Thiazolidinediones linked to regression of fibrosis in non-alcoholic steatohepatitis

1. Based on this meta-analysis of available randomized controlled trials (RCTs), use of thiazolidinediones in patients with non-alcoholic steatohepatitis (NASH) demonstrated regression of liver fibrosis. The observed effect was largely attributed to pioglitazone rather than rosiglitazone.

2. The improvement in liver fibrosis was observed in patients with and without diabetes.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Non-alcoholic steatohepatitis (NASH) is a common and increasingly prevalent cause of chronic liver disease, liver failure, and need for transplant. Advanced fibrosis on biopsy or radiologic evaluation is associated with significantly increased mortality, while milder degrees of fibrosis have more favorable prognosis. Reversal of liver fibrosis in other forms of chronic liver disease has been linked to improved liver-related outcomes. Interventions to reverse fibrosis in NASH patients have not been found to be effective thus far. Treatment with thiazolidinediones have been investigated with regards to treatment of NASH.

The current study is a meta-analysis of available RCTs and demonstrated that thiazolidinedione therapy was associated with improvement in advanced fibrosis, and in some cases NASH resolution. The observed effect was primarily driven by pioglitazone rather than rosiglitazone use. The benefit of thiazolidinedione therapy was observed in both diabetic and non-diabetic patients. Weight gain and lower limb edema were the most commonly observed side effects. The meta-analysis encompassed many well-designed trials with low risk of bias, and had consistent effect size across the studies leading to statistical homogeneity. The lack of power to assess for major adverse outcomes or determine optimal dose and duration of therapy are important limitations.

Click to read the study, published in JAMA Internal Medicine

Relevant Reading: The role of thiazolidinediones in non-alcoholic steatohepatitis – A systematic review and meta-analysis

In-Depth [ systematic review and meta-analysis]: This study included all RCTs enrolling patients with NASH diagnosed by either biopsy or radiographic evaluation, and who received thiazolidinedione as their intervention therapy. The primary outcome was improvement in advanced fibrosis as defined by the NASH Clinical Research Network Fibrosis Scale (Improving from stage F3-4 to F0-2). Secondary outcomes included at least 1 stage improvement on the fibrosis scale, and NASH resolution. The following adverse events were also evaluated: weight gain, edema, congestive heart failure, fractures, cancer, and anemia. Trials were excluded if they were non-randomized, enrolled fewer than 10 patients, included patients with secondary steatohepatitis, or did not report on the primary or secondary outcomes of the meta-analysis.

The 8 RCTs (5 pioglitazone, 3 rosiglitazone) included for analysis encompassed 516 patients with follow-up between 6 and 24 months. Thiazolidinedione therapy was associated with improved advanced fibrosis (OR 3.15; 95%CI 1.25-7.93; p = 0.01), improvement of at least 1 stage (OR 1.66; 95%CI 1.12-2.47; p = 0.01), and NASH resolution (OR 3.22; 95%CI 2.17-4.79; p < 0.001). Results for all outcomes were the same for analysis restricted to non-diabetic patients. When analyzed separately, pioglitazone demonstrated improvement in advanced fibrosis (OR 4.53; 95%CI 1.52-13.52) while rosiglitazone did not (OR 1.30; 95%CI 0.23-7.20). The average weight gain associated with thiazolidinedione therapy was 2.7%. Lower limb edema was also more common in the intervention arm (OR 2.36; 95%CI 1.15-4.84; p = 0.02).

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