Insulin Resistance in Non-alcoholic Fatty Liver Disease

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Terminated
• CT.gov ID: NCT01289639
• Collaborator: (none)
• Enrollment: 11
• Location: 1
• Arms: 3
• Duration (Months): 106
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The study is designed to investigate the relationship between insulin resistance and non-alcoholic fatty liver disease (NAFLD) and to investigate potential mechanisms underlying insulin resistance in NAFLD by determining associations between hepatic and peripheral insulin sensitivity, hepatic steatosis, dyslipidemia, inflammatory cytokines, glucose metabolism, beta-cell function and body fat distribution.

Condition or Disease	Intervention/Treatment	Phase
Fatty Liver	Drug: fenofibrate; Drug: pioglitazone; Drug: placebo	N/A

Detailed Description

NAFLD and nonalcoholic steatohepatitis (NASH) are common liver disorders that are strongly associated with obesity, type 2 diabetes and dyslipidemia. The underlying pathophysiology of fatty infiltration of the liver is thought to be related to insulin resistance, which is an almost universal finding in patients with NAFLD. It is also possible that fat infiltration and inflammation in the liver may impair insulin sensitivity, either locally in the liver, or peripherally via the actions of inflammatory cytokines. We hypothesize that insulin resistance is a major causal factor leading to fat deposition in the liver and NAFLD, and thus interventions aimed at improving insulin sensitivity will result in a reduction of hepatic inflammation and steatosis.

Specific Aim 1: To determine in a cross-sectional study whether NAFLD is associated with altered peripheral and hepatic insulin sensitivity and to study their relationships with hepatic steatosis, dyslipidemia, inflammatory cytokines, glucose metabolism, beta-cell function and body fat distribution. Specific Aim 2: To determine in a 6 month placebo-controlled double-blinded treatment study if treatment with pioglitazone, an insulin sensitizer, or fenofibrate, a triglyceride lowering agent, will improve both hepatic as well as peripheral insulin sensitivity and thereby improve hepatic steatosis and inflammation in subjects with NAFLD.

The results of the proposed study will have important implications for our understanding of the mechanisms underlying insulin resistance and abnormalities in lipid and glucose metabolism in subjects with NAFLD and for the design of future studies aimed at the prevention and treatment of this condition.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: Insulin Resistance in Non-alcoholic Fatty Liver Disease (Protocol Drug Change From Project Career Development Award (CDA)-2-044-08S)
• Study Start Date: Oct 1, 2005
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo matching placebo 1 po qd	Drug: placebo; placebo 1 capsule po qd
Experimental: Fenofibrate micronized fenofibrate 200 mg 1 po qd	Drug: fenofibrate; micronized fenofibrate 200 mg 1 po qd; Other Names: micronized fenofibrate
Experimental: Pioglitazone pioglitazone 30 mg po qd	Drug: pioglitazone; pioglitazone 30 mg po qd; Other Names: Actos

Outcome Measures

Primary Outcome Measures

1. Liver/Spleen Ratio Measured as the Ratio in Hounsfield Units Between the Liver and the Spleen on Computed Tomography (CT) Scan [6 months]

Secondary Outcome Measures

1. Change in Alanine Aminotransferase (ALT) Levels [0-6 months]

2. Change in Liver/Spleen Ratio Measure by the Density Ratio in Hounsfield Units Between the Liver and the Spleen by CT [0-6 months]

3. Change in Peripheral Insulin Sensitivity [0-6 months]

   Change in the rate of glucose disposal (Rd) during the low dose clamp. During a clamp procedure, insulin is infused at a dose based on body size and a glucose solution is infused and the rate adjusted every 5 minutes based on a blood glucose reading to maintain the blood glucose stable at 90 mg/dl (normal level). Using glucose isotopes and the rate of the glucose infusion, we are then able to calculate how much glucose the liver is producing and how much glucose is being taken up into tissues. This provides a measure of insulin sensitivity.

4. Change in Intra-abdominal Fat Area by CT Scan [0-6 months]

5. Change in Hepatic Insulin Sensitivity [0-6 months]

   Hepatic insulin sensitivity was determined using stable glucose isotope measurements during the low dose hyperinsulinemic euglycemic clamp to determine the rate of endogenous glucose production in the fasting state and in response to a low dose glucose infusion. The ability of insulin to suppress glucose, which is mainly produced by the liver, thus provides a measure of hepatic insulin sensitivity and is expressed as a percentage of the basal state. Change in the ability of low dose insulin to suppress endogenous glucose production during a labeled hyperinsulinemic euglycemic clamp.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

Control subjects: nl liver enzymes and no history of liver disease Case subjects: NAFLD on liver biopsy within the past 3 years or presumed NAFLD with otherwise unexplained elevated alanine aminotransferase (ALT) and fatty liver by computerized tomography (CT) scan or ultrasound

• Able to comply with taking 1 pill a day for 6 months and follow-up safety visits

Exclusion Criteria:

• Cases: cirrhosis on liver biopsy or by clinical exam or fibrosis score

• Causes of liver dysfunction other than NASH

• Use of medications associated with hepatic steatosis:

• glucocorticoids

• estrogens

• tamoxifen

• amiodarone

• accutane

• sertraline

• Use of medications that cause insulin resistance:

• niacin

• glucocorticoids

• anti-HIV drugs or atypical antipsychotics

• Use of lipid-lowering medications except stable dose statin

• Use of anti-NASH drugs such as ursodeoxycholic acid, betaine milk thistle

• Use of coumadin

• Use of nitrates

• Significant alcohol consumption: Average >20 grams/day

• In subjects with diabetes, a hemoglobin A1c (HbA1c) >7.5% or use of insulin, metformin, rosiglitazone or pioglitazone

• Liver transaminases: ALT >5x upper limit of normal,

• Iron saturation >50%

• Creatinine >1.5 mg/dl for men and >1.4 mg/dl for women

• Hematocrit <33%

• Pregnancy or lactation

• Significant weight loss within the past 6 months or since the liver biopsy

• History of significant coronary artery disease or congestive heart failure, retinopathy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Puget Sound Health Care System, Seattle	Seattle	Washington	United States	98108

Sponsors and Collaborators

• VA Office of Research and Development

Investigators

• Principal Investigator: Kristina M Utzschneider, MD, VA Puget Sound Health Care System, Seattle

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT01289639
• Other Study ID Numbers: CDA-2-044-08S-2
• First Posted: Feb 4, 2011
• Last Update Posted: Aug 17, 2017
• Last Verified: Jul 1, 2017

• Keywords provided by VA Office of Research and Development: non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; insulin resistance; pioglitazone; fenofibrate
• Additional relevant MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Insulin Resistance; Pioglitazone; Fenofibrate

Study Results

Participant Flow

Arm/Group Title	Arm 1	Arm 2	Arm 3
Arm/Group Description	matching placebo for fenofibrate 1 capsule po qd matching placebo for pioglitazone 1 capsule po qd	micronized fenofibrate 200 mg 1 po qd matching placebo for pioglitazone 1 po qd	pioglitazone 30 mg po qd matching placebo for fenofibrate 1 po qd
Period Title: Overall Study
STARTED	5	6	0
COMPLETED	4	6	0
NOT COMPLETED	1	0	0

Baseline Characteristics

Arm/Group Title	Arm 1	Arm 2	Arm 3	Total
Arm/Group Description	matching placebo for fenofibrate 1 po qd matching placebo for pioglitazone 1 po qd	micronized fenofibrate 200 mg 1 po qd matching placebo for pioglitazone 1 po qd	pioglitazone 30 mg po qd matching placebo for fenofibrate 1 po qd	Total of all reporting groups
Overall Participants	5	6	0	11
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.2 (7.3)	54.17 (5.08)	51.91 (6.41)
Sex: Female, Male (Count of Participants)
Female	2 40%	2 33.3%	4 Infinity
Male	3 60%	4 66.7%	7 Infinity
Region of Enrollment (participants) [Number]
United States	5 100%	6 100%	11 Infinity

Outcome Measures

1. Primary Outcome

Title	Liver/Spleen Ratio Measured as the Ratio in Hounsfield Units Between the Liver and the Spleen on Computed Tomography (CT) Scan
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1	Arm 2	Arm 3
Arm/Group Description	matching placebo for fenofibrate 1 capsule po qd matching placebo for pioglitazone 1 capsule po qd	micronized fenofibrate 200 mg 1 po qd matching placebo for pioglitazone 1 po qd	pioglitazone 30 mg po qd matching placebo for fenofibrate 1 po qd
Measure Participants	4	6	0
Mean (Standard Error) [ratio]	.85 (.08)	.60 (.17)

2. Secondary Outcome

Title	Change in Alanine Aminotransferase (ALT) Levels
Time Frame	0-6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1	Arm 2	Arm 3
Arm/Group Description	matching placebo for fenofibrate 1 capsule po qd matching placebo for pioglitazone 1 capsule po qd	micronized fenofibrate 200 mg 1 po qd matching placebo for pioglitazone 1 po qd	pioglitazone 30 mg po qd matching placebo for fenofibrate 1 po qd
Measure Participants	4	6	0
Mean (Standard Error) [U/L]	-11.5 (12.9)	-15.2 (4.5)

3. Secondary Outcome

Title	Change in Liver/Spleen Ratio Measure by the Density Ratio in Hounsfield Units Between the Liver and the Spleen by CT
Time Frame	0-6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1	Arm 2	Arm 3
Arm/Group Description	matching placebo for fenofibrate 1 capsule po qd matching placebo for pioglitazone 1 capsule po qd	micronized fenofibrate 200 mg 1 po qd matching placebo for pioglitazone 1 po qd	pioglitazone 30 mg po qd matching placebo for fenofibrate 1 po qd
Measure Participants	4	6	0
Mean (Standard Error) [ratio]	.09 (.10)	-0.16 (0.1)

4. Secondary Outcome

Title	Change in Peripheral Insulin Sensitivity
Description	Change in the rate of glucose disposal (Rd) during the low dose clamp. During a clamp procedure, insulin is infused at a dose based on body size and a glucose solution is infused and the rate adjusted every 5 minutes based on a blood glucose reading to maintain the blood glucose stable at 90 mg/dl (normal level). Using glucose isotopes and the rate of the glucose infusion, we are then able to calculate how much glucose the liver is producing and how much glucose is being taken up into tissues. This provides a measure of insulin sensitivity.
Time Frame	0-6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1	Arm 2	Arm 3
Arm/Group Description	matching placebo for fenofibrate 1 capsule po qd matching placebo for pioglitazone 1 capsule po qd	micronized fenofibrate 200 mg 1 po qd matching placebo for pioglitazone 1 po qd	pioglitazone 30 mg po qd matching placebo for fenofibrate 1 po qd
Measure Participants	4	5	0
Mean (Standard Error) [mg/minute/kg lean mass]	0.21 (0.51)	-0.42 (0.49)

5. Secondary Outcome

Title	Change in Intra-abdominal Fat Area by CT Scan
Time Frame	0-6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1	Arm 2	Arm 3
Arm/Group Description	matching placebo for fenofibrate 1 capsule po qd matching placebo for pioglitazone 1 capsule po qd	micronized fenofibrate 200 mg 1 po qd matching placebo for pioglitazone 1 po qd	pioglitazone 30 mg po qd matching placebo for fenofibrate 1 po qd
Measure Participants	4	6	0
Mean (Standard Error) [mm2]	885 (874)	108 (3416)

6. Secondary Outcome

Title	Change in Hepatic Insulin Sensitivity
Description	Hepatic insulin sensitivity was determined using stable glucose isotope measurements during the low dose hyperinsulinemic euglycemic clamp to determine the rate of endogenous glucose production in the fasting state and in response to a low dose glucose infusion. The ability of insulin to suppress glucose, which is mainly produced by the liver, thus provides a measure of hepatic insulin sensitivity and is expressed as a percentage of the basal state. Change in the ability of low dose insulin to suppress endogenous glucose production during a labeled hyperinsulinemic euglycemic clamp.
Time Frame	0-6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1	Arm 2	Arm 3
Arm/Group Description	matching placebo for fenofibrate 1 capsule po qd matching placebo for pioglitazone 1 capsule po qd	micronized fenofibrate 200 mg 1 po qd matching placebo for pioglitazone 1 po qd	pioglitazone 30 mg po qd matching placebo for fenofibrate 1 po qd
Measure Participants	4	5	0
Mean (Standard Error) [% change from baseline]	23.3 (7.8)	4.9 (9.3)

Adverse Events

Time Frame	Baseline and monthly.
Arm/Group Title	Arm 1		Arm 2		Arm 3
Arm/Group Description	matching placebo for fenofibrate 1 capsule po qd matching placebo for pioglitazone 1 capsule po qd		micronized fenofibrate 200 mg 1 po qd matching placebo for pioglitazone 1 po qd		pioglitazone 30 mg po qd matching placebo for fenofibrate 1 po qd
All Cause Mortality
	Arm 1		Arm 2		Arm 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1		Arm 2		Arm 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/6 (0%)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Arm 1		Arm 2		Arm 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/5 (60%)		4/6 (66.7%)		0/0 (NaN)
Blood and lymphatic system disorders
leg edema	0/5 (0%)	0	2/6 (33.3%)	2	0/0 (NaN)	0
General disorders
vasovagal reaction	2/5 (40%)	2	0/6 (0%)	0	0/0 (NaN)	0
Musculoskeletal and connective tissue disorders
gout attack	1/5 (20%)	1	2/6 (33.3%)	3	0/0 (NaN)	0
Renal and urinary disorders
increased serum creatinine	0/5 (0%)	0	2/6 (33.3%)	2	0/0 (NaN)	0

Limitations/Caveats

Due to low enrollment, the study was stopped prematurely. Due to the low number of subjects enrolled, statistical analysis was not possible on the intervention study.

More Information

Certain Agreements

All Principal Investigators ARE 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.