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

Discussion

To date, conclusions about the efficacy and safety of insulin sensitizers for the treatment of NASH have been difficult due to the small sample size and heterogeneity of available trials. Our study is the largest and most comprehensive meta-analysis of randomized controlled trials evaluating the role of glitazones and metformin in these patients. We found that glitazones significantly improved steatosis, hepatocyte ballooning and serum ALT levels compared with controls, but not lobular inflammation or fibrosis. However, in patients without diabetes, glitazones resulted in significant decreases in all histological outcomes, including fibrosis. In contrast, metformin was found to be an ineffective treatment for NASH as it was not superior to controls for any histological or biochemical outcome.

Given that glitazones have potential serious side effects[35] and will probably need to be taken long-term,[36,37] it is important to determine which subset of patients, if any, would most benefit from prolonged glitazone therapy. This meta-analysis offers novel insights into tailoring NASH therapy and suggests that glitazone treatment should be focused on patients who have not yet developed diabetes. Pooled data from trials that enrolled only patients without diabetes[25–27] demonstrated a significant decrease in all biochemical and histological outcomes, including fibrosis (P = 0.008), the endpoint ultimately thought to be the most important in NASH treatment in preventing disease progression. Furthermore, Ratziu et al. found that absence of diabetes was an independent predictor of histological response in NASH patients treated with rosiglitazone (OR=0.14, 95% CI 0.02–0.79, P = 0.026).[29] Together, these findings suggest that patients without overt diabetes may be particularly susceptible to the insulin sensitizing properties of glitazones and that early intervention may prevent worsening of insulin resistance, as well as its downstream complications such as NASH progression.

There are several potential mechanisms to explain the differential benefit of glitazones on inflammation and fibrosis in patients with and without diabetes. First, glitazones may prevent the development of insulin resistance by preservation of pancreatic beta cell function and by increasing the effectiveness of endogenous insulin, as seen in studies of high-risk populations such as patients with impaired glucose tolerance (IGT), impaired fasting glucose (IFG), or a history of gestational diabetes.[38–40] Specifically, the DREAM trial, a large, multicentre trial that randomized 5269 patients with IFG or IGT to receive rosiglitazone or placebo for a median of 3 years found that rosiglitazone reduced the risk of developing diabetes or death by 60% compared with placebo, with an absolute risk difference of 14.4%.[38] Our findings suggest that glitazones may arrest NASH progression, perhaps through a similar mechanism of delayed or halted development of insulin resistance and/or preventing worsening of insulin resistance in those who do not already have overt diabetes. Second, any improvement in fibrosis from glitazone use is probably indirect and mediated through anti-inflammatory pathways given that PPAR-gamma is minimally expressed in activated hepatic stellate cells.[41] Therefore, in diabetics, the potent anti-inflammatory effects of glitazones[42] may be surpassed by the pro-inflammatory state associated with insulin resistance state and diabetes,[43] thereby potentially making this class of drugs less effective for NASH treatment among patients with diabetes.

In the recently published PIVENS trial,[25] pioglitazone failed to meet the composite primary endpoint, which required a decrease in NAFLD Activity Score (NAS)[44] of at least two points with at least one point decrease in ballooning and no worsening of fibrosis (P = 0.04; P < 0.025 considered significant due to three-arm design). This trial was a three-arm randomized controlled trial comparing 96 weeks of pioglitazone, vitamin E, and placebo for treatment of nondiabetic patients with NASH. However, when each histological component that comprises the NAS was assessed individually, pioglitazone did result in a significant decrease in steatosis, hepatocyte ballooning and lobular inflammation compared with controls (P < 0.001, 0.01 and <0.001 respectively). A trend towards greater mean decrease in fibrosis (week 96 fibrosis stage -baseline fibrosis stage) was found for pioglitazone compared with controls (−0.36 ± 0.96 and 0.13 ± 0.89 respectively); however, it did not reach statistical significance (P = 0.10). Amongst the trials that enrolled only nondiabetic patients including the PIVENS study,[25–27] our meta-analysis found a significant decrease in fibrosis with glitazone therapy compared with controls in patients without diabetes (P = 0.008) with minimal heterogeneity between trials for this outcome (I 2 = 0%). Although the PIVENS trial is the largest randomized controlled trial to date, change in fibrosis was only a secondary endpoint and therefore it is likely that the trial may have been underpowered to detect a difference of this magnitude. Our meta-analysis suggests that glitazone therapy may improve fibrosis for select populations such as those without diabetes.

This meta-analysis has a few limitations that warrant discussion. First, selection and referral bias should be considered given that all of the included trials were conducted in tertiary care centres. Second, our method for weighting studies made assumptions that resulted in the largest variance for the pooled effect size. Therefore, it is possible that 95% confidence intervals for the WMD are wider and more conservative than what would be expected if the within-person correlations were known. However, sensitivity analyses did not alter the statistical significance for each outcome, thereby demonstrating the robustness of the findings. Third, the NASH Clinical Research Network (NASH CRN) recently created a comprehensive scoring system for clinical trials, the NAFLD Activity Score (NAS);[44] however, not all trials reported this score and therefore we were not able to use the NAS as an endpoint in our analysis. Finally, as with all studies that utilize histological endpoints, our findings are limited by the inherent sampling variability with resultant inaccuracies sometimes associated with liver biopsies. We feel that the notable strengths of this meta-analysis, including the strict inclusion criteria (RCTs with a histological definition of NAFLD/NASH) and the assessment of both histological and biochemical outcomes, outweigh its limitations.

In summary, it is evident from our findings that whereas metformin is not an effective treatment for NASH, the use of glitazones, on the other hand, results in a significant biochemical improvement as well as decrease in important histological components of NASH such as steatosis and hepatocyte ballooning, but not lobular inflammation or fibrosis. In patients without diabetes, glitazones produce a significant improvement in all biochemical and histological outcomes, most significantly including fibrosis. Despite this novel finding, there is insufficient evidence at this time to make a strong recommendation for the use of glitazones in patients without diabetes. Future studies are needed to investigate the outcomes and potential benefits and toxicities of long-term glitazone treatment in this subgroup of patients with NASH. Moreover, additional studies in nondiabetics are also needed to determine if glitazones offer incremental benefit over anti-oxidants such as vitamin E, which may be equally efficacious or more efficacious,[25] without detrimental side effects such as weight gain.

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