Pioglitazone therapy given for 18 months benefited patients with nonalcoholic steatohepatitis (NASH) similarly regardless of whether they had type 2 diabetes mellitus or prediabetes, according to the results of a randomized prospective trial.

The primary outcome, at least a 2-point reduction in nonalcoholic fatty liver disease activity score compared with placebo, without worsening fibrosis, was met by 48% of NASH patients with T2DM and by 46% of those with prediabetes, reported Fernando Bril, MD, of the division of endocrinology, diabetes, and metabolism at the University of Florida, Gainesville, and his associates. The report was published in Clinical Gastroenterology and Hepatology .

NASH resolved completely in 44% with T2DM and 26% of patients without it, respectively, perhaps indicating that pioglitazone acts slightly differently when patients with NASH have T2DM, according to the investigators. “Although the effects on fibrosis appear to be similar in both groups, pioglitazone may contribute to halting [its] rapid progression [in T2DM],” they wrote. “These differences will deserve further exploration in larger clinical trials.”

The trial (NCT00994682) enrolled 101 patients with biopsy-confirmed NASH, of whom 52 had T2DM and 49 had prediabetes based on clinical history, baseline fasting plasma glucose, hemoglobin A1c, and an oral glucose tolerance test, as per American Diabetes Association guidelines. After a 4-week run-in period, patients were randomly assigned to receive either pioglitazone (45 mg per day) or placebo for 18 months. All patients received lifestyle counseling and a hypocaloric (500-kcal reduced) diet.

Compared with placebo, pioglitazone improved most secondary outcomes similarly regardless of whether patients were T2DM or prediabetes. The two exceptions were fibrosis and insulin sensitivity of adipose tissue. Patients with T2DM only experienced improved fibrosis in the setting of pioglitazone therapy (P = .035 vs. baseline). In prediabetic patients, fibrosis lessened moderately over time, regardless of whether they received pioglitazone or placebo. Insulin sensitivity of adipose tissue improved much more markedly with treatment in patients with T2DM (P less than .001 vs. baseline) than in those with prediabetes (P = .002 for T2DM vs. prediabetes).

Compared with placebo, pioglitazone improved hepatic and skeletal muscle insulin sensitivity similarly, regardless of diabetes status. Likewise, intrahepatic triglyceride content, as measured by proton magnetic resonance spectroscopy, fell by 11% in pioglitazone recipients with T2DM and by 9% of those with prediabetes, a nonsignificant difference. Pioglitazone also led to a statistically similar decrease in plasma alanine aminotransferase level regardless of whether patients had T2DM (50 U/L) or were prediabetic (36 U/L).

This trial’s key takeaway is that pioglitazone improves liver histology in NASH whether or not patients are diabetic, said the researchers. “We believed that it was essential to compare its efficacy in patients with [and] without T2DM because of the vast number of patients with prediabetes and NASH and given the significant metabolic and cardioprotective effects of pioglitazone among patients without T2DM,” they wrote. The natural history of NASH is worse in the presence of T2DM, which might explain pioglitazone’s superior effects on fibrosis and insulin sensitivity of adipose tissue in this population, they added.

The Burroughs Wellcome Fund, the American Diabetes Association, and the Veteran’s Affairs Merit Award supported the work. Senior author Kenneth Cusi, MD, disclosed nonfinancial support from Takeda Pharmaceuticals, grants from Novartis and Janssen Research and Development, and consulting relationships with Eli Lilly, Tobira Therapeutics, and Pfizer. The other authors had no conflicts.