Pioglitazone may halt the progression of nonalcoholic steatohepatitis (NASH) in patients with prediabetes or Type 2 diabetes, a randomised trial shows.
The primary outcome of the trial, which is published in the Annals of Internal Medicine, was a reduction of least 2 points in two different histological categories of the nonalcoholic fatty liver disease activity score (NAS), without worsening of fibrosis.
This outcome was achieved by 58% of the 50 patients who received pioglitazone 45 mg/day for 18 months, report Kenneth Cusi (University of Florida, Gainsville, USA) and co-researchers.
By contrast, just 17% of the 51 patients who received placebo achieved the primary outcome, giving a significant 41 percentage point difference.
In an accompanying editorial, Eduardo Vilar-Gomez (University of Seville, Spain) and Leon Adams (University of Western Australia, Nedlands) suggest that the cumulative evidence so far may be less than ideal. "However, long-term confirmatory studies are unlikely to be performed given the impracticability and riskiness of serial liver biopsies", they say.
They advise physicians to consider using pioglitazone, but bearing its known side effects in mind. "Thus, treatment should be considered for patients at the greatest risk (those with NASH and fibrosis) and should be balanced against the common risk for weight gain and the uncommon risks for fracture and heart failure."
During treatment, all patients were assigned to a hypocaloric diet, with a 500 calorie/day deficit. The NASH diagnosis was definite in 84% and 88% of the pioglitazone and placebo groups, respectively, while 48% and 55%, respectively, had Type 2 diabetes with the others having prediabetes.
By 18 months, 51% of the pioglitazone group versus 19% of the placebo group had resolution of NASH. Pioglitazone was associated with significantly greater improvements in steatosis, inflammation and ballooning, relative to placebo, and a nonsignificant improvement in fibrosis.
A total of 29 patients from the pioglitazone group completed an open-label 36-month extension study, during which their NAS improvements were maintained, but with no additional benefit.
Vilar-Gomez and Adams say this is in line with the previously reported effects of rosiglitazone, and suggests "that histologic improvement parallels the initial improvement in insulin sensitivity and plateaus when the insulin-sensitizing effects stabilize".
But they note that discontinuation of pioglitazone reportedly worsens insulin sensitivity and liver histology outcomes. "Thus, a rationale for long-term treatment may be to reduce fibrosis progression rather than to normalize liver histologic parameters", they say.
Ann Intern Med 2016; Advance online publication
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