Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, Type 2 Diabetes Mellitus
Conditions
Keywords
Additional relevant MeSH terms:, Hypoglycemic Agents, Physiological Effects of Drugs, Pharmacologic Actions, Pioglitazone
Brief summary
Obesity and Type 2 diabetes are creating a silent epidemic, Non-alcoholic fatty liver disease, which is a chronic liver disease associated with insulin resistance, impaired glucose intolerance, and hepatic fat accumulation. The thiazolidinedione pioglitazone improves glucose/lipid metabolism and histology in NASH by improving insulin resistance in the liver/peripheral/adipose tissues and reducing subclinical inflammation. The aim of this study is to assess the underlying mechanisms at the clinical and molecular level and the long-term efficacy and safety of pioglitazone in NASH in a multiethnic cohort of subjects (predominantly Hispanics, Caucasians and African-Americans - the most common ethnic groups locally) and examine the response including patients with normal glucose tolerance, impaired glucose tolerance or established type 2 diabetes mellitus (T2DM).
Detailed description
NASH is a disease characterized by elevated plasma aminotransferases and histopathological changes in liver characterized by hepatocellular steatosis, chronic inflammation and perisinusoidal fibrosis. NASH affects (\ 30-40%) of obese and type 2 diabetic subjects. While the pathogenesis of NASH is poorly understood, there is consensus that insulin resistance and its associated abnormalities in lipid metabolism play a key role in the development of liver fat accumulation. Insulin resistance in nonalcoholic steatohepatitis is frequently associated with chronic hyperinsulinemia, hyperglycemia, and an excessive supply of plasma free fatty acids to the liver. This in turn promotes hepatic lipogenesis. Pioglitazone, a thiazolidinedione (TZD), reverses these abnormalities by ameliorating insulin resistance in adipose tissue, liver and muscle. TZDs decrease excessive ectopic triglyceride accumulation in liver and muscle, reduce visceral fat, and redistribute fat to subcutaneous adipose stores. We have shown in a proof-of-concept 6-month study that pioglitazone is safe and effective for the treatment of T2DM. Patients with nonalcoholic steatohepatitis are also characterized by a low plasma adiponectin level. Thiazolidinediones increase plasma adiponectin levels, may activate AMP-activated protein kinase, stimulate hepatic/muscle fatty acid oxidation, and inhibit hepatic fatty acid synthesis in NASH nonalcoholic steatohepatitis. Thiazolidinediones also have antiinflammatory effects which are believed to be of value for therapy for NASH. In order to evaluate this hypothesis, the investigators will treat for up to 36 months a group of patients with impaired (IGT) glucose tolerance and T2DM patients recruited from the University Hospital and medical school clinics and by newspaper add targeting the San Antonio and South Texas geographical area, with pioglitazone in a randomized, double-blinded, placebo-controlled trial. The primary endpoint will be liver histologic response assessed by liver biopsy performed at 18 and at 36 months of treatment.
Interventions
DRUGPioglitazone study drug
30 mg per day orally for 8 weeks, and if well tolerated, titrated to 45 mg per day until the end of 18 months
DRUGPlacebo
An oral tablet identical to pioglitazone will be given once daily but without active drug for 18 months.
DRUGPioglitazone Open Label
Patients in both arms were placed open label pioglitazone for an additional 18 months after successfully completing the double-blind, placebo-controlled portion of the study design.
Sponsors
The University of Texas at San Antonio
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
1. Be able to communicate meaningfully with the investigators and be legally competent to provide written informed consent. 2. Age range between 18 to 70 years (inclusive). 3. Female patients must be non-lactating and must either be at least one year post-menopausal, or be using adequate mechanical contraceptive precautions (i.e. intrauterine device, diaphragm with spermicide, condom with spermicide), or be surgically sterilized (i.e. bilateral tubal ligation, bilateral oophorectomy). Female patients who have undergone a hysterectomy are eligible for participation in the study. Female patients (except for those patients who have undergone a hysterectomy or a bilateral oophorectomy) are eligible only if they have a negative pregnancy test throughout the study period. Patients on oral contraceptives or an hormonal implant will be excluded (patches are acceptable as they deliver much lower estrogen systemically). 4. Participants must have the following laboratory values: * Hemoglobin ≥ 12 gm/dl in males, or ≥ 11 gm/dl in females, * WBC count ≥ 3,000/mm3 * Neutrophil count ≥ 1,500/mm3 * Platelets ≥ 100,000/mm3 * Albumin ≥3.0 g/dl * Serum creatinine ≤ 1.8 mg/dl * Creatinine phosphokinase ≤ 2 times upper limit of normal * AST and ALT ≤ 3.0 times upper limit of normal * Alkaline phosphatase ≤ 2.5 times upper limit of normal 5. A diagnosis of NASH by liver biopsy performed within the past 6 months,
Exclusion criteria
1. Any cause of chronic liver disease other than NASH (such as -but not restricted to- alcohol or drug abuse, medication, chronic hepatitis B or C, autoimmune, hemochromatosis, Wilson's disease, alpha1-antitrypsin deficiency). 2. Any clinical evidence or history of ascitis, bleeding varices, or spontaneous encephalopathy. 3. Current history of alcohol abuse (alcohol consumption greater than 20 grams of ethanol per day). 4. Prior surgical procedures to include gastroplasty, jejuno-ileal or jejunocolic bypass. 5. Prior exposure to organic solvents such as carbon tetrachloride. 6. Total parenteral nutrition (TPN) within the past 6 months. 7. Subjects with type 1 diabetes mellitus. 8. Patients on chronic medications with known adverse effects on glucose tolerance levels unless the patient has been on a stable dose of such agents for 4 weeks before entry into the study. Patients on estrogens or other hormonal replacement therapy, tamoxifen, raloxifene, oral glucocorticoids or chloroquine will be excluded. 9. Patients with a history of clinically significant heart disease (New York Heart Classification greater than grade II), peripheral vascular disease (history of claudication), or diagnosed pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation). 10. Patients with severe osteoporosis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Liver Histology (Using Kleiner et al Criteria, Hepatology 2005) | At 18 months | Number of patients with reduction of at least 2 points in the nonalcoholic fatty liver disease activity score (NAS) (with reduction in at least 2 different histological categories) without worsening of fibrosis. NAS is the sum of the separate scores for steatosis (0-3), hepatocellular ballooning (0-2) and lobular inflammation (0-3), and ranges from 0-8 . The scoring system is based on the following grading: Steatosis: 0 = \<5%; 1 = 5-33%; 2 = \>33-66%; 3 = \>66%. Lobular Inflammation: 0 = No foci 1 = \<2 foci/200x; 2 = 2-4 foci/200x, 3 = \>4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Resolution of NASH | Month 18 | Resolution of NASH was defined as absence of NASH after 18 months of therapy in patients with definite NASH (presence of zone 3 accentuation of macrovesicular steatosis of any grade, hepatocellular ballooning of any degree, and lobular inflammatory infiltrates of any amount) at baseline. |
| Mean Individual Histological Scores | Baseline and Month 18 | Mean change in individual scores compared to baseline. Steatosis: 0 = \<5%; 1 = 5-33%; 2 = \>33-66%; 3 = \>66%. Lobular Inflammation: 0 = No foci 1 = \<2 foci/200x; 2 = 2-4 foci/200x, 3 = \>4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis |
| Individual Histological Scores | Month 18 | Number of patients with improvement of at least 1 grade in each of the histological parameters. Steatosis: 0 = \<5%; 1 = 5-33%; 2 = \>33-66%; 3 = \>66%. Lobular Inflammation: 0 = No foci 1 = \<2 foci/200x; 2 = 2-4 foci/200x, 3 = \>4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal, 1A = Mild, zone 3, perisinusoidal delicate fibrosis; 1B = Moderate, zone 3, perisinusoidal dense fibrosis; 1C = Portal/periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis |
| Liver Transaminases (AST and ALT). | 18 and 36 months | — |
| Liver Fat by Magnetic Resonance and Spectroscopy (MRS). | 18 months | Liver fat content was calculated as the fat fraction: 100\*(area under the curve \[AUC\] of fat peak / \[AUC of fat peak + AUC of water peak\]). |
| Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | 18 and 36 months | Homeostatic model assessment of insulin resistance (HOMA-IR) is a method for assessing insulin resistance (IR) from basal fasting plasma glucose (FPG) and fasting plasma insulin (FPI). It is calculated as (FPG x FPI)/405. |
| Hepatic Insulin Sensitivity | 18 months | Suppression of endogenous glucose production (Supp EGP) by low dose insulin (i.e., percentage of reduction of EGP with low dose insulin infusion compared to the baseline state). This was calculated as: 100\*((EGP without insulin - EGP with insulin infusion)/EGP without insulin). All measurements are obtained at the same time point during an euglycemic insulin clamp. |
| Adipose Tissue Insulin Sensitivity | 18 months | Suppression of free fatty acids by low dose insulin (i.e., percentage of reduction of plasma FFA with low dose insulin infusion compared to the baseline state). This was calculated as: 100\*((plasma FFA without insulin - plasma FFA with insulin infusion)/plasma FFA without insulin). All measurements are obtained at the same time point during an euglycemic insulin clamp. |
| Osteoporotic Fractures | 18 and 36 months | Number of patients with osteoporotic fractures |
| Body Mass Index (BMI) | Months 18 and 36 | — |
| Total Body Fat | Months 18 | Total body fat measured by dual-energy x-ray absorptiometry (DXA) |
| Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (Adiponectin). | 18 and 36 months | — |
| Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (CK-18). | 18 and 36 months | — |
| Prevention of the Onset of T2DM and/or Reversal From IFG/IGT to NGT in Non-diabetics. | 18 months | Number of patients developing T2DM and number of patients regressing to NGT among patients with prediabetes (IFG/IGT). |
| Molecular Pathways of Liver Glucose and Lipid Signaling; Inflammatory Pathways; Oxidative Stress; Other. | At 18 (2nd liver biopsy) and 36 (3rd liver biopsy) months. | — |
| Bone Mineral Density | 18 and 36 months | Bone mineral density measured at the levels of spine, femoral neck, hip, and wrist by DXA. |
| Skeletal Muscle Insulin Sensitivity | 18 months | Rate of glucose disappearance (Rd) during high-dose insulin infusion. The rate of plasma glucose disappearance was calculated using Steele's non-steady-state equation. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the general population of San Antonio, Texas, via newspaper advertisements and from the endocrinology and hepatology clinics at UTHSCSA and the Veterans Affairs Medical Center.
Pre-assignment details
Once eligibility was met by histologically confirmed NASH, patients were randomized. The number of patients consented was 176, screen failed was 38, did not complete run-in phase was 37 (12 consent withdrawn, 9 lost to follow-up, 4 discontinued by PI decision, and 12 for other reasons). The remaining 101 patients were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were prescribed a hypocaloric diet (500- kcal/d deficit from the calculated weight maintaining diet) and received placebo pills with identical physical characteristics and in identical bottles to pioglitazone pills. After 18 months of treatment, metabolic measurements (OGTT and euglycemic insulin clamp), DXA, 1H-MRS, and liver biopsy were repeated, at which point the medication code was disclosed to investigators and patients. Patients whose NASH resolved after 18 months were instructed to discontinue the study because pioglitazone treatment or a repeated liver biopsy were considered unethical and were not indicated, whereas those with persistent disease were invited to start open-label pioglitazone therapy, titrated as described for the other arm. | 51 |
| Pioglitazone Participants were prescribed a hypocaloric diet (500- kcal/d deficit from the calculated weight maintaining diet) and received pioglitazone 30mg/d (titrated after 2 months to 45 mg/d). After 18 months of treatment, metabolic measurements (OGTT and euglycemic insulin clamp), DXA, 1H-MRS, and liver biopsy were repeated, at which point the medication code was disclosed to investigators and patients. Patients initially assigned to pioglitazone were asked to continue at the same dose. | 50 |
| Total | 101 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Bilnd | Adverse Event | 1 | 0 |
| Double Bilnd | Lost to Follow-up | 3 | 3 |
| Double Bilnd | Withdrawal by Subject | 5 | 6 |
| Pioglitazone Open Label | Lost to Follow-up | 3 | 2 |
| Pioglitazone Open Label | Physician Decision | 6 | 1 |
| Pioglitazone Open Label | Withdrawal by Subject | 4 | 4 |
Baseline characteristics
| Characteristic | Total | Pioglitazone | Placebo |
|---|---|---|---|
| 2-hour plasma glucose | 207 mg/dl STANDARD_DEVIATION 71 | 211 mg/dl STANDARD_DEVIATION 78 | 203 mg/dl STANDARD_DEVIATION 64 |
| Age, Continuous | 50 years STANDARD_DEVIATION 11 | 52 years STANDARD_DEVIATION 10 | 49 years STANDARD_DEVIATION 11 |
| Ballooning grade | 0.9 units on a scale STANDARD_DEVIATION 0.4 | 0.8 units on a scale STANDARD_DEVIATION 0.4 | 0.9 units on a scale STANDARD_DEVIATION 0.4 |
| Body mass index | 34.4 kg/m^2 STANDARD_DEVIATION 4.8 | 34.3 kg/m^2 STANDARD_DEVIATION 4.8 | 34.5 kg/m^2 STANDARD_DEVIATION 4.8 |
| Diagnosis of definite NASH | 87 participants | 42 participants | 45 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 68 Participants | 31 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 19 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Fasting free fatty acids | 0.52 mmol/L STANDARD_DEVIATION 0.19 | 0.49 mmol/L STANDARD_DEVIATION 0.18 | 0.54 mmol/L STANDARD_DEVIATION 0.19 |
| Fasting plasma glucose | 122 mg/dl STANDARD_DEVIATION 28 | 124 mg/dl STANDARD_DEVIATION 29 | 121 mg/dl STANDARD_DEVIATION 27 |
| Fasting plasma insulin | 16 μU/mL STANDARD_DEVIATION 11 | 15 μU/mL STANDARD_DEVIATION 11 | 16 μU/mL STANDARD_DEVIATION 12 |
| Fibrosis stage | 1.0 units on a scale STANDARD_DEVIATION 1 | 1.1 units on a scale STANDARD_DEVIATION 1.1 | 0.9 units on a scale STANDARD_DEVIATION 0.9 |
| Hemoglobin A1c | 6.3 percentage STANDARD_DEVIATION 1 | 6.4 percentage STANDARD_DEVIATION 1 | 6.3 percentage STANDARD_DEVIATION 1 |
| Inflammation grade | 1.7 units on a scale STANDARD_DEVIATION 0.5 | 1.7 units on a scale STANDARD_DEVIATION 0.6 | 1.7 units on a scale STANDARD_DEVIATION 0.5 |
| NAFLD activity score (NAS) Liver histology | 4.5 score on a scale STANDARD_DEVIATION 1.3 | 4.5 score on a scale STANDARD_DEVIATION 1.5 | 4.5 score on a scale STANDARD_DEVIATION 1.2 |
| Plasma ALT | 60 U/L STANDARD_DEVIATION 33 | 62 U/L STANDARD_DEVIATION 33 | 57 U/L STANDARD_DEVIATION 33 |
| Plasma AST | 45 U/L STANDARD_DEVIATION 22 | 47 U/L STANDARD_DEVIATION 21 | 43 U/L STANDARD_DEVIATION 22 |
| Plasma HDL-C | 37 mg/dl STANDARD_DEVIATION 9 | 36 mg/dl STANDARD_DEVIATION 9 | 37 mg/dl STANDARD_DEVIATION 9 |
| Plasma LDL-C | 109 mg/dl STANDARD_DEVIATION 38 | 109 mg/dl STANDARD_DEVIATION 44 | 109 mg/dl STANDARD_DEVIATION 33 |
| Plasma total cholesterol | 185 mg/dl STANDARD_DEVIATION 44 | 187 mg/dl STANDARD_DEVIATION 46 | 182 mg/dl STANDARD_DEVIATION 42 |
| Plasma triglycerides | 201 mg/dl STANDARD_DEVIATION 144 | 224 mg/dl STANDARD_DEVIATION 171 | 179 mg/dl STANDARD_DEVIATION 109 |
| Sex: Female, Male Female | 30 Participants | 14 Participants | 16 Participants |
| Sex: Female, Male Male | 71 Participants | 36 Participants | 35 Participants |
| Steatosis grade | 2.0 units on a scale STANDARD_DEVIATION 0.8 | 2.0 units on a scale STANDARD_DEVIATION 0.8 | 1.9 units on a scale STANDARD_DEVIATION 0.8 |
| Total body fat | 33 percentage of fat mass STANDARD_DEVIATION 7 | 33 percentage of fat mass STANDARD_DEVIATION 7 | 34 percentage of fat mass STANDARD_DEVIATION 8 |
| Use of diabetes medications Insulin | 11 participants | 5 participants | 6 participants |
| Use of diabetes medications Metformin | 36 participants | 19 participants | 17 participants |
| Use of diabetes medications Sulfonylurea | 28 participants | 12 participants | 16 participants |
| Use of statins | 38 participants | 19 participants | 19 participants |
| Weight | 98.7 kg STANDARD_DEVIATION 16.7 | 98.2 kg STANDARD_DEVIATION 16.5 | 99.2 kg STANDARD_DEVIATION 17 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 51 | 15 / 50 | 12 / 36 | 10 / 40 |
| serious Total, serious adverse events | 5 / 51 | 5 / 50 | 10 / 36 | 9 / 40 |
Outcome results
Primary
Liver Histology (Using Kleiner et al Criteria, Hepatology 2005)
Number of patients with reduction of at least 2 points in the nonalcoholic fatty liver disease activity score (NAS) (with reduction in at least 2 different histological categories) without worsening of fibrosis. NAS is the sum of the separate scores for steatosis (0-3), hepatocellular ballooning (0-2) and lobular inflammation (0-3), and ranges from 0-8 . The scoring system is based on the following grading: Steatosis: 0 = \<5%; 1 = 5-33%; 2 = \>33-66%; 3 = \>66%. Lobular Inflammation: 0 = No foci 1 = \<2 foci/200x; 2 = 2-4 foci/200x, 3 = \>4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis.
Time frame: At 18 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Liver Histology (Using Kleiner et al Criteria, Hepatology 2005) | 9 Participants |
| Pioglitazone | Liver Histology (Using Kleiner et al Criteria, Hepatology 2005) | 29 Participants |
Secondary
Adipose Tissue Insulin Sensitivity
Suppression of free fatty acids by low dose insulin (i.e., percentage of reduction of plasma FFA with low dose insulin infusion compared to the baseline state). This was calculated as: 100\*((plasma FFA without insulin - plasma FFA with insulin infusion)/plasma FFA without insulin). All measurements are obtained at the same time point during an euglycemic insulin clamp.
Time frame: 18 months
Population: Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group) and 83 at month 18 (42 and 41, respectively).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Adipose Tissue Insulin Sensitivity | 46.1 % of suppression of FFA |
| Pioglitazone | Adipose Tissue Insulin Sensitivity | 65.9 % of suppression of FFA |
Secondary
Body Mass Index (BMI)
Time frame: Months 18 and 36
Population: Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group), 83 at month 18 (42 and 41, respectively), and 63 at month 36 (29 and 34, respectively).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Body Mass Index (BMI) | BMI Month 18 | 34.6 kg/m^2 | Standard Deviation 5 |
| Placebo | Body Mass Index (BMI) | BMI Month 36 | 36.7 kg/m^2 | Standard Deviation 5.7 |
| Pioglitazone | Body Mass Index (BMI) | BMI Month 18 | 34.6 kg/m^2 | Standard Deviation 4.8 |
| Pioglitazone | Body Mass Index (BMI) | BMI Month 36 | 35.2 kg/m^2 | Standard Deviation 4.8 |
Secondary
Bone Mineral Density
Bone mineral density measured at the levels of spine, femoral neck, hip, and wrist by DXA.
Time frame: 18 and 36 months
Population: Data analysis included 78 patients at month 18 and 62 at month 36 (based on DXA availability).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Bone Mineral Density | Wrist BMD at month 36 | 0.75 g/cm^2 | Standard Deviation 0.08 |
| Placebo | Bone Mineral Density | Hip BMD at month 36 | 1.02 g/cm^2 | Standard Deviation 0.12 |
| Placebo | Bone Mineral Density | Spine BMD at month 18 | 1.04 g/cm^2 | Standard Deviation 0.17 |
| Placebo | Bone Mineral Density | Femoral Neck BMD at month 18 | 0.84 g/cm^2 | Standard Deviation 0.13 |
| Placebo | Bone Mineral Density | Hip BMD at month 18 | 1.05 g/cm^2 | Standard Deviation 0.13 |
| Placebo | Bone Mineral Density | Wrist BMD at month 18 | 0.76 g/cm^2 | Standard Deviation 0.08 |
| Placebo | Bone Mineral Density | Spine BMD at month 36 | 1.06 g/cm^2 | Standard Deviation 0.14 |
| Placebo | Bone Mineral Density | Femoral Neck BMD at month 36 | 0.84 g/cm^2 | Standard Deviation 0.14 |
| Pioglitazone | Bone Mineral Density | Femoral Neck BMD at month 36 | 0.84 g/cm^2 | Standard Deviation 0.12 |
| Pioglitazone | Bone Mineral Density | Wrist BMD at month 36 | 0.77 g/cm^2 | Standard Deviation 0.09 |
| Pioglitazone | Bone Mineral Density | Hip BMD at month 18 | 1.05 g/cm^2 | Standard Deviation 0.13 |
| Pioglitazone | Bone Mineral Density | Hip BMD at month 36 | 1.06 g/cm^2 | Standard Deviation 0.16 |
| Pioglitazone | Bone Mineral Density | Spine BMD at month 36 | 1.10 g/cm^2 | Standard Deviation 0.21 |
| Pioglitazone | Bone Mineral Density | Spine BMD at month 18 | 1.10 g/cm^2 | Standard Deviation 0.17 |
| Pioglitazone | Bone Mineral Density | Wrist BMD at month 18 | 0.78 g/cm^2 | Standard Deviation 0.09 |
| Pioglitazone | Bone Mineral Density | Femoral Neck BMD at month 18 | 0.86 g/cm^2 | Standard Deviation 0.12 |
Secondary
Hepatic Insulin Sensitivity
Suppression of endogenous glucose production (Supp EGP) by low dose insulin (i.e., percentage of reduction of EGP with low dose insulin infusion compared to the baseline state). This was calculated as: 100\*((EGP without insulin - EGP with insulin infusion)/EGP without insulin). All measurements are obtained at the same time point during an euglycemic insulin clamp.
Time frame: 18 months
Population: Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group) and 83 at month 18 (42 and 41, respectively).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Hepatic Insulin Sensitivity | 37.7 % of suppression of EGP |
| Pioglitazone | Hepatic Insulin Sensitivity | 55.3 % of suppression of EGP |
Secondary
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
Homeostatic model assessment of insulin resistance (HOMA-IR) is a method for assessing insulin resistance (IR) from basal fasting plasma glucose (FPG) and fasting plasma insulin (FPI). It is calculated as (FPG x FPI)/405.
Time frame: 18 and 36 months
Population: Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group), 83 at month 18 (42 and 41, respectively), and 63 at month 36 (29 and 34, respectively).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | HOMA-IR month 18 | 4.3 Arbitrary units |
| Placebo | Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | HOMA-IR month 36 | 2.3 Arbitrary units |
| Pioglitazone | Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | HOMA-IR month 18 | 1.4 Arbitrary units |
| Pioglitazone | Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | HOMA-IR month 36 | 1.6 Arbitrary units |
Secondary
Individual Histological Scores
Number of patients with improvement of at least 1 grade in each of the histological parameters. Steatosis: 0 = \<5%; 1 = 5-33%; 2 = \>33-66%; 3 = \>66%. Lobular Inflammation: 0 = No foci 1 = \<2 foci/200x; 2 = 2-4 foci/200x, 3 = \>4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal, 1A = Mild, zone 3, perisinusoidal delicate fibrosis; 1B = Moderate, zone 3, perisinusoidal dense fibrosis; 1C = Portal/periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis
Time frame: Month 18
Population: Multiple imputation was used to impute missing histologic data for patients who did not complete 18 months of therapy.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Individual Histological Scores | Steatosis | 13 Participants |
| Placebo | Individual Histological Scores | Inflammation | 11 Participants |
| Placebo | Individual Histological Scores | Ballooning | 12 Participants |
| Placebo | Individual Histological Scores | Fibrosis | 13 Participants |
| Pioglitazone | Individual Histological Scores | Fibrosis | 20 Participants |
| Pioglitazone | Individual Histological Scores | Steatosis | 35 Participants |
| Pioglitazone | Individual Histological Scores | Ballooning | 25 Participants |
| Pioglitazone | Individual Histological Scores | Inflammation | 25 Participants |
Secondary
Liver Fat by Magnetic Resonance and Spectroscopy (MRS).
Liver fat content was calculated as the fat fraction: 100\*(area under the curve \[AUC\] of fat peak / \[AUC of fat peak + AUC of water peak\]).
Time frame: 18 months
Population: Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group) and 83 at month 18 (42 and 41, respectively).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Liver Fat by Magnetic Resonance and Spectroscopy (MRS). | 11 percentage of fat in liver | Standard Deviation 7 |
| Pioglitazone | Liver Fat by Magnetic Resonance and Spectroscopy (MRS). | 7 percentage of fat in liver | Standard Deviation 5 |
Secondary
Liver Transaminases (AST and ALT).
Time frame: 18 and 36 months
Population: Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group), 83 at month 18 (42 and 41, respectively), and 63 at month 36 (29 and 34, respectively).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Liver Transaminases (AST and ALT). | ALT at month 18 | 44 U/L | Standard Deviation 33 |
| Placebo | Liver Transaminases (AST and ALT). | AST at month 18 | 38 U/L | Standard Deviation 31 |
| Placebo | Liver Transaminases (AST and ALT). | ALT at month 36 | 32 U/L | Standard Deviation 17 |
| Placebo | Liver Transaminases (AST and ALT). | AST at month 36 | 30 U/L | Standard Deviation 10 |
| Pioglitazone | Liver Transaminases (AST and ALT). | AST at month 36 | 27 U/L | Standard Deviation 8 |
| Pioglitazone | Liver Transaminases (AST and ALT). | ALT at month 18 | 27 U/L | Standard Deviation 12 |
| Pioglitazone | Liver Transaminases (AST and ALT). | ALT at month 36 | 27 U/L | Standard Deviation 13 |
| Pioglitazone | Liver Transaminases (AST and ALT). | AST at month 18 | 29 U/L | Standard Deviation 10 |
Secondary
Mean Individual Histological Scores
Steatosis: 0 = \<5%; 1 = 5-33%; 2 = \>33-66%; 3 = \>66%. Lobular Inflammation: 0 = No foci 1 = \<2 foci/200x; 2 = 2-4 foci/200x, 3 = \>4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis
Time frame: Month 36
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Mean Individual Histological Scores | Steatosis | 1.56 units on a scale |
| Placebo | Mean Individual Histological Scores | Inflammation | 1.30 units on a scale |
| Placebo | Mean Individual Histological Scores | Ballooning | 0.33 units on a scale |
| Placebo | Mean Individual Histological Scores | Fibrosis | 0.89 units on a scale |
| Pioglitazone | Mean Individual Histological Scores | Fibrosis | 0.66 units on a scale |
| Pioglitazone | Mean Individual Histological Scores | Steatosis | 0.97 units on a scale |
| Pioglitazone | Mean Individual Histological Scores | Ballooning | 0.22 units on a scale |
| Pioglitazone | Mean Individual Histological Scores | Inflammation | 0.81 units on a scale |
Secondary
Mean Individual Histological Scores
Mean change in individual scores compared to baseline. Steatosis: 0 = \<5%; 1 = 5-33%; 2 = \>33-66%; 3 = \>66%. Lobular Inflammation: 0 = No foci 1 = \<2 foci/200x; 2 = 2-4 foci/200x, 3 = \>4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis
Time frame: Baseline and Month 18
Population: Multiple imputation was used to impute missing histologic data for patients who did not complete 18 months of therapy.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Mean Individual Histological Scores | Steatosis | -0.2 units on a scale |
| Placebo | Mean Individual Histological Scores | Inflammation | -0.1 units on a scale |
| Placebo | Mean Individual Histological Scores | Ballooning | -0.2 units on a scale |
| Placebo | Mean Individual Histological Scores | Fibrosis | 0 units on a scale |
| Pioglitazone | Mean Individual Histological Scores | Fibrosis | -0.5 units on a scale |
| Pioglitazone | Mean Individual Histological Scores | Steatosis | -1.1 units on a scale |
| Pioglitazone | Mean Individual Histological Scores | Ballooning | -0.6 units on a scale |
| Pioglitazone | Mean Individual Histological Scores | Inflammation | -0.6 units on a scale |
Secondary
Molecular Pathways of Liver Glucose and Lipid Signaling; Inflammatory Pathways; Oxidative Stress; Other.
Time frame: At 18 (2nd liver biopsy) and 36 (3rd liver biopsy) months.
Secondary
Number of Participants With Resolution of NASH
Resolution of NASH was defined as absence of NASH after 18 months of therapy in patients with definite NASH (presence of zone 3 accentuation of macrovesicular steatosis of any grade, hepatocellular ballooning of any degree, and lobular inflammatory infiltrates of any amount) at baseline.
Time frame: Month 18
Population: Multiple imputation was used to impute missing histologic data for patients who did not complete 18 months of therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Resolution of NASH | 10 Participants |
| Pioglitazone | Number of Participants With Resolution of NASH | 26 Participants |
Secondary
Osteoporotic Fractures
Number of patients with osteoporotic fractures
Time frame: 18 and 36 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Osteoporotic Fractures | 0 Participants |
| Pioglitazone | Osteoporotic Fractures | 0 Participants |
Secondary
Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (Adiponectin).
Time frame: 18 and 36 months
Population: Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group), 83 at month 18 (42 and 41, respectively), and 63 at month 36 (29 and 34, respectively).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (Adiponectin). | Adiponectin month 18 | 9.1 μg/ml |
| Placebo | Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (Adiponectin). | Adiponectin month 36 | 24.0 μg/ml |
| Pioglitazone | Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (Adiponectin). | Adiponectin month 18 | 22.8 μg/ml |
| Pioglitazone | Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (Adiponectin). | Adiponectin month 36 | 24.2 μg/ml |
Secondary
Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (CK-18).
Time frame: 18 and 36 months
Population: Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group), 83 at month 18 (42 and 41, respectively), and 63 at month 36 (29 and 34, respectively).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (CK-18). | CK-18 month 18 | 314 U/L |
| Placebo | Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (CK-18). | CK-18 month 36 | 245 U/L |
| Pioglitazone | Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (CK-18). | CK-18 month 18 | 186 U/L |
| Pioglitazone | Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (CK-18). | CK-18 month 36 | 151 U/L |
Secondary
Prevention of the Onset of T2DM and/or Reversal From IFG/IGT to NGT in Non-diabetics.
Number of patients developing T2DM and number of patients regressing to NGT among patients with prediabetes (IFG/IGT).
Time frame: 18 months
Population: Only patients with prediabetes are included in this analysis
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Prevention of the Onset of T2DM and/or Reversal From IFG/IGT to NGT in Non-diabetics. | Patients developing T2DM | 1 Participants |
| Placebo | Prevention of the Onset of T2DM and/or Reversal From IFG/IGT to NGT in Non-diabetics. | Patients regressing to NGT | 10 Participants |
| Pioglitazone | Prevention of the Onset of T2DM and/or Reversal From IFG/IGT to NGT in Non-diabetics. | Patients developing T2DM | 2 Participants |
| Pioglitazone | Prevention of the Onset of T2DM and/or Reversal From IFG/IGT to NGT in Non-diabetics. | Patients regressing to NGT | 1 Participants |
Secondary
Skeletal Muscle Insulin Sensitivity
Rate of glucose disappearance (Rd) during high-dose insulin infusion. The rate of plasma glucose disappearance was calculated using Steele's non-steady-state equation.
Time frame: 18 months
Population: Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group) and 83 at month 18 (42 and 41, respectively).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Skeletal Muscle Insulin Sensitivity | 5.4 mg/kgLBM/min |
| Pioglitazone | Skeletal Muscle Insulin Sensitivity | 9.6 mg/kgLBM/min |
Secondary
Total Body Fat
Total body fat measured by dual-energy x-ray absorptiometry (DXA)
Time frame: Months 18
Population: Data include 101 observations at baseline (51 in the placebo group and 50 in the pioglitazone group), 83 at month 18 (42 and 41, respectively).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Body Fat | 36 Percentage of body weight that is fat | Standard Deviation 8 |
| Pioglitazone | Total Body Fat | 36 Percentage of body weight that is fat | Standard Deviation 7 |