in patients with NAFLD, but these
studies have had serious limitations posed by their cross-sectional (12, 14) or retrospective (15-
E
17) nature. More importantly, most lacked a histological diagnosis of NASH (12, 15, 16, 18-22),
as recently reviewed elsewhere (23). The few prospective studies in patients with NASH have
C
been of short duration (≤12 months) and included only between 5-43 patients (24-28). Overall,
results on plasma aminotransferases, hepatic steatosis, and histology were rather inconsistent,
with even some of these studies showing mild beneficial effects of statins in NASH (29).
N
The aim of the current study was to perform a long-term prospective evaluation about the
safety of statins in patients with prediabetes or T2DM and biopsy-proven NASH.
A
Research Design and Methods

V
Subjects
A total of 101 subjects were recruited from the general population of San Antonio, Texas
between December 2008 and 2014, as part of a randomized controlled trial assessing the long-
D
term efficacy of pioglitazone in patients with NASH. Complete inclusion/exclusion criteria and
results from the main study have been previously reported (30). In summary, patients between 18
A
to 70 years old, with prediabetes or T2DM, and biopsy-proven NASH were included. They were
identified either from responses to local newspaper advertisements and diagnosed with NAFLD
during a screening with magnetic resonance spectroscopy (1H-MRS) or from referrals from
hepatology clinics. Participants were in good general health without evidence of any significant
chronic diseases as determined by history, physical exam, routine blood and urine chemistries
and electrocardiography. Patients with established cardiovascular disease were not excluded
from the trial as long as they were stable for at least 6 months before screening. Volunteers were
excluded if they had a history of alcohol abuse (≥30 grams/day in men or ≥20 grams/day in
2
women), liver disease other than NASH (i.e., hepatitis B or C, autoimmune hepatitis,
hemochromatosis, Wilson’s disease, drug-induced hepatitis), type 1 diabetes, a history of
clinically significant renal, pulmonary or congestive heart failure (New York Heart Classification
greater than grade II). The study was approved by the UTHSCSA Institutional Review Board
and an informed written consent was obtained from each patient prior to participation.
Study design.
After enrollment, there was a run-in phase of ~4 weeks, in which baseline metabolic studies were
performed (see below). During this phase, patients not taking a statin were prescribed therapy if
LE
indicated (31, 32). In those patients already on a statin, the dosage was titrated as needed to
achieve LDL-C targets, in accordance with prevailing guidelines at the time (31).
Baseline metabolic measurements included: 1) fasting plasma glucose, hemoglobin A1c,
lipid profile, liver function tests, insulin, free fatty acids; 2) total body fat by dual energy X-ray
absorptiometry (DXA); 3) liver fat content by 1H-MRS; 4) euglycemic hyperinsulinemic clamp
IC
with 3-[3H] glucose for the measurement of glucose turnover; 5) 75-gram oral glucose tolerance
test (OGTT) to establish the diagnosis of normal glucose tolerance or T2DM according to current
criteria (32); and 6) liver biopsy to establish the diagnosis of NASH and the grade and stage of
T
the disease.
After the above baseline metabolic measurements were performed, patients were prescribed a
R
hypocaloric diet (500–kcal/d deficit from the calculated weight-maintaining diet) and followed
every 1-2 months at the clinical research center by research staff. During follow-up visits vital
signs, physical examination, home glucose monitoring results if individuals had diabetes, adverse
A
events, medication compliance and blood chemistries were assessed. Based on guidelines
criteria, those patients who were not started on statins during the run-in phase were prescribed
one when required (or on occasions the dose titrated) during follow-up as needed to reach lipid
E
treatment goals. In those that completed 18, and 36 months of follow-up, we repeated the
metabolic studies and liver biopsy as part of the trial evaluating the use of pioglitazone vs.
C
placebo in patients with NASH (30). Liver 1H-MRS and euglycemic hyperinsulinemic clamp
were only performed at baseline and month 18. In order to assess the safety of statins regarding
N
liver function, we measured plasma alanine aminotransferase (ALT) and aspartate

aminotransferase (AST) at enrollment, at baseline and in every follow-up visit.
Measurements of total body and liver fat content.
A
Total body fat content was measured by DXA (Hologic Inc, Waltham, MA). For the
measurement of hepatic fat content, localized proton nuclear magnetic resonance spectra of the
V
liver were acquired on a Siemens TIM-Trio 3.0T MRI whole body scanner and using
methodology previously described (33). A liver fat content of >5.5% was considered diagnostic
D
of NAFLD (34).
Euglycemic hyperinsulinemic clamp
A
After an overnight fast, subjects underwent a 2-step euglycemic hyperinsulinemic clamp with the
infusion of 3-[3H] glucose as previsouly described (35). A primed (25 µCi x [fasting
glucose/100])–continuous (0.25 µCi/minute) infusion of 3-[3H] glucose (DuPont-NEN, Boston,
MA) was initiated and continued until the end of the study. After the basal equilibration period,
insulin was administered as a primed-continuous infusion at 10 mlU/(m2 · minute) for 120
minutes to assess suppression of endogenous glucose production (EGP), followed by another 2
hours at an infusion rate of 80 mlU/(m2 · minute) for 120 minutes to assess skeletal muscle
insulin stimulated glucose disposal (Rd). A variable infusion of 20% glucose was adjusted based
3
on the negative feedback principle to maintain the plasma glucose concentration at

approximately 90-100 mg/dL with a coefficient of variation <5%.
Liver biopsy.
An ultrasound-guided liver biopsy was performed in patients with elevated liver transaminases
when all other causes of liver disease were ruled out, or in patients with normal liver
transaminases if they were diagnosed with NAFLD by 1H-MRS and had significant risk factors
for the development of NASH such as T2DM, MetS and/or insulin resistance. Biopsies were
evaluated by a pathologist that was unaware of the subjects’ identity or clinical information.
LE
Histological characteristics for the diagnosis of NASH were determined using standard criteria
(36).
Statistical analysis.
Data were summarized in percentages for categorical variables and as mean ± standard error for
IC
numeric variables, except for plasma triglyceride concentration that were expressed as median
(interquantile range). Comparisons between two groups were performed with Chi2 or Fisher’s
Exact test for categorical variables and Kruskal-Wallis or Student’s t-test for numeric variables
depending on their distribution. Changes in continuous variables within groups (before vs. after)
T
were tested by means of Wilcoxon signed-rank test or paired t-test depending on variables’
distribution. A two-tailed p value of less than 0.05 was considered to indicate statistical
R
significance. Analyses were performed with Stata 11.1 (StataCorp LP, College Station, TX).
A
Results
Patients’ characteristics at enrollment

We enrolled and followed 101 patients with biopsy-proven NASH. Table 1 summarizes patients’
E
characteristics divided by whether they were on a statin or not at enrollment. There were no
significant differences between statin users and non-statin users in BMI, total body fat and
presence of the MetS. As expected, patients on statins were slightly older (55±1 vs. 48±1 years,
C
p<0.001), and had a trend towards higher prevalence of T2DM (63% vs. 44%, p=0.07). We also
observed a strong trend towards a lower percentage of females among patients already on statin
N
therapy at enrollment (18% vs. 37%, p=0.05). While patients on statins had lower plasma levels
of total cholesterol (166±6 vs. 196±6 mg/dl, p<0.001) and low density lipoprotein cholesterol
A
(LDL-C; 93±5 vs. 119±5 mg/dl, p<0.001), we found no differences regarding plasma triglyceride
or HDL-C concentration between both groups.
Patients on a statin had lower levels of plasma ALT concentration (57±5 vs. 75±5 U/L,
V
p=0.03), and this was associated with lower liver fat content by 1H-MRS (14±1% vs. 19±1%,
p=0.02). However, there were no significant differences in the histological severity of NASH
D
between statin and non-statin users in either steatosis, inflammation, ballooning or fibrosis
(Table 1).
A
Only 37% of patients with NASH at enrollment were on statins and 12% on other lipid-
lowering drugs (fenofibrate [n=2], gemfibrozil [n=7], niacin [n=2], and fish oil [n=1]) despite the
overall high cardiovascular risk of this population. Most patients not prescribed a statin had a
clear indication based on the guidelines at the time (31, 32), given the high prevalence of obesity
(81%), T2DM (51%), MetS (89%) and dyslipidemia (59% with plasma triglyceride levels >150
mg/dl, 55% with LDL-C >100 mg/dl and 74% with low HDL-C). The statin most frequently
used at enrollment was simvastatin (84% of statin users), followed by rosuvastatin (11%),
influenced largely by the local healthcare plan formulary guidelines at the time of the study.
Statins doses were classified as low (lower or equal to 10mg of simvastatin, 20mg of lovastatin,
4
or 10-20mg pravastatin), medium (20-40mg of simvastatin, 40-80mg pravastatin, 10-20mg of

atorvastatin or 5-10mg of rosuvastatin) and high (40-80mg of atorvastatin or 20-40mg of
rosuvastatin) according to recent guidelines (37). Only 8% of the patients were receiving high-
intensity statin therapy at enrollment, while the majority (79%) of patients were receiving
moderate-intensity therapy. Overall, patients on statins at enrollment were undertreated with high
percentages of patients out of lipid targets according to current guidelines (51% with triglyceride
> 150 mg/dl, 35% with LDL-C > 100 mg/dl and 65% with low HDL-C).
Short-term safety of statin therapy (before and after run-in phase)
LE
At the beginning of the run-in phase (average of ~4 weeks), patients had the statin up-titrated or
were started on a statin according to prevailing guidelines at the time (31, 32). Patients not
prescribed a statin at this time had a contraindication for these drugs, or were unwilling to start
them.
Among patients who were newly prescribed a statin during the run-in phase, most were
IC
started cautiously on a low- or medium-dose (45% and 48%, respectively). As expected, statin
initiation led to a significant reduction in plasma total cholesterol (p<0.002) and LDL-C
(p=0.003). No deleterious effects on plasma aminotransferase concentration or the proportion of
T
patients with elevated plasma aminotransferases were observed after statin initiation. None of the
patients newly started on a statin experienced any significant increase in plasma ALT or AST
R
levels (defined as a 2-fold elevation) during the run-in phase. Indeed, patients newly prescribed a
statin and also those already taking a statin before enrollment showed a slight reduction of
plasma ALT during this phase (from 64±4 to 56±3 IU/L, p=0.007). This was associated with a
A
small reduction in BMI (from 34.4±0.5 to 34.1±0.5 kg/m2, p=0.007). During this phase, 13
patients with plasma ALT or AST levels above 80U/L were prescribed a statin in spite of their
significant elevation of plasma aminotransferase concentration. There was no further increase in
E
plasma aminotransferase levels among this group of patients. In fact, mean plasma ALT and
AST significantly decreased during the run-in phase after statin initiation in this group of patients
C
(from 109±6 to 83±5 IU/L, p=0.001 for plasma ALT and 66±5 to 53±5 IU/L, p=0.01 for plasma
AST).
N
Among patients who were already on a statin at enrollment, 28% had their dose up-titrated
during the run-in period, resulting in an increase in the number of patients in the medium- and
high-dose group (from 28% to 33% and from 28% to 36%, respectively). Statin dose up-titration
A
during this phase led to a further decrease in plasma total cholesterol (189±12 vs. 145±9 mg/dl,
p=0.01), LDL-C (114±15 vs. 68±7, p=0.004) and a trend towards lower plasma triglyceride (190
V
[126 - 299] vs. 126 [111 – 154] mg/dl, p=0.06) concentrations. Overall, no change in mean
plasma ALT or AST levels was observed in this group during this period or later. Regarding the
hepatic safety of statin titration, only one patient in whom the statin was increased from low- to
D
medium-dose had a two-fold increase in plasma ALT concentration that spontaneously returned
to baseline at the next follow-up visit without any active measure. Two patients not receiving
A
statins during the run-in phase also showed an elevation in plasma aminotransferase levels that
returned to normal spontaneously.
Follow-up
A total of 86 subjects on statins and 15 not on statins with biopsy-proven NASH were followed
as part of a pioglitazone vs. placebo randomized clinical trial (30) for a total of 194 patient-years
of statin therapy (range: 0.1–3 years). Eighteen patients out the 101 were prematurely
discontinued from the study after a mean follow-up of 7 months (range: 1–16 months) either
because of lost to follow-up or other causes unrelated to statin use. Most due to safety concerns
5
with pioglitazone and bladder cancer at time of a report suggesting such an association, as
detailed elsewhere (30). We found no significant differences in clinical and laboratory
parameters between patients discontinued and the rest of the participants. Of these patients, 12
were on statins at the time of disenrollment and the remaining 6 were never prescribed a statin.
Only 1 patient discontinued statins during follow-up against medical advice. No drug-related
adverse events were identified in this patient.
After all patients were started on statins, 67% of them were on simvastatin, while 21% were
on rosuvastatin and the remaining 12% were equally divided between atorvastatin and
pravastatin. At the end of the study, only 30% of patients were receiving a low-dose of statin
LE
while the rest were on medium- or high-dose therapy (46% and 24%, respectively).
Approximately 21% of patients on a statin were on combination therapy at the end of the study
(fenofibrate [n=4], gemfibrozil [n=11], niacin [n=2], and fish oil [n=1]).
IC
Long-term safety
As can be observed in Figure 1A, plasma ALT levels tended to decrease over time in all patients
on pioglitazone, whether they were on statin therapy or not, likely due to the effects of the
thiazolidinedione on liver histology (30). Before pioglitazone initiation, plasma ALT reductions
T
were already observed, but were similar for all groups as plotted in Figure 1A. No significant
increase in mean plasma aminotransferase levels was evidenced during the 3-year follow-up,
R
either in patients that were started or were already on a statin at study enrollment.
In those patients randomized to placebo (Figure 1B), mean plasma ALT levels remained
abnormally elevated (>40 U/L) throughout the first 18 months. Of note, patients not on a statin
A
showed persistently higher levels of plasma ALT when compared to patients taking statins. The
difference in plasma ALT levels between patients not on statins and those who started statin
treatment occurred early-on (it reached statistical significance by the end of the run-in phase;
E
p=0.002) and persisted for the first 18 months of follow-up. This reduction in plasma ALT
during the run-in in patients starting statins was associated with weight loss as mentioned above
C
(Figure 1B). All groups normalized their mean plasma ALT levels after pioglitazone initiation in
the open-label phase. Those patients that had started a statin during the study showed a non-
N
significant increase in plasma ALT at month 24 that decreased spontaneously at months 32 and
34. An overall similar pattern was observed when plasma AST levels were plotted over time
(Figure 2).
A
For further analyses, we took into account those patients that showed at least a doubling of
ALT/AST levels during follow-up. Overall, 5 patients showed at least a two-fold increase in liver
V
enzymes levels after the run-in phase (including the above mentioned patient that was
discontinued for this reason). Two of these 5 patients were not on statins when their plasma
aminotransferase levels increased. Of the other three, 2 were already taking a statin at
D
enrollment, and only one was newly started on the medication. In all cases liver
aminotransferases returned to normal without changing the statin dosing. Regarding muscular
A
adverse events, 11 patients complained of muscle cramps or muscle aches. None of these had an
elevation in plasma creatine phospokinase and symptoms spontaneously resolved without any
treatment.
Long term efficacy
In order to assess possible long-term beneficial effects of statins in patients with NASH, we
compared clinical and laboratory parameters of those patients starting a statin during the study
and that had not been randomized to active medication (pioglitazone) during the trial (Table 2).
6
As expected, after 18 months of statin use, all lipid parameters improved. Both plasma ALT
(66±8 vs. 38±5 U/L, p<0.001) and AST (48±6 vs. 31±3 U/L, p=0.006) levels showed significant
improvement after 18 months of statin therapy. This remained true when we analyzed the
proportion of patients with abnormal plasma ALT concentration (ALT>40 IU/L) before and after
18 months of follow-up. In agreement with this biochemical improvement, liver fat by 1H-MRS
also decreased after 18 months (13±2 vs. 8±2%, p<0.001). These improvements were strongly
associated with changes in BMI (35.1±0.9 vs. 34.6±0.9 kg/m2, p=0.06, corresponding to a
reduction of 1.5kg) and a small, but significant improvement in the suppression of free fatty
acids by low dose insulin during the euglycemic insulin clamp (41±5% vs. 49±4%, p=0.02). We
LE
observed no changes in liver or skeletal muscle insulin resistance after 18 months of therapy with
statins. None of the above changes in plasma ALT or liver fat by 1H-MRS translated into any
histologic improvement in the NAS (3.9±0.3 vs. 3.7±0.5, p=0.40), or any of the individual
components of the score: steatosis (1.7±0.2 vs. 1.4±0.2, p=0.10), inflammation (1.5±0.1 vs.
IC
1.6±0.2, p=0.50) and ballooning (0.8±0.1 vs. 0.7±0.1, p=0.43). There were no differences in
fibrosis stage (0.6±0.2 vs. 0.5±0.2, p=0.50) either. Of note, we observed no significant metabolic
or histologic changes among patients already receiving a statin at enrollment that continued
T
statin therapy for 18 months (Table 3).
Discussion
R
The clinical dilemma of elevated plasma aminotransferases in an obese patient with the MetS
and/or T2DM is common among practitioners. Moreover, this situation is likely to increase in
A
parallel with the worsening of the epidemics of obesity and T2DM. Clinicians are confronted
with treating with a statin a patient with high cardiovascular risk vs. withholding such treatment
in the face of a perceived risk of harm in the setting of NASH. Few studies have served as
E
guidance and these have usually suffered from a number of limitations: either retrospective in
nature, small sample size (5-43 patients), short duration of follow-up (mostly between 6-12
C
months) and/or using surrogate markers of liver disease (AST/ALT or liver imaging) rather than
the gold-standard liver biopsy (12, 15-22, 24-28). The current report is the largest prospective
N
study assessing the safety of statins in patients with biopsy-proven NASH with a cohort of 101
patients closely followed for a total follow-up of 194 patient-years. Our results offer compelling
evidence that statins can be safely used in patients with NASH and should not be denied to these
A
patients who have already have a very high risk of cardiovascular disease.
At enrollment, we found that only 37% of patients were receiving a statin, with an additional
V
12% on other lipid-lowering therapies. This very low use of statins among patients with NASH is
in accordance with prior studies (12). Of note, this low statin use occurred in spite of a high
prevalence of obesity (81%), T2DM (51%), MetS (89%). For instance, the majority of patients
D
had dyslipidemia, with 55% having a plasma LDL-C >100 mg/dl, 59% plasma triglycerides
>150 mg/dl and 74% a HDL-C <40 mg/dl in males or <50 mg/dl in females. There are several
A
potential explanations for this. On one hand, patient compliance with lipid-lowering therapy
remains a challenge (38). It is also well established that primary care providers may not be
aggressive enough in starting or titrating-up statin therapy to meet established treatment goals
(39). Female patients appear to be at particular risk for statin therapy undertreatment, despite
compelling evidence suggesting a similar benefit with statin therapy in both genders (40, 41).
However, the most likely cause (expressed by many referring primary care doctors) was the
concern over safety of prescribing lipid-lowering agents in the face of elevated liver enzymes or
knowledge that the patient had NASH. Supporting this view, there was an inverse correlation
7
between the magnitude of the liver aminotransferases elevation in patients with NASH and the
use of statins: while 36% of patients were on statins at enrollment, this percentage declined to
33% and 21% when patients with plasma ALT above 40 U/L or above 80 U/L were respectively
considered. Despite higher plasma aminotransferases and liver fat content by 1H-MRS in non-
statin users, both statin and non-statin users had similar severity of liver disease at baseline based
on histology. This indicates that elevated plasma aminotransferases and imaging (even 1H-MRS)
are a poor reflection of liver disease in NASH, and offer inadequate information to make clinical
decisions. This discordance between aminotransferases and histology has been reported before in
clinical trials (42-44). The National Lipid Association Statin Safety Assessment Task Force has
LE
clearly stated that patients with NAFLD or NASH may safely receive statin therapy,
recommending their use, but there is still strong resistance to do so in clinical practice (45). In
the current study, 75% of patients not taking a statin at enrollment were safely prescribed one.
Because of this, our results are important in creating a paradigm shift for the use of statins in
IC
patients with NASH.
Most patients on a statin at study entry were not at goal (Table 1). About a third had a
plasma LDL-C above 100 mg/dl, more than 50% had an elevated plasma triglyceride
T
concentration, and as many as two-thirds a low HDL-C. Indeed, in 75% the plasma non-HDL-C
level was above 100 mg/dl. Again, lack of upward statin titration was related to the fear of liver
toxicity in patients with elevated plasma aminotransferases. However, after a 3-year period of
R
follow-up, statin therapy proved to be safe. The fact that more patients were able to reach plasma
LDL-C rather than the non-HDL-C target highlights the difficulties of improving plasma
A
triglyceride and HDL-C concentration in such patients and the potential for combination therapy
with fibrates in this population. Fibrates, with or without statins, have been tested for the
treatment of NAFLD with rather neutral effects on liver fat content on imaging or histology,
E
although in some reports plasma aminotransferases were reported to decrease (46). In this regard,
no patient on combination therapy experienced a significant increase in CPK or liver enzymes.
C
Taken together, fibrates also appear to be safe when added to statins in this population.
Finally, there has been some interest on the potential role of statins to improve liver histology
in NASH and biochemical parameters. In cell culture and animal models, statins may improve
N
NASH by several potential mechanisms (10). For instance, in macrophages and monocytes,
statins have shown to activate the peroxisome proliferator-activated receptor gamma (PPAR-γ)
A
(47). They have also shown to activate PPAR-α and promote fatty acid oxidation in vivo (48).
Other possible mechanisms include improvement of plasma levels of tumor necrosis factor-
alpha, interleukin-6, and C-reactive protein, markers frequently associated with advanced
V
histology in NASH (49). However, it is unlikely that statins have a major effect on liver
histology in humans with NASH. While several uncontrolled studies have reported reductions in
D
plasma aminotransferases and steatosis on imaging, these reports were characterized by their
small numbers of subjects, concomitant use of lifestyle intervention, lack of appropriate controls
A
and short follow-up (8, 29). Confirming that statins do not improve liver histology in NASH,
patients in the placebo arm on statins had no significant change in hepatic steatosis,
necroinflammation or fibrosis after 18 months of follow-up. The modest reduction in plasma
aminotransferases and hepatic triglyceride content by 1H-MRS we observed in these patients
(Table 2) was likely related to weight reduction in this subset of patients (35.1±0.9 vs. 34.6±0.9
kg/m2, p=0.06, corresponding to a reduction of 1.5kg in body weight). Moreover, the ALT/AST
changes we report are similar to those in the placebo arms of other RCTs in patients with NASH.
For instance, in our prior RCT of pioglitazone vs. placebo in patients with NASH (43), plasma
8
ALT and AST also improved in the placebo arm from 61 to 40 IU/L (p=0.03) and AST from 42
to 33 IU/L (p=0.08). Reductions of plasma ALT/AST of similar magnitude have been reported
for the placebo arms of the PIVENS (42) and FLINT (50) trials in patients with NASH. These
findings suggest that a small decrease in plasma aminotransferases is to be expected in placebo-
treated patients, and highlight the need for adequate controls in intervention studies in patients
with NASH. While we recognize that this study is a post-hoc analysis of a randomized, single-
center study with a relatively small sample size, the difficulty of performing paired percutaneous
liver biopsies, makes this current work the largest prospective study assessing the histologic
safety of statins in patients with NASH. Statin compliance was not formally assessed during
LE
follow-up, but study drug compliance was overall good (95% by pill counting), suggesting a
similarly high rate of compliance for statin use.
In summary, in the largest prospective study to date in patients with biopsy-proven NASH,
we report that statins can be safely prescribed in this population. These are timely findings that
IC
call for a change in current practice as patients with NASH have the highest cardiovascular risk
but dyslipidemia remains often undertreated. We hope that this work will increase awareness
about the need and safety of statin use in patients with NASH and that in the future they will not
T
be deprived from this much needed therapy. However, more work is needed in order to fully
understand their role in this setting.
Acknowledgments
R
This work was supported by the Burroughs Wellcome Fund (K.C.), by the American Diabetes
A
Association (1-08-CR-08; K.C.), and by the Veterans Affairs Medical Research Fund.
Corresponding author: Kenneth Cusi, M.D., F.A.C.P., F.A.C.E., Professor of Medicine,

Chief, Endocrinology, Diabetes and Metabolism Division University of Florida, 1600
E
SW Archer Road, room H-2. Gainesville, Florida 32610, Ph: 352-273-8662. Fax: 352-
846-2231, Email: Kenneth.Cusi@medicine.ufl.edu
C
Authors Contributions
F.B. contributed to patient recruitment and follow-up, data collection, statistical analysis,
N
manuscript writing, and takes responsibility for the integrity of the data and the accuracy of the
data analysis; P.P.S., R.L., B.O., J.H. contributed to patient recruitment and follow-up, and data
A
collection; F.T. read the liver biopsies; K.C provided funding, contributed to patient recruitment
and follow-up, data collection, manuscript writing, and takes responsibility for the integrity of
V
the data and the accuracy of the data analysis.
References
D
1. Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic

steatohepatitis: Selected practical issues in their evaluation and management. Hepatology
A
2009;49:306-317.
2. Targher G, Bellis A, Fornengo P, Ciaravella F, Pichiri I, Cavallo Perin P, Trimarco B,
Marchesini G. Prevention and treatment of nonalcoholic fatty liver disease. Dig Liver Dis
2010;42:331-340.
3. Kotronen A, Westerbacka J, Bergholm R, Pietilainen KH, Yki-Jarvinen H. Liver fat in
the metabolic syndrome. J Clin Endocrinol Metab 2007;92:3490-3497.
4. Bril F, Sninsky JJ, Baca AM, Superko HR, Portillo Sanchez P, Biernacki D, Maximos M,
Lomonaco R, Orsak B, Suman A, Weber MH, McPhaul MJ, Cusi K. Hepatic steatosis and
9
insulin resistance, but not steatohepatitis, promote atherogenic dyslipidemia in NAFLD. J Clin
Endocrinol Metab 2016;101:644-652.
5. Targher G, Bertolini L, Rodella S, Tessari R, Zenari L, Lippi G, Arcaro G. Nonalcoholic
fatty liver disease is independently associated with an increased incidence of cardiovascular
events in type 2 diabetic patients. Diabetes Care 2007;30:2119-2121.
6. Perseghin G. The role of non-alcoholic fatty liver disease in cardiovascular disease. Dig
Dis 2010;28:210-213.
7. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic
steatohepatitis: pathophysiology and clinical implications. Gastroenterology 2012;142:711-725
LE
e716.
8. Bril F, Lomonaco R, Cusi K. The challenge of managing dyslipidemia in patients with
nonalcoholic fatty liver disease. Clinical Lipidology 2012;7:471-481.
9. Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology
IC
2005;41:690-695.
10. Argo CK, Loria P, Caldwell SH, Lonardo A. Statins in liver disease: a molehill, an
iceberg, or neither? Hepatology 2008;48:662-669.
T
11. Blais P, Lin M, Kramer JR, El-Serag HB, Kanwal F. Statins are underutilized in patients
with nonalcoholic fatty liver disease and dyslipidemia. Dig Dis Sci 2016;61:1714-1720.
12. Browning JD. Statins and hepatic steatosis: perspectives from the Dallas Heart Study.
Hepatology 2006;44:466-471.
13. R
Nascimbeni F, Aron-Wisnewsky J, Pais R, Tordjman J, Poitou C, Charlotte F, Bedossa P,
A
Poynard T, Clement K, Ratziu V, Group Ls. Statins, antidiabetic medications and liver histology
in patients with diabetes with non-alcoholic fatty liver disease. BMJ Open Gastroenterol
2016;3:e000075.
E
14. Dongiovanni P, Petta S, Mannisto V, Mancina RM, Pipitone R, Karja V, Maggioni M,

Kakela P, Wiklund O, Mozzi E, Grimaudo S, Kaminska D, Rametta R, Craxi A, Fargion S,
C
Nobili V, Romeo S, Pihlajamaki J, Valenti L. Statin use and non-alcoholic steatohepatitis in at

risk individuals. J Hepatol 2015;63:705-712.
15. Chalasani N, Aljadhey H, Kesterson J, Murray MD, Hall SD. Patients with elevated liver
N
enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004;126:1287-1292.
16. Vuppalanchi R, Teal E, Chalasani N. Patients with elevated baseline liver enzymes do not
A
have higher frequency of hepatotoxicity from lovastatin than those with normal baseline liver
enzymes. Am J Med Sci 2005;329:62-65.
17. Ekstedt M, Franzen LE, Mathiesen UL, Holmqvist M, Bodemar G, Kechagias S. Statins
V
in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological
follow-up study. J Hepatol 2007;47:135-141.
D
18. Gomez-Dominguez E, Gisbert JP, Moreno-Monteagudo JA, Garcia-Buey L, Moreno-

Otero R. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients.
A
Aliment Pharmacol Ther 2006;23:1643-1647.

19. Foster T, Budoff MJ, Saab S, Ahmadi N, Gordon C, Guerci AD. Atorvastatin and
antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study
randomized clinical trial. Am J Gastroenterol 2011;106:71-77.
20. Athyros VG, Mikhailidis DP, Didangelos TP, Giouleme OI, Liberopoulos EN,
Karagiannis A, Kakafika AI, Tziomalos K, Burroughs AK, Elisaf MS. Effect of multifactorial
treatment on non-alcoholic fatty liver disease in metabolic syndrome: a randomised study. Curr
Med Res Opin 2006;22:873-883.
10
21. Antonopoulos S, Mikros S, Mylonopoulou M, Kokkoris S, Giannoulis G. Rosuvastatin as

a novel treatment of non-alcoholic fatty liver disease in hyperlipidemic patients. Atherosclerosis
2006;184:233-234.
22. Lewis JH, Mortensen ME, Zweig S, Fusco MJ, Medoff JR, Belder R, Pravastatin in
Chronic Liver Disease Study I. Efficacy and safety of high-dose pravastatin in
hypercholesterolemic patients with well-compensated chronic liver disease: Results of a
prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology
2007;46:1453-1463.
23. Eslami L, Merat S, Malekzadeh R, Nasseri-Moghaddam S, Aramin H. Statins for non-
LE
alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cochrane Database Syst Rev
2013;12:CD008623.
24. Kimura Y, Hyogo H, Yamagishi S, Takeuchi M, Ishitobi T, Nabeshima Y, Arihiro K,
Chayama K. Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in
IC
nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as
a biomarker for the attenuation of NASH. J Gastroenterol 2010;45:750-757.

25. Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using
T
simvastatin in the treatment of nonalcoholic steatohepatitis: A randomized placebo-controlled
trial. J Clin Gastroenterol 2009;43:990-994.
26. Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic
27. R
steatohepatitis: results of a pilot study. Atherosclerosis 2004;174:193-196.
Georgescu EF, Georgescu M. Therapeutic options in non-alcoholic steatohepatitis
A
(NASH). Are all agents alike? Results of a preliminary study. J Gastrointestin Liver Dis
2007;16:39-46.
28. Kiyici M, Gulten M, Gurel S, Nak SG, Dolar E, Savci G, Adim SB, Yerci O, Memik F.
E
Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis. Can J

Gastroenterol 2003;17:713-718.
C
29. Barb D, Cusi K. Reply to "statins and non-alcoholic steatohepatitis". Metabolism

2017;66:e3-e5.
30. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, Tio F, Hardies J, Darland
N
C, Musi N, Webb A, Portillo-Sanchez P. Long-term pioglitazone treatment for patients with

nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: A randomized trial. Ann
A
Intern Med 2016;165:305-315.

31. Executive summary of the third report of the National Cholesterol Education Program
(NCEP). Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults
V
(Adult Treatment Panel III). JAMA 2001;285:2486-2497.

32. Standards of medical care in diabetes-2015: summary of revisions. Diabetes Care
D
2015;38 Suppl:S4.
33. Bril F, Ortiz-Lopez C, Lomonaco R, Orsak B, Freckleton M, Chintapalli K, Hardies J,
A
Lai S, Solano F, Tio F, Cusi K. Clinical value of liver ultrasound for the diagnosis of
nonalcoholic fatty liver disease in overweight and obese patients. Liver Int 2015;35:2139-2146.
34. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy
SM, Hobbs HH. Prevalence of hepatic steatosis in an urban population in the United States:
impact of ethnicity. Hepatology 2004;40:1387-1395.
35. Bril F, Barb D, Portillo-Sanchez P, Biernacki D, Lomonaco R, Suman A, Weber MH,
Budd JT, Lupi ME, Cusi K. Metabolic and histological implications of intrahepatic triglyceride
content in nonalcoholic fatty liver disease. Hepatology 2017;65:1132-1144.
11
36. Sanyal AJ, Brunt EM, Kleiner DE, Kowdley KV, Chalasani N, Lavine JE, Ratziu V,
McCullough A. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology
2011;54:344-353.
37. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH,
Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith
SC, Jr., Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J,
Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman
JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC, Jr., Tomaselli GF,
American College of Cardiology/American Heart Association Task Force on Practice G. 2013
LE
ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic
cardiovascular risk in adults: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines. Circulation 2014;129:S1-45.
38. Schedlbauer A, Davies P, Fahey T. Interventions to improve adherence to lipid lowering
IC
medication. Cochrane Database Syst Rev 2010:CD004371.
39. Koren MJ. Statin use in a "real-world" clinical setting: aggressive lipid lowering
compared with usual care in the Aggressive Lipid-Lowering Initiation Abates New Cardiac
T
Events (ALLIANCE) trial. Am J Med 2005;118 Suppl 12A:16-21.
40. Zhang H, Plutzky J, Shubina M, Turchin A. Drivers of the Sex Disparity in Statin
Therapy in Patients with Coronary Artery Disease: A Cohort Study. PLoS One
2016;11:e0155228.
41. R
Cholesterol Treatment Trialists C, Fulcher J, O'Connell R, Voysey M, Emberson J,
A
Blackwell L, Mihaylova B, Simes J, Collins R, Kirby A, Colhoun H, Braunwald E, La Rosa J,

Pedersen TR, Tonkin A, Davis B, Sleight P, Franzosi MG, Baigent C, Keech A. Efficacy and
safety of LDL-lowering therapy among men and women: meta-analysis of individual data from
E
174,000 participants in 27 randomised trials. Lancet 2015;385:1397-1405.

42. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM,
C
Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM,
Kleiner DE, Hoofnagle JH, Robuck PR, Nash CRN. Pioglitazone, vitamin E, or placebo for
nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675-1685.
N
43. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A,
Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan
A
GA, Schenker S, Cusi K. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic

steatohepatitis. N Engl J Med 2006;355:2297-2307.
44. Maximos M, Bril F, Portillo Sanchez P, Lomonaco R, Orsak B, Biernacki D, Suman A,
V
Weber M, Cusi K. The role of liver fat and insulin resistance as determinants of plasma
aminotransferase elevation in nonalcoholic fatty liver disease. Hepatology 2015;61:153-160.
D
45. Bays H, Cohen DE, Chalasani N, Harrison SA, The National Lipid Association's Statin
Safety Task F. An assessment by the Statin Liver Safety Task Force: 2014 update. J Clin Lipidol
A
2014;8:S47-57.
46. Fabbrini E, Mohammed BS, Korenblat KM, Magkos F, McCrea J, Patterson BW, Klein
S. Effect of fenofibrate and niacin on intrahepatic triglyceride content, very low-density
lipoprotein kinetics, and insulin action in obese subjects with nonalcoholic fatty liver disease. J
Clin Endocrinol Metab 2010;95:2727-2735.
47. Yano M, Matsumura T, Senokuchi T, Ishii N, Murata Y, Taketa K, Motoshima H,
Taguchi T, Sonoda K, Kukidome D, Takuwa Y, Kawada T, Brownlee M, Nishikawa T, Araki E.
Statins activate peroxisome proliferator-activated receptor gamma through extracellular signal-
12
regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2

expression in macrophages. Circ Res 2007;100:1442-1451.
48. Sanguino E, Roglans N, Alegret M, Sanchez RM, Vazquez-Carrera M, Laguna JC.
Atorvastatin reverses age-related reduction in rat hepatic PPARalpha and HNF-4. Br J
Pharmacol 2005;145:853-861.
49. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin
resistance in NASH: TNF-alpha or adiponectin? Hepatology 2004;40:46-54.
50. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek
MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, Kowdley KV, McCullough A, Terrault N,
LE
Clark JM, Tonascia J, Brunt EM, Kleiner DE, Doo E, Network NCR. Farnesoid X nuclear
receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a
multicentre, randomised, placebo-controlled trial. Lancet 2015;385:956-965.
IC
Figure 1. Plasma ALT levels over time in patients not taking a statin (empty squares), those on
statins from enrollment (black dots), and those newly started on a statin during the study (dotted
line). Patients were divided based on their original randomization to pioglitazone (panel A) or
placebo (panel B).
T
Figure 2. Plasma AST levels over time in patients not taking a statin (empty squares), those on
R
statins from enrollment (black dots), and those newly started on a statin during the study (dotted
line). Patients were divided based on their original randomization to pioglitazone (panel A) or
A
placebo (panel B).
Table 1. Patients’ clinical characteristics at enrollment

E
Not on statins at enrollment (n On statins at enrollment (n = p

= 63) 38)
Age, years 48 ± 1 55 ± 1 <0.001
C
Gender (male), % 63% 82% 0.05

Body mass index, kg/m2 34.5 ± 0.5 34.3 ± 0.9 0.82
Total body fat, % 34 ± 1 33 ± 1 0.66
N
Liver fat, % 19 ± 1 14 ± 1 0.02

Metabolic Syndrome, % 89% 89% 0.93
Type 2 diabetes mellitus, % 44% 63% 0.07
A
Total cholesterol, mg/dl 196 ± 6 166 ± 6 <0.001

LDL-C, mg/dl 119 ± 5 93 ± 5 <0.001
Triglycerides, mg/dl 166 (133-224) 152 (82-227) 0.23
V
HDL-C, mg/dl 36 ± 1 38 ± 2 0.23

On other lipid-lowering 8% 18% 0.13
drug, %
D
ALT, IU/ml 75 ± 5 57 ± 5 0.03

AST, IU/ml 53 ± 4 43 ± 3 0.09
Fasting plasma glucose, 122 ± 4 127 ± 5 0.44
A
mg/dl
A1c, % 6.2 ± 0.1 6.5 ± 0.2 0.11
Systolic blood pressure, 133 ± 2 131 ± 2 0.45
mmHg
Diastolic blood pressure, 77 ± 1 75 ± 2 0.19
mmHg
Hypertension, % 71% 87% 0.07
NAFLD activity score 4.4 ± 0.2 4.6 ± 0.2 0.49
(NAS)
Steatosis 2.0 ± 0.1 2.0 ± 0.1 0.85
Inflammation 1.6 ± 0.1 1.8 ± 0.1 0.12
13
Ballooning 0.9 ± 0.1 0.8 ± 0.1 0.86

Fibrosis 0.9 ± 0.1 1.3 ± 0.2 0.05
Numeric variables expressed as mean ± SE, except for triglycerides: median (interquantile range). Qualitative data
expressed as percentages. p values were calculated with Chi2 or Fisher Exact test for categorical variables and t test
or Kruskal-Wallis for numerical variables depending on their distribution.
Table 2. Clinical, metabolic and liver histological profile before and after 18 months in patients
in whom statin therapy was added during follow-up but only on placebo during the trial.
Patients newly started on a statin (n=19)
p value
At enrollment After 18 months
LE
2
BMI, kg/m 35.1 ± 0.9 34.6 ± 0.9 0.06
Liver fat by 1H-MRS, % 13 ± 2 8±2 <0.001
ALT, IU/L 66 ± 8 38 ± 5 <0.001
AST, IU/L 48 ± 6 31 ± 3 0.006
Patients with ALT > 40 U/L, % 67% 39% 0.10
IC
Hemoglobin A1c, % 6.2 ± 0.2 6.2 ± 0.2 0.86
Total cholesterol, mg/dl 201 ± 11 148 ± 10 <0.001

Triglycerides, mg/dl 166 (132–210) 141 (94–189) 0.04
HDL, mg/dl 37 ± 2 41 ± 2 0.01

LDL, mg/dl 127 ± 8 77 ± 6 <0.001
T
Muscle insulin sensitivity (Rd, mg/kg LBM/min) 5.8 ± 0.7 5.5 ± 0.6 0.45
Suppression of EGP, % 43 ± 5 37 ± 5 0.34
Suppression of FFA, % 41 ± 5 49 ± 4 0.02
-
-
NAFLD activity score (NAS)
Steatosis
Inflammation
R
3.9 ± 0.3
1.7 ± 0.2
1.5 ± 0.1
3.7 ± 0.5
1.4 ± 0.2
1.6 ± 0.2
0.40
0.10
0.50
A
- Ballooning 0.8 ± 0.1 0.7 ± 0.1 0.43
- Fibrosis 0.6 ± 0.2 0.5 ± 0.2 0.50

expressed as percentages. p values were calculated with Chi2 or Fisher Exact test for categorical variables and paired
E
t-test or Wilcoxon matched-pairs signed-ranks test depending on variable’s distribution for continuous variables.
Table 3. Clinical, metabolic and liver histological profile before and after 18 months in patients
C
already on statin therapy at enrollment and only on placebo during the trial.
Patients already on a statin at enrollment
N
(n=18) p value
At enrollment After 18 months
BMI, kg/m2 35.1 ± 1.5 34.9 ± 1.4 0.77
A
Liver fat by 1H-MRS, % 14 ± 3 12 ± 2 0.40

ALT, IU/L 46 ± 7 39 ± 4 0.22
AST, IU/L 33 ± 2 32 ± 3 0.91
V
Patients with ALT > 40 U/L, % 50% 39% 0.50

Hemoglobin A1c, % 6.7 ± 0.3 6.4 ± 0.2 0.05
Total cholesterol, mg/dl 155 ± 7 148 ± 9 0.55
Triglycerides, mg/dl 137 (79–196) 137 (88–198) 0.96
D
HDL, mg/dl 39 ± 2 40 ± 2 0.47

LDL, mg/dl 84 ± 5 79 ± 8 0.59
Muscle insulin sensitivity (Rd, mg/kg LBM/min) 4.4 ± 0.3 5.1 ± 0.5 0.15
A
Suppression of EGP, % 42 ± 5 39 ± 6 0.49

Suppression of FFA, % 39 ± 6 42 ± 7 0.61
NAFLD activity score (NAS) 4.8 ± 0.2 4.3 ± 0.3 0.16
- Steatosis 2.0 ± 0.2 2.0 ± 0.2 0.99
- Inflammation 1.9 ± 0.1 1.6 ± 0.1 0.06
- Ballooning 0.9 ± 0.1 0.7 ± 0.1 0.27
- Fibrosis 1.1 ± 0.2 1.1 ± 0.2 0.85
expressed as percentages. p values were calculated with Chi2 or Fisher Exact test for categorical variables and paired
t-test or Wilcoxon matched-pairs signed-ranks test depending on variable’s distribution for continuous variables.
14
ADVANCE ARTICLE:
ADVANCE JCEM ENDOCRINOLOGY & METABOLISM
ARTICLE: Endocrinology
A
D
V
A
N
C
E
A
R
T
IC
LE
ADVANCE ARTICLE:
ADVANCE JCEM ENDOCRINOLOGY & METABOLISM
ARTICLE: Endocrinology
A
D
V
A
N
C
E
A
R
T
IC
LE

Liver Safety of Statins in Prediabetes or T2DM and Nonalcoholic Steatohepatitis

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Liver Safety of Statins in Prediabetes or T2DM and Nonalcoholic Steatohepatitis

Uploaded by

Copyright:

Available Formats

Liver Safety of Statins in Prediabetes or T2DM and Nonalcoholic

Steatohepatitis: Post-hoc Analysis of a Randomized Trial

The Journal of Clinical Endocrinology & Metabolism

Submitted: April 12, 2017

Liver Safety of Statins in Prediabetes or T2DM and Nonalcoholic

Main outcome measure

346 patients with T2DM and NAFLD (13).

Research Design and Methods

liver function, we measured plasma alanine aminotransferase (ALT) and aspartate

on the negative feedback principle to maintain the plasma glucose concentration at

Patients’ characteristics at enrollment

or 10-20mg pravastatin), medium (20-40mg of simvastatin, 40-80mg pravastatin, 10-20mg of

(p=0.003). No deleterious effects on plasma aminotransferase concentration or the proportion of

Corresponding author: Kenneth Cusi, M.D., F.A.C.P., F.A.C.E., Professor of Medicine,

the data and the accuracy of the data analysis.

1. Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic

iceberg, or neither? Hepatology 2008;48:662-669.

14. Dongiovanni P, Petta S, Mannisto V, Mancina RM, Pipitone R, Karja V, Maggioni M,

Nobili V, Romeo S, Pihlajamaki J, Valenti L. Statin use and non-alcoholic steatohepatitis in at

18. Gomez-Dominguez E, Gisbert JP, Moreno-Monteagudo JA, Garcia-Buey L, Moreno-

Aliment Pharmacol Ther 2006;23:1643-1647.

21. Antonopoulos S, Mikros S, Mylonopoulou M, Kokkoris S, Giannoulis G. Rosuvastatin as

a biomarker for the attenuation of NASH. J Gastroenterol 2010;45:750-757.

Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis. Can J

29. Barb D, Cusi K. Reply to "statins and non-alcoholic steatohepatitis". Metabolism

C, Musi N, Webb A, Portillo-Sanchez P. Long-term pioglitazone treatment for patients with

Intern Med 2016;165:305-315.

(Adult Treatment Panel III). JAMA 2001;285:2486-2497.

Blackwell L, Mihaylova B, Simes J, Collins R, Kirby A, Colhoun H, Braunwald E, La Rosa J,

174,000 participants in 27 randomised trials. Lancet 2015;385:1397-1405.

GA, Schenker S, Cusi K. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic

regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2

Table 1. Patients’ clinical characteristics at enrollment

Not on statins at enrollment (n On statins at enrollment (n = p

Gender (male), % 63% 82% 0.05

Liver fat, % 19 ± 1 14 ± 1 0.02

Total cholesterol, mg/dl 196 ± 6 166 ± 6 <0.001

HDL-C, mg/dl 36 ± 1 38 ± 2 0.23

ALT, IU/ml 75 ± 5 57 ± 5 0.03

Ballooning 0.9 ± 0.1 0.8 ± 0.1 0.86

Total cholesterol, mg/dl 201 ± 11 148 ± 10 <0.001

HDL, mg/dl 37 ± 2 41 ± 2 0.01

- Fibrosis 0.6 ± 0.2 0.5 ± 0.2 0.50

Liver fat by 1H-MRS, % 14 ± 3 12 ± 2 0.40

Patients with ALT > 40 U/L, % 50% 39% 0.50

HDL, mg/dl 39 ± 2 40 ± 2 0.47

Suppression of EGP, % 42 ± 5 39 ± 6 0.49

You might also like