NAFLD is a liver disease that is characterized histologically by hepatic steatosis, lobular inflammation, and hepatocellular ballooning [24
], and it was reported that at least 3% of the patients progressed to cirrhosis [3
]. The disorder is thought to be common because the incidence of its typical features, fatty liver disease, obesity, and type 2 DM, is increasing [25
]. Multiple pharmacologic interventions have been attempted with variable success. Particularly, trials of glucose lowering agents such as metformin and pioglitazone have yielded promising results [18
]. In this study, drastic improvement of serum AST and ALT level was shown not only in pioglitazone group but also in liraglutide group and sitagliptin group, suggesting that treatment of diabetes improved insulin resistance and led to amelioration of liver inflammation in NAFLD patients with type 2 DM.
However, the improvement of liver inflammation and liver fibrosis is different matter. Since in a randomized controlled trial intended for NAFLD patients, pioglitazone demonstrated alteration of liver inflammation but did not affect on improvement of liver fibrosis [6
]. Since this current study was based on outpatient clinic medial care, liver biopsy was not applied in our study population. Noninvasive measurement methods of liver stiffness, such as transient elastography, were not available in our institute. Thus, we applied APRI index to evaluate the degree of liver fibrosis [22
]. In this current study, APRI index significantly improved between liraglutide group and pioglitazone group but not in sitagliptin group. The calculation of APRI index depended on changes in AST level and it might be one of the limitations of this study. Nonetheless, the alteration of APRI index might be expected in these two groups. On the other hand, sitagliptin group had already lower serum AST level at the time of administration. It might be the main cause of no change in the APRI index at the end of followup. Although we could not clarify the true outcome of liraglutide on liver fibrosis, it was reported that GLP-1 analogue directly inhibited fibroblast growth factor 21 which promoted the progression of liver fibrosis in mice model [15
]. Further more studies are needed.
Obesity is considered one of the most important risk factors for NAFLD [27
]. Weight reduction via lifestyle intervention is generally recommended as an initial step in the management of NAFLD [27
], and its effectiveness was proven in a randomized controlled trial [8
]. However, lifestyle intervention depends on patient's own efforts and sometimes difficult to achieve the aim [28
]. In this current study, the body weight dramatically changed after the administration of each treatment. Significant body weight reduction was shown in liraglutide group, significant body weight gain was shown in pioglitazone group, and body weight did not change in sitagliptin group. These results were supported by previous reports [13
]. Besides, multivariate logistic regression analysis indicated that administration of liraglutide as an independent factor for body weight reduction. Although the first step in the management of NAFLD is lifestyle intervention, liraglutide may support body weight reduction via suppressing appetite and finally affect on improvement of NAFLD.
Since this current study based on a retrospective cohort, there were lots of limitations. The first limitation is that the difference of dosing period of each medicine. The median dosing period of pioglitazone was about 1200 days. On the other hand, the median dosing period of liraglutide and sitagliptin was about 340 days and 250 days, respectively. There was approximately fourfold difference, and the long-term outcome of liraglutide and sitagliptin was still unknown. The second limitation is that liraglutide is administered by subcutaneous injection. Sitagliptin and pioglitazone are oral drugs and considered to be less invasive than liraglutide. Continuing subcutaneous injection every day may be a great stress for patients even if weekly subcutaneous injective GLP-1 analogue (exenatide long-acting release) will be available in the near future. The last limitation is that this study cohort was consisted in patients treated with combination use of metformin agent. Metformin agent was reported to have some effects on liver steatosis and inflammation [26
In conclusion, we have demonstrated the improvement of liver inflammation and diabetes in NAFLD patients with type 2 DM treated by liraglutide, sitagliptin, and pioglitazone. However, APRI index did not alter in sitagliptin group, and body weight significantly increased in pioglitazone group. Aggravation of liver fibrosis score might lead future liver cirrhosis, and body weight gain could exacerbate liver inflammation and other metabolic disorders. Administration of liraglutide led not only to good control of type 2 DM but also improvement of liver inflammation, alteration of liver fibrosis, and reduction of body weight. Particularly, body weight reduction was a favorable outcome of applying liraglutide in NAFLD patients with type 2 DM.