Fatty Liver, Nonalcoholic, Obesity
Conditions
Keywords
obesity, insulin sensitivity, statin (HMG-CoA Reductase Inhibitor), fatty liver
Brief summary
HMG co-A reductase inhibitors, commonly called statins, are an effective treatment for dyslipidemia and atherosclerotic heart disease with proven mortality benefit. While the lipid-lowering effects of statins are well-known, other metabolic effects, including effects on glucose tolerance and ectopic fat distribution, are less completely understood. Recent studies have shown that some statins may increase the risk of diabetes. Further, research has suggested that statins may have some benefit in nonalcoholic fatty liver disease (NAFLD), a condition associated with obesity that includes increased fat in the liver (steatosis) and, in some cases, inflammation and hepatocellular damage (steatohepatitis). Pitavastatin, approved by the United States Food and Drug Administration (FDA) in 2009, is the most recent statin to enter the market. Unlike most statins, pitavastatin is not primarily metabolized through cytochrome P450 (CYP450), and thus has reduced potential for interactions with other medications that are metabolized by CYP450. Previous studies have suggested that pitavastatin may be neutral to glucose homeostasis and may improve hepatic lipid. Neither of these effects has been proven definitively, however, and the current proposal aims to characterize in detail the effects of pitavastatin on glucose homeostasis, hepatic steatosis, and steatohepatitis.
Interventions
DRUGpitavastatin
OTHERPLACEBO
Sponsors
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
40 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Men age 40-65yo 2. BMI ≥ 27kg/m2 and waist circumference ≥102cm, high probability risk factors for NAFLD 3. At least one of the following indicating insulin resistance: Fasting glucose ≥100mg/dL and \<126mg/dL, HOMA-IR \>2.0, and/or 2 hour glucose ≥140mg/dL and \<200mg/dL following standard glucose tolerance test. 4. 10-year cardiovascular disease risk ≥5% by American Heart Association(AHA)/American College of Cardiology (ACC) Pooled Cohort Equations CV Risk Calculator or LDL ≥ 100mg/dL 5. No use of any statin within 1 year of study entry and not being actively considered for statin therapy by a treating provider.
Exclusion criteria
1. Diagnosis of diabetes or use of anti-diabetic medications. 2. Use of erythromycin, rifampin, cyclosporin, colchicine, or gemfibrozil. 3. Use of statin therapy within 1 year prior to study entry as above. Use of any other lipid-modifying therapy (including fish oil, fibrates, niacin, gemfibrozil) within 6 months of study entry. 4. Contraindication to statin therapy. 5. Creatinine \> upper limit of normal or known renal disease 6. AST or ALT \> 3 times the upper limit of normal 7. hemoglobin \< 10g/dL 8. Contraindication to undergoing a magnetic resonance scan. 9. Atherosclerotic cardiovascular disease or low-density lipoprotein cholesterol (LDL-C) ≥ 190mg/dL. 10. Triglyceride ≥500mg/dL
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin-stimulated Glucose Uptake | 6 months | insulin-stimulated glucose uptake measured by euglycemic hyperinsulinemic clamp |
| Liver Fat | 6 months | liver fat content as measured by 1H-magnetic resonance spectroscopy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hepatic Insulin Sensitivity | 6 months | hepatic insulin sensitivity assessed by glucose infusion rate corrected for fluctuations in serum glucose (M) during low-dose insulin clamp |
| Alanine Aminotransferase (ALT) | 6 months | alanine aminotransferase at the 6 month timepoint |
| Quantitative Insulin Sensitivity Check Index (QUICKI) | 6 months | quantitative insulin sensitivity check index (QUICKI) at 6 months. Measure = 1/((log(glucose in mg/dL) + log(insulin in uU/mL)) |
| Hemoglobin A1c (HbA1c) | 6 months | — |
| Aspartate Aminotransferase (AST) | 6 months | aspartate aminotransferase at 6 month timepoint |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pitavastatin pitavastatin 4mg daily by mouth for 6 months
pitavastatin | 25 |
| Placebo Identical placebo 4mg by mouth daily for 6 months
PLACEBO | 25 |
| Total | 50 |
Baseline characteristics
| Characteristic | Pitavastatin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 52.8 years STANDARD_DEVIATION 6.5 | 52.9 years STANDARD_DEVIATION 7 | 52.8 years STANDARD_DEVIATION 6.7 |
| Fasting glucose (mg/dL) | 98 mg/dL STANDARD_DEVIATION 9 | 97 mg/dL STANDARD_DEVIATION 9 | 97 mg/dL STANDARD_DEVIATION 9 |
| Homeostasis model of insulin resistance (HOMA-IR) | 2.1 HOMA-IR Score STANDARD_DEVIATION 1.9 | 1.6 HOMA-IR Score STANDARD_DEVIATION 1 | 1.8 HOMA-IR Score STANDARD_DEVIATION 1.5 |
| Liver fat content (hepatic fat fraction, %) | 17 % STANDARD_DEVIATION 11 | 14 % STANDARD_DEVIATION 11 | 16 % STANDARD_DEVIATION 11 |
| Low density lipoprotein cholesterol (LDL-C, mg/dL) | 116 mg/dL STANDARD_DEVIATION 18 | 125 mg/dL STANDARD_DEVIATION 22 | 120 mg/dL STANDARD_DEVIATION 20 |
| Race/Ethnicity, Customized Non-white | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 24 Participants | 21 Participants | 45 Participants |
| Region of Enrollment United States | 25 participants | 25 participants | 50 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 25 Participants | 25 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 |
| other Total, other adverse events | 16 / 25 | 25 / 25 |
| serious Total, serious adverse events | 2 / 25 | 1 / 25 |
Outcome results
Primary
Insulin-stimulated Glucose Uptake
insulin-stimulated glucose uptake measured by euglycemic hyperinsulinemic clamp
Time frame: 6 months
Population: All patients with results for baseline and final. In addition to 3 participants who did not finish the study, 2 participants were unable to undergo clamp.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pitavastatin | Insulin-stimulated Glucose Uptake | 5.9 mg/kg/minute | Standard Deviation 2.1 |
| Placebo | Insulin-stimulated Glucose Uptake | 5.9 mg/kg/minute | Standard Deviation 1.6 |
Primary
Liver Fat
liver fat content as measured by 1H-magnetic resonance spectroscopy
Time frame: 6 months
Population: All participants with baseline and final data were analyzed. In addition to patients who discontinued from the study, some patients were unable to have MRI scan due to inability to fit in the scanner or unanticipated claustrophobia.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pitavastatin | Liver Fat | 17 % liver fat (hepatic fat fraction) | Standard Deviation 11 |
| Placebo | Liver Fat | 14 % liver fat (hepatic fat fraction) | Standard Deviation 10 |
Secondary
Alanine Aminotransferase (ALT)
alanine aminotransferase at the 6 month timepoint
Time frame: 6 months
Population: all patients with available data at baseline and final
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pitavastatin | Alanine Aminotransferase (ALT) | 37 U/L | Standard Deviation 38 |
| Placebo | Alanine Aminotransferase (ALT) | 27 U/L | Standard Deviation 17 |
Secondary
Aspartate Aminotransferase (AST)
aspartate aminotransferase at 6 month timepoint
Time frame: 6 months
Population: all patients with available data at baseline and final
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pitavastatin | Aspartate Aminotransferase (AST) | 31 U/L | Standard Deviation 23 |
| Placebo | Aspartate Aminotransferase (AST) | 26 U/L | Standard Deviation 12 |
Secondary
Hemoglobin A1c (HbA1c)
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pitavastatin | Hemoglobin A1c (HbA1c) | 5.7 % (hemoglobin A1c) | Standard Deviation 0.5 |
| Placebo | Hemoglobin A1c (HbA1c) | 5.7 % (hemoglobin A1c) | Standard Deviation 0.3 |
Secondary
Hepatic Insulin Sensitivity
hepatic insulin sensitivity assessed by glucose infusion rate corrected for fluctuations in serum glucose (M) during low-dose insulin clamp
Time frame: 6 months
Population: all patients with available data at baseline and final (note, in addition to 3 patients who discontinued, some patients were unable to undergo clamp procedure)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pitavastatin | Hepatic Insulin Sensitivity | 1.5 mg/kg/minute | Standard Deviation 1 |
| Placebo | Hepatic Insulin Sensitivity | 1.6 mg/kg/minute | Standard Deviation 0.7 |
Secondary
Quantitative Insulin Sensitivity Check Index (QUICKI)
quantitative insulin sensitivity check index (QUICKI) at 6 months. Measure = 1/((log(glucose in mg/dL) + log(insulin in uU/mL))
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pitavastatin | Quantitative Insulin Sensitivity Check Index (QUICKI) | 0.16 QUICKI index | Standard Deviation 0.02 |
| Placebo | Quantitative Insulin Sensitivity Check Index (QUICKI) | 0.15 QUICKI index | Standard Deviation 0.02 |