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

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


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

In This Article

Abstract and Introduction


Background Non-alcoholic fatty liver disease generally has a benign course; however, patients with non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma. Currently, there is a lack of consensus about optimal NASH treatment.
Aim To assess the efficacy of insulin-sensitizing agents on histological and biochemical outcomes in randomized control trials of biopsy-proven NASH.
Methods Multiple online databases and conference abstracts were searched. Random effects meta-analyses were performed, with assessment for heterogeneity and publication bias.
Results Nine trials were included; five trials using thiazolidinediones (glitazones), three using metformin and one trial using both drugs. There was no publication bias. Compared with controls, glitazones resulted in improved steatosis (WMD = 0.57, 95% CI 0.36–0.77, P = <0.001), hepatocyte ballooning (WMD = 0.36, 95% CI 0.24–0.49, P < 0.001) and ALT (WMD = 16.4, 95% CI 7.7–25.0, P < 0.001), but not inflammation (P = 0.09) or fibrosis (P = 0.11). In patients without diabetes, glitazones significantly improved all histological and biochemical outcomes, most importantly including fibrosis (WMD = 0.29, 95% CI 0.078–0.51, P = 0.008). Metformin failed to improve any pooled outcome.
Conclusions Treatment of NASH with glitazones, but not metformin, demonstrates a significant histological and biochemical benefit, especially in patients without diabetes. Additional studies are needed to investigate long-term outcomes of glitazone therapy in patients without diabetes.


Non-alcoholic fatty liver disease (NAFLD) is a growing health concern in the United States. It is the most common cause of liver disease, afflicting up to 30–40% of the general population and 60–91% of patients with underlying diabetes or morbid obesity.[1–4] NAFLD has been shown to be an independent risk factor for increased cardiovascular morbidity and mortality.[5–8] Whereas the majority of patients with NAFLD have simple steatosis that has a benign course, about 20% of patients will have a more severe form known as non-alcoholic steatohepatis (NASH), a histological diagnosis that consists of steatosis, hepatocyte ballooning and lobular inflammation with or without fibrosis. Compared with patients with simple steatosis, those with NASH are more likely to progress to cirrhosis, liver failure, or hepatocellular carcinoma.[9] However, there are currently no established treatments for NASH other than lifestyle modification and weight loss, which are often difficult to achieve and even harder to maintain.[10–12]

A predominant feature of NAFLD is insulin resistance, the central mechanism in the development of hepatic steatosis. Insulin resistance leads to altered adipokine production and increased outflow of free fatty acids, resulting in hepatocellular accumulation of toxic lipid-derived metabolites and activation of multiple inflammatory pathways.[13–15] Over time, this process can lead to activation of fibrogenic hepatic stellate cells.[16] Therefore, several studies have explored the ability of insulin sensitizers to improve biochemical and histological features of fibrosis and inflammation in NAFLD. The two main groups of insulin-sensitizing drugs that have been evaluated for NASH treatment are thiazolidinediones and metformin. Thiazolidinediones (also known as the 'glitazones') are high-affinity ligands of peroxisome proliferator-activated receptor-γ (PPAR-γ), that stimulate the storage of free fatty acids in subcutaneous adipocytes as opposed to liver and omental fat, thereby improving insulin sensitivity.[17] Metformin is an insulin-sensitizer that acts by decreasing hepatic glucose production and increasing skeletal muscle glucose uptake.

Conclusions about the role of insulin-sensitizing agents such as thiazolidinediones (glitazones) or metformin for the treatment of NASH from currently available studies are limited due to small sample size, heterogeneous study endpoints and a range of methodological quality. The purpose of this meta-analysis is to summarize the currently available evidence for the efficacy of insulin-sensitizing agents on biochemical and histological endpoints in NASH.


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