Pioglitazone associated with improved advanced fibrosis in patients with NASH

A recent meta-analysis looked at randomized clinical trials that examined the effect of thiazolidinediones on liver histology in patients with nonalcoholic steatohepatitis (NASH).

Advanced fibrosis in patients with NASH may be improved by pioglitazone use, according to a recent meta-analysis.

Researchers looked at literature published through Aug. 15, 2016, and selected randomized clinical trials that examined the effect of thiazolidinediones on liver histology in patients with NASH. The study's primary outcome was dichotomous improvement in advanced fibrosis on biopsy of the liver, which was defined as improvement in fibrosis stage from F3-F4 to F0-F2. Secondary outcomes were a one-point improvement or greater in any stage of fibrosis and resolution of NASH. Adverse effects of thiazolidinediones were also evaluated. Results were published online Feb. 27 by JAMA.

Eight trials involving 516 patients were included in the study, five that evaluated pioglitazone and three that evaluated rosiglitazone. Trial durations ranged from six to 24 months, daily rosiglitazone dose ranged from 4 to 8 mg, and daily pioglitazone dose ranged from 30 to 45 mg. For all studies, use of thiazolidinediones was associated with improvement in advanced fibrosis (odds ratio [OR], 3.15; 95% CI, 1.25 to 7.93; P=0.01), improvement in any stage of fibrosis (OR, 1.66; 95% CI, 1.12 to 2.47; P=0.01), and resolution of NASH (OR, 3.22; 95% CI, 2.17 to 4.79; P<0.001). Similar improvements were seen for all three outcomes when analyses were restricted to trials that enrolled nondiabetic patients. The improvements were all seen with pioglitazone but not rosiglitazone. Because the sample sizes of the included trials were small, serious adverse effects could not be evaluated, but weight gain and lower-limb edema appeared to be more common with thiazolidinedione therapy.

The authors noted that histologic features rather than clinical outcomes were evaluated and that they could not determine why pioglitazone but not rosiglitazone was associated with benefits. However, they concluded that pioglitazone treatment “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.”

The author of an accompanying invited commentary noted that several questions remain to be answered before pioglitazone can be recommended to treat NASH, including whether it affects clinical outcomes and whether it is associated with risks (e.g. bladder cancer and congestive heart failure). However, he noted that it might make sense to consider pioglitazone use 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 diabetes, while potentially benefiting from its putative benefits in NASH,” the author wrote. “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.”