Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida; Division of Endocrinology, Diabetes and Metabolism, Malcom Randall VAMC, Gainesville, Florida.
Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida.
Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, Florida.
Pathology Divisions, University of Texas Health Science Center at San Antonio (UTHSCSA); Audie L. Murphy Veterans Administration Medical Center (VAMC) San Antonio, Texas.
Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida; Division of Endocrinology, Diabetes and Metabolism, Malcom Randall VAMC, Gainesville, Florida. Electronic address: Kenneth.Cusi@medicine.ufl.edu.
BACKGROUND & AIMS:
Pioglitazone is effective for long-term treatment of patients with nonalcoholic steatohepatitis (NASH) with prediabetes or type-2 diabetes. However, it is not clear how the presence of type-2 diabetes affects the drug's efficacy. We compared metabolic and histologic responses to pioglitazone in patients with NASH and prediabetes vs type-2 diabetes.
We 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 from 2008 through 2014. 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), subjects were randomly assigned to groups given pioglitazone or placebo (45 mg/day) for 18 months; all procedures performed at baseline were then repeated. The primary outcome was 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 versus placebo). Secondary outcomes included NASH resolution, individual histologic components, intrahepatic triglyceride content (measured by 1H magnetic resonance spectroscopy), and insulin sensitivity (measured by euglycemic insulin clamp).
The primary outcome was met by 48% patients with type-2 diabetes vs 46% without diabetes. Resolution of NASH was achieved in 44% of patients with type-2 diabetes vs 26% without diabetes. A significant reduction in fibrosis, from baseline, was observed in only patients with type-2 diabetes (p=0.035). Intrahepatic triglyceride content was reduced by 11±2% in patients with diabetes vs a reduction of 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), but non-significant differences in responses in hepatic (p=0.49) and skeletal muscle (p=0.32) insulin sensitivity.
In a prospective study, we found pioglitazone to be effective in patients with and without type-2 diabetes. However, pioglitazone reduced liver fibrosis and increased adipose tissue insulin sensitivity at significantly greater levels in patients with type-2 diabetes than in patients with prediabetes. Further studies are needed to determine the mechanisms by which pioglitazone reduces liver disease in patients with type-2 diabetes. ClinicalTrials.gov: NCT00994682.