NASH is a progressive liver disease globally and can lead to cirrhosis and HCC, especially in patients with older age, obesity and T2DM (6). IR is the key player of NASH independent of obesity or visceral adiposity, even in the absence of DM (2). Therefore, the therapeutic exploration targeting on amelioration of IR was the initial effort for NASH treatment. The current study, to our knowledge, was the first one in Asia aiming to assess the treatment efficacy and safety of insulin sensitizer. Our results demonstrated that there were significantly improvements of transaminase and hs-CRP levels as well as other metabolic profile in patients receiving 24 weeks of TZD. Liver steatosis improvement was significantly identified both on histologic and MRI-PDFF in TZD-treated arm. In addition, TZD-treated patients had significant NAS reduction in histology. They also carried a significantly higher chance of NASH improvement without fibrosis worsening (46.7%) and NASH resolution (26.7%) compared to their counterparts. Although TZD-treated patients had a higher incidence of insomnia and anxiety, it was well-tolerated without treatment discontinuation or occurrence of significant BW gain in TZD-treated arm.
PPAR-γ is a ligand-activated nuclear receptor that forms a heterodimer with retinoid X receptor alpha and regulates gene transcription, mitigating IR in peripheral tissues. Pioglitazone, a PPARγ agonist, has been used as an anti-diabetes drug aiming to decreases IR (16, 17). The effects of increasing skeletal muscle glucose disposal and decreasing hepatic gluconeogenesis have made it the initial therapeutic exploration for NASH in the past. Previous study by Belfort et al. compared diet alone with the combination of diet and pioglitazone for 24 weeks in 55 documented NASH patients. It demonstrated that pioglitazone-treated group had a significant improvement in transaminase levels, steatosis, intrahepatic IR, and necroinflammation (9). In another multicenter placebo-controlled trial, PIVENS study by Sanyal, et al, 80 patients with NASH were treated for 96 weeks with pioglitazone 30 mg daily (18). Pioglitazone arm was associated with highly significant reductions in transaminase level, steatosis, and inflammation, as well as IR improvements. It also led to the resolution of steatohepatitis in a significant proportion of subjects. Recent study including 101 NASH patients with prediabetes or T2DM showed that extending pioglitazone 45 mg daily to 3 years significantly decreased transaminase levels, improved liver and peripheral insulin sensitivity, reduced steatosis, and improve liver histology (19). Our results echoed the main findings of previous studies showing pioglitazone effectively improved liver biochemical profile, steatosis, and necroinflammation. Of note was that we demonstrated there was a significant decrease of fat content in TZD-treated arm on both histologic and MRI-PDFF manifestations. It addressed previous study showing TZD improves IR and liver steatosis by an adiponectin-mediated effect on insulin sensitivity and hepatic fatty acid metabolism (20). The significant reduction of hs-CRP and UA levels, the major surrogate biomarkers for proinflammation and inflammation, may imply the decrease of metabolic risks in the aspect. However, our study demonstrated that IR reduction during TZD treatment, reflected by HOMA-IR, showed a substantial decrease pattern from baseline to EOT. However, it then resumed to baseline state at EOF. Our results thus raised a doubt regarding the efficacy of 24 weeks TZD treatment in the significant reduction of IR, at least in Taiwanese. The doubt may be partly attributed to a lower BMI, a lower baseline IR, a lower NAS, and/or the single ethnicity of the current study. Further collaborative study across different regions and demographic varieties will be needed to clarify the important issue.
Fibrosis is the major determining factor associated with outcomes of NASH patients. Regression and/or improvement of fibrosis could subsequently lead to NASH improvement and resolution. Previous study by Cusi, et al demonstrated that pioglitazone 45 mg daily for 3 years was effective to achieve regression of fibrosis stage for 1 and more in 39% TZD-treated patients, whereas ballooning improvement was observed in 51% TZD-treated patients (19). Our results demonstrated that patients of TZD-treated arm had a higher chance to achieve NASH improvement without worsening of fibrosis and it was beneficial for NASH resolution. The two features have recently been regarded as the histologic endpoints of major trials (21, 22). However, the incidence of NASH resolution in TZD-treated patients (26.7%) of our study was significantly lower than 47–51% of the previous studies (18, 19). It might be attributed to the lower fibrosis severity of our patients. Meanwhile, TZD-treated arm of the current study did not achieve the significant amelioration of hepatocyte ballooning and fibrosis improvement on histology. Further assessment with continuous non-invasive FIB-4 score also disclosed the failure to significantly fibrosis reduction in TZD-treated patients. The somewhat discordant results may be attributed to the difference between studies in terms of baseline necroinflammation, fibrosis stage, ethnicity, BMI, dosing, and treatment duration. It also raised the issue indicating the optimal treatment duration and dosing across demographic and metabolic factors.
In addition to viral hepatitis infection, the importance of NAFLD/NASH has progressively been concerned in recent decades in Asia (3, 23). Sharma, et al performed a randomized controlled trial in India by comparing TZD and pentoxifylline (anti-TNF-𝛼) for 24 weeks in generally low-BMI NASH patients (24). They demonstrated that both pentoxifylline and TZD were effective in improving transaminases, IR and adiponectin levels significantly. Our study provided concordant results showing that pioglitazone effectively improved transaminase, UA, and hs-CRP levels besides reduced necroinflammation and steatosis. Our study further demonstrated the significant reduction of liver fat by MRI-PDFF. It may imply that pioglitazone could be a therapeutic approach at least in Asians. Generally, Asians have a higher visceral fat and carry a higher risk of metabolic abnormalities than other ethnicities and are more susceptible to NASH and disease progression dependent on the same BMI (7, 25, 26). Of note is that a high percentage (15–21%) of Asia-Pacific NAFLD subjects have been found to be lean or non-obese (27). The Asian carbohydrate-rich diet may be transformed into triglycerides and accumulates in liver, which may activate carbohydrate responsive element-binding protein. The process may further lead to liver steatosis and/or NASH in the end (4, 28). All of the racial characteristics could contribute to the disparate association between NAFLD/NASH and BMI in Asian population (29).
On the other side, the safety profile is a concern because weight gain and heart failure exacerbation have been listed as the major AE in previous Western studies (9, 10, 18, 19). The current study showed that the safety profile was acceptable and pioglitazone was well-tolerated without significant adverse events reported previously. Therefore, the long-term outcomes in both cardiovascular events and liver-related events deserve further investigation in this first-in-Asia randomized controlled trial. The optimal dosing and treatment duration also need investigation. The link between disease course and outcomes across genetic predispositions and BMI also awaits exploration.
There were some limitations of the current study. Firstly, certain lifestyle, environmental, genetic and ethnic factors may contribute in NASH development. Our study did not recruit the genetic factor, environmental factor, and lifestyle patterns into analysis since NASH is generally a complex dynamic scenario interacted by the major factors. Recently, several genetic predispositions have been demonstrated to be associated with the development, disease course, and disease outcomes in chronic liver diseases. The role of the genetic variants in the treatment efficacy of TZD deserves further investigation. Secondly, our patients had a lower baseline NAS and fibrosis score, which may raise the concern of definite NASH diagnosis on histology. It may imply that the current diagnostic criteria may not cover the whole spectrum of NASH histopathologically. Thirdly, despite the randomized, double-blind design, there were significant difference between groups in terms of gender, BMI, and FPG level, which might affect the outcome of the results. Lastly, NASH is usually associated with many metabolic disorders and the patients may have many drugs for disease control in a long-term fashion. The drug-drug interaction between TZD and other drugs might lead to potential therapeutic impact on the results.
In conclusion, the first-in-Asia randomized controlled trial demonstrated that 24 weeks pioglitazone treatment was effective in reducing liver and metabolic biochemistry in NASH patients. Histologic improvement was also significantly observed in terms of steatosis reduction, inflammation, and NASH improvement without worsening of fibrosis. Pioglitazone was safe and well-tolerated. Further studies of TZD in Asian NASH patients to assess long-term clinical benefit and/or in combination with other potential agents are needed.