Bril F, et al. - In patients with nonalcoholic steatohepatitis (NASH) and prediabetes vs type-2 diabetes, the physicians compared metabolic and histologic responses to pioglitazone. Pioglitazone was found to be effective in patients with and without type-2 diabetes. However, in patients with type-2 diabetes, pioglitazone reduced liver fibrosis and increased adipose tissue insulin sensitivity at significantly greater levels than in patients with prediabetes. To determine the mechanisms by which pioglitazone reduces liver disease in patients with type-2 diabetes, further studies were required.

Methods

• From 2008 through 2014, the physicians performed a prospective study of adults with biopsy-proven NASH (52 with type-2 diabetes and 49 with prediabetes), enrolled from the general population of San Antonio, Texas.
• They randomly assigned subjects to groups given pioglitazone or placebo (45 mg/day) for 18 months, after a run-in period of approximately 4 weeks, when all baseline measurements were made (liver magnetic resonance proton spectroscopy, euglycemic insulin clamp with glucose turnover measurements, dual-energy absorptiometry, and liver biopsy).
• Then, they repeated all procedures performed at baseline.
• A reduction in non-alcoholic fatty liver disease activity score of 2 points or more (for at least 2 components) without worsening of fibrosis (and expressed as difference vs placebo) was the primary outcome.
• NASH resolution, individual histologic components, intrahepatic triglyceride content (measured by ¹H magnetic resonance spectroscopy), and insulin sensitivity (measured by euglycemic insulin clamp) were included as secondary outcomes.

Results

• In this study, 48% patients with type-2 diabetes met the primary outcome compared to 46% patients without diabetes.
• Here, 44% of patients with type-2 diabetes reported the achivement of resolution of NASH, while this resolution was achieved in 26% patients without diabetes.
• Only patients with type-2 diabetes (p=0.035) had a significant reduction in fibrosis, from baseline.
• In patients with diabetes, intrahepatic triglyceride content was reduced by 11±2% vs 9±2% in patients without diabetes (p=0.62).
• Plasma level of alanine aminotransferase was reduced by 50±10 U/L in patients with diabetes vs a reduction of 36±5 U/L in patients without diabetes (p=0.22).
• Pioglitazone associated with a significantly greater insulin sensitivity in adipose tissue of patients with diabetes vs without diabetes (p < 0.001).
• However, it was associated with non-significant differences in responses in hepatic (p=0.49) and skeletal muscle (p=0.32) insulin sensitivity.