Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatitis: A Meta-analysis

Abstract

Importance: Nonalcoholic steatohepatitis (NASH) is projected to be the leading cause of liver transplantation by 2020. Advanced fibrosis (stage F3-F4) on liver biopsy independently predicts all-cause and liver-related mortality in NASH. There are no known efficacious treatments for advanced fibrosis related to NASH. Thiazolidinedione therapy has been extensively evaluated in NASH, and new randomized clinical trials (RCTs) of its efficacy have been completed.

Objective: To synthesize the evidence about the association of thiazolidinedione therapy with advanced liver fibrosis in NASH.

Data sources: MEDLINE, Ovid MEDLINE In-Process, Cochrane Library, EMBASE, clinicaltrials.gov, PubMed, and Scopus databases (without language restrictions), as well as other registries and scientific meeting presentations, from database inception through August 15, 2016.

Study selection: Randomized clinical trials evaluating the effect of thiazolidinedione therapy on histologic features of the liver in biopsy-proven NASH.

Data extraction and synthesis: Two investigators extracted study data independently and in duplicate and rated the risk of bias using the Cochrane Risk of Bias Tool.

Main outcomes and measures: The primary outcome was a dichotomous improvement in advanced fibrosis on liver biopsy, defined as an improvement in fibrosis stage from F3-F4 to F0-F2. Secondary outcomes were at least a 1-point improvement in fibrosis of any stage and NASH resolution. This meta-analysis also evaluated adverse effects of thiazolidinedione therapy, including weight gain, lower limb edema, congestive heart failure, bone fractures, cancer, and anemia. With the use of random-effects models, dichotomous variables are presented as odds ratios (ORs) with 95% CIs, and continuous variables are presented as weighted mean differences with 95% CIs.

Results: This study analyzed 8 RCTs (5 evaluating pioglitazone use and 3 evaluating rosiglitazone maleate use) enrolling 516 patients with biopsy-proven NASH for a duration of 6 to 24 months. Among all studies combined, thiazolidinedione therapy was associated with improved advanced fibrosis (OR, 3.15; 95% CI, 1.25-7.93; P = .01; I2 = 0%), fibrosis of any stage (OR, 1.66; 95% CI, 1.12-2.47; P = .01; I2 = 0%), and NASH resolution (OR, 3.22; 95% CI, 2.17-4.79; P < .001; I2 = 0%). Analyses restricted to RCTs enrolling patients without diabetes yielded similar results for improvement in advanced fibrosis (OR, 2.95; 95% CI, 1.04-10.90; P = .02; I2 = 0%), improvement in fibrosis of any stage (OR, 1.76; 95% CI, 1.02-3.03; P = .02; I2 = 0%), and NASH resolution (OR, 3.40; 95% CI, 1.95-5.93; P < .001; I2 = 0%). All effects were accounted for by pioglitazone use. Weight gain and lower limb edema occurred more frequently with thiazolidinedione therapy (initial body weight +2.70%; 95% CI, 1.96%-4.34%; P = .001). The small sample size of included RCTs prevented evaluation of more serious adverse effects of thiazolidinedione therapy.

Conclusions and relevance: Pioglitazone use improves advanced fibrosis in NASH, even in patients without diabetes. Whether this finding translates to improvement in risk for clinical outcomes requires further study.

Figure 1.. Evidence Acquisition Flow Diagram

NAFLD indicates nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; and RCTs, randomized clinical trials.

Figure 2.. Thiazolidinedione Therapy (TZD) and Improvement in Advanced Fibrosis, Improved Fibrosis of Any Stage, and Nonalcoholic Steatohepatitis (NASH) Resolution

A, Improvement in advanced fibrosis (stage F3-F4) in patients with biopsy-proven NASH, defined as the number of patients with NASH whose fibrosis stage had changed from F3-F4 to F0-F2 at the end of treatment. B, Improvement in advanced fibrosis (stage F3-F4) in patients with NASH with advanced fibrosis, defined as the number of patients with NASH with advanced (F3-F4) fibrosis at baseline whose fibrosis stage had changed from F3-F4 to F0-F2 at the end of treatment. In contrast to A, only patients with NASH and advanced fibrosis were included as the denominator in B.

Figure 3.. Improved Fibrosis of Any Stage and Nonalcoholic Steatohepatitis (NASH) Resolution

A, Improvement by at least 1 stage in liver fibrosis of any stage in patients with biopsy-proven NASH. B, Effects of thiazolidinedione therapy on NASH resolution, defined as the number of patients with NASH who showed NASH resolution at the end of treatment. OR indicates odds ratio.