Low-Dose Pioglitazone in Patients With NASH (AIM 2)

Prior treatment

• Use of medications that could induce steatosis, such as estrogen or other hormonal replacement therapy, amiodarone, methotrexate, tamoxifen, raloxifene, pharmacological doses of oral glucocorticoids (≥10 mg per day of prednisone or equivalent), or chloroquine.
• Use of vitamin E (doses ≥800 IU/dy) or pioglitazone or any FDA-approved drug for NASH to be approved during the study.
• Prior or scheduled surgical procedures, including gastroplasty or jejunoileal or jejunocolic bypass.
• Prior exposure to organic solvents, such as carbon tetrachloride.
• History of clinically significant heart disease such as congestive heart failure (New York Heart Association Classification greater than grade II-IV), unstable cardiovascular disease such as unstable angina (i.e., new or worsening symptoms of coronary heart disease within the past 6 months), acute coronary syndrome or coronary artery intervention within the past 6 months, acute myocardial infarction in the past 6 months; history of (within prior 6 months) or current unstable cardiac dysrhythmias.
• Hemostasis disorders or current treatment with anticoagulants.

Other illness

• Past or current history of alcohol use (\>20 g/d of ethanol in females or \>30g/d in males). Alcohol abuse will be ruled out on the basis of physicians' judgment, self-reported alcohol use, and family members' report of the patient's alcohol use. In addition, the Alcohol Use Disorders Identification Test (AUDIT) score will be used to assess alcohol use.
• Presence of other medical conditions known to cause fatty liver disease.
• Patients with other forms of diabetes other than T2DM.
• History of malignancy in the past 5 years and/or active neoplasm with the exception of resolved superficial nonmelanoma skin cancer.
• History of bladder disease and/or hematuria or has current hematuria unless due to a recent urinary tract infection.

Lab values

• Receipt of long-term therapy with medications known to have adverse effects on glucose tolerance, unless the patient has been receiving a stable dose of such agents for 4 weeks before study entry.
• Any clinical or laboratory evidence of cirrhosis or hepatic decompensation, such as history of ascites, esophageal bleeding varices, or spontaneous encephalopathy.
• Uncontrolled hypertension (systolic blood pressure \>160 mmHg and/or diastolic blood pressure \>100 mmHg); clinically evident peripheral vascular disease (history of claudication); stroke or transient ischemic attack within the prior 6 months; clinically significant pulmonary disease (dyspnea on exertion of ≤1 flight; abnormal breath sounds on auscultation), or kidney disease as defined above per plasma creatinine elevation or significant proteinuria (macroalbuminuria).

Age

• Any cause of chronic liver disease other than NASH, including but not restricted to alcohol or drug abuse, medication, chronic hepatitis B or C virus infection, autoimmune liver disease, hemochromatosis, Wilson disease (if younger than age 50), α1-antitrypsin deficiency, history of exposure to hepatotoxic drugs or history of primary or metastatic liver cancer.

Other

• Total parenteral nutrition within the past 6 months.
• Pregnancy or lactation in women. Must have a negative pregnancy test or at least be two-year post-menopausal. Women with childbearing potential (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile) must be using a highly effective method of contraception (i.e. combined (estrogen and progesterone containing) hormonal/ progesterone-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner). The contraceptive method will have to be followed for at least one menstruation cycle after the end of the study.
• Any other criteria that based on the assessment of the research team the patient is deemed to be a poor research candidate.

• Able to communicate meaningfully with the investigator and legally competent to provide written informed consent.
• Aged 21 to 75 years.
• Patients with a diagnosis T2DM based on prior medical history, medication use, or results from a fasting plasma glucose or hemoglobin A1c, according to American Diabetes Association guidelines.
• Patients will be allowed to participate the glycosylated hemoglobin (HbA1c) is ≤ 9.5% on diet alone or on a stable dose (for at least 2 months) of the following diabetes medications: metformin, sulfonylurea, acarbose, DPP-IV inhibitors, SGLT2 inhibitors or insulin. The insulin total daily dose should be stable (defined as within 20% for the prior 2 months prior to study entry). A GLP-1 receptor agonist will be allowed if on a stable dose for 6 months prior to enrollment and body weight stable (defined as within 3%) in the prior 3 months. Diabetes medications will be continued at stable doses during the entire study (except if glycemic control deteriorates based on HbA1c; addition of metformin, sulfonylurea, acarbose, DPP-IV or insulin will be allowed if needed; pioglitazone, GLP-1RA or SGLT2 inhibitors will not).
• Hemoglobin level of at least 11.0 g/L (men) or at least 10.0 g/L (women), leukocyte count of at least 3.0 × 109 cells/L, neutrophil count of at least 1.5 × 109 cells/L, platelet count of at least 100 × 109 cells/L, albumin level of at least 2.5 g/L, serum creatinine level of 2.5 mg/dL or less, INR \> 1.4, bilirubin \> 1.3 mg/dL (unless if non-conjugated bilirubin elevated in the setting of Gilbert's syndrome), and AST and ALT levels no more than 8 times the ULN.