M Kawaguchi-Suzuki1,2,3, F Bril4, S Kalavalapalli4, K Cusi4,5, R F Frye1,2. 1. Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, USA. 2. Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA. 3. Pacific University School of Pharmacy, College of Health Professions, Hillsboro, OR, USA. 4. Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA. 5. Endocrinology, Diabetes and Metabolism, Malcom Randall VA Medical Center, Gainesville, FL, USA.
Abstract
BACKGROUND: Pioglitazone is a safe and effective option to manage patients with type 2 diabetes and nonalcoholic steatohepatitis (NASH). However, there is marked variability in treatment response. AIM: To evaluate the relationship between concentrations of pioglitazone and its active metabolites and treatment outcomes in patients with NASH. METHODS: Pioglitazone concentrations were measured in patients with NASH treated with pioglitazone 45 mg/day for 18 months; liver biopsy samples were obtained at baseline and after treatment. The primary outcome was a ≥2-point reduction in NAFLD activity score (NAS) with at least one-point improvement in more than one liver histology category and without worsening of fibrosis. A novel marker, the pioglitazone exposure index, was calculated to consider the concentrations of pioglitazone as well as the two active metabolites. RESULTS: The response to pioglitazone was concentration-dependent as evidenced by the significant relationship between both pioglitazone concentration and pioglitazone exposure index with changes in NAS (r=.48, P=.0002 and r=.51, P<.0001, respectively), steatosis (r=.41, P=.002 and r=.46, P=.0005), and inflammation (r=.44, P=.0009 and r=.40, P=.0003). The pioglitazone exposure index was also associated with a change in ballooning (P=.04). The pioglitazone exposure index was higher in patients with NASH resolution (2.85±1.38 vs 1.78±1.48, P=.018). A predictive model for the primary outcome was developed that incorporated baseline NAS and pioglitazone exposure index (AUC=0.77). CONCLUSIONS: This study demonstrates the importance of pioglitazone exposure to variable response in patients with NASH, and indicates potential factors that may identify patients most likely to benefit from chronic pioglitazone treatment.
BACKGROUND:Pioglitazone is a safe and effective option to manage patients with type 2 diabetes and nonalcoholic steatohepatitis (NASH). However, there is marked variability in treatment response. AIM: To evaluate the relationship between concentrations of pioglitazone and its active metabolites and treatment outcomes in patients with NASH. METHODS:Pioglitazone concentrations were measured in patients with NASH treated with pioglitazone 45 mg/day for 18 months; liver biopsy samples were obtained at baseline and after treatment. The primary outcome was a ≥2-point reduction in NAFLD activity score (NAS) with at least one-point improvement in more than one liver histology category and without worsening of fibrosis. A novel marker, the pioglitazone exposure index, was calculated to consider the concentrations of pioglitazone as well as the two active metabolites. RESULTS: The response to pioglitazone was concentration-dependent as evidenced by the significant relationship between both pioglitazone concentration and pioglitazone exposure index with changes in NAS (r=.48, P=.0002 and r=.51, P<.0001, respectively), steatosis (r=.41, P=.002 and r=.46, P=.0005), and inflammation (r=.44, P=.0009 and r=.40, P=.0003). The pioglitazone exposure index was also associated with a change in ballooning (P=.04). The pioglitazone exposure index was higher in patients with NASH resolution (2.85±1.38 vs 1.78±1.48, P=.018). A predictive model for the primary outcome was developed that incorporated baseline NAS and pioglitazone exposure index (AUC=0.77). CONCLUSIONS: This study demonstrates the importance of pioglitazone exposure to variable response in patients with NASH, and indicates potential factors that may identify patients most likely to benefit from chronic pioglitazone treatment.
Authors: Arun J Sanyal; Naga Chalasani; Kris V Kowdley; Arthur McCullough; Anna Mae Diehl; Nathan M Bass; Brent A Neuschwander-Tetri; Joel E Lavine; James Tonascia; Aynur Unalp; Mark Van Natta; Jeanne Clark; Elizabeth M Brunt; David E Kleiner; Jay H Hoofnagle; Patricia R Robuck Journal: N Engl J Med Date: 2010-04-28 Impact factor: 91.245
Authors: Renata Belfort; Stephen A Harrison; Kenneth Brown; Celia Darland; Joan Finch; Jean Hardies; Bogdan Balas; Amalia Gastaldelli; Fermin Tio; Joseph Pulcini; Rachele Berria; Jennie Z Ma; Sunil Dwivedi; Russell Havranek; Chris Fincke; Ralph DeFronzo; George A Bannayan; Steven Schenker; Kenneth Cusi Journal: N Engl J Med Date: 2006-11-30 Impact factor: 91.245