Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatitis

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 SYNTHESISTwo investigators extracted study data independently and in duplicate and rated the risk of bias using the Cochrane Risk of Bias Tool. MAIN OUTCOMES AND MEASURESThe 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. RESULTSThis 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; I 2 = 0%), fibrosis of any stage (OR, 1.66; 95% CI, 1.12-2.47; P = .01; I 2 = 0%), and NASH resolution (OR, 3.22; 95% CI, 2.17-4.79; P < .001; I 2 = 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; I 2 = 0%), improvement in fibrosis of any stage (OR, 1.76; 95% CI, 1.02-3.03; P = .02; I 2 = 0%), and NASH resolution (OR, 3.40; 95% CI, 1.95-5.93; P < .001; I 2 = 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 with...

Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation

“…Thirty male or female patients between the ages of 18 and 60 (Table S1 and S2) were randomized to: 1) twice daily 200 mg dose of MK-4074; 2) once daily 30 mg doses of pioglitazone; or 3) placebo for 4 weeks. A pioglitazone arm was included as a comparator since it has previously been shown to reduce liver TGs and fibrosis (Bajaj et al, 2003; Belfort et al, 2006; Cusi et al, 2016; Musso et al, 2017; Promrat et al, 2004; Sanyal et al, 2010). Hepatic fat content was assessed using magnetic resonance imaging (MRI) prior to first administration and following 4 weeks of treatment.…”

“…Several studies have demonstrated a significant reduction in liver fat following the administration of pioglitazone (Bajaj et al, 2003; Belfort et al, 2006; Cusi et al, 2016; Musso et al, 2017; Promrat et al, 2004; Sanyal et al, 2010). Pioglitazone increases insulin sensitivity, which reduces activation of SREBP-1c and subsequently lowers rates of lipogenesis in liver (Araujo et al, 2016; Bell et al, 2012).…”

“…Despite the large disease burden, the only available therapy for NAFLD is weight loss and possibly vitamin E supplementation in select individuals (Chalasani et al, 2012). Pioglitazone has also shown promising results and reduces liver TGs and fibrosis but is not currently approved for the treatment of NAFLD (Bajaj et al, 2003; Belfort et al, 2006; Cusi et al, 2016; Musso et al, 2017; Promrat et al, 2004; Sanyal et al, 2010). …”

Management of nonalcoholic fatty liver disease: Lessons learned from type 2 diabetes

“…Fifty‐one percent of patients that received pioglitazone 45 mg daily for 72 weeks had resolution of NASH and improvement in several histologic features, including liver fibrosis. Finally, a meta‐analysis of five clinical trials that evaluated the use of pioglitazone for NASH showed significant improvement in advanced fibrosis even in patients without diabetes 21. Pioglitazone as a treatment for NASH should be used with caution due to several safety concerns, including weight gain and potential risk for congestive heart failure, bone fractures, and bladder cancer.…”

Therapeutic Potential of Peroxisome Proliferator-Activated Receptor Modulation in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

“…Two strategies directly aiming at preventing and reducing fibrosis in NASH are in clinical development with the caspase inhibitor emricasan in phase IIa and galectin 3 inhibitors in phase I [228,229,[232][233][234]. Although there is also some limited evidence that PPARγ activation itself might have anti-fibrotic activity [235], combination of anti-fibrotic approaches with PPAR agonists holds therapeutic promise. By preventing apoptosis of hepatocytes and reducing the formation of fibrotic tissue, caspase inhibitors or galectin 3 inhibitors could protect the liver architecture and retain hepatic function which might also result in synergistic efficacy Beyond combining agents to improve metabolic balance with direct anti-inflammatory or anti-fibrotic mechanisms also targeting metabolic anti-NASH effects in different tissues holds promise for synergistic activity.…”