Meta-analysis: Insulin Sensitizers for the Treatment of Non-alcoholic Steatohepatitis

M. O. Rakoski; A. G. Singal; M. A. M. Rogers; H. Conjeevaram

Disclosures

Aliment Pharmacol Ther. 2010;32(10):1211-1221. 

In This Article

Results

Literature Search

A total of 185 citations were retrieved using our search strategy, and all citations were downloaded into EndNote. Search of abstracts from the annual meetings of American Association for Study of Liver Diseases (AASLD), American College of Gastroenterology (ACG), European Association for the Study of the Liver (EASL) and Digestive Disease Week (DDW) for the period from 2005–2009 yielded 12 potentially relevant abstracts. Recursive searches of article references identified three additional articles. After review of the titles and abstracts of all of these articles (n = 200), 181 were excluded. Nineteen studies underwent full text review to determine their eligibility. Of these, two were initially in abstract form. A full manuscript was provided by one author after being contacted for more information. The other abstract was published soon after abstract presentation and therefore full manuscript was included in this meta-analysis. After review of the 19 full text articles, a total of nine studies were included in this meta-analysis (Figure 1, Table 1).[25–33] Although important as the original study that investigated the use of insulin sensitizers for the management of NAFLD, we excluded Caldwell's important trial involving troglitazone because this trial was not a randomized controlled trial and therefore did not meet our inclusion criteria.[34] There did not appear to be any publication bias by Egger's test (P = 0.73) or funnel plot analysis (data not shown).

Figure 1.

Map of the literature search and selection process. RCT, randomized controlled study; bx, biopsy.

Study Description

Of the nine trials included in our meta-analysis, six investigated the use of glitazones.[25–30] These studies used either pioglitazone or rosiglitazone, with a treatment duration of 96 weeks,[25] 48 weeks,[26,27,29,30] or 24 weeks.[28] All six trials excluded patients with benign steatosis and enrolled only patients with NASH. Of note, Idilman et al. had three arms (rosiglitazone, metformin, control); therefore, this study was included in subgroup analysis for both glitazones and metformin.[30]

Four trials investigated the use of metformin[30–33] using dosages ranging from 500 mg[31] to 3000 mg[33] daily. Duration of treatment was 24 weeks in two studies[32,33] and 48 weeks in the other two.[30,31] All trials enrolled only patients with NASH except one which also included patients with simple steatosis.[33] One trial[32] did not report results of histological outcomes other than fibrosis and therefore only three trials[30,31,33] were included for analysis of steatosis, hepatocyte ballooning and lobular inflammation.

Outcomes

Primary outcome: histological response. Table 2 summarizes the pooled treatment effect WMD (weighted mean difference) of insulin sensitizers for all analyses. Analysing all nine studies together, insulin sensitizing agents resulted in a significant improvement in fibrosis (P = 0.011) and steatosis (P = 0.003) compared with controls, but not ballooning (P = 0.10) or inflammation (P = 0.29).

In subgroup analysis, glitazones resulted in a significant reduction in steatosis (P < 0.001) and hepatocyte ballooning (P < 0.001) compared with controls (Table 2, Figure 2). Glitazones did not result in improvement in lobular inflammation (P = 0.09) or fibrosis (P = 0.11) compared with the control group. Metformin did not improve pooled treatment effects for any of the histological outcomes (Table 2); specifically, there was no associated improvement in fibrosis (P = 0.51).

Figure 2.

Forest plots demonstrating pooled effect of glitazones on histological outcomes: a. steatosis, b. hepatocyte ballooning, c. inflammation and d. fibrosis.

Secondary outcomes: biochemical and anthropometric response. When analysing all included studies, insulin sensitizing agents did result in improvement in ALT (P = 0.014) compared with controls (Table 2). Glitazones resulted in a highly significant decrease in ALT compared with controls (P < 0.001), whereas metformin did not improve pooled treatment effects for biochemical outcome (P = 0.10).

Overall, BMI improved (i.e. decreased from baseline) to a greater extent in the control group than in the group receiving insulin sensitizers (WMD = −1.23; P < 0.001). In particular, BMI improved in the controls compared with the patients receiving glitazones only (P = 0.010), whereas metformin use did not result in significant change in BMI compared with the control group (P = 0.39) (Table 2).

Sensitivity Analyses

As described previously, variance imputation was initially performed using a within-participant correlation of zero (ρ = 0.0). Sensitivity analysis using other values of ρ (ρ = 0.4, ρ = 0.8) revealed no difference in trends for each outcome, yielding similar findings for all statistical analyses (data not shown).

An additional sensitivity analysis was performed to assess any effect of study quality. Four of the nine trials were considered low quality,[26,30–32] primarily due to inadequate descriptions of allocation concealment or blinding, whereas the others were considered high quality[25,27–29,33] (Table S1). At the time of baseline and end of study biopsies, pathologists in all studies were blinded to randomization. Intention-to-treat analysis was used in all but two trials.[27,30]

Other preplanned subset analyses failed to affect significantly any of our primary or secondary outcomes. There was only one study[33] that enrolled patients with simple steatosis; in addition, those with NASH and removal of this study did not affect overall outcomes. Active diet and/or exercise education during the clinical trial[27,28,30,31] did not affect outcomes, nor did study duration.

Sensitivity analyses for glitazone trials. Given the large I 2 for one of the primary outcomes in the glitazone trials (inflammation, I 2 = 73.8%), additional sensitivity analyses were performed for the glitazone subset. The first assessed undue influence from the PIVENS trial, the largest RCT for NASH treatment to date. Exclusion of the PIVENS data did not change the primary outcomes of our meta-analysis (Table 3). Specifically, after excluding the PIVENS trial from analysis, glitazones continued to demonstrate a significant improvement in steatosis (P = 0.01) and ballooning (P < 0.001) compared with controls, but not inflammation (P = 0.39) and fibrosis (P = 0.33) (Table 3).

An additional sensitivity analysis was performed to assess any change in pooled outcomes related to study quality. When including only high quality studies,[25,27–29] significance of primary and secondary outcomes remained the same, except that a significant decrease in inflammation was found (WMD = 0.37; 95% CI 0.04–0.70; P = 0.03) (Table 3).

The final glitazone sensitivity analysis assessed trials that specifically excluded patients with diabetes.[25–27] All three trials used pioglitazone at a dose of 30 mg/day for a minimum duration of 48 weeks. When patients with diabetes were excluded, pioglitazone resulted in a significant decrease in all histological and biochemical outcomes, including fibrosis (WMD = 0.29; 95% CI 0.078–0.51; P = 0.008) (Figure 3, Table 3). In addition, there was a significant increase in BMI (P < 0.001).

Figure 3.

Forest plots demonstrating pooled effects of glitazones on histological outcomes in trials that excluded patients with diabetes: (a) steatosis, (b) hepatocyte ballooning, (c) inflammation and (d) fibrosis.

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