© 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(13)60092-2

 

 

Contributors: AS and SS proposed the study. OM and BT performed literature search and wrote the first draft. All authors have read and approved the final version. SS is the guarantor.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

 

 

 

 

(Hepatobiliary Pancreat Dis Int 2013;12:584-588)

 

KEY WORDS: non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; anti-diabetic agents; Sitagliptin; Exenatide; Liraglutide

Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disorder in Western countries and is increasingly being recognized in developing nations.^[1] It encompasses a spectrum of pathological processes that ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) and to cirrhosis.^[2] The pathophysiology of NAFLD is thought to be a two-step process: an accumulation of triglycerides in hepatocytes due to insulin resistance and hepatocyte injury secondary to oxidative stress.^[3] The reported prevalence of histologically proven NAFLD among potential living liver donors ranged from 20% to 51% in two different studies from the United States and South Korea.^{[4, 5]} In a study using sonographic screening for 400 middle age Americans, the prevalence of NAFLD was 46%. In the same study, 29.9% of those with sonographic evidence of NAFLD were found to have NASH on liver biopsy.^[6] Obesity and insulin resistance, as seen in type 2 diabetes mellitus (T2DM), are well-documented risk factors for NAFLD.^[7] The prevalence of NAFLD in obese and diabetic populations is 90% and 69%, respectively.^{[8, 9]} NAFLD is also associated with other components of the metabolic syndrome like hypertension and dyslipidemia.^[10] Due to the increasing prevalence of obesity and T2DM, the United States is expected to face a NAFLD epidemic by 2030 with a prevalence of 50%.^[11]

 

Current management for NAFLD can be divided into those targeting components of metabolic syndrome with weight reduction and insulin sensitizers, those targeting the liver with antioxidants (vitamin E) and liver transplantation for decompensated cirrhosis.^[11] Multiple trials have shown that improving insulin sensitivity can result in biochemical and histologic improvements in patients with NASH.^[2] Insulin sensitizers that are available in the United States market are Metformin, Rosiglitazone, and Pioglitazone. Metformin and Rosiglitazone are not currently recommended for NASH treatment. Metformin has failed to show an appreciable benefit and Rosiglitazone was found to be associated with serious side-effects that led to restrictions on its use.^[2] The most recent guidelines The Diagnosis and Management of Non-Alcoholic Fatty Liver Disease: Practice Guidelines by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association by Chalasani et al recommended Pioglitazone as the only insulin sensitizer for use in the treatment of patients with biopsy-proven NASH.^[2] The PIVENS trial, a large randomized clinical trial in NASH patients has shown that Pioglitazone use for 96 weeks results in resolution of NASH in 47% of patients (21% in the placebo group) but without significant improvement in fibrosis.^[12] However, Pioglitazone has considerable side-effects such as weight gain, bone loss, congestive heart failure, and bladder cancer.^[13] In this report, we review studies that examine clinical effectiveness and safety profile of novel anti-diabetic agents that were not looked at in the most recent guidelines for the treatment of NAFLD and NASH.

 

 

A systematic review of the published literature that discussed the clinical effectiveness and safety of novel anti-diabetic agents in the management of NAFLD or NASH was conducted. The databases included PubMed, MEDLINE and Ovid, which were searched between January 1990 and January 2013.

 

The following key words were used in the search process: non-alcoholic steatohepatitis, NASH, non-alcoholic fatty liver disease, NAFLD, dipeptidyl peptidase IV inhibitors, DPP IV inhibitors, glucagon-like peptide-1 analogues, GLP-1 analogues, Exenatide, Liraglutide, Sitagliptin, Saxagliptin, and Vidagliptin. The following filters were applied: English language, human studies, and research support (US, non-US, governmental and nongovernmental). Case reports and systematic reviews were excluded from our search. The retrieved studies were screened for inclusion and exclusion criteria. Studies that enrolled patients with a diagnosis of NAFLD or NASH and involved use of newer classes of anti-diabetic agents for a duration of at least 3 months were included. With regards to the diagnosis of NAFLD or NASH, in case of lack of histologic evidence, the study has to include both biochemical and radiographic evidence at baseline to be included in our review. Meta-analysis was deemed inappropriate due to heterogeneity of data in the available studies.

 

A total of 9 articles were found and manually reviewed by a team of two researchers. Out of 9 studies retrieved by the search, 4 met eligibility criteria and were included in our review. The classes of anti-diabetic medications examined in the 4 studies were DPP IV inhibitors and GLP-1 analogues. These trials recruited a relatively small number of patients (10-82 patients). The follow-up duration ranged from 4 to 41 months. The studies included in the article are summarized in the Table.

 

 

GLP-1 is an incretin secreted by the small intestine in response to food intake.^[14] It improves glucose homeostasis via glucose-dependant stimulation of insulin secretion, inhibition of postprandial glucagon secretion and delayed gastric emptying.^[15] Once secreted, GLP-1 has a short half-life due to rapid degradation by DPP IV. DPP IV inhibitors and GLP-1 analogues are novel agents that overcome rapid degradation and have been used successfully in the treatment of T2DM.^[16] GLP-1 analogues have albumin-binding abilities that prolong their half-life.^{[17, 18]}

 

Sitagliptin is one of the DPP IV inhibitors that have been recently studied for a role in the treatment of NAFLD.^[19] The study was an open-label, single-arm, pilot study that enrolled 15 adult patients with T2DM and histologically proven NASH. Patients were advised to follow a healthy diet but physical activity was discretionary. At the time of enrollment, there were 5 patients with NASH score of 3-4 (labeled as borderline NASH) and 10 patients with NASH score of 5 or more (labeled as definite NASH). Sitagliptin 100 mg oral tablet daily was given for a period of one year. Laboratory findings after one year of treatment revealed significant improvement in ALT and AST as well as significant reduction in hepatocyte ballooning and NASH score. The decrease in steatosis was of borderline statistical significance. In contrast, there was no significant improvement in lobular inflammation and fibrosis. There was no improvement noted in insulin resistance, represented by homeostasis model of assessment-insulin resistance, in the NASH group. Adverse reaction of diarrhea was reported in one patient.

 

A Japanese study by Iwasaki et al^[20] recruited 30 patients with T2DM and NAFLD. The diagnosis of NAFLD was based on ultrasonographic and biochemical evidence. Sitagliptin oral tablet 50 mg daily was administered for 4 months. A significant decline was noted in ALT and AST after 16 weeks of the treatment. No significant change in body mass index (BMI) was observed. No significant adverse event was reported.

 

GLP-1 analogues are well tolerated subcutaneous injections that have been used successfully to achieve glycemic control in patients with T2DM.^[16] Ohki et al^[21] performed a retrospective analysis of 82 patients with T2DM and NAFLD. The results were divided into three groups: Liraglutide-treated group (0.3-0.9 mg subcutaneous injection daily), Sitagliptin-treated group (50-100 mg oral tablet daily), and Pioglitazone treated group (15 mg oral tablet daily). The diagnosis of NAFLD was based on ultrasonography and elevated ALT levels for more than 6 months. All patients had uncontrolled T2DM despite exercise and diet therapy. The study group used AST to platelet counts ratio index (APRI) to evaluate liver fibrosis. An index of 1.5-1.9 was considered indicative of bridging fibrosis while an index of 2 or more was considered indicative of cirrhosis. The mean follow-up period was 520 days (17 months). The Liraglutide treated group had a significant decrease in BMI, ALT, AST, and APRI. The Sitagliptin-treated group showed improvement in ALT but no significant change in BMI, AST, or APRI. The Pioglitazone-treated group showed a significant decline in ALT, AST, and APRI with a significant increase in BMI. Apart from weight gain in the Pioglitazone group, no other adverse event was reported.

 

Kenny et al^[22] published an open-label prospective case series that examined the effect of Exenatide on the liver histology of eight patients with T2DM and biopsy proven NAFLD. The patients were given subcutaneous Exenatide twice a day (5-10 µg) for 28 weeks. Liver histology assessment was based on NAFLD activity score. The score ranged from 3 to 5. NAFLD activity score improved in five patients while it remained unchanged in two subjects and worsened in one subject. Overall, fibrosis improvement was seen in 50%, no fibrosis change in 38%, and worsening fibrosis in 12% of the patients. Hepatocyte ballooning was improved in 50% of the patients. One subject developed hepatocyte ballooning on the follow-up biopsy. Ballooning remained the same in all other study subjects. Significant improvement was noted in ALT and weight loss. The mean weight loss was 4.9 kg. Two subjects developed abdominal discomfort with one subject ceasing therapy on week 20.

 

The aforementioned outcome could have resulted from indirect improvement of fatty liver secondary to optimizing glycemic control.^[20] Additionally, weight reduction usually experienced by patients taking GLP-1 can explain the reduction in liver fat pronounced in these patients. The lack of improvement in insulin resistance in some of the patients treated with DPP IV inhibitors suggest that there might be other potential mechanisms by which these medications can improve NAFLD. A recent study showed that increased serum activity and increased hepatic immunohistochemical staining intensity of DPP IV is proportionally associated with the intensity of fatty infiltration.^[23] Svegliati-Baroni et al^[24] demonstrated that in hepatocytes isolated from rats with NASH, GLP-1 receptor activation with Exenatide improves hepatic insulin sensitivity and fatty acid oxidation. They also showed that human liver has GLP-1 receptors but patients with NASH have decreased expression of these receptors. Another report showed that GLP-1 analogues directly inhibit fibroblast growth factor-21 which promotes progression to liver fibrosis in the mouse model.^[25] Additionally, a recent study suggested a correlation between changes in glycemic control and changes in hepatic steatosis, in the absence of changes in body weight or body fat composition, in T2DM patients taking GLP-1 analogues.^[26] It was postulated that this correlation was due to the effect of improved glucose tolerance, with reduced hyperinsulinemia and hyperglycemia, on reducing the rate of hepatocyte lipogenesis that is typically increased in T2DM patients.^[27] All of these observations suggest a direct role for DPP IV inhibitors and GLP-1 analogues in the treatment of NAFLD/NASH.

 

 

The new anti-diabetic, Ipragliflozin, is a sodium-glucose cotransporter 2 (SGLT2) that was recently approved as an oral treatment of T2DM. A recent animal study by Tahara et al^[27] investigated the effect of this new class on mice liver. It showed a significant decrease in the markers of liver oxidative stress and inflammation which resulted in significant improvement in aminotransferases after four weeks of treatment. However, there are no human studies to validate these findings. Therefore, this study was not thoroughly discussed in our review.^[28]

 

NAFLD has become increasingly prevalent and is expected to be the main indication for liver transplant by 2020.^[22] The current NAFLD treatment is directed at the components of metabolic syndrome and also aims to reverse liver injury. With regards to the pharmacologic therapy directed toward the components of metabolic syndrome, Pioglitazone, an insulin sensitizer, is the only option recommended by the most recent guidelines for the treatment of NASH.^[2] Pioglitazone has shown to improve liver histology in patients with NASH but its safety profile raises the need for safer alternatives. This review demonstrates that the new anti-diabetic medications may have significant advantages over Pioglitazone in the management of NASH in terms of efficacy and tolerability. These promising results should guide future randomized controlled trials to establish the role of these agents in diabetic and non-diabetic NAFLD/NASH patients.

 

 

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