Pioglitazone improves advanced liver disease even in nondiabetics

Last Updated: 2017-02-27

By Reuters Staff

NEW YORK (Reuters Health) - Treatment with pioglitazone improves advanced fibrosis in patients with nonalcoholic steatohepatitis (NASH), even in patients without diabetes, according to results of a meta-analysis published today.

Clinical guidelines recommend identifying patients with nonalcoholic fatty liver disease (NAFLD) 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,” write the authors from Turin, Italy, in JAMA Internal Medicine.

“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,” report Dr. Giovanni Musso and colleagues from Humanitas Gradenigo Hospital and the University of Turin.

They pooled eight randomized controlled trials evaluating the effect of thiazolidinedione therapy on histologic features of the liver in a total of 516 patients with biopsy-proven NASH. Five trials evaluated pioglitazone (average daily dose 30 or 45 mg) and three evaluated rosiglitazone (average daily dose 4 and 8 mg). The trials lasted for between six and 24 months.

In an analysis combining all eight trials, thiazolidinedione therapy led to improvement in advanced fibrosis (odds ratio, 3.15; p=0.01), fibrosis of any stage (OR, 1.66; p=0.01), and NASH resolution (OR, 3.22; p<0.001).

Analyses restricted to trials enrolling nondiabetic NASH patients yielded similar results on all three outcomes (odds ratios, 2.95, 1.76 and 3.40, respectively).

Pioglitazone use (and not rosiglitazone use) accounted for all of the benefits observed with thiazolidinedione therapy, the authors note, and they aren't sure why.

“Possible differences can be explained by the differential effects of pioglitazone and rosiglitazone on inflammation and fibrosis mechanisms, such as through up-regulation of adiponectin, activation of adenosine monophosphate-activated protein kinase, and induction of hepatic stellate cell senescence,” they offer.

Aside from weight gain and lower limb edema, no major adverse events were reported during the trials, the authors say. However, due to the small number of trials and small sample size of the trials they couldn't evaluate more serious adverse effects of thiazolidinedione therapy.

This analysis, conclude Dr. Musso and colleagues, suggests that pioglitazone use for up to 24 months can help reverse advanced fibrosis stage in NASH “and may thus improve long-term prognosis in this subgroup of patients who are at higher risk of poor liver-related outcomes.”

In a linked editorial, Dr. Hal Yee Jr., of the University of California, San Francisco, says this analysis makes a “significant contribution” regarding the potential role pioglitazone may have in the management of NASH, but several “substantive questions” remain to be addressed before it can be recommended as a treatment for patients with NASH.

Namely, “Does pioglitazone alter clinical outcomes, such as development of ascites or encephalopathy, need for liver transplantation, or liver-related death? What are the potential risks associated with the use of pioglitazone? Should patients with NASH be treated with pioglitazone? Might there be a subpopulation of patients with NASH in whom pioglitazone could be considered in their treatment?”

For now, Dr. Yee says, “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.”

The study had no commercial funding and the authors have disclosed no conflicts of interest.

SOURCE: http://bit.ly/2mwPL6M and http://bit.ly/2mwLnVv

JAMA Intern Med 2017.