Editorial :
Hiroshi Bando The combination of Type 2 Diabetes Mellitus (T2DM)
and Non-Alcoholic Fatty Liver Disease (NAFLD) has been a crucial problem. NAFLD
means wide from Hepatic Steatosis (HS) to Nonalcoholic Steatohepatitis (NASH).
NAFLD may be the predictor of causing Cardiovascular Disease (CVD). A dynamic
association is found between NAFLD and Hepatic Insulin Resistance (IR).
Treatments for T2DM and NAFLD include Glucagon-Like Peptide 1 Receptor Agonist (GLP-1
RA), Dipeptidyl-Peptidase 4 Inhibitors (DPP-4i) and Sodium-Glucose
Cotransporter 2 inhibitors (SGLT2i). An advanced NASH-specific agent is the Farnesoid
X Receptor (FXR) agonist Obeticholic Acid (OCA). Further development of
research and pharmaceutical industry will be expected. Type
2 diabetes mellitus (T2DM) has become a major health problem worldwide [1].
Furthermore, the increase in obesity has brought a crucial issue of fatty liver
or Non-Alcoholic Fatty
Liver Disease (NAFLD). NAFLD has been the most common chronic liver disease
in the world [2]. In fact, T2DM has high incidence of the complication of
NAFLD, and NAFLD increases the risk of type 2 diabetes. Furthermore, T2DM may
increase the risk for the progression from fatty liver to Nonalcoholic
Steatohepatitis (NASH). NASH may will increase the risk of Liver Cirrhosis (LC)
and Hepatocellular Carcinoma (HCC). In
recent years, with the development of research, it has been reported that NASH
fibrosis has improved [3]. In addition, various agents are used for diabetes
may cause liver dysfunction. This article introduces clinical topics about T2DM
and liver disease. The medical
word NAFLD is an umbrella term. Then, it means multiple progressive liver
disorders, from simple Hepatic
Steatosis (HS) to NASH [4]. Approximately 35% of the cases with NASH shows
progress to liver fibrosis and possibly to develop to HCC [5]. In European
countries, NAFLD has been more prevalent with about 20-30 % of total population
and been possibly influencing 45-75% of patients with T2DM [6]. In recent decade,
the prevalence of NAFLD has been increasing, which are along with the
progressing situation of T2DM and obesity
[7]. As a matter of fact, both of T2DM and NAFLD have common risk factors
epidemiologically [8]. T2DM has been a major chronic common disease for long,
while NAFLD has been relatively rather new. Consequently, various treatments
for both diseases will be necessary to evaluate from combined points of view
[9]. NAFLD has been recently the most
prevalent hepatic disease in the world and the most common etiology of hepatic
disease for awaiting liver transplantation
in adults of United States [10,11]. The presence of both T2DM and NAFLD will
significantly show more incidence for developing NASH and LC, compared with the
situation of NAFLD without continuing elevated glucose
variability [8]. Some controversies are found that NAFLD may be the predictor
of causing Cardiovascular Disease (CVD) with several discussions [12]. It is
impressive situation that high mortality of NAFLD would be not from LC or HCC,
but from exacerbated risk profiles of CVD associated with comorbidity of T2DM
and other CVD risk factors [13]. Consequently, patients with both T2DM and
NAFLD may have elevated CVD risk associated with increased mortality rates. As
to NAFLD, there are recent advances of diagnosis and treatment of several phase
III trials for NASH- specific therapies. There has been a dynamic
association between NAFLD and Hepatic Insulin Resistance (IR). Therefore,
several attempts were found administrating ant diabetic
agents to treat NAFLD [14]. Systematic review was conducted for
glucagon-like peptide 1 receptor agonist (GLP-1 RA), Dipeptidyl-Peptidase 4 inhibitors
(DPP-4i), and sodium-glucose cotransporter 2 inhibitors (SGLT2i) to treat T2DM,
NAFLD relating with the improvement in Hepatosteatosis (HS) or Steatohepatitis
(SH) [14]. These trials may support a future management paradigm for NAFLD in
diabetics. However, further consideration will be needed. The relationship
between commonly used for diabetes and hepatic function would be described as
follows. Regarding metformin, early
studies showed improvement of surrogate outcomes, while no significant was
found in the assessment of histological improvement [15]. In retrospective
study of 191 cases of T2DM with biopsy-proven NASH and bridging fibrosis,
metformin showed lower risk of overall mortality
and liver transplant (HR:0.42) and HCC (sHR:0.25), respectively [16]. For
current recommendations, pioglitazone
or vitamin E are utilized as treatment options with biopsy-proven NASH [15].
However, vitamin E can be recommended for only non-DM cases, and thiazolidinedione’s
show the risk of congestive heart failure, weight gain, possibly bladder cancer
and bone loss [15,17,18]. Among them, pioglitazone is the only diabetic
medication in recent guidance from the American Association for the Study of
Liver Diseases (AASLD) to treat cases with biopsy-proven NASH with or without
T2DM [19]. GLP-1 RAs especially increase
insulin secretion, decrease glucagon secretion, slow gastric emptying, and
decrease appetite [20]. GLP-1A was investigated for patients with NASH (the
LEAN study), which was multicenter, double-blind, randomized,
placebo-controlled phase two study [21]. Liraglutide
group showed significant effect of NASH resolution compared with control group
(p=0.019). Furthermore, semaglutide has been investigated in combination with
other agents inhibiting hepatic de
novo lipogenesis (DNL) and affecting acid-enterohepatic access. GLP-1A has
been reported to show the risk of acute pancreatitis, but the conflicting
evidence is recently found [22]. SGLT2i inhibits glucose reabsorption
in the proximal tubule of the kidney, which brings significant decrease of
glucose and calorie. Consequently, SGLT2i shows effective function of weight
reduction, improved insulin sensitivity and the reduction in liver fat content
[23]. Serum
aminotransferases were reduced by the administration of several kinds of SGLT2i
agents. There was a recent study for empagliflozin for two groups of patients
with T2DM and NAFLD [24]. It is an E-LIFT Trial, which stands for Effect of
Empagliflozin on Liver Fat in Patients with Type 2 Diabetes and Nonalcoholic
Fatty Liver Disease: A Randomized Controlled Trial. Liver fat was measured by
the magnetic resonance imaging proton density fat fraction (MRI-PDFF). In
comparison with control group, empagliflozin
group showed significantly decreased liver fat by the measurement of MRI-PDFF.
The data was from 16.2% to 11.3%, p<0.0001 in Empagliflozin group, and 16.4%
to 15.5%, not significant, p= 0.057. Further studies on RCTs are necessary to
determine the efficacy of SGLT2i on liver histology in NASH. For NASH
management in the future, combination therapy would be recommended in
patients with coexisting T2DM and NASH. One attracting combined agents in order
to improve NASH and to reduce CVD risk may be included as follows: i) low dose
pioglitazone and GLP-1A, ii) low dose pioglitazone and SGLT-2i. As regards to
such combined therapy, future detail investigations would be needed to explore
clinical effect in diabetic medical practice [19]. In pharmaceutical
industry worldwide, a new NASH-specific agent has been harnessing attention
from federal and private funders. There were many trials on governmental
registration. Among them, the farnesoid
X receptor (FXR) agonist obeticholic
acid (OCA) is an advanced agent [25]. FXR has been a nuclear receptor,
which shows high expression in small intestine and liver. They regulate
lipid/glucose homeostasis, increase insulin sensitivity, and modify the
situation of liver fibrosis. In summary, recent topics
concerning T2DM and NAFLD were described. Effective measures for many patients
suffering these will be indispensable, and be expected in the near future. Type 2 diabetes mellitus, Non-alcoholic fatty
liver disease, Dipeptidyl-peptidase 4 inhibitors, Agonist obeticholic acid.Recent Perspectives for Combined Status of Type 2 Diabetes Mellitus (T2DM) and Non-Alcoholic Fatty Liver Disease (NAFLD)
Abstract
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Corresponding author
Hiroshi Bando, Tokushima University/Medical Research, Nakashowa 1-61, Tokushima 770-0943, Japan Tel: +81-90-3187-2485, E-mail: pianomed@bronze.ocn.ne.jp
Citation
Bando H. Recent perspectives for combined status of type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) (2021) Edel J Biomed Res Rev 3: 9-11 Keywords
