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Pioglitazone improves advanced fibrosis in nonalcoholic steatohepatitis

In patients with advanced liver fibrosis with or without diabetes, pioglitazone may halt disease progression to end-stage liver disease, according to data published in JAMA Internal Medicine.

“Nonalcoholic steatohepatitis (NASH) is projected to be the leading cause of liver transplantation by 2020,” Giovanni Musso, MD, from Humanitas Gradenigo Hospital in Italy, and colleagues wrote. “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.”

The researchers searched several databases, registries and scientific meeting presentations through Aug. 15, 2016 for data from randomized clinical trials that analyzed the efficacy of thiazolidinedione therapy for NASH to determine its effect in advanced liver fibrosis. They evaluated whether a dichotomous improvement in advanced fibrosis on liver biopsy (improving from fibrosis stage F3-F4 to F0-F2) and at least a one-point improvement in fibrosis of any stage and NASH resolution resulted from thiazolidinedione therapy. Adverse effects of thiazolidinedione therapy, including weight gain, lower limb edema, congestive heart failure, bone fractures, cancer and anemia were also assessed.

A total of 516 patients with biopsy-proven NASH from eight randomized clinical trials conducted between 6 and 24 months were studied of which five trials evaluated pioglitazone use and three evaluated rosiglitazone maleate use. Results from all studies indicated that thiazolidinedione therapy 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%). Patients without diabetes displayed similar results for improvement in advanced fibrosis (OR = 2.95; 95% CI, 1.04-10.9; 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%).

Thiazolidinedione therapy resulted in more frequent occurrence of weight gain and lower limb edema (initial body weight +2.7%; 95% CI, 1.96-4.34; P = .001). Musso and colleagues noted that they were unable to evaluate more serious adverse effects of thiazolidinedione therapy due to the small sample size of trials studied.

“Recent guidelines recommend identification of patients with [nonalcoholic fatty liver disease] with advanced fibrosis to target them for more intensive monitoring of the onset of complications but acknowledge the lack of therapeutic options that effectively reverse advanced stages of liver disease,” Musso and colleagues concluded. “The new finding in this meta-analysis is that treatment with the antidiabetic drug pioglitazone reverses the more advanced stages of liver disease in NASH regardless of the presence of diabetes, which provides a rationale for evaluating the effect of this drug on clinical outcomes in this subgroup of patients at higher risk of liver-related complications.”

In a related editorial, Hal F. Yee Jr, MD, PhD, from the department of medicine at the University of California, San Francisco, wrote that although this study enhances the understanding of the role that thiazolidinedione therapy may have in the management of NASH, essential questions, such as if pioglitazone alters clinical outcomes or has any potential risks, need to be answered before clinicians can recommend the drug as a treatment for patients with NASH.

“Pioglitazone has been approved by the FDA, alone or in combination with other medications, for the treatment of type 2 diabetes based on extensive clinical trials showing benefits that outweigh risks,” he added. “Therefore, it may make sense to consider the use of pioglitazone in patients with type 2 diabetes who have NASH and evidence of advanced fibrosis. Treating such patients would not incur any incremental risk of adverse events because they might already be taking pioglitazone as part of the management of their diabetes, while potentially benefiting from its putative benefits in NASH. For most patients with NASH, prior guidance to reduce weight, exercise, and refrain from heavy consumption of alcohol would seem prudent until we have data showing therapies that improve clinical outcomes.” – by Alaina Tedesco

Disclosures: Musso and Yee reports no relevant financial disclosures.