Kenneth Cusi, MD; Beverly Orsak, RN; Fernando Bril, MD; Romina Lomonaco, MD; Joan Hecht, RN; Carolina Ortiz-Lopez, MD; Fermin Tio, MD; Jean Hardies, PhD; Celia Darland, RD; Nicolas Musi, MD; Amy Webb, MD; Paola Portillo-Sanchez, MD
Note: Dr. Cusi, as principal investigator of the study, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Acknowledgment: The authors thank the volunteers and the nursing, nutrition, and laboratory staff at the Clinical Translational Science Institute for their skilled work; Jonathan J. Shuster, PhD, Professor and Co-Director of Biostatistics, Epidemiology, and Research Design at the Clinical Translational Science Institute at the University of Florida for his support and advice during manuscript preparation; and Takeda Pharmaceuticals for providing the pioglitazone and placebo tablets.
Grant Support: By the Burroughs Wellcome Fund (1006762.01 [Dr. Cusi]) and the American Diabetes Association (1-08-CR-08 [Dr. Cusi]). Additional support was provided by the National Center for Research Resources (MO1-RR-01346), the UTHSCSA Clinical Research Center and Research Imaging Center, and the Veterans Affairs Medical Research Fund.
Disclosures: Dr. Cusi reports nonfinancial support from Takeda Pharmaceuticals (provision of study medication and placebo); grants from Novartis and Janssen Research & Development; and consultancies for Eli Lilly and Company, Tobira Therapeutics, and Pfizer outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-1774.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: The authors chose not to provide readers access to the study protocol with this article. Statistical code: Available from Dr. Cusi (e-mail, firstname.lastname@example.org). Data set: Not available.
Requests for Single Reprints: Kenneth Cusi, MD, Professor of Medicine, Chief, Division of Endocrinology, Diabetes and Metabolism, University of Florida, 1600 SW Archer Road, Room H-2, Gainesville, FL 32610; e-mail, Kenneth.Cusi@medicine.ufl.edu.
Current Author Addresses: Drs. Cusi, Bril, Lomonaco, and Portillo-Sanchez: University of Florida, 1600 SW Archer Road, Room H-2, Gainesville, FL 32610.
Ms. Orsak; Ms. Hecht; Drs. Ortiz-Lopez, Tio, Hardies, Musi, and Webb; and Ms. Darland: University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, DTL Room 3.380S, San Antonio, TX 78229.
Author Contributions: Conception and design: K. Cusi, A. Webb.
Analysis and interpretation of the data: K. Cusi, F. Bril, C. Ortiz-Lopez, F. Tio, J. Hardies, N. Musi, A. Webb, P. Portillo-Sanchez.
Drafting of the article: K. Cusi, F. Bril.
Critical revision of the article for important intellectual content: K. Cusi, F. Bril, P. Portillo-Sanchez.
Final approval of the article: K. Cusi, B. Orsak, F. Bril, R. Lomonaco, J. Hecht, C. Ortiz-Lopez, F. Tio, J. Hardies, C. Darland, N. Musi, A. Webb, P. Portillo-Sanchez.
Provision of study materials or patients: K. Cusi, B. Orsak, R. Lomonaco, C. Darland, A. Webb.
Statistical expertise: K. Cusi, F. Bril.
Obtaining of funding: K. Cusi.
Administrative, technical, or logistic support: K. Cusi, J. Hecht, N. Musi.
Collection and assembly of data: K. Cusi, B. Orsak, F. Bril, R. Lomonaco, C. Ortiz-Lopez, P. Portillo-Sanchez.
The metabolic defects of nonalcoholic steatohepatitis (NASH) and prediabetes or type 2 diabetes mellitus (T2DM) seem to be specifically targeted by pioglitazone. However, information about its long-term use in this population is limited.
To determine the efficacy and safety of long-term pioglitazone treatment in patients with NASH and prediabetes or T2DM.
Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT00994682)
Patients (n = 101) with prediabetes or T2DM and biopsy-proven NASH were recruited from the general population and outpatient clinics.
All patients were prescribed a hypocaloric diet (500–kcal/d deficit from weight-maintaining caloric intake) and then randomly assigned to pioglitazone, 45 mg/d, or placebo for 18 months, followed by an 18-month open-label phase with pioglitazone treatment.
The primary outcome was a reduction of at least 2 points in the nonalcoholic fatty liver disease activity score in 2 histologic categories without worsening of fibrosis. Secondary outcomes included other histologic outcomes, hepatic triglyceride content measured by magnetic resonance and proton spectroscopy, and metabolic parameters.
Among patients randomly assigned to pioglitazone, 58% achieved the primary outcome (treatment difference, 41 percentage points [95% CI, 23 to 59 percentage points]) and 51% had resolution of NASH (treatment difference, 32 percentage points [CI, 13 to 51 percentage points]) (P < 0.001 for each). Pioglitazone treatment also was associated with improvement in individual histologic scores, including the fibrosis score (treatment difference, −0.5 [CI, −0.9 to 0.0]; P = 0.039); reduced hepatic triglyceride content from 19% to 7% (treatment difference, −7 percentage points [CI, −10 to −4 percentage points]; P < 0.001); and improved adipose tissue, hepatic, and muscle insulin sensitivity (P < 0.001 vs. placebo for all). All 18-month metabolic and histologic improvements persisted over 36 months of therapy. The overall rate of adverse events did not differ between groups, although weight gain was greater with pioglitazone (2.5 kg vs. placebo).
Long-term pioglitazone treatment is safe and effective in patients with prediabetes or T2DM and NASH.
Burroughs Wellcome Fund and American Diabetes Association.
Kenneth Cusi, Beverly Orsak, Fernando Bril, Romina Lomonaco, Joan Hecht, Carolina Ortiz-Lopez, et al. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Ann Intern Med. 2016;165:305–315. doi: 10.7326/M15-1774
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Published: Ann Intern Med. 2016;165(5):305-315.
Published at www.annals.org on 21 June 2016
Cardiology, Coronary Risk Factors, Diabetes, Endocrine and Metabolism, Gastroenterology/Hepatology.
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