Pioglitazone on nonalcoholic steatohepatitis: A systematic review and meta-analysis of 15 RCTs : Medicine

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Research Article: Systematic Review and Meta-Analysis

Pioglitazone on nonalcoholic steatohepatitis: A systematic review and meta-analysis of 15 RCTs

Zhao, Yan Mastera,b; Zhao, Wenli PhDc,d; Wang, Hongwu PhDe; Zhao, Ye PhDf; Bu, Huaien PhDg; Takahashi, Hirokazu PhDh,*

Author Information
doi: 10.1097/MD.0000000000031508
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Abstract

1. Introduction

Nonalcoholic steatohepatitis (NASH) affects about 3% to 6% of adults and its prevalence is increasing.[1] NASH is a major cause of chronic liver disease. It is closely related to obesity, dyslipidemia, diabetes and metabolic syndrome. In a small number of patients with NASH, the disease may progress and eventually lead to advanced fibrosis, cirrhosis and hepatocellular carcinoma.[2] Most NASH patients have no symptom or nonspecific symptom, most commonly, patients with NASH were identified after examination for unrelated conditions.[1] According to current studies, NASH is an inflammatory subtype of nonalcoholic fatty liver disease (NAFLD), which is also the most serious form. It is characterized by inflammatory infiltration, hepatocyte damage and excessive fat accumulation, with or without fibrosis.[3] However, the exact pathogenesis of NASH is still unclear. At present, we know the following aspects. First, high fat diet plays an important role in the pathogenesis of NAFLD. Lipid in diet, lipolysis of visceral fat and production of new fat have different contributions to lipid storage in liver; Lipolysis and new adipogenesis are strictly controlled by many hepatocyte nuclear receptors, which account for the largest proportion in the free fatty acids (FFAs) pool of the liver. Liver FFAs are partially oxidized as energy source, partially stored as triglyceride (TG), and finally as very low-density lipoprotein module. However, the whole process can’t be done to dispose of excess fat and TGs will accumulate in the liver.[4] Secondly, Insulin resistance is 1 of the key factors in the occurrence of NASH, which leads to the increase of liver new adipogenesis and the weakening of the inhibition of adipose tissue decomposing fat, thus increasing the flow of FFAs to the liver.[5] Insulin resistance can also promote adipose tissue dysfunction, thereby changing the production and secretion of adipokine n and inflammatory cytokines.[6] Thirdly, fat mainly accumulates in the liver in the form of triglycerides, but triglycerides themselves are not toxic. Therefore, the grade or severity of steatosis cannot predict liver injury, inflammation or fibroma.[7] Lipotoxicity refers to the imbalance of lipid environment and (or) intracellular lipid composition, resulting in the accumulation of harmful lipids, which may be related to organelle dysfunction, cell injury and death. Increased lipotoxicity occurs simultaneously from high levels of FFAs, free cholesterol and other lipid metabolites, therefore, mitochondrial dysfunction is activated by oxidative stress, reactive oxygen species and endoplasmic reticulum stress.[8] Fourthly, a large number of hepatocyte cytochrome enzymes are found in mitochondria, which participate in hepatocyte injury and develop into NASH by promoting oxidative stress, inflammation, protein modification and insulin resistance. Hepatocyte cytochrome enzymes hydrolyzes various small molecules, such as FFAs and ethanol, into byproducts (toxic superoxide anion), which changes the respiratory chain of mitochondria and destroys mitochondrial components.[9] Fifthly, endoplasmic reticulum is an intracellular organelle, most of which secrete and membrane proteins are folded, and are sensitive to FFAs. This leads to the accumulation of unfolded or misfolded proteins. This accumulation activates the unfolded protein response to reconstruct homeostasis in the body; if this response fails, other pressure sensor proteins. For example, inositol requires enzyme 1, activating transcription factor 6 and protein kinase receptor like endoplasmic reticulum kinase (perk), which triggers autophagy.[10,11] Inositol requires enzyme 1 splices and activates transcription factor X-box binding protein 1.[12] X-box binding protein 1 interacts with various inflammatory cascades by activating the amino-terminal kinase and inhibitor of nuclear factor kappa B kinase-nuclear factor kappa B signal transduction and reactive oxygen species production.[13] Lastly, the mechanism of NASH is related to intestinal barrier dysfunction, which may increase bacterial translocation and lead to liver inflammation. Indeed, the level of circulating endotoxin in NASH patients is higher than that of healthy individuals.[14] Endotoxin can induce inflammatory reaction by activating hepatitis cells.[15] According to studies published in 2015, CX3C chemokine receptor 1 plays a role in controlling intestinal barrier permeability. Deletion of CX3C chemokine receptor 1 has a negative effect on intestinal barrier function and aggravates steatohepatitis in NASH mice.[16] Some findings suggest that the intestinal barrier dysfunction increases liver permeability and bacterial translocation, leading to NASH induction.[17] Therefore, the pathogenesis of NASH maybe caused by multiple factors, and more research is needed to solve the mystery.

There are also many statements about its treatment. At present, there is no recognized drug therapy, and the progress of treatment is slow.[18] Dietary and lifestyle changes are now the primary treatment for patients with NASH.[19] Mediterranean diet can effectively reduce liver fat, even if not lose weight, is the most recommended diet. It is characterized by a reduction in carbohydrate intake, especially sugar and refined carbohydrates, and an increase in monounsaturated fatty acids and omega-3 fatty acids.[20] Experimental studies show that a diet rich in omega-3 polyunsaturated fatty acids can improve insulin sensitivity,[21] it can reduce the content of triglyceride in liver and improve steatohepatitis.[22] Monounsaturated fatty acids have a good effect on blood lipid level.[23] Exercise also has recognized benefits in improving overall cardiovascular health, which is the leading cause of death in NAFLD patients. These benefits, including improved liver and peripheral insulin resistance, may not be associated with weight loss.[24] One study shows that the group with high exercise intensity (>250 min/wk) has favorable changes in metabolic parameters and a significant decrease in liver fat content compared with those less than 250 min/wk.[25] Bariatric surgery is suitable for patients with severe or morbid obesity, and a variety of operations have been performed. Most patients undergoing bariatric surgery also have NAFLD. It is well known that weight loss can improve insulin sensitivity and play a beneficial role in reducing visceral fat. A new study reports that bariatric surgery can improve body mass index (BMI), insulin resistance index and other markers significantly, and NASH disappeared in 85% of patients.[26]

Although the above general treatments have obvious effect, there is no FDA approval for specific drugs for NASH. However, the pioglitazone, a thiazolidinedione insulin sensitizer through peroxisome proliferator activated receptor (PPAR-γ), has shown some benefit in some randomized controlled trials.[1] Studies show that the pioglitazone can improve insulin and glucose parameters, increase lipid storage in the subcutaneous adipose tissue, increase the adiponectin, and reduce the lipid toxicity of liver.[27] However, there are still some problems worthy of attention in the clinical application of pioglitazone. Increased risk of prostate or pancreatic cancer, weight gain, fluid retention, female fracture and increased cardiovascular events.[18] Therefore, pioglitazone in the treatment of NASH is still controversial, which needs to be further clarified. We performed a meta-analysis to investigate the relationship between pioglitazone and NASH.

2. Methods

2.1. Research strategy

The National Library of Medicine, Cochrane Library, Elsevier, China National Knowledge Infrastructure, Web of Science and WANFANG databases were searched from their earliest records to November 2021 using the following key words: NASH and pioglitazone. The search was performed by combining the search terms with the subject words.

2.2. Inclusive criteria

The inclusion criteria are randomized controlled clinical trials. The treatment group is treated with pioglitazone alone or on the basis of conventional treatments, while the control group is treated with placebo or conventional treatment (including diet, exercise, etc.) for NASH. Trials investigating the impact of pioglitazone on at least one outcome of glutamic-pyruvic transaminase (ALT), glutamic oxalacetic transaminase (AST), BMI, weight, fasting plasma glucose (FPG), gamma-glutamyl transpeptidase (GGT), homeostasis model assessment of insulin resistance (HOMA-IR), glycated hemoglobin A1c (HbA1c), fasting insulin (FNS), fibrosis and histological improvements are considered for inclusion.

2.3. Exclusion criteria

We exclude repetitive articles; nonintervention studies such as case-control studies, case reports and experiences, theoretical studies and reviews; and nonclinical trials, such as animal tests.

2.4. Quality evaluation and data extraction

The methodological quality of the included studies is evaluated based on the quality assessment criteria recommended in the Cochrane systematic review manual. The main evaluation criteria include the following: a randomly assigned method, allocation concealment, use of blinding, data integrity, selectively reported results, and the presence of bias (“low risk” indicates a low risk of bias; “high risk” indicates a high risk of bias; and “unclear risk” indicates that the literature does not provide sufficient information for bias assessment). The data quality was evaluated by 2 independent researchers. Inconsistent opinions were resolved via a discussion or by soliciting the advice of a third party regarding the inclusion of a particular study.

2.5. Statistical analysis

All statistical analyses were performed using Review Manager (version5.3). The risk ratio is used for count data, while the standardized mean difference (SMD) is adopted for continuous variables as effect size. Respectively, both are demonstrated with the effect size and 95% confidence intervals (CI). If there is no heterogeneity among the studies, that is, a P-value greater than .10 or I2 less than 50%. It is explained that the heterogeneity of the research is small, and the fixed effect model is used to analyze. A P-value less than .10 or I2 greater than 50% suggested that there is obvious heterogeneity among the included studies, and the random effect model is used to combine the effect volume. The bias of the study is analyzed by funnel plot.

3. Results

3.1. Study selection

A total of 1822 articles are searched from English and Chinese databases. 1135 of which are duplicated and 1120 are generally excluded based on the inclusion criteria. Finally, 15 eligible articles are included in the meta-analysis. The study selection procedure is outlined in Figure 1.

F1
Figure 1.:
PRISMA 2009 flow diagram.

3.2. Study characteristics and quality

The study information is shown in Table 1, and the quality of the study evaluation is shown in Table 2.

Table 1 - Study characteristics.
Author Year Age M/F Duration (wk) Treatment Control Evaluation indicator
Cases Pioglitazone Cases Measures
Sanyal[28] 2010 T:47.0 ± 12.6
C:45.4 ± 11.2
68/95 96 80 30 mg/d 83 Placebo ALT, AST, weight, TG, FPG, BMI, GGT, total effective rate
Gastaldelli[29] 2010 49-57 - 24 26 45 mg/d 21 Placebo Plasma adiponectin, insulinsensitivity
Aithal[30] 2008 27-73 45/29 48 37 30 mg/d 37 Placebo Weight, ALT, HbA1c, FPG, GGT
Sanchez[31] 2019 51 ± 1 55/23 72 39 45m g/d 39 Placebo FPG, HbA1c, HOMA-IR
Fasting plasma insulin
Cusi[32] 2016 T:52 ± 10
C:49 ± 11
71/30 72 51 45 mg/d 50 Placebo Weight, BMI, ALT, AST, FPG, TG, fasting plasma insulin, total effective rate
Balas[33] 2007 T:51 ± 1.6
C:48.4 ± 3.1
16/19 24 21 45 mg/d 14 Placebo HbA1c, weight, BMI
Belfort[34] 2006 T:51 ± 7
C:51 ± 10
21/26 24 26 45 mg/d 21 Placebo Weight, BMI, ALT, AST, FPG, TG, fasting plasma insulin
Xiang[35] 2007 T:44.5 ± 27
C:43.5 ± 20
27/16 24 22 15 mg/d 21 Placebo ALT, GGT, TG, HOMA-IR
Chen[36] 2018 T:39.4 ± 10.2
C:38.6 ± 9.4
72/48 24 60 15 mg/d + RT 60 RT Total effective rate
Guo[37] 2014 45.0 ± 6.2 42/38 12 40 15 mg/d + RT 40 RT FPG, BMI, ALT, AST, HOMA-IR, TG, total effective rate
He[38] 2008 40.0 ± 6.0 49/37 16 46 30 mg/d + RT 40 RT FPG, HbA1c, TG, HOMA-IR
Jin[39] 2010 T:50.3 ± 12.8
C:53.7 ± 10.1
65/55 24 60 30 mg/d + RT 60 RT ALT, AST, GGT, FPG, FNS
Total effective rate
Li[40] 2014 67.1 ± 15.6 - 52 60 15 mg/d + RT 56 RT FNS, BMI, FPG, HbA1c, TG, ALT, AST, HOMA-IR, total effective rate
Xiang[41] 2009 T:48.0 ± 5.7
C:47.3 ± 6.1
23/20 12 23 15 mg/d + RT 20 RT FPG, HbA1C, TG, ALT
Total effective rate
Xie[42] 2014 T:53.4 ± 10.3
C:50.3 ± 10.5
35/29 24 32 30 mg/d + RT 32 RT BMI, ALT, GGT, FPG, TG, FNS
HOMA-IR, total effective rate

Table 2 - Study quality evaluation.
Included studies Random allocation Allocation concealment Double blind method Evaluation of blindness Data integrity Selective report others
Sanyal 2010 Unclear Low risk Unclear Low risk Low risk Low risk Unclear
Gasaldelli 2010 Unclear Unclear High risk Low risk Low risk Low risk Low risk
Aithal2008 Low risk Low risk Lowrisk Low risk Low risk Low risk Unclear
Sanchez 2019 Low risk Unclear Low risk Low risk Unclear Low risk Low risk
Cusi 2016 Low risk Low risk Low risk Low risk Low risk Low risk Low risk
Balas 2007 Unclear Unclear Unclear Low risk Low risk Unclear Unclear
Belfort 2006 Unclear Low risk Low risk Unclear Low risk Low risk Low risk
Xiang 2007 Unclear Unclear Unclear High risk Low risk Low risk Unclear
Chen 2018 Low risk Unclear Unclear Unclear Low risk Unclear Unclear
Guo 2014 Unclear Unclear Unclear Unclear Low risk Low risk Unclear
He 2008 Unclear Unclear Unclear Unclear Unclear Unclear Unclear
Jin 2010 Low risk Unclear Unclear Low risk Low risk Low risk Unclear
Li2014 Unclear Unclear Unclear Unclear Low risk Low risk Low risk
Xiang 2009 Unclear Unclear Unclear Unclear Low risk Low risk Unclear
Xie 2014 Unclear Unclear Unclear Unclear Low risk Unclear Low risk

3.3. Meta-analysis of outcome

3.3.1. Total effective rate.

In general, 8 studies use the total effective rate as an indicator of the effectiveness of pioglitazone-guided interventions. The results are shown in Figure 2. A total of 462 patients with NASH are included in this evaluation (284 in the experimental group and 178 in the control group). The heterogeneity test shows that the heterogeneity is large (I2 = 0.89), so the random effect model is used. The results show that the difference is significant, the effective rate of the experimental group is 78% higher than that of the control group [risk ratio = 1.78, 95% CI: (1.31–2.43)].

F2
Figure 2.:
Changes in total effective rate of the experimental group compared with the control group.

3.3.2. Weight.

Five studies use the weight as an indicator of the effectiveness of pioglitazone-guided interventions. A total of 420 patients with NASH are included in this evaluation (215 in the experimental group and 205 in the control group), according to the results of meta-analysis (P = .57, I2 = 0%). No heterogeneity is found between the studies, that is why the fixed effect model is used to calculate. There is no significant difference in changes in weight between the experimental group and the control group. The results are shown in Figure 3.

F3
Figure 3.:
The experimental group compared with the control group in weight changes after treatment.

3.3.3. Body mass index.

Seven studies use BMI as an indicator of the effectiveness of pioglitazone-guided interventions. A total of 606 patients with NASH are included in this evaluation (310 in the experimental group and 296 in the control group). The heterogeneity was large (P = .002, I2 = 0.71), so the random effects model is used. Changes in BMI between the experimental group and the control group are no significant, as shown in Figure 4.

F4
Figure 4.:
The experimental group compared with the control group in BMI changes after treatment. BMI = body mass index.

3.3.4. FPG level.

Eleven studies use the FPG level as an indicator of the effectiveness of pioglitazone-guided interventions. A total of 972 patients with NASH are included in this evaluation (494 in the experimental group and 478 in the control group). The heterogeneity is large (P < .00001, I2 = 0.90). So, the random effect model is used. The meta-analysis shows that the FPG level of NASH patients treated with pioglitazone are lower than those received the placebo or conventional treatments [SMD = −0.95, 95% CI: (−1.38 to −0.53)], as shown in Figure 5.

F5
Figure 5.:
The experimental group compared with the control group in FPG changes after treatment. FPG = fasting plasma glucose.

3.3.5. ALT level.

Ten studies use the ALT level as an indicator of the effectiveness of pioglitazone-guided interventions. A total of 851 patients with NASH are included in this evaluation (431 in the experimental group and 420 in the control group). The heterogeneity is large (P < .00001, I2 = 0.89). So, the random effect model is used. Changes in the ALT level between the experimental group and the control group are significant. The ALT level of NASH patients treated with pioglitazone are lower than those received the placebo or conventional treatments [Z = 3.69, P = .0002, MD = −11.76, 95% CI: (−18.01 to −5.51)], as shown in Figure 6.

F6
Figure 6.:
The experimental group compared with the control group in ALT changes after treatment. ALT = glutamic-pyruvic transaminase.

3.3.6. AST level.

Six studies use the AST level as an indicator of the effectiveness of pioglitazone-guided interventions. A total of 627 patients with NASH are included in this evaluation (317 in the experimental group and 310 in the control group). The heterogeneity is small (P = .16, I2 = 0.37). So, the fixed effect model is used. The meta-analysis shows that the AST level of NASH patients treated with pioglitazone are lower than those received the placebo or conventional treatments [Z = 7.40, P < .0001, MD = −3.01, 95% CI: (−3.81 to −2.22)], as shown in Figure 7.

F7
Figure 7.:
The experimental group compared with the control group in AST changes after treatment. AST = glutamic oxalacetic transaminase.

3.3.7. GGT level.

Six studies use the GGT level as an indicator of the effectiveness of pioglitazone-guided interventions. A total of 580 patients with NASH are included in this evaluation (291 in the experimental group and 289 in the control group). The heterogeneity is large (P = .0002, I2 = 0.79). So, the random effect model is used. Changes in the GGT level between the experimental group and the control group are significant. The GGT level of NASH patients treated with pioglitazone are lower than those received the placebo or conventional treatments [Z = 2.43, P = .02, MD = −23.77, 95% CI: (−42.98 to −4.57)], as shown in Figure 8.

F8
Figure 8.:
The experimental group compared with the control group in GGT changes after treatment. GGT = gamma-glutamyl transpeptidase.

3.3.8. TG level.

Nine studies use the TG level as an indicator of the effectiveness of pioglitazone-guided interventions. A total of 743 patients with NASH are included in this evaluation (380 in the experimental group and 363 in the control group). The heterogeneity is large (P < .00001, I2 = 0.85). So, the random effect model is used. The meta-analysis shows that the TG level of NASH patients treated with pioglitazone are lower than those received the placebo or conventional treatments [Z = 3.06, P = .092, MD = −0.62, 95% CI: (−1.01 to −0.22)], as shown in Figure 9.

F9
Figure 9.:
The experimental group compared with the control group in TG changes after treatment. TG = triglyceride.

3.3.9. HOMA-IR.

Six studies use the HOMA-IR as an indicator of the effectiveness of pioglitazone-guided interventions. A total of 467 patients with NASH are included in this evaluation (239 in the experimental group and 228 in the control group). The heterogeneity is large (P < .00001, I2 = 0.99). So, the random effect model is used. Changes in the HOMA-IR between the experimental group and the control group are significant. The HOMA-IR level of NASH patients treated with pioglitazone are lower than those received the placebo or conventional treatments [Z = 3.22, P = .001, MD = −2.33, 95% CI: (−3.75 to −0.91)], as shown in Figure 10.

F10
Figure 10.:
The experimental group compared with the control group in HOMA-IR changes after treatment. HOMA-IR = homeostasis model assessment of insulin resistance.

3.3.10. HbA1c level.

Six studies use the HbA1c level as an indicator of the effectiveness of pioglitazone-guided interventions. A total of 432 patients with NASH are included in this evaluation (226 in the experimental group and 206 in the control group). The heterogeneity is large (P < .00001, I2 = 1.00). So, the random effect model is used. Changes in the HbA1c level between the experimental group and the control group are significant. The HbA1c level of NASH patients treated with pioglitazone are lower than those received the placebo or conventional treatments [Z = 4.50, P < .00001, MD = −1.90, 95% CI: (−2.72 to −1.07)], as shown in Figure 11.

F11
Figure 11.:
The experimental group compared with the control group in HbA1c changes after treatment. HbA1c = glycated hemoglobin A1c.

3.3.11. FNS level.

Five studies use the FNS level as an indicator of the effectiveness of pioglitazone-guided interventions. A total of 406 patients with NASH are included in this evaluation (208 in the experimental group and 1987 in the control group). The heterogeneity is large (P < .00001, I2 = 0.96). So, the random effect model is used. Changes in the FNS level between the experimental group and the control group are significant. The FNS level of NASH patients treated with pioglitazone are lower than those received the placebo or conventional treatments [Z = 3.42, P = .0006, SMD = −2.25, 95% CI: (−3.53 to −0.96)], as shown in Figure 12.

F12
Figure 12.:
The experimental group compared with the control group in FNS changes after treatment. FNS = fasting insulin.

3.3.12. Adverse reactions.

No major adverse reactions are reported in all studies, although some patients had adverse events (21 cases of lower extremity edema, 1 case of right upper abdominal pain, 1 case of weight gain, 1 case of rash, 1 case of vertigo, 1 case of diarrhea, 1 case of headache, 3 cases of mild liver enzyme elevation). After symptomatic medication, the symptoms disappeared automatically, which did not affect the follow-up study. However, its safety is still worthy of further study.

3.3.13. Publication bias.

As shown in Figure 13, based on the FPG level, funnel plot is applied to evaluate the publication biases of all 15 studies. The results show no publication bias.

F13
Figure 13.:
Funnel plot.

4. Discussion

4.1. Analysis of pioglitazone efficacy

In this meta-analysis, pioglitazone has a certain effect on patients with NASH. It can effectively improve the degree of NASH, liver function and blood glucose. Also, there is no major adverse events in the study. The change of each index comes from different mechanism. As demonstrated in the meta-analysis, the total effective rate of the experimental group for NASH patients rose by about 78% compared with that of the control group. The main reason may be that pioglitazone can improve the sensitivity of target tissue to insulin, reduce insulin resistance and regulate blood lipid.[43] Most other parameters are lower in the experimental group than those in the control group. But there is no significant changing difference in weight or BMI. The main reason for the decline of FPG level may be that pioglitazone regulates the genes’ transcription related to insulin, so it may control the generation, transportation and utilization of the blood glucose. Pioglitazone downgrades fasting glucose by enhancing insulin-induced suppression of gluconeogenesis and glycogenolysis rather than by glucagon reduction.[44] The main reason for the decline of HbA1c and TG level may be that pioglitazone can also increase uncoupling protein 1 expression in adipocytes and promote the energy consumption.[45] Moreover, pioglitazone can significantly reduce ALT, AST, and GGT. All results indicate that pioglitazone can control the liver enzyme spectrum caused by fatty liver.

Considering the mechanism on reducing the steatosis and inflammation of liver, pioglitazone can promote the differentiation of white adipocytes, increase the number of small adipocytes and reduce the number of large adipocytes after activating PPAR γ in the body. Small adipocytes are more sensitive to insulin, which can promote glucose uptake, promote energy consumption and reduce the storage of excess energy in adipose tissue.[46] A declining of FNS and HOMA-IR indicates that pioglitazone does not promote the secretion of islet β cells, however, it can increase the tissues’ insulin sensitivity. The main reason for the decline of FNS and HOMA-IR level may be that pioglitazone can down regulate the expression of tumor necrosis factor-α, leptin and resistin genes, and these cytokines are closely related to insulin resistance, which may be 1 of the mechanisms of pioglitazone enhancing insulin sensitivity.[47]

4.2. Limitations

Although the 15 articles included in this meta-analysis prove that pioglitazone is useful, there are still some limitations: Firstly, there are some differences in the condition and basic treatments of NASH among the studies, which is also the reason for the heterogeneity of some indicators. Secondly, only Chinese and English literatures are included, and other languages are not involved. Language restrictions may lead to inappropriate results. Thirdly, all clinical studies have small sample size which may affect the reliability of the analysis results. Finally, the RCTs included in this study are biased in research design, methodology and result reporting. The details provided, such as randomization method, allocation concealment and blind method, are insufficient. Therefore, the evidence strength of the results is affected.

4.3. Applications prospects

In recent years, NASH becomes a serious public health problem. Its symptoms and related complications seriously affect the quality of patients’ lives.[48] Pioglitazone is an insulin sensitizer that selectively activates PPAR-γ.[49] PPARs are the main regulators of genes related to the glucose metabolism and the fat metabolism.[50] Pioglitazone can promote the uptake and the storage of fatty acids and up-regulate the expression of the insulin receptor substrate-1.[51] It can reduce the level of serum fatty acids and improve the insulin sensitivity of liver, muscle and adipose tissue. So, pioglitazone can achieve the purpose of treating NASH.[52] The liver damage caused by NASH is mainly manifested by the abnormal biochemical indexes of liver function. ALT, AST and GGT are commonly used in clinical practice to reflect the liver function.[53] Among them, ALT mainly exists in mitochondria of hepatocytes, and the intracellular concentration is 1000 to 3000 times higher than that of serum.[54] The concentration of AST in normal human serum is very low.[55] GGT mainly exists in the intrahepatic bile duct epithelium and the cytoplasm of hepatocytes. When the intrahepatic and extrahepatic bile duct obstruction can lead to the increase of GGT in serum. When the liver lesions are serious, a large number of hepatocytes and serious damage, GGT will increase.[56] In this meta-analysis, liver function indexes are significantly different before and after the pioglitazone treatment. ALT, AST and GGT are significantly decreased. However, some studies have shown that weight gain is common in patients taking thiazolidine 2 ketone drugs, which can cause fluid retention and congestive heart failure.[57] In addition, studies on the effect of pioglitazone withdrawal also show a significant rebound in the ALT.[58]

5. Conclusion

Pioglitazone intake is effective in NASH management, including the total effective rate and other related clinical indexes. The treatment of NASH needs to be further verified.

Acknowledgments

The authors thank Dr Bin Wang for assistance with data extraction.

Author contributions

All authors contributed to the design and concept, performed the literature searches, wrote the manuscript and critiqued the successive versions, and approved the final manuscript. YZ coordinated the effort and integrated the sections and comments.

Conceptualization: Wenli Zhao, Huaien Bu.

Data curation: Yan Zhao.

Formal analysis: Yan Zhao, Ye Zhao.

Funding acquisition: Hongwu Wang.

Investigation: Yan Zhao, Ye Zhao.

Methodology: Wenli Zhao, Hongwu Wang, Ye Zhao, Hirokazu Takahashi.

Project administration: Hirokazu Takahashi.

Resources: Huaien Bu, Hirokazu Takahashi.

Software: Wenli Zhao.

Supervision: Huaien Bu, Hirokazu Takahashi.

Validation: Hirokazu Takahashi.

Writing – original draft: Huaien Bu.

Writing – review & editing: Huaien Bu.

    References

    [1]. Sheka AC, Adeyi O, Thompson J, et al. Nonalcoholic steatohepatitis: a review. JAMA. 2020;323:1175–83.
    [2]. Caligiuri A, Gentilini A, Marra F. Molecular pathogenesis of NASH. Int J Mol Sci. 2016;17:1575–609.
    [3]. Marra F, Lotersztajn S. Pathophysiology of NASH: perspectives for a targeted treatment. Curr Pharm Des. 2013;19:5250–69.
    [4]. Marchesini G, Petta S, Dalle Grave R. Diet, weight loss, and liver health in nonalcoholic fatty liver disease: pathophysiology, evidence, and practice. Hepatology. 2016;63:2032–43.
    [5]. Bugianesi E, Moscatiello S, Ciaravella MF, et al. Insulin resistance in nonalcoholic fatty liver disease. Curr Pharm Des. 2010;16:1941–51.
    [6]. Guilherme A, Virbasius JV, Puri V, et al. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol. 2008;9:367–77.
    [7]. Machado MV, Diehl AM. Pathogenesis of nonalcoholic steatohepatitis. Gastroenterology. 2016;150:1769–77.
    [8]. Cusi K. Role of insulin resistance and lipotoxicity in non-alcoholic steatohepatitis. Clin Liver Dis. 2009;13:545–63.
    [9]. Jian T, Yu C, Ding X, et al. Hepatoprotective effect of seed coat of euryale ferox extract in non-alcoholic fatty liver disease induced by high-fat diet in mice by increasing IRs-1 and inhibiting CYP2E1. J Oleo Sci. 2019;68:581–9.
    [10]. Puri P, Mirshahi F, Cheung O, et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology. 2008;134:568–76.
    [11]. Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease. J Hepatol. 2011;54:795–809.
    [12]. Tilg H, Adolph TE, Moschen AR. Multiple parallel hits hypothesis in NAFLD - Revisited after a decade. Hepatology. 2021;73:833–42.
    [13]. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010;140:900–17.
    [14]. Farhadi A, Gundlapalli S, Shaikh M, et al. Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis. Liver Int. 2008;28:1026–33.
    [15]. Schuster S, Cabrera D, Arrese M, et al. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol. 2018;15:349–64.
    [16]. Schneider KM, Bieghs V, Heymann F, et al. CX3CR1 is a gatekeeper for intestinal barrier integrity in mice: limiting steatohepatitis by maintaining intestinal homeostasis. Hepatology. 2015;62:1405–16.
    [17]. Rahman K, Desai C, Iyer SS, et al. Loss of junctional adhesion molecule a promotes severe steatohepatitis in mice on a diet high in saturated fat, fructose, and cholesterol. Gastroenterology. 2016;151:733–46.e12.
    [18]. Lazaridis N, Tsochatzis E. Current and future treatment options in non-alcoholic steatohepatitis (NASH). Expert Rev Gastroenterol Hepatol. 2017;11:357–69.
    [19]. Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol. 2018;53:362–76.
    [20]. Romero-Gómez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017;67:829–46.
    [21]. Storlien LH, Kraegen EW, Chisholm DJ, et al. Fish oil prevents insulin resistance induced by high-fat feeding in rats. Science. 1987;237:885–8.
    [22]. Sekiya M, Yahagi N, Matsuzaka T, et al. Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression. Hepatology. 2003;38:1529–39.
    [23]. Mensink RP, Zock PL, Kester AD, et al. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr. 2003;77:1146–55.
    [24]. Rinella ME, Sanyal AJ. Management of NAFLD: a stage-based approach. Nat Rev Gastroenterol Hepatol. 2016;13:196–205.
    [25]. Oh S, Shida T, Yamagishi K, et al. Moderate to vigorous physical activity volume is an important factor for managing nonalcoholic fatty liver disease: a retrospective study. Hepatology. 2015;61:1205–15.
    [26]. Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology. 2015;149:379–88; quiz e15.
    [27]. Kothari S, Dhami-Shah H, Shah SR. Antidiabetic drugs and statins in nonalcoholic fatty liver disease. J Clin Exp Hepatol. 2019;9:723–30.
    [28]. Sanyal AJ, Chalasani N, Kowdley KV, et al. NASH CRNNASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85.
    [29]. Gastaldelli A, Harrison S, Belfort-Aguiar R, et al. Pioglitazone in the treatment of NASH: the role of adiponectin. Aliment Pharmacol Ther. 2010;32:769–75.
    [30]. Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176–84.
    [31]. Portillo-Sanchez P, Bril F, Lomonaco R, et al. Effect of pioglitazone on bone mineral density in patients with nonalcoholic steatohepatitis: a 36-month clinical trial. J Diabetes. 2019;11:223–31.
    [32]. Cusi K, Orsak B, Bril F, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med. 2016;165:305–15.
    [33]. Balas B, Belfort R, Harrison SA, et al. Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis. J Hepatol. 2007;47:565–70.
    [34]. Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–307.
    [35]. Xiang Y, Ye J, Li X. Safety and effectiveness of pioglitazone in the treatment of non-alcoholic fatty liver disease. Chin J Clin Hepatol. 2007;23:434–5.
    [36]. Chen K, Zhao Y. Efficacy and safety of pioglitazone in the treatment of nonalcoholic fatty liver disease. Health Guide. 2018;17:304.
    [37]. Guo J, Chen Y. Effect of piglitazone on plasma leptin and insulin resistance in patients with IGT complicated by nonalcoholic fatty liver. Med Sci J Central South China. 2014;42:379–81.
    [38]. He D, Li J, Liu T, et al. The effect of pioglitazone on serum adiponerctin levels in patients with impaired glucose tolerance with non – alcoholic fatty liver. Liaocheng Second People’s Hospital of Shandong Province. Central Plains Med J. 2008;35:5–7.
    [39]. Jin H, Zhou Y, Ming K. Efficacy of pioglitazone in treatment of 60 patients with nonalcoholic steatohepatitis. Pharm Care Res. 2010, 10: 221–223.
    [40]. Li H, Jiang T, Kang K. Efficacy of pioglitazone and metformin in the treatment of newly diagnosed type 2 diabetes mellitus complicated with nonalcoholic fatty liver disease. Chin J Gerontol. 2014;34:4454–6.
    [41]. Xiang X, Zhang H, Liu X, et al. Effect of pioglitazone on plasma homocysteine level in patients with type 2 diabetes mellitus complicated with nonalcoholic fatty liver disease. Clin Focus. 2009;24:1349–50.
    [42]. Xie L, Liang B, Li J, et al. Therapeutic efficacy of pioglitazone combined with non-drug treatment on nonalcoholic fatty liver disease. J Guangdong Med College. 2014;32:776–80.
    [43]. Al-Majed A, Bakheit AH, Abdel Aziz HA, et al. Pioglitazone. Prof Drug Subs Exc Rel Methodol. 2016;41:379–438.
    [44]. Basu R, Shah P, Basu A, et al. Comparison of the effects of pioglitazone and metformin on hepatic and extra-hepatic insulin action in people with type 2 diabetes. Diabetes. 2008;57:24–31.
    [45]. Kubota N, Terauchi Y, Kubota T, et al. Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways. J Biol Chem. 2006;281:8748–55.
    [46]. Zhao W, Payne V, Tommasi E, et al. Administration of the peroxisomal proliferator-activated receptor gamma agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment. Int J Radiat Oncol Biol Phys. 2007;67:6–9.
    [47]. Tahara N, Matsui T, Yamagishi S. Change in serum PEDF level after pioglitazone treatment is independently correlated with that in HOMA-IR. Int J Cardiol. 2014;172:244–6.
    [48]. Wan X, Xu C, Yu C, et al. Role of NLRP3 inflammasome in the progression of NAFLD to NASH. Can J Gastroenterol Hepatol. 2016;2016:6489012.
    [49]. Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology. 2010;52:774–88.
    [50]. Sacks D, Baxter B, Campbell BCV, et al. Multisociety consensus quality improvement revised consensus statement for endovascular therapy of acute ischemic stroke. Int J Stroke. 2018;13:612–32.
    [51]. Kodama Y, Taura K, Miura K, et al. Antiapoptotic effect of c-Jun N-terminal Kinase-1 through Mcl-1 stabilization in TNF-induced hepatocyte apoptosis. Gastroenterology. 2009;136:1423–34.
    [52]. Promrat K, Lutchman G, Uwaifo GI, et al. pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;39:188–96.
    [53]. Mager DR, Iñiguez IR, Gilmour S, et al. The effect of a low fructose and low glycemic index/load (FRAGILE) dietary intervention on indices of liver function, cardiometabolic risk factors, and body composition in children and adolescents with nonalcoholic fatty liver disease (NAFLD). J Parenter Enteral Nutr. 2015;39:73–84.
    [54]. Yang H, Li D, Song X, et al. Joint associations of serum uric acid and ALT with NAFLD in elderly men and women: a Chinese cross-sectional study. J Transl Med. 2018;16:285.
    [55]. Nier A, Brandt A, Conzelmann IB, et al. Non-alcoholic fatty liver disease in overweight children: role of fructose intake and dietary pattern. Nutrients. 2018;10:1329.
    [56]. Hossain IA, Rahman Shah MM, Rahman MK, et al. Gamma glutamyl transferase is an independent determinant for the association of insulin resistance with nonalcoholic fatty liver disease in Bangladeshi adults: association of GGT and HOMA-IR with NAFLD. Diabetes Metab Syndr. 2016;10(1 Suppl 1):S25–29.
    [57]. Wong VW, Chitturi S, Wong GL, et al. Pathogenesis and novel treatment options for non-alcoholic steatohepatitis. Lancet Gastroenterol Hepatol. 2016;1:56–67.
    [58]. Lutchman G, Modi A, Kleiner DE, et al. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology. 2007;46:424–9.
    Keywords:

    meta-analysis; nonalcoholic steatohepatitis; pioglitazone; randomized controlled trial; systematic review

    Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.