Efficacy and safety of sitagliptin for the treatment of diabetes mellitus complicated by chronic liver injury

We have described the efficacy and safety of sitagliptin as a treatment for patients
with DM complicated by chronic liver injury. The present study shows that the administration
of sitagliptin for an average of 13.7 months resulted in 0.61% decrease in the level
of HbA1c, as well as decreased ALT and ?GT levels in 122 patients including 19 patients
with LC. The ALT and ?GT levels did not decrease significantly when analyzed with
respect to the causes of chronic liver injury, but the data suggest at least that
no deterioration of AST, ALT and ?GT levels was caused by sitagliptin. In particular,
this study can be considered valuable in demonstrating that sitagliptin decreased
HbA1c levels without causing any deterioration in liver enzymes even in patients with
LC.

Recently, several studies have examined the relationships between DPP-4 or incretin
hormones and liver. DPP-4 plays a role in fibroblast activation in the liver by activating
hepatic stellate cells (Piazza et al. 1989]; Levy et al. 1999]), while sitagliptin, a DPP-4 inhibitor, attenuates hepatic fibrosis by suppressing
activated hepatic stellate cells in rats (Kaji et al. 2014]). The GLP-1 receptor is present on human hepatocytes and has been shown to play a
direct role in decreasing hepatic steatosis in vitro by modulating components of the
insulin signaling pathway (Gupta et al. 2010]). GLP-1 suppresses hepatic lipogenesis by activating the cAMP-activated protein kinase
(AMPK) pathway (Shlomo et al. 2011]). Although the investigations in vivo are still insufficient, the data suggest that
DPP-4 inhibitors and GLP-1 receptor agonists may improve hepatic steatosis and suppress
the progression of hepatic fibrosis.

NAFLD is the leading cause of chronic liver injury in T2DM, as was seen in this study.
NAFLD is considered to be a hepatic manifestation of the metabolic syndrome, and is
particularly associated with insulin resistance, obesity, hypertension, and abnormalities
in glucose and lipid metabolism (Chitturi et al. 2002]). The histological changes seen in NAFLD range over a wide spectrum, extending from
simple steatosis, which is generally non-progressive, to NASH, liver cirrhosis and
liver failure, and, sometimes, even hepatocellular carcinoma (Ludwig et al. 1980]). It is expected that DPP-4 inhibitors and GLP-1 receptor agonists will be especially
effective in treating T2DM patients with NAFLD, because several studies have shown
that the serum concentration of DPP-4 is high in NAFLD patients where it is related
to insulin resistance (Firneisz et al. 2010]), and that the expression of GLP-1 receptor is reduced in NASH patients (Ding et
al. 2006]). A previous study showed that the administration of sitagliptin (50 mg/day) for
16 weeks resulted in significant decreases in serum HbA1c, AST, ALT and ?GT levels
in 30 NAFLD patients with T2DM (Iwasaki et al. 2011]), a finding that suggests sitagliptin improves the effects of fatty liver. Although
significant decreases in the serum levels of AST, ALT and ?GT were not found for 62
NAFLD patients in our study, further investigations are necessary to assess the efficacy
of sitagliptin in NAFLD patients. Although our study included NAFLD patients co-treated
with thiazolidine, which has the efficacy of improving liver histology and fibrosis
in NASH patients (Boettcher et al. 2012]), the conclusion has not been changed even if these patients were excluded from the
analysis because the number of these patients was only 3.

We also investigated the efficacy and safety of sitagliptin also in ALD and LC patients.
In particular, efficacy and safety of sitagliptin in LC patients have not been sufficiently
investigated until now. LC can be defined as the end stage of chronic liver disease
with progressive fibrosis, and can be fatal due to the development of hepatocellular
carcinoma or liver failure (Bataller and Brenner 2005]). It is often difficult to treat patients with T2DM complicated by liver diseases
using oral hypoglycemic agents, because most existing oral hypoglycemic agents are
metabolized in the liver, which may lead to an increase in hypoglycemic episodes or
a deterioration of liver function. Since the DPP-4 inhibitor sitagliptin is only minimally
metabolized in liver with over 80% excreted intact in urine (Drucker and Nauck 2006]), it is expected that sitagliptin will reduce serum glucose levels without causing
a deterioration in liver enzymes even in LC patients. This study investigated 19 patients
with LC including those with severely impaired hepatic functional reserves (5 patients
classified as Child-Pugh B and 2 patients as Child-Pugh C), with no apparent deterioration
in liver enzymes. Although the number of patients is low, the result can be considered
valuable. Since a previous study showed that sitagliptin attenuates hepatic fibrosis
by suppressing activated hepatic stellate cells in vitro (Kaji et al. 2014]), it is worthy investigating further whether sitagliptin suppresses the progression
of hepatic fibrosis in LC patients.

Although we believe our findings to be valuable, the limitations of this study are
as follows. First, this study is a retrospective, observational study, and the duration
of sitagliptin administration was not the same in all cases. Second, the number of
patients was insufficient (122 patients), and, moreover, the causes of chronic liver
injury in 20 patients were unknown due to the lack of sufficient clinical data. Third,
we only assessed liver enzymes such as serum AST, ALT and ?GT levels, and the assessments
for true liver function, such as serum albumin, prothrombin, cholinesterase and bilirubin,
are insufficient. Fourth, the degree of hepatic fibrosis was not assessed using objective
markers such as serum hyaluronic acid or type IV collagen 7S domain, or other modalities
such as Fibroscan. Further investigations are necessary to assess efficacy and safety
of sitagliptin for the treatment of patients with DM complicated by chronic liver
injury.