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Page 4 of 11 Brodosi et al. Hepatoma Res 2020;6:82 I http://dx.doi.org/10.20517/2394-5079.2020.88

promotes the differentiation of adipocytes, decreases leptin and IL-6 concentration, increases adiponectin
[35]
levels, and above all, reduces insulin resistance, the driver of NAFLD . Pioglitazone has been tested in
NAFLD at the target dose of 30-45 mg/day in several RCTs with histologic outcomes, showing a reduction
of necroinflammation (NAFLD activity score - NAS) [36-40] , as well as improvement in fibrosis in a systematic
[41]
meta-analysis . Pioglitazone also reduces the risk of cardiovascular and cerebrovascular outcomes [42,43] ,
[44]
as well as of HCC (odds ratio, OR = 0.83, 95%CI: 0.72-0.95) . This makes pioglitazone the treatment of
choice of NASH, independent of the presence of T2DM. Notably, treatment discontinuation is followed
[45]
by NASH recurrence . Pioglitazone treatment is associated with moderate weight gain, and the risks of
non-osteoporotic fractures and, particularly, of heart failure are also increased; for these reasons the drug
[46]
should not be used in elderly patients . Adverse events are probably rare at lower doses (15 mg/day), but
the effects on the liver are also unknown. At present, the use of pioglitazone is off-label outside T2DM and
informed consent is needed before treatment in individuals without diabetes.

Dipeptidyl-peptidase-4 inhibitors
DPP-4Is (sitagliptin, vildagliptin, saxagliptin and alogliptin) decrease blood glucose by preventing
[47]
the rapid degradation in incretins, thus increasing glucose-dependent insulin release . This class of
antidiabetic drugs has progressively entered the market in the past 15 years, showing a moderate effect
on glucose control, and no risk of hypoglycemia or adverse cardiovascular outcomes. A meta-analysis
[48]
by Carbone et al. on the effects of incretin treatment in patients with NASH and T2DM including 66
participants treated with sitagliptin for between 16 and 36 weeks found a significant mean reduction of
alanine aminotransferase (ALT) in the two sitagliptin-treated cohorts (mean 17.7 U/L; 95%CI: 12.4-23.1;
P < 0.001). In a small cohort with T2DM and NASH, the administration of sitagliptin 100 mg/day for one
year determined a significant improvement in hepatocyte ballooning (P = 0.014) and total NAS (P = 0.04),
as well as a decrease in ALT and aspartate aminotransferase (AST), an index more closely correlated with
[49]
chronic liver damage . Similar data on liver enzymes were reported in 44 patients treated for six months
[50]
with DPP-4Is , whereas the improvement of NAS was confirmed in 40 NASH patients , randomized to
[51]
lifestyle changes vs. lifestyle changes associated with sitagliptin (NAS: -1.9 ± 1.4 vs. -0.7 ± 1.1; P = 0.006).
On the contrary, no differences in aminotransferases, liver fat content or liver stiffness were reported
in a 24-week RCT including patients with pre-diabetes or early diabetes [52,53] , treated with sitagliptin
(100 mg per day), as well as in two studies in which sitagliptin was tested against placebo for 12 weeks (no
differences in serum liver enzymes, hepatic fat content, fibrosis). No differences were reported in surrogate
biomarkers of fibrosis, namely NAFLD fibrosis score [NFS], Fibrosis-4 score [FIB-4], aminotransferase-to-
platelet ratio index [APRI] [51,53] . In summary, the use of DPP-4Is in T2DM with NAFLD appears to be safe,
but without any systematic advantage on progressive liver disease. There are no specific studies on their

possible effects on the risk of HCC in T2DM.

Glucagon-like petide-1 receptor agonists
GLP-1RAs (exenatide, lixisenatide, liraglutide, dulaglutide, semaglutide) are potent injectable anti-diabetic
drugs, mimicking the effects of endogenous incretins on insulin release, gastrointestinal motility, and the
[47]
central nervous system (reduced appetite and food intake ). CVOTs demonstrated that GLP-1RAs, as a
class but with some differences between rapid- (exenatide b.i.d. and lixisenatide) and long-acting drugs,
[23]
[54]
reduce the risk of major cardiovascular events in T2DM , and lead to a systematic weight loss . In
patients with NAFLD and T2DM, liraglutide was initially reported to reduce liver inflammation (AST, ALT)
and liver fibrosis scores (APRI index). These favorable effects might possibly derive from or be enhanced by
the concomitant weight and HbA1c reduction . Eguchi et al. also found a reduction in NAS and Brunt’s
[55]
[56]
classification grade after a 96-week treatment with liraglutide in ten patients with biopsy-proven NASH/
NAFLD.