Obesity and Nonalcoholic Fatty Liver Disease

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT00262964
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 51
• Location: 1
• Arms: 4
• Duration (Months): 50
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

The primary goal of this study is to provide a better understanding of: 1) the pathogenesis and pathophysiology of non-alcoholic fatty liver disease (NAFLD) in obese subjects, and 2) the effect of marked weight loss on the histologic and metabolic abnormalities associated with NAFLD. The following hypotheses will be tested:

1. obesity causes hepatic fat accumulation because of excessive fatty acid release from fat tissue and increased free fatty acid availability,

2. increased hepatic (liver) fat content causes insulin-resistant glucose (sugar) production by the liver and altered liver protein synthesis,

3. increased hepatic fat content causes increased lipid (fat) peroxidation, hepatic inflammation, necrosis and fibrosis, and

4. marked weight loss improves NAFLD once patients are weight stable.

Condition or Disease	Intervention/Treatment	Phase
Non-alcoholic Fatty Liver Disease	Drug: Niacin; Drug: fenofibrate; Drug: placebo	N/A

Detailed Description

Obesity is a major risk factor for non-alcoholic fatty liver disease (NAFLD), which represents a spectrum of liver diseases. NAFLD is a major health problem in the US because of its high prevalence and causal relationship with serious liver abnormalities. However, the mechanism(s)responsible for developing NAFLD in obese persons and the effects on liver function are not known. This gap in knowledge has made it difficult to identify effective therapy. The results from these studies will lay the groundwork for the development of novel therapeutic interventions for NAFLD in obese patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: Obesity and Nonalcoholic Fatty Liver Disease
• Study Start Date: Oct 1, 2004
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NAFLD-Niacin Subjects, having previously diagnosed with NAFLD, were given Niacin for 16 weeks. The dosage was 500mg/day for week 1, 1000mg/day for week 2, 1500mg/day for week three and 2000mg/day for weeks 4 through 16.	Drug: Niacin; Subjects randomized to Niacin therapy will be treated with Niacin at night for 16 wks to reduce plasma free fatty acid concentrations. The dose of medication will be gradually increased: 500 mg/day during week 1, 1000 mg/day during week 2, 1500 mg/day during week 3, and 2000mg/day during weeks 4-16.; Other Names: niaspan
No Intervention: Control Subjects were found to have intrahepatic triglyceride levels below the threshold for Non-Alcoholic Fatty Liver Disease (NAFLD). For this study that threshold was set at 10% intrahepatic triglyceride content as determined by magnetic resonance spectroscopy. These control subjects did not participate in any intervention. Only baseline features were characterized for this arm.
Experimental: NAFLD-fenofibrate Subjects diagnosed with NAFLD were randomized to fenofibrate, an oral medication, nightly for eight weeks. Subjects will be given a dose of 200mg/day.	Drug: fenofibrate; Subjects randomized to fenofibrate will be treated with 200 mgs per day for eight weeks.; Other Names: Tricor
Placebo Comparator: NAFLD-placebo These subjects were diagnosed with Non-Alcoholic Fatty Liver Disease (NAFLD) and received an 8 week course of a placebo pill. Their baseline characteristics were averaged into the overall NAFLD baseline characteristics along with the baseline data for the two intervention groups.	Drug: placebo; Subjects randomized to placebo will be treated with one placebo pill per day for eight weeks.

Outcome Measures

Primary Outcome Measures

1. Hepatic Insulin Sensitivity Index (HISI) [baseline cross-sectional data]

   Hepatic insulin sensitivity, assessed as a function of glucose production rate and plasma insulin concentration. The Hepatic Insulin Sensitivity Index(HISI) is the reciprocal of glucose rate of appearance [10000/(μmol/min)] multiplied by insulin concentration[mU/L]. The 10000 in the formula is a conventional adjustment so that insulin sensitivity measures are more readable. As yet there is no normal range for HISI, since is a surrogate marker for hepatic insulin sensitivity that has not yet been validated.

2. Percent Increase in Skeletal Muscle Insulin Sensitivity During Insulin Infusion. [baseline cross-sectional data pre and post nine hour euglycemic clamp]

   A precise measure of the ability of insulin to stimulate glucose uptake by skeletal muscle. Skeletal muscle insulin sensitivity, measured as the increase from baseline in skeletal muscle glucose uptake during insulin infusion(percentage)as part of a nine hour euglycemic hyperinsulinemic clamp study.

3. Adipose Tissue Insulin Sensitivity [baseline cross-sectional data pre and post nine hour euglycemic clamp]

   The ability of insulin to suppress the release of fatty acids from adipose tissue: Adipose tissue insulin sensitivity, measured as the suppression from baseline of free fatty acid release from adipose tissue (lipolysis) during insulin infusion as part of a nine hour euglycemic hyperinsulinemic clamp study.

4. Hepatic Fat Content for Fenofibrate and Niacin Groups [baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin)]

   Hepatic fat content as measured by magnetic resonance spectroscopy. A PRESS sequence was used. The results from three 10 cubic centimeter voxels positioned within the liver were averaged. The measure is a ratio of triglyceride signal to total signal.

5. Adipose Tissue Insulin Sensitivity in Fenofibrate and Niacin Groups [baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin)]

   The baseline and post-treatment measures of adipose tissue insulin sensitivity (ATIS) were compared. ATIS at both timepoints is the suppression from fasting levels of free fatty acid release from adipose tissue (lipolysis) during an insulin infusion as part of a euglycemic clamp study. It is the percent decrease from time zero to the end of the nine hour euglycemic hyperinsulinemic clamp

6. Change From Baseline in Skeletal Muscle Insulin Sensitivity [baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)]

   Changes in skeletal muscle insulin sensitivity (SMIS). SMIS was measured as the increase in skeletal muscle glucose uptake from time zero to the end of a nine hour euglycemic clamp and insulin infusion study. This increase is the percentage change from time zero to end of insulin infusion at nine hours.

7. Change From Baseline in Hepatic Insulin Sensitivity Index [baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)]

   Hepatic insulin sensitivity, assessed as a function of glucose production rate and plasma insulin concentration. The Hepatic Insulin Sensitivity Index (HISI) is measured as the reciprocal of glucose rate of appearance [10000/(μmol/min)] multiplied by insulin concentration[mU/L]. The 10000 in the formula is a conventional adjustment so that insulin sensitivity measures are more readable. As yet there is no normal range for HISI, since is a surrogate marker for hepatic insulin sensitivity that has not yet been validated.

Secondary Outcome Measures

1. Very Low Density Lipoprotein - Triglyceride Production Rate [baseline cross-sectional data]

   Very low density lipoprotein triglyceride (VLDL-TG) production rate, a measure of hepatic secretion of VLDL-triglyceride per liter of plasma per minute (μmol/L/min).

2. Change From Baseline in Very Low Density Lipoprotein Apolipoprotein B Production Rate [baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin)]

   VLDL-apolipoprotein B (apoB) concentrations were measured as part of a VLDL metabolism study utilizing stable isotope tracers. VLDL apoB production rate, a measure of hepatic secretion of VLDL-apolipoproteinB-100 per liter of plasma per minute.

3. Change From Baseline in VLDL-Tg Clearance Rate [baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)]

   Very low density lipoprotein triglyceride (VLDL-Tg) clearance rate, a measure of VLDL-triglyceride removal from plasma per minute.

4. Change From Baseline in VLDL-Tg Production Rate [baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)]

   VLDL-TG production rate, a measure of hepatic secretion of VLDL-triglyceride per liter of plasma per minute.

5. Change From Baseline in Very Low-density Lipoprotein Triglyceride Concentration [baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)]

   Change from baseline in very low-density lipoprotein triglyceride concentration (VLDL-Tg)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

All

• 18 - 45 years old

• Class I obesity, i.e. Body Mass Index (BMI) between 30 and 45.

• weight less than 300 lbs.

Exclusion Criteria:

• Active or previous infection with hepatitis B or C, as well as other liver disease.

• History of alcohol abuse

• Diabetes

• Medications that cause liver damage or steatosis.

• Women who are pregnant or lactating.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Samuel Klein, MD, Washington University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT00262964
• Other Study ID Numbers: DK37948; R01DK037948
• First Posted: Dec 7, 2005
• Last Update Posted: Jul 11, 2018
• Last Verified: Jun 1, 2018

• Keywords provided by Washington University School of Medicine: non-alcoholic fatty liver disease; obesity; fatty liver disease
• Additional relevant MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Obesity; Niacin; Fenofibrate

Study Results

Participant Flow

Recruitment Details	Beginning and ending recruitment dates: Beginning - 10/20/04; Ending - 09/24/07. Recruitment occurred only at Washington University in St. Louis.
Pre-assignment Detail	We screened 138 subjects. 80 would-be participants failed the screening. This was often due to not having Non-alcoholic Fatty Liver Disease. Other subjects were excluded due to use of various medications or the presence of some excluded disease such as type 2 diabetes. Of the 58 that passed screening 51 chose to enroll in the study.

Arm/Group Title	NAFLD - Niacin	NAFLD - Fenofibrate	Controls	NAFLD - no Drug
Arm/Group Description	subjects diagnosed with NAFLD were randomized to a sixteen week regimen of niacin.	Subjects diagnosed with NAFLD were randomized to an eight week regimen of fenofibrate	Subjects with normal intrahepatic fat triglyceride(IHTG) levels (<10%). IHTG was measured using magnetic resonance spectroscopy and defined as the extrapolated ratio of triglyceride signal to water signal at time t = 0.	Subjects with elevated intrahepatic triglyceride (IHTG) levels (>10%) who were measured only once (baseline). These subjects did not undergo drug therapy, in contrast to the NAFLD-niacin and NAFLD-fenofibrate group subjects. IHTG was measured using magnetic resonance spectroscopy and defined as the extrapolated ratio of triglyceride signal to water signal at time t = 0.
Period Title: Overall Study
STARTED	11	11	17	12
COMPLETED	11	11	17	12
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Controls	NAFLD	Total
Arm/Group Description	Subjects with normal intra-hepatic triglyceride content (defined by less than 10% lipid to water signal in magnetic resonance spectroscopy).	Subjects diagnosed with Non-Alcoholic Fatty Liver Disease(NAFLD). Determination of NAFLD was by magnetic resonance spectroscopy of intra-hepatic triglyceride content (defined by greater than 10% lipid to water signal). This group included subjects later randomized into the NAFLD-Niacin, NAFLD-Fenofibrate, and NAFLD-no intervention arms.	Total of all reporting groups
Overall Participants	17	34	51
Age, Customized (participants) [Number]
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	17 100%	34 100%	51 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41 (3)	45 (3)	42 (3)
Sex: Female, Male (Count of Participants)
Female	13 76.5%	24 70.6%	37 72.5%
Male	4 23.5%	10 29.4%	14 27.5%
Region of Enrollment (participants) [Number]
United States	17 100%	34 100%	51 100%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	35.11 (4.33)	36.73 (4.66)	36.19 (4.57)
Body Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	99.8 (11.6)	104.1 (15.6)	102.7 (14.4)
fat as percentage of total body composition (percentage of total body weight) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of total body weight]	42.1 (6.9)	39.3 (6.0)	40.3 (6.4)
plasma glucose level (mg/dl) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dl]	94.2 (6.0)	96.0 (8.6)	95.4 (7.8)
plasma insulin level (mU/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mU/L]	11.4 (4.5)	21.2 (9.9)	17.9 (9.6)

Outcome Measures

1. Primary Outcome

Title	Hepatic Insulin Sensitivity Index (HISI)
Description	Hepatic insulin sensitivity, assessed as a function of glucose production rate and plasma insulin concentration. The Hepatic Insulin Sensitivity Index(HISI) is the reciprocal of glucose rate of appearance [10000/(μmol/min)] multiplied by insulin concentration[mU/L]. The 10000 in the formula is a conventional adjustment so that insulin sensitivity measures are more readable. As yet there is no normal range for HISI, since is a surrogate marker for hepatic insulin sensitivity that has not yet been validated.
Time Frame	baseline cross-sectional data

Outcome Measure Data

Analysis Population Description

number of subjects determined by power calculations. Analysis was per protocol. Intrahepatic triglyceride was determined by magnetic resonance spectroscopy.

Arm/Group Title	NAFLD	Controls
Arm/Group Description	subjects with intra-hepatic triglyceride content greater than 10%.	subjects with normal intra-hepatic triglyceride levels
Measure Participants	34	17
Mean (Standard Error) [[10000/(μmol/min)x(mU/L)]]	0.8 (0.14)	1.4 (0.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NAFLD, Controls
	Comments	null hypothesis was no difference in hepatic insulin sensitivity between normal and high IHTG subjects
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.019
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Very Low Density Lipoprotein - Triglyceride Production Rate
Description	Very low density lipoprotein triglyceride (VLDL-TG) production rate, a measure of hepatic secretion of VLDL-triglyceride per liter of plasma per minute (μmol/L/min).
Time Frame	baseline cross-sectional data

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NAFLD	Controls
Arm/Group Description	Subjects with intrahepatic triglyceride content greater than 10% per Magnetic Resonance Spectroscopy	subjects with normal levels of intra-hepatic trigleceride
Measure Participants	34	17
Mean (Standard Error) [μmol/L/min]	6.7 (0.5)	3.8 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NAFLD, Controls
	Comments	null hypothesis was that VLDL-TG production would not differ between the two groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	a priori threshold for significance was P<0.05.
	Method	t-test, 2 sided
	Comments

3. Primary Outcome

Title	Percent Increase in Skeletal Muscle Insulin Sensitivity During Insulin Infusion.
Description	A precise measure of the ability of insulin to stimulate glucose uptake by skeletal muscle. Skeletal muscle insulin sensitivity, measured as the increase from baseline in skeletal muscle glucose uptake during insulin infusion(percentage)as part of a nine hour euglycemic hyperinsulinemic clamp study.
Time Frame	baseline cross-sectional data pre and post nine hour euglycemic clamp

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NAFLD	Controls
Arm/Group Description	Subjects with intrahepatic triglyceride signal greater than 10% per MR spectroscopy	subjects with normal levels of intra-hepatic trigleceride
Measure Participants	34	17
Mean (Standard Error) [percent increase]	173 (13)	303 (23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NAFLD, Controls
	Comments	null hypothesis was no difference in skeletal muscle insulin sensitivity between groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	a priori threshold for significance was set at p = 0.05.
	Method	t-test, 2 sided
	Comments

4. Primary Outcome

Title	Adipose Tissue Insulin Sensitivity
Description	The ability of insulin to suppress the release of fatty acids from adipose tissue: Adipose tissue insulin sensitivity, measured as the suppression from baseline of free fatty acid release from adipose tissue (lipolysis) during insulin infusion as part of a nine hour euglycemic hyperinsulinemic clamp study.
Time Frame	baseline cross-sectional data pre and post nine hour euglycemic clamp

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NAFLD	Controls
Arm/Group Description	Subjects with elevated intrahepatic triglyceride (>10% signal compared to H2O) measured by MR Spectroscopy.	subjects with normal intrahepatic triglyceride levels
Measure Participants	34	17
Mean (Standard Error) [percent decrease]	66 (2)	75 (1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NAFLD, Controls
	Comments	null hypothesis was that there would be no difference in adipose tissue insulin sensitivity due to IHTG levels.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.002
	Comments
	Method	t-test, 2 sided
	Comments

5. Primary Outcome

Title	Hepatic Fat Content for Fenofibrate and Niacin Groups
Description	Hepatic fat content as measured by magnetic resonance spectroscopy. A PRESS sequence was used. The results from three 10 cubic centimeter voxels positioned within the liver were averaged. The measure is a ratio of triglyceride signal to total signal.
Time Frame	baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin)

Outcome Measure Data

Analysis Population Description

10 (or more) subjects in each group would be sufficient for detecting changes in IHTG.

Arm/Group Title	NAFLD - Fenofibrate	NAFLD - Niacin
Arm/Group Description	Subjects diagnosed with NAFLD were randomized to an eight week regimen of fenofibrate	subjects given niacin for 16 weeks
Measure Participants	11	11
Baseline	23.2 (10.2)	21.0 (10.4)
8 wk (fenofibrate), 16 wk (niacin)	23.6 (11.2)	19.7 (8.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NAFLD
	Comments	Student's t-test for paired samples was used to evaluate any difference between the two groups. The null hypothesis was that the IHTG percentage would be the same before and after treatment for subjects receiving fenofibrate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.301
	Comments	A P-value < 0.05 was considered statistically significant.
	Method	t-test, 2 sided
	Comments	Treatment effects determined by repeated-measures ANOVA. When significant interactions between time and group were found, a Student's t-test was used.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Controls
	Comments	A Student's t-test for paired samples was used to evaluate the effect of treatment. The null hypothesis was that the IHTG percentage for the NAFLD-niacin group at baseline and post-treatment would not change.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.315
	Comments	A P-value < 0.05 was considered statistically significant.
	Method	t-test, 2 sided
	Comments	Treatment effects determined by repeated-measures ANOVA. When significant interactions between time and group were found, a Student's t-test was used.

6. Secondary Outcome

Title	Change From Baseline in Very Low Density Lipoprotein Apolipoprotein B Production Rate
Description	VLDL-apolipoprotein B (apoB) concentrations were measured as part of a VLDL metabolism study utilizing stable isotope tracers. VLDL apoB production rate, a measure of hepatic secretion of VLDL-apolipoproteinB-100 per liter of plasma per minute.
Time Frame	baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NAFLD - Fenofibrate	NAFLD - Niacin
Arm/Group Description	Subjects diagnosed with NAFLD were randomized to an eight week regimen of fenofibrate	subjects given Niacin for 16 weeks
Measure Participants	11	11
Baseline	0.5 (0.05)	0.4 (0.04)
8 wk (fenofibrate), 16 wk (niacin)	0.4 (0.05)	0.4 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Controls
	Comments	a Student's t-test for paired samples was used to evaluate the effect of treatment. Null hypothesis was that VLDL-apoB would be the same before and after 16 weeks on niacin in subjects with NAFLD.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.708
	Comments	A P-value < 0.05 was considered statistically significant.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NAFLD
	Comments	A Student's t-test for paired samples was used to evaluate the effect of treatment. Null hypothesis was that VLDL-apoB would be the same before and after 8 weeks on fenofibrate in subjects with NAFLD.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.022
	Comments	A P-value < 0.05 was considered statistically significant.
	Method	t-test, 2 sided
	Comments

7. Secondary Outcome

Title	Change From Baseline in VLDL-Tg Clearance Rate
Description	Very low density lipoprotein triglyceride (VLDL-Tg) clearance rate, a measure of VLDL-triglyceride removal from plasma per minute.
Time Frame	baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NAFLD - Fenofibrate	NAFLD - Niacin
Arm/Group Description	Subjects with intrahepatic triglyceride signal greater than 10% per MR spectroscopy given an eight week course of fenofibrate	subjects with elevated levels of intra-hepatic trigleceride given a 16 week course of niacin
Measure Participants	11	11
Baseline	35 (9)	34 (8)
8 weeks (fenofibrate) or 16 weeks (niacin)	56 (12)	52 (23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NAFLD
	Comments	the null hypothesis was that fenofibrate would not change the VLDL-Tg clearance rate
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.020
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Controls
	Comments	the null hypothesis was that niacin would not change the VLDL-Tg clearance rate
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.358
	Comments	a priori threshold for significance was <0.05.
	Method	t-test, 2 sided
	Comments

8. Secondary Outcome

Title	Change From Baseline in VLDL-Tg Production Rate
Description	VLDL-TG production rate, a measure of hepatic secretion of VLDL-triglyceride per liter of plasma per minute.
Time Frame	baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NAFLD - Fenofibrate	NAFLD - Niacin
Arm/Group Description	Subjects with intrahepatic triglyceride signal greater than 10% per MR spectroscopy receiving fenofibrate for eight weeks.	subjects with elevated levels of intra-hepatic trigleceride (>10% signal by MR spectroscopy) given a 16 week course of niacin
Measure Participants	11	11
Baseline	6.4 (0.7)	7.7 (1.6)
8 weeks (fenofibrate) or 16 weeks (niacin)	6.0 (0.6)	4.5 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NAFLD
	Comments	Null hypothesis is that fenofibrate would not effect VLDL-Tg production rates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.758
	Comments	a priori threshold for statistical significance was set at <0.05.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Controls
	Comments	Null hypothesis is that niacin would not effect VLDL-Tg production rates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.023
	Comments	the a priori threshold for statistical significance was set at <0.05.
	Method	t-test, 2 sided
	Comments

9. Secondary Outcome

Title	Change From Baseline in Very Low-density Lipoprotein Triglyceride Concentration
Description	Change from baseline in very low-density lipoprotein triglyceride concentration (VLDL-Tg)
Time Frame	baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NAFLD - Fenofibrate	NAFLD - Niacin
Arm/Group Description	Subjects diagnosed with NAFLD were randomized to an eight week regimen of fenofibrate	subjects given Niacin for 16 weeks
Measure Participants	11	11
Baseline	1.09 (0.28)	1.04 (0.24)
8 weeks (fenofibrate) or 16 weeks (niacin)	0.50 (0.10)	0.64 (0.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NAFLD
	Comments	Null hypothesis was that fenofibrate would not affect VLDL-Tg concentration. We compare the pre and post-treatment results of subjects receiving an 8 week course of fenofibrate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.024
	Comments	the a priori threshold for statistical significance was p <0.05
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Controls
	Comments	The null hypothesis was that niacin would not affect VLDL-Tg concentration. We compare the pre and post-treatment results of subjects receiving a 16 week course of niacin.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	the a priori threshold for statistical significance was p<0.05
	Method	t-test, 2 sided
	Comments

10. Primary Outcome

Title	Adipose Tissue Insulin Sensitivity in Fenofibrate and Niacin Groups
Description	The baseline and post-treatment measures of adipose tissue insulin sensitivity (ATIS) were compared. ATIS at both timepoints is the suppression from fasting levels of free fatty acid release from adipose tissue (lipolysis) during an insulin infusion as part of a euglycemic clamp study. It is the percent decrease from time zero to the end of the nine hour euglycemic hyperinsulinemic clamp
Time Frame	baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NAFLD - Fenofibrate	NAFLD - Niacin
Arm/Group Description	Subjects diagnosed with NAFLD were randomized to an eight week regimen of fenofibrate	subjects given niacin for 16 weeks
Measure Participants	11	11
Baseline	68 (4)	63 (4)
8 weeks (fenofibrate) or 16 weeks (niacin)	69 (2)	35 (10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NAFLD
	Comments	Null hypothesis was that fenofibrate would not affect adipose tissue insulin sensitivity. We compare the baseline and post-treatment results for adipose tissue insulin sensitivity in the subjects who received fenofibrate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.768
	Comments	A priori threshold for significance was set for p<0.05.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Controls
	Comments	Null hypothesis was that niacin would not affect adipose tissue insulin sensitivity. Here we compare the baseline and post-treatment adipose tissue insulin sensitivity results for subjects who received a 16 week course of niacin
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.019
	Comments	A priori threshold for significance was set for p<0.05.
	Method	t-test, 2 sided
	Comments

11. Primary Outcome

Title	Change From Baseline in Skeletal Muscle Insulin Sensitivity
Description	Changes in skeletal muscle insulin sensitivity (SMIS). SMIS was measured as the increase in skeletal muscle glucose uptake from time zero to the end of a nine hour euglycemic clamp and insulin infusion study. This increase is the percentage change from time zero to end of insulin infusion at nine hours.
Time Frame	baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NAFLD - Fenofibrate	NAFLD - Niacin
Arm/Group Description	Subjects diagnosed with NAFLD were randomized to an eight week regimen of fenofibrate	subjects given niacin for 16 weeks
Measure Participants	11	11
Baseline	188 (36)	183 (22)
8 weeks (fenofibrate) or 16 weeks (niacin)	169 (28)	142 (26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NAFLD
	Comments	The null hypothesis was that fenofibrate would not affect skeletal muscle insulin sensitivity. Here we compare the pre and post-treatment results in subjects receiving an 8 week course of fenofibrate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.318
	Comments	The a priori threshold for significance was set at p<0.05.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Controls
	Comments	The null hypothesis was that niacin would not affect skeletal muscle insulin sensitivity. Here we compare the pre and post-treatment results for subjects receiving a 16 week course of niacin.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.025
	Comments	The a priori threshold for significance was set at p<0.05.
	Method	t-test, 2 sided
	Comments

12. Primary Outcome

Title	Change From Baseline in Hepatic Insulin Sensitivity Index
Description	Hepatic insulin sensitivity, assessed as a function of glucose production rate and plasma insulin concentration. The Hepatic Insulin Sensitivity Index (HISI) is measured as the reciprocal of glucose rate of appearance [10000/(μmol/min)] multiplied by insulin concentration[mU/L]. The 10000 in the formula is a conventional adjustment so that insulin sensitivity measures are more readable. As yet there is no normal range for HISI, since is a surrogate marker for hepatic insulin sensitivity that has not yet been validated.
Time Frame	baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NAFLD - Fenofibrate	NAFLD - Niacin
Arm/Group Description	Subjects with elevated intrahepatic triglyceride given an eight week course of fenofibrate	subjects with elevated levels of intra-hepatic trigleceride given a 16 week course of niacin.
Measure Participants	11	11
Baseline	0.7 (0.1)	0.8 (0.4)
8 weeks (fenofibrate) or 16 weeks (niacin)	0.8 (0.1)	0.5 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NAFLD
	Comments	The null hypothesis was that fenofibrate would not affect hepatic insulin sensitivity. Here we compare the pre and post-treatment results of subjects receiving an 8 week course of fenofibrate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.419
	Comments	The a priori threshold for significance was set at p<0.05.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Controls
	Comments	The null hypothesis was that niacin would not affect skeletal muscle insulin sensitivity. Here we compare the pre and post-treatment results of subjects receiving a 16 week course of niacin.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.018
	Comments	The a priori threshold for significance was set at p<0.05.
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	Adverse event data was collected from baseline testing through post-treatment testing. The "NAFLD - no drug" and control groups were only followed through the baseline testing.
Arm/Group Title	NAFLD - Fenofibrate		NAFLD - Niacin		NAFLD - no Drug		Controls
Arm/Group Description	Subjects diagnosed with NAFLD were randomized to an weight week regimen of fenofibrate		subjects with intra-hepatic triglyceride signal greater than 10% placed on daily niacin for 16 weeks. The dose of medication will be gradually increased according to the protocol of most clinical trials (59): 500 mg/day during wk 1, 1000 mg/day during wk 2, 1500 mg/day during wks 3, and 2000mg/day during wks 4-16.		subjects with elevated hepatic triglyceride who did not receive any drug intervention		subjects with normal hepatic triglyceride.
All Cause Mortality
	NAFLD - Fenofibrate		NAFLD - Niacin		NAFLD - no Drug		Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	NAFLD - Fenofibrate		NAFLD - Niacin		NAFLD - no Drug		Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/11 (0%)		0/12 (0%)		0/17 (0%)
Other (Not Including Serious) Adverse Events
	NAFLD - Fenofibrate		NAFLD - Niacin		NAFLD - no Drug		Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/11 (9.1%)		0/11 (0%)		0/12 (0%)		0/17 (0%)
Hepatobiliary disorders
elevation of liver enzymes	1/11 (9.1%)	1	0/11 (0%)	0	0/12 (0%)	0	0/17 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.