Current and upcoming pharmacotherapy
for non-alcoholic fatty liver disease
Yaron Rotman,
1
Arun J Sanyal
2
1
Liver and Energy Metabolism
Unit, Liver Diseases Branch,
National Institute of Diabetes
and Digestive and Kidney
Diseases, National Institute of
Health, Bethesda, Maryland,
USA
2
Division of Gastroenterology,
Hepatology and Nutrition,
Department of Internal
Medicine, Virginia
Commonwealth University
School of Medicine, Richmond,
Virginia, USA
Correspondence to
Dr Yaron Rotman, Liver and
Energy Metabolism Unit, Liver
Diseases Branch, NIDDK, NIH,
10 Center Drive, Building 10,
Room 9C434, MSC 1800,
Bethesda, MD 20892-1800,
USA; rotmany@niddk.nih.gov
Received 13 June 2016
Revised 29 August 2016
Accepted 30 August 2016
Published Online First
19 September 2016
To cite: Rotman Y,
Sanyal AJ. Gut
2017;66:180–190.
ABSTRACT
Given the high prevalence and rising incidence of non-
alcoholic fatty liver disease (NAFLD), the absence of
approved therapies is striking. Although the mainstay of
treatment of NAFLD is weight loss, it is hard to
maintain, prompting the need for pharmacotherapy as
well. A greater understanding of disease pathogenesis in
recent years was followed by development of new
classes of medications, as well as potential repurposing
of currently available agents. NAFLD therapies target
four main pathways. The dominant approach is targeting
hepatic fat accumulation and the resultant metabolic
stress. Medications in this group include peroxisome
proliferator-activator receptor agonists (eg, pioglitazone,
elafibranor, saroglitazar), medications targeting the bile
acid-farnesoid X receptor axis (obeticholic acid),
inhibitors of de novo lipogenesis (aramchol, NDI-
010976), incretins (liraglutide) and fibroblast growth
factor (FGF)-21 or FGF-19 analogues. A second
approach is targeting the oxidative stress, inflammation
and injury that follow the metabolic stress. Medications
from this group include antioxidants (vitamin E),
medications with a target in the tumour necrosis factor
α pathway (emricasan, pentoxifylline) and immune
modulators (amlexanox, cenicriviroc). A third group has
a target in the gut, including antiobesity agents such as
orlistat or gut microbiome modulators (IMM-124e, faecal
microbial transplant, solithromycin). Finally, as the
ongoing injury leads to fibrosis, the harbinger of liver-
related morbidity and mortality, antifibrotics (simtuzumab
and GR-MD-02) will be an important element of
therapy. It is very likely that in the next few years several
medications will be available to clinicians treating
patients with NAFLD across the entire spectrum of
disease.
INTRODUCTION
Non-alcoholic fatty liver disease (NAFLD), defined
as excess accumulation of fat in the liver, has
become the most common cause for chronic liver
disease in the Western world and is estimated to
impact at least 30% of Americans
12
or Chinese
3
with the prevalence appearing to rise in recent
years.
45
Non-alcoholic steatohepatitis (NASH) is a
subset of NAFLD, estimated to affect 2–5% of
Americans, in which increased liver fat is accom-
panied by cellular injury, inflammatory infiltrate
and, subsequently, liver fibrosis, which can progress
to cirrhosis with its associated complications.
6
Although fatty liver by itself is associated with
other features of the metabolic syndrome such as
obesity, diabetes mellitus type 2, hypertension and
dyslipidemia, increased liver-related mortality is
essentially limited to patients with NASH.
7
Increased triglyceride deposition in the liver
reflects an input/output imbalance of hepatic free
fatty acid (FFA) metabolism. In obesity-associated
NAFLD, there is an increase of FFA delivery to the
liver, especially during the fed state, due to adipose
tissue insulin resistance.
89
In addition, de novo
lipogenesis is increased,
10
driven by the hyperinsu-
linemia as well as excess availability of carbohy-
drates. Compensatory increase in very low density
lipoprotein (VLDL) secretion is not sufficient to
overcome the excess formation of triglycerides
11
while it is unclear whether β-oxidation is increased
or decreased in these subjects.
12
The accumulated triglycerides in steatosis appear
to be relatively inert with benign outcome; hepato-
cellular injury is driven by lipotoxicity from FFAs
and their derivatives,
13
as well as overloading of
mitochondrial capacity. This initial metabolic stress
activates multiple cell stress pathways, including
generation of reactive oxygen species, endoplasmic
reticulum stress and apoptosis. Injury signals from
stressed or dying hepatocytes, lipids and chemo-
kines activate an immune response, including
recruitment and activation of variety of immune
cells, further increasing cellular injury. Key media-
tors are the Kupffer cells and macrophages, which
are further activated by bacterial products from the
gut microbiome.
Hepatocellular injury and immune cell activity
converge to activate hepatic stellate cells, causing a
change in their phenotype and deposition of colla-
gen, resulting in increased fibrosis and hepatic
architectural distortion.
Although the injury patterns are common and
conserved, there is variability between patients with
NAFLD in the degree of activation of each individ-
ual pathway, likely accounting for the heterogeneity
of clinical phenotypes and severity. This may be
secondary to different external stimuli (ie, dietary
composition), genetic components and modulation
by the gut microbiome, among other factors.
The remarkable progress that has been made in
previous years in understanding disease pathogen-
esis has led to an explosion of medical therapies
targeting various aspects of the fat accumulation
and injury pathways. These can be grouped into
four general classes (figure 1), according to their
intended targets: (1) Medications with a primary
metabolic target, geared to reduce hepatic fat accu-
mulation and metabolic stress. (2) Medications
addressing oxidative stress or the inflammation and
injury components of NASH. (3) Medications with
a primary gut target, modulating the interaction
between the gut and the liver in NAFLD. (4)
Antifibrotics, aiming to decrease the progressive
fibrosis and resultant complications.
180 Rotman Y, Sanyal AJ. Gut 2017;66:180–190. doi:10.1136/gutjnl-2016-312431
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MEDICATIONS WITH A PRIMARY M ETABOLIC TARGET
PPAR agonists
The peroxisome proliferator-activator receptors (PPARs) are a
family of nuclear receptors that bind a wide range of fatty acids
and fatty acid derivatives and transcriptionally regulate a wide
variety of metabolic processes (table 1). There are three PPARs
—α, β/δ and γ—that share the same target DNA sequence but
differ in ligand selectivity and tissue distribution.
14
PPARα is expressed extensively in the liver, adipose tissue,
heart, skeletal muscle and kidney;
15
its activity increases in the
fasting state and transcriptionally drives the expression of a
large number of genes, including those regulating gluconeogen-
esis, β -oxidation, lipid transport and the hormone fibroblast
growth factor (FGF)-21. In various animal models, PPARα dele-
tion, either at germline level
16
or in hepatocytes only,
17
is asso-
ciated with worsening of hepatic steatosis. Fibrates, which are
synthetic agonists of PPARα, are used extensively for clinical
treatment of hypertriglyceridemia, but have not shown a consist-
ent beneficial effect for the treatment of NAFLD,
18
possibly
related to their effect on PPARα outside the liver. PPARδ,
another member of the PPAR family, has a wider expression dis-
tribution pattern, and beyond hepatocytes is also expressed in
high levels in skeletal muscle and macrophages
19
and its activa-
tion improves insulin sensitivity, decreases hepatic glucose pro-
duction, increases fatty acid oxidation and decreases
macrophage and Kupffer cell activation. PPARδ activation has
also been shown to decrease atherosclerotic disease in animal
models.
20
Treatment with a PPARδ agonist in a pilot study
decreased hepatic fat content, likely through an increase in fatty
acid oxidation,
21
but development has been halted due to safety
concerns. Elafibranor (GFT-505) is a dual PPARα/δ agonist,
aiming to combine the beneficial effects of activating the two
receptors. Animal data demonstrate that a beneficial effect of
elafibranor on serum triglycerides, cholesterol and high density
lipoprotein (HDL), and a reduction in hepatic fat that is
mediated, at least in part, by non-PPARα-dependent mechan-
ism.
22 23
Post hoc analysis of short-term (4–12 weeks) phase II
clinical trials using elafibranor for the treatment of metabolic
syndrome demonstrated a significant reduction in ALT in sub-
jects in the top two quartiles at baseline
22 24
and has shown an
improvement in liver, adipose and peripheral tissue insulin sensi-
tivity,
24
making it a potentially attractive therapeutic agent for
NASH. Recently, a phase IIb randomized double-blind placebo
controlled trial (RDBPCT), GOLDEN-505, assessed the
Obeticholic acid
PPRE
RXR
PPAR
α/γ/δ
FXRE
FXR
RXR
Intestine
Aramchol
NDI-010976
Sevelamer
SHP-626
Orlistat
IMM-124e
FMT
Solithromycin
Pioglitazone
Elabranor
Saroglitazar
Vitamin E
Pentoxifylline
Emricasan
GS-4997
Amlexanox
Cenicriviroc
Hormones
GLP-1 (liraglutide)
FGF-19 (NGM-282)
FGF-21 (BMS-986036 )
GHRH (Tesamorelin)
Fibrosis
Dietary fat
Bacterial products
Blie acids
Fat deposition &
metabolic stress
Oxidative stress
Apoptosis
Inammation
Injury
Simtuzumab
GR-MD-01
DNL
Figure 1 Targets of upcoming therapies for non-alcoholic fatty liver disease (NAFLD). DNL, de novo lipogenesis; FGF, fibroblast growth factor;
FMT, faecal microbial transplant; FXR, farnesoid X receptor; FXRE, FXR response element; GHRH, growth hormone-releasing hormone; GLP-1,
glucagon-like peptide-1; PPAR, peroxisome proliferator-activated receptor; PPRE, PPAR response element; RXR, retinoid X receptor.
Rotman Y, Sanyal AJ. Gut 2017;66:180–190. doi:10.1136/gutjnl-2016-312431 181
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effectiveness of elafibranor (80 or 120 mg/day) or placebo for
1 year to treat biopsy-proven NASH.
25
The study included 276
patients with mild–severe NASH and allowed for inclusion of
diabetics, but excluded patients with cirrhosis. The primary end
point of the study was ambitiously selected as histological reso-
lution of NASH without worsening of fibrosis, based on recom-
mendations from a recent US Food and Drug Administration/
American Association for the Study of Liver Diseases (AASLD)
workshop.
26
The primary end point was achieved in 23% and
21% of patients in the 80 mg and 120 mg/day groups, respect-
ively, and in 17% of controls; the difference between the groups
was not statistically significant. A more stringent definition of
NASH resolution was assessed post hoc, and using that criteria,
NASH resolution was achieved in 19% of the 120 mg/day
group compared with 12% of placebo-treated subjects
(p=0.045). The failure to show benefit appears to be primarily
due to a high response rate in the placebo groups of mild–mod-
erate (NAFLD activity score (NAS)
27
3–5) disease and in fact,
when subjects with mild disease at baseline (NAS=3) were
excluded from the analysis, the 120 mg/day dose was signifi-
cantly superior than placebo across both response definitions.
The 120 mg/day dose had a modest effect on alanine amino-
transferase (ALT) (decrease of 9.5 U/L compared with placebo)
and in patients with diabetes improved insulin sensitivity. A
phase III trial (NCT02704403) is currently recruiting subjects
with NASH and NAS≥4, aiming to determine the effects of
72 weeks of treatment with 120 mg/day on NASH resolution
without worsening of fibrosis. For the first time in therapeutic
trials of NAFLD, a clinical co-primary end point is included,
assessing the effect of elafibranor on mortality, cirrhosis and
liver-related clinical outcomes.
PPARγ, another member of the PPAR family, is predominantly
expressed in the adipose tissue, controlling lipogenesis, glucose
metabolism and adipose tissue differentiation. Thiazolidinediones
(TZDs), synthetic PPARγ agonists, are insulin sensitisers with
proven efficacy for treatment of diabetes and have been shown in
Table 1 Clinical trials of medications for non-alcoholic fatty liver disease (NAFLD)
Medication Mechanism Current status
Histological
benefit shown
Studied in
cirrhotics
Studied in diabetics
with NAFLD
Medications with a primary metabolic target
Pioglitazone PPARγ agonist Phase III concluded* Yes (secondary analyses only) No No
Elafibranor PPARα/δ agonist Phase III Yes (secondary analyses only) No Yes
Saroglitazar PPARα/γ agonist Phase III* Pending† Yes Yes
Obeticholic acid FXR agonist Phase III* Yes No Yes
Liraglutide GLP-1 receptor agonist Phase II concluded* Yes Yes Yes
Aramchol SCD inhibitor Phase IIb Pending† No Yes
Volixibat (SHP-626) ASBT inhibitor Phase II Pending† No Yes
BMS-986036 FGF-21 analogue Phase II Not studied ? Yes
NGM-282 FGF-19 analogue Phase II Not studied ? ?
Tesamorelin GHRH analogue Phase II* (HIV patients) Pending† No Yes
NDI-010976 ACC inhibitor Phase I concluded Not studied No No
GS-9674 FXR agonist Phase I Not studied No No
Dur-928 Sulfated oxysterol Phase I Not studied Yes Yes
AZD4076 miR-103/107 antagonist Phase I Not studied No No
Rosuvastatin HMG-CoA reductase inhibitor Uncontrolled pilot concluded* Yes No No
INT-767 FXR/TGR5 agonist Preclinical
Sevelamer Bile acid sequestrant Preclinical*
Medications targeting oxidative stress and inflammation
Vitamin E Antioxidant Phase III‡ Yes No No
Pentoxifylline PDE inhibitor Phase II concluded Yes No Yes
Cenicriviroc CCR2/CCR5 antagonist Phase IIb Pending† No Yes
Emricasan Caspase inhibitors Phase IIb Pending† No Yes
GS-4997 ASK1 inhibitor Phase II Pending† No Yes
Amlexanox IKKε/TBK1 inhibitor Phase II* Not studied No Yes
PXS-4728A VAP-1 inhibitor Phase I concluded Not studied No No
Medications targeting the gut
Orlistat Intestinal lipase inhibitor Phase II concluded* Inconclusive Yes Yes
IMM-124e IgG-rich bovine colostrum Phase II Not studied No Yes
Solithromycin Antibiotic Phase II Pending† No Yes
Faecal microbial transplant Modulation of gut microbiome Pilot Not studied No Yes
Antifibrotics
Simtuzumab LOXL2 antibody Phase II Pending§ Yes Yes
GR-MD-02 Galectin-3 inhibitor Phase II Pending§ Yes Yes
*Currently approved for non-NAFLD indication.
†Histological outcome is studied in an ongoing trial.
‡Currently available over the counter.
§Histological and portal pressure outcom es are studied in an ongoing trial.
ACC, acetyl-CoA carboxylase; ASBT, apical sodium-dependent bile acid transporter; GLP, glucagon-like peptide; FGF, fibroblast growth factor; FXR, farnesoid X receptor; GHRH, growth
hormone-releasing hormone; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; LOXL2, lysyl oxidase-like; PDE, phosphodiesterase; PPAR, peroxisome proliferator-activator receptor;
SCD, stearoyl CoA desaturase; VAP, vascular adhesion protein.
182 Rotman Y, Sanyal AJ. Gut 2017;66:180–190. doi:10.1136/gutjnl-2016-312431
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multiple trials to be effective for the treatment of NASH.
28–30
In
the PIVENS RDBPCT, the largest trial of a PPARγ agonist to date,
80 patients with NASH but not diabetes or cirrhosis received pio-
glitazone 30 mg/day for 96 weeks and were compared with 83
placebo-treated subjects.
30
Pioglitazone treatment was associated
with histological improvement in 34% of subjects compared with
19% of controls. The significance level of p=0.04 did not meet
the prespecified cut-off, despite apparent effectiveness, mainly due
to discrepancies in the interpretation of entry liver biopsies in this
group. Unfortunately, concerns with the safety profile of TZDs
(especially regarding cardiovascular safety of rosiglitazone) and a
side effect profile that includes weight gain due to redistribution of
body fat have led to poor acceptance of these agents for the treat-
ment of NASH in clinical practice.
31
The glitazars are a class of medications designed as dual
PPARα/γ agonists, aiming to synergise the beneficial effects of
PPARα and PPARγ agonism. However, development of most
compounds in this class has been halted due to safety concerns.
The only glitazar in clinical use, saroglitazar, is currently
approved in India for the treatment of diabetic dyslipidemia.
32 33
In a mouse model of NASH, treatment with saroglitazar
induced histological improvement as well as a decrease in liver
fat content and ALT.
34
A retrospective analysis of patients with
NAFLD treated with saroglitazar for dyslipidemia demonstrated
significant and marked decrease in ALT (from 64±6 to 28±3,
p<0.01) after 24 weeks of treatment.
35
In PRESS VIII, a phase
II open-label study, the effi cacy of saroglitazar was evaluated in
32 patients with biopsy-proven NASH and a 52% reduction in
ALT was demonstrated after 12 weeks of treatment.
36
A phase
III RDBPCT of saroglitazar for 52 weeks in non-cirrhotic
patients with biopsy-proven NASH is currently ongoing in
India, with the primary end point defined as improvement in
NASH histology with no worsening of fibrosis (Clinical Trials
Registry—India CTRI/2015/10/006236).
Novel selective modulators of PPARα (pemafibrate, K-877)
and PPARγ (INT-131), a PPARδ agonist (HPP-593) and a PPARα/
γ agonist (DSP-8658), are currently in clinical trials for other
indications (mainly diabetic dyslipidemia). Whether these agents
will prove to have a bene ficial effect on NAFLD is yet unknown.
Although TZDs are typically considered to act through
PPARγ agonism, there is evidence to suggest other mechanisms
as well. In an animal model, MSDC-0602, an experimental
TZD with poor affinity to PPARγ, was able to suppress hepatic
glucose production and de novo lipogenesis in mice with
hepatocyte-specificPPARγ knockout,
37
likely through inter-
action with mitochondrial proteins Mcp1 and Mcp2.
38
Clinical
trials in human NASH are planned but have not begun to date.
Targeting the FXR-bile acid axis
The interaction of bile acids with the farnesoid X receptor
(FXR), their intracellular receptor, negatively regulates bile acid
synthesis and acts transcriptionally to decrease hepatic lipogen-
esis and steatosis,
39
as well as decrease hepatic gluconeogenesis
and improve peripheral insulin sensitivity.
40
Obeticholic acid
(6-ethylchenodeoxycholic acid (OCA)) is a synthetic lipophilic
bile acid acting as FXR agonist and was recently evaluated as
potential treatment for NASH in a phase IIb multicentre clinical
trial. In the RDBPCT FLINT study,
41
283 non-cirrhotic patients
with biopsy-proven NASH (NAS ≥4) were randomised to
receive OCA (25 mg/day) or placebo for 72 weeks. The primary
end point of the study was histological improvement, defined as
a decrease of two points in the NAS with no worsening of fibro-
sis. Histological improvement was seen in 45% of patients
treated with OCA compared with 21% of those treated with
placebo (p=0.0002). Resolution of NASH was seen in 22% of
patients versus 13% of controls (p=0.08) and improvement in
fibrosis score was detected in 35% versus 19% in controls
(p=0.004). A concomitant significant decrease in liver enzymes
was noted. Interestingly, patients treated with OCA had a signifi-
cant decrease in body mass index (BMI) (decrease of 0.7 vs gain
of 0.1 kg/m
2
in the placebo group, p=0.01); whether this was
responsible, at least in part, for the histological improvement is
unclear. However, patients treated with OCA had a reversible
significant increase in total and low density lipoprotein
(LDL)-cholesterol and decrease in HDL-cholesterol. These
changes were of low magnitude, appeared predominantly at
treatment initiation and improved with treatment continuation,
suggesting adaptation or initiation of cholesterol-reducing medi-
cations. Whether these changes will be sustained with prolonged
treatment and whether they will be associated with an increase
in cardiovascular risk remains to be shown. The main side effect
of OCA was pruritus, noted in 23% of OCA-treated patients
and requiring intervention or treatment discontinuation in
several patients. Thus, although OCA appears effective for the
treatment of NASH, its long-term safety and tolerability is still
unclear. A phase III trial (NCT02548351) is currently recruiting
patients with non-cirrhotic NASH and will compare the effects
of OCA or placebo for 72 weeks on two co-primary histological
outcomes—resolution of NASH without worsening of fibrosis
or improvement of fibrosis without worsening of NASH.
Similar to the elafibranor phase III trial, a clinical end point is
included to assess the effect of treatment on mortality and liver-
related outcomes at 6 years.
Other FXR agonists are being tested in clinical trials.
GS-9674, a synthetic non-steroidal FXR agonist, is currently in
a phase I study. In contrast to OCA, GS-9674 and similar agents
are less likely to undergo enterohepatic circulation and may
have more predictable pharmacokinetics.
42
INT-767 is a bile
acid analogue that acts as a dual agonist on FXR and on TGR5,
the transmembrane G-protein bile acid receptor. In an animal
model, INT-767 improved histological features of NASH and
modulated the activation of hepatic monocytes.
43
A phase I trial
in human subjects is scheduled to start. In contrast to OCA,
treatment with ursodeoxycholic acid (UDCA), a naturally occur-
ring secondary bile acid, has not been shown to improve histo-
logical features of NASH,
44 45
despite lowering liver enzymes.
The difference between the effects of UDCA and OCA may be
related to the poor affinity of UDCA to FXR or even its ability
to antagonise FXR activity.
46
Other UDCA derivatives, such as
nor-UDCA or tauroursodeoxycholic acid, were not tested in
humans for the treatment of NAFLD.
An alternative approach to direct targeting of FXR has been
the use of bile acid sequestrants that disrupt the enterohepatic
circulation and result in reduction in serum lipids. An RDBPCT
assessing the effectiveness of 24 weeks of colesevelam treatment
in patients with biopsy-proven NASH
47
failed to show histo-
logical improvement and in fact demonstrated a rise in liver
enzymes and liver fat content with colesevelam treatment.
These findings are consistent with a reduction in FXR and liver
X receptor (LXR)
48
activation, as seen in animal models as
well.
48
All sequestrants may not be the same, as sevelamer, a
phosphate-binding medication with bile salt binding capacity,
49
has been shown in an animal model of steatohepatitis to
improve liver fat, inflammation and fibrosis
50
in an
FXR-independent effect.
51
Similarly to the effect of sequestra-
tion, enterohepatic circulation of bile acids can be disrupted by
inhibiting the ileal apical sodium-dependent bile acid trans-
porter (ASBT), the major route of reabsorption of bile acids in
Rotman Y, Sanyal AJ. Gut 2017;66:180–190. doi:10.1136/gutjnl-2016-312431 183
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the terminal ileum. ASBT inhibitors cause an increase in faecal
bile acids and improve glycaemic control in animal models.
52
An oral inhibitor of ASBT, volixibat (SHP-626), recently con-
cluded phase I studies and a phase II trial in patients with
NASH is enrolling (NCT02787304).
Inhibition of de novo lipogenesis
Aramchol is a conjugate of cholic and arachidic acid that was
shown to inhibit stearoyl CoA desaturase (SCD) and de novo
lipogenesis in cell and animal models.
53 54
In a recent phase II
RDBPCT, 300 mg/day of aramchol given for 3 months signifi-
cantly decreased hepatic fat content by 12.5%.
55
The study
enrolled predominantly subjects with NAFLD but not NASH
and did not use histological end points. Treatment was not asso-
ciated with improvement in liver enzymes, raising a concern that
the reduction in hepatic fat was not accompanied by an
improvement in in flammation or cellular injury. A phase IIb
study (NCT02279524) is currently evaluating the effects of
higher doses (400 and 600 mg/day) for 1 year in patients with
non-cirrhotic biopsy-proven NASH (NAS≥4). The primary end
point is decrease in liver fat content by MRI, while histological
end points such as improvement or resolution of NASH are
defined as secondary end points.
Malonyl-CoA acts as a key gatekeeper of fatty acid metabol-
ism, controlling the balance between de novo lipogenesis and
fatty acid oxidation.
56
It serves as the building block for fatty
acid synthesis and elongation, while inhibiting the entry of fatty
acids to the mitochondria for β-oxidation. Acetyl-CoA carboxyl-
ase (ACC) is the key enzyme generating malonyl-CoA from
acetyl-CoA and regulating this process. Inhibition of ACC by
antisense oligonucleotides in a murine model of NAFLD
increases fatty acid oxidation, decreases lipogenesis, decreased
hepatic fat content and improved insulin sensitivity.
56
An allo-
steric inhibitor of ACC, NDI-010976, was recently tested in
obese subjects in a phase I trial
57
and demonstrated dose-
dependent inhibition of de novo lipogenesis, reaching up to
98% decrease from baseline following a single dose, making it a
potential treatment for NAFLD.
Dur-928 is an endogenous sulfated oxysterol that has been
shown to decrease hepatic fat content in animal models via
inhibition of LXR and SREBP
58
and is being developed as an
oral agent for the treatment of NASH. A phase Ib study
(ACTRN12615001355561) to evaluate its safety in patients
with NASH compared with controls is currently ongoing.
Incretins and DPP-4 inhibitors
Glucagon-like peptide 1 (GLP-1) is an incretin hormone derived
from the proglucagon polyprotein that is also the precursor to
glucagon.
59
GLP-1 is secreted by intestinal L-cells in response to
meal ingestion and acts on the pancreas to improve glycaemic
control by stimulating insulin secretion from pancreatic β-cells
and inhibiting α-cell glucagon secretion. Beyond the pancreas,
GLP-1 improves peripheral insulin sensitivity, increases hepatic
glucose uptake and glycogen synthesis, delays gastric emptying
and decreases appetite.
60
Several long-acting GLP-1 receptor
agonists (GLP-1RAs) are approved for the treatment of type 2
diabetes mellitus. In retrospective analyses of GLP-1RA trials in
diabetic subjects, beneficial effects on liver enzymes and hepatic
fat content were shown. For example, liraglutide treatment for
26 weeks was associated with an average decrease of 8.2 U/L in
ALT activity in subjects with baseline elevated ALT, but this
appeared to be fully explained by the concomitant decrease in
weight and HbA1c.
61
Similar findings were reported for exena-
tide
62
and lixisenatide.
62
Recently, the LEAN study
63
was an
RDBPCT specifically designed to examine the utility of liraglu-
tide to treat NASH. Fifty-two subjects with histologically proven
NASH (only 33% of whom were diabetics) were randomised to
receive liraglutide (1.8 mg/day) or placebo for 48 weeks. At the
end of the study, histological resolution of NASH without wor-
sening of fibrosis, the primary end point, was seen in 39% of
the patients assigned to liraglutide versus 9% of the placebo
group ( p=0.02). Mechanistically, liraglutide treatment improved
hepatic insulin sensitivity, with resultant reduction in hepatic
endogenous glucose production, decreased hepatic de novo lipo-
genesis and promoted an improvement in adipose tissue insulin
sensitivity with reduction of lipolysis and delivery of FFAs to
the liver.
64
As expected, treatment with liraglutide was asso-
ciated with weight loss; histological responders lost on average
2.1 kg more than non-responders. Unfortunately, the study was
not powered to show whether the beneficial effect on the liver
was independent from the effect of weight loss alone.
A potentially alternative approach for augmentation of
endogenous incretin effects is by use of small-molecule inhibi-
tors of dipeptidyl peptidase 4 (DPP-4), the enzyme responsible
for rapid degradation of GLP-1. Studies of sitagliptin, a DPP-4
inhibitor, were small and limited to diabetic patients with fatty
liver. Only one study used histological end points.
65
In this
small, uncontrolled trial with 15 patients, treatment with
100 mg/day of sitagliptin for 1 year was associated with
improvement in liver enzymes, hepatocyte ballooning, histo-
logical activity scores and steatosis. A modest decrease in liver
fat content by magnetic resonance spectroscopy (MRS) was also
shown after 24 weeks of sitagliptin
66
or vildagliptin.
66
Other
studies, on the other hand, failed to show an effect of sitagliptin
treatment on liver fat content
67
or liver enzymes.
68
Recently,
Cui et al
69
performed the largest study to date, enrolling 50
subjects with NAFLD and pre-diabetes or early diabetes in an
RDBPCT. In that study, 24 weeks of treatment with sitagliptin
100 mg/day were not associated with improvement in liver fat,
liver enzymes or liver stiffness. Thus, DPP-4 inhibition does not
seem to be highly effective for the treatment of NASH.
Lipid-lowering agents
As metabolic syndrome is closely associated with fatty liver
disease, many of the patients have dyslipidemia and increased
risk for cardiovascular disease. Furthermore, in patients with
NASH, there is evidence for excess accumulation of free choles-
terol in the liver, which could play a role in disease pathogen-
esis.
70 71
Statin use is generally safe in patients with chronic
liver disease, including those with NAFLD.
72
In a retrospective
analysis, statin use was associated with decreased risk of NASH
and advanced fibrosis in a large cohort of patients who under-
went a liver biopsy for possible NASH.
73
However, this could
also reflect hesitancy of providers to prescribe statins to patients
with advanced liver disease and in fact there is clear evidence
for underuse of statins in patients with NAFLD.
74
Prospective
clinical trials using statins to treat the liver disease are few and
limited but generally demonstrated a beneficial effect of statins
on liver fat content (reviewed in ref.
72
). In a recent prospective
uncontrolled trial, 20 patients with biopsy-proven NASH (base-
line NAS score of 8) and dyslipidemia were treated for
12 months with 10 mg/day of rosuvastatin. In total, 19 of the
20 patients reportedly had a complete resolution of NASH
including complete resolution of steatosis, inflammation and
ballooning, despite experiencing no weight loss.
75
Whether
such phenomenal findings can be replicated in a larger con-
trolled trial remains to be seen.
184 Rotman Y, Sanyal AJ. Gut 2017;66:180–190. doi:10.1136/gutjnl-2016-312431
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