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Page 2 of 11 Brodosi et al. Hepatoma Res 2020;6:82 I http://dx.doi.org/10.20517/2394-5079.2020.88

INTRODUCTION
The clinical and economic burden associated with non-alcoholic fatty liver disease (NAFLD) is becoming
of paramount importance for national health systems globally. Most recent data indicate that approximately
[1]
25% of adults may be classified as NAFLD , one in 4 to 5 patients with NAFLD have non-alcoholic
[1]
steatohepatitis (NASH) , and 1.5% have advanced fibrosis , the hallmark of disease progression to
[2]
[3]
cirrhosis .
The hepatic disease is part of a multifaced involvement of other tissues and organs, primarily the
[4]
cardiovascular system and the kidney , within the frame of the metabolic syndrome , that adds to the
[5]
[6]
liver in driving long-term outcomes . For this reason, there is a compelling need to adjust treatment to
[8]
[7]
minimize cardiovascular risk in all patients with NAFLD, as suggested by national and international
guidelines.
Despite much research and investment by pharmaceutical companies, no drugs have so far been approved
for treatment by regulatory authorities, and adherence to healthier lifestyle remains the only accepted
[9]
treatment strategy . Several drugs failed the agreed treatment outcomes (reduced fibrosis without
[10]
worsening of NASH or reduced necroinflammation, no worsening of fibrosis ) for approval during phase
[11]
2 or phase 3 randomized controlled studies (RCTs) ; only obeticholic acid fulfilled the targets in a phase
[12]
3 study , but the Food and Drug Administration required additional studies considering the low benefit/
[13]
risk ratio .
Individuals with Type 2 diabetes mellitus (T2DM) constitute a large cohort of NAFLD cases. The prevalence
of NAFLD in T2DM is as high as 60% , and T2DM increases the risk of disease progression to cirrhosis
[14]
as well as the occurrence of hepatocellular carcinoma (HCC) [15-17] . The relationship between T2DM and
NAFLD appears to be bidirectional, with T2DM increasing the risk of NAFLD and NAFLD favoring the
[18]
development of altered glucose regulation and T2DM . Initially considered the hepatic manifestation of
metabolic syndrome , and consequently as a likely effect of diabetes , it has also been suggested that
[19]
[20]
[21]
liver fat accumulation and NAFLD might indeed be the metabolic driver of T2DM . This evidence makes
the development of T2DM an additional outcome of NAFLD treatment and prompts the need for strict
control of glucose metabolism in NAFLD cases.

In the past 15 years the treatment of T2DM has completely changed. Second-generation sulfonylureas and
glinides, very effective oral drugs long considered the standard of treatment before prescribing insulin
injection, have been moved as third-line treatment and limited to rare settings in most recent international
guidelines, because of poor durability and a high risk of hypoglycemia and coronary artery disease [22-24] .
Very effective and safer drugs dipeptidylpeptidase-4 inhibitors (DPP-4Is), glucagon-like peptide-1 receptor
agonists [(GLP-1Ras) and sodium-glucose transporter-2 inhibitors (SGLT-2Is)] were added to the classical
armamentarium (metformin, acarbose, sulfonylureas and glinides, insulin) with definite advantages on
[22]
the impending risk of hypoglycemia, cardiovascular disease and heart failure . Their efficacy and safety
has been demonstrated in registration studies as well as in large cardiovascular outcome trials (CVOTs)
required by regulatory agencies such as the FDA and European Medicines Agency . The effects on liver
[25]
fat accumulation have been tested vs. sulfonylureas/glinides, or are under investigation. Also, pioglitazone,
an insulin-sensitizer of limited use following a series of warning data on class safety, initially involving
[27]
[26]
rosiglitazone , has shown positive effects on cardiovascular outcomes . In patients with NAFLD,
[28]
irrespective of the presence of T2DM, is was associated a reduced risk of advanced fibrosis , and its use is
[8]
now recommended by national and international guidelines .
The present review is aimed at defining the role of novel anti-diabetic drugs for the treatment of NAFLD
in patients with T2DM, with particular reference to the prevention of HCC. Data were retrieved from ad