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

Inclusion criteria:

1. Able to communicate meaningfully with the investigator and legally competent toprovide written informed consent.

2. Aged 21 to 75 years.

3. Patients with a diagnosis T2DM based on prior medical history, medication use, orresults from a fasting plasma glucose or hemoglobin A1c, according to AmericanDiabetes Association guidelines.

4. 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 followingdiabetes medications: metformin, sulfonylurea, acarbose, DPP-IV inhibitors, SGLT2inhibitors or insulin. The insulin total daily dose should be stable (defined aswithin 20% for the prior 2 months prior to study entry). A GLP-1 receptor agonistwill be allowed if on a stable dose for 6 months prior to enrollment and body weightstable (defined as within 3%) in the prior 3 months. Diabetes medications will becontinued at stable doses during the entire study (except if glycemic controldeteriorates based on HbA1c; addition of metformin, sulfonylurea, acarbose, DPP-IVor insulin will be allowed if needed; pioglitazone, GLP-1RA or SGLT2 inhibitors willnot).

5. Hemoglobin level of at least 11.0 g/L (men) or at least 10.0 g/L (women), leukocytecount 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.

Exclusion criteria:

1. Past or current history of alcohol use (>20 g/d of ethanol in females or >30g/d inmales). 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 beused to assess alcohol use.

2. Receipt of long-term therapy with medications known to have adverse effects onglucose tolerance, unless the patient has been receiving a stable dose of suchagents for 4 weeks before study entry.

3. Use of medications that could induce steatosis, such as estrogen or other hormonalreplacement therapy, amiodarone, methotrexate, tamoxifen, raloxifene,pharmacological doses of oral glucocorticoids (≥10 mg per day of prednisone orequivalent), or chloroquine.

4. Use of vitamin E (doses ≥800 IU/dy) or pioglitazone or any FDA-approved drug forNASH to be approved during the study.

5. Any cause of chronic liver disease other than NASH, including but not restricted toalcohol 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 ofprimary or metastatic liver cancer.

6. Presence of other medical conditions known to cause fatty liver disease.

7. Any clinical or laboratory evidence of cirrhosis or hepatic decompensation, such ashistory of ascites, esophageal bleeding varices, or spontaneous encephalopathy.

8. Prior or scheduled surgical procedures, including gastroplasty or jejunoileal orjejunocolic bypass.

9. Prior exposure to organic solvents, such as carbon tetrachloride.

10. Total parenteral nutrition within the past 6 months.

11. Patients with other forms of diabetes other than T2DM.

12. History of clinically significant heart disease such as congestive heart failure (New York Heart Association Classification greater than grade II-IV), unstablecardiovascular disease such as unstable angina (i.e., new or worsening symptoms ofcoronary heart disease within the past 6 months), acute coronary syndrome orcoronary artery intervention within the past 6 months, acute myocardial infarctionin the past 6 months; history of (within prior 6 months) or current unstable cardiacdysrhythmias.

13. Uncontrolled hypertension (systolic blood pressure >160 mmHg and/or diastolic bloodpressure >100 mmHg); clinically evident peripheral vascular disease (history ofclaudication); stroke or transient ischemic attack within the prior 6 months;clinically significant pulmonary disease (dyspnea on exertion of ≤1 flight; abnormalbreath sounds on auscultation), or kidney disease as defined above per plasmacreatinine elevation or significant proteinuria (macroalbuminuria).

14. Pregnancy or lactation in women. Must have a negative pregnancy test or at least betwo-year post-menopausal. Women with childbearing potential (i.e. fertile, followingmenarche and until becoming post-menopausal unless permanently sterile) must beusing a highly effective method of contraception (i.e. combined (estrogen andprogesterone containing) hormonal/ progesterone-only hormonal contraceptionassociated with inhibition of ovulation, intrauterine device, intrauterinehormone-releasing system, bilateral tubal occlusion, vasectomized partner). Thecontraceptive method will have to be followed for at least one menstruation cycleafter the end of the study.

15. History of malignancy in the past 5 years and/or active neoplasm with the exceptionof resolved superficial nonmelanoma skin cancer.

16. History of bladder disease and/or hematuria or has current hematuria unless due to arecent urinary tract infection.

17. Hemostasis disorders or current treatment with anticoagulants.

18. Any other criteria that based on the assessment of the research team the patient isdeemed to be a poor research candidate.