Metabolic Syndrome XNCT00470262
Effects of PPAR Ligands on Ectopic Fat Accumulation and Inflammation
A study testing Fenofibrate 145mg PO QD and Pioglitazone 45 mg PO QD in people with Metabolic Syndrome X and Prediabetic State, run by VA Office of Research and Development at 1 site in United States.
Trial summary
The relationship between obesity and insulin resistance is known, however the mechanism(s) associating obesity with insulin resistance is not well understood. Inflammation and accumulation of fat in non fat tissue (like muscle) are conditions found on obesity which could be the potential link between obesity and… Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Metabolic Syndrome X, Prediabetic State
- What is being tested?
- Fenofibrate 145mg PO QD and Pioglitazone 45 mg PO QD
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 27 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2007to Jun 2014
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Impaired glucose tolerance and/or impaired fasting glucose and/or metabolic syndrome
- Age 18-65
- BMI 28-38
Who cannot join
- Renal insufficiency: creatinine.1.4
- Liver disease: ALT.2x normal, congestive heart failure, history of documented coronary artery disease, concomitant use HMG CoA-reductase inhibitors (statins)
- Concurrent use of ASA, steroids and other anti-inflammatory agents
Trial locations and contacts
1 site in 1 country.
United States1 site
VA Eastern Colorado Health Care System, Denver
Denver, Colorado, 80220
About this study
Official title: Effects of PPAR Ligands on Ectopic Fat Accumulation and Inflammation in Subjects With Impaired Glucose Tolerance
The relationship between obesity and insulin resistance is known, however the mechanism(s) associating obesity with insulin resistance is not well understood. Inflammation and accumulation of fat in non fat tissue (like muscle) are conditions found on obesity which could be the potential link between obesity and insulin resistance. This study is designed to test the effects of two different drugs on numerous features of the obesity and insulin resistance in subjects with impaired glucose tolerance. Impaired glucose tolerance is a condition where blood sugar is too high after drinking a sugary drink containing 75 grams of sugar. Impaired glucose tolerant subjects are insulin resistant and at risk of developing diabetes. The drugs to be used are fenofibrate and pioglitazone. Fenofibrate is used to reduce the amount of fat (triglycerides) in the blood while pioglitazone is routinely used to make the body more sensitive to insulin in patients with diabetes. The purpose of this study is to compare the effects of either of these two medications (pioglitazone and fenofibrate) alone or the combination of both on fat accumulation in body (muscle) and inflammation. The amount of fat accumulation in muscle is thought to affect insulin sensitivity. In addition, the changes in the level of proteins produced by fat tissues will be studied in response to the two medications in this study. These proteins are thought to be involved in diabetes and insulin resistance.
These studies are designed to examine fundamental clinical mechanisms underlying the metabolic syndrome and diabetes.
Read the detailed description
The correlation between obesity, inflammation and ectopic fat accumulation is well recognized; however, the mechanism(s) responsible for obesity induced insulin resistance is not well understood. The investigators will focus on lipotoxicity and inflammation as the link between obesity and insulin resistance. The factors leading to inflammation and ectopic lipid accumulation in obesity and the best intervention to reverse this pathophysiology are not clear. In this study, the investigators will examine inflammation in adipose tissue and muscle lipid mechanism in response to Peroxisome Proliferator Activated Receptors (PPAR) and ligands have synergistic anti-inflammatory effects in adipose tissue and activation of PPAR and decrease muscle lipid oxidation and redistribution of lipid from muscle to adipocytes respectively. The combination of both medications will be particularly effective in reducing inflammation and muscle lipid accumulation.
In this study, IGT subjects will be randomized to treatment with PPAR ligand (fenofibrate), PPAR ligand (pioglitazone) or combination of both for 10 weeks. Baseline studies will include assessment of body composition, insulin sensitivity, muscle and fat biopsies. All studies will be repeated after treatment with fenofibrate, pioglitazone or combination of both.
Specific Aims (SA) are as follows:
SA 1. Insulin sensitivity and Intramyocellular lipid (IMCL) from muscle biopsy specimens will be measured in response to different treatments (PPAR , and combination of both ligands).
SA 2. The rate of fatty acid oxidation and the number of mitochondria in muscle will be measured in response to PPAR ligands.
SA 3. The anti-inflammatory effects of PPAR and ligands will be studied by the measurement of the number of adipose tissue macrophages and the rate of macrophages apoptosis in fat biopsy specimens. In addition, the plasma levels and expression of proinflammatory proteins will be studied in response to different treatment.
SA 4. The rate of SUMOylation of PPAR (a novel mechanism regulating anti-inflammatory effects of PPAR ligands) will be studied in response to PPAR , ligand or combination of both.
These studies are designed to examine fundamental clinical mechanisms underlying the metabolic syndrome and diabetes.
Potential Impact on Veterans Health Care: The national obesity/diabetes epidemic is magnified in the VA, and the cost of caring for these patients is enormous. This study will provide data on the mechanism of action of these drugs, which will improve the investigators' understanding of these drugs, impaired glucose tolerance, and treatment of metabolic syndrome. From the clinical perspective, this study uses drugs to treat patients with IGT, which is rapidly becoming recognized as a "disease" because of its association with coronary artery disease risk factors, and because of its high rate of progression to T2DM. If these drugs were shown to improve the care of patients, then they would eventually be a cost savings to the VA, either by choosing the less expensive drug, or by using the drug that delays the progression of the disease, and improves the care of the patient by preventing complications.
- Conditions
- Metabolic Syndrome X, Prediabetic State
- Being tested
- Fenofibrate 145mg PO QD, Pioglitazone 45 mg PO QD
- Keywords
- fatty acid oxidation complex, fenofibrate, Inflammation, Peroxisome Proliferator-Activated Receptors, pioglitazone, Prediabetic State, insulin resistance
- Medical subject headings
- Metabolic Syndrome, Prediabetic State, Inflammation, Insulin Resistance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Fenofibrate 145mg PO QDDrug
Also called Tricor
Subjects will be randomized to either fenofibrates or combination of both fenofibrate and pioglitazone
Pioglitazone 45 mg PO QDDrug
Also called Actos
Subjects will be randomized to either fenofibrate 145 mg PO QD or a combination of both fenofibrate 145 mg PO QD and pioglitazone 45 mg PO QD
| Study group | Role | What they receive |
|---|---|---|
| Fenofibrate 145 mg PO QD and Pioglitazone 45 mg PO QD | Other | Treatment with pioglitazone and fenofibrate in subjects with pre diabetes Receives: Drug: Fenofibrate 145mg PO QD; Drug: Pioglitazone 45 mg PO QD |
| Fenofibrate 145 mg PO QD | Other | Treatment with fenofibrate in subjects with pre diabetes Receives: Drug: Fenofibrate 145mg PO QD |
What is being measured
The primary outcome is the main question the study is designed to answer.
Insulin Sensitivity
Insulin sensitivity was measure through frequently sampled intravenous glucose tolerance test. Subjects presented to research center fasting. Blood samples were collected at -21, -11, and -1 minutes. At time t=0 initiates the start of the IVGTT and the injection of glucose into the non-sampling arm. The glucose dose was calculated as 11.4g/m2 of body surface area, given as a 50% dextrose solution. This glucose injection was administered over 60 seconds or less. At time t=20 minutes, an insulin dose of 0.04u/kg was administered over 30 seconds. Blood samples were collected at times t=2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 40, 50, 70, 90, 100, 120, 140, 160, and 180. If blood sugar did not return to a steady state the test was continued to t= 210 or t= 240.
Measured: 3 months
Secondary outcomes (1)
IMCL
Intramyocellular lipid was measured using immunohistochemistry (using oil Red O staining) in muscle biopsy specimens. Oil red O-stained muscle sections were magnified with an Olympus Provis (Tokyo, Japan) light microscope, and images were digitally captured by using a connected charge-coupled device camera (Sony, Tokyo, Japan). Fiber-typed and oil red O-stained fibers were matched. The oil red O staining intensity of either type 1 or 2 muscle fibers was quantified using National Institutes of Health Image program (http://rsb.info.nih.gov/nih-image/). By adjusting a density threshold, the software was set to recognize the presence of one fat droplet only if its highlighted surface was exceeding 0.40 μm2 or larger. Muscle lipid content was calculated by total area of lipid droplets in a given muscle fiber divided by the total area of the same fiber. The mean number of fibers analyzed per sample was 40 for type 1 and 2 muscle fibers
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 May 2007 (estimated)
- Study startJan 2007
- Primary completionDec 2012
- Study completionJun 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Metabolic Syndrome XStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 27 participants (actual)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- Neda Rasouli, MD, Principal investigator, VA Eastern Colorado Health Care System, Denver
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00470262
- Sponsor's protocol ID
- ENDA-020-06S
- Other IDs
- 09-0710
- Status last verified
- Jun 2016
- First submitted
- 4 May 2007
- Last updated
- 21 Jul 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Ipsen EO, Madsen KS, Chi Y, Pedersen-Bjergaard U, Richter B, Metzendorf MI, Hemmingsen B. Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus. Cochrane Database Syst Rev. 2020 Nov 19;11(11):CD013516. doi: 10.1002/14651858.CD013516.pub2.
PubMed 33210751
Study at a glance
From the registry record, last updated by the sponsor on 21 Jul 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of PPAR Ligands on Ectopic Fat Accumulation and Inflammation in Subjects With Impaired Glucose Tolerance
- ClinicalTrials.gov ID
- NCT00470262
- Acronym / sponsor ID
- ENDA-020-06S
- Conditions
- Metabolic Syndrome X, Prediabetic State
- Keywords
- fatty acid oxidation complex, fenofibrate, Inflammation, Peroxisome Proliferator-Activated Receptors, pioglitazone, Prediabetic State, insulin resistance
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 27 participants (actual)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Study start
- Jan 2007
- Primary completion
- Dec 2012 (actual)
- Study completion
- Jun 2014 (actual)
- First posted
- 7 May 2007 (estimated)
- Results
- Posted 21 Jul 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The relationship between obesity and insulin resistance is known, however the mechanism(s) associating obesity with insulin resistance is not well understood. Inflammation and accumulation of fat in non fat tissue (like muscle) are conditions found on obesity which could be the potential link between obesity and insulin resistance. This study is designed to test the effects of two different drugs on numerous features of the obesity and insulin resistance in subjects with impaired glucose tolerance. Impaired glucose tolerance is a condition where blood sugar is too high after drinking a sugary drink containing 75 grams of sugar. Impaired glucose tolerant subjects are insulin resistant and at risk of developing diabetes. The drugs to be used are fenofibrate and pioglitazone. Fenofibrate is used to reduce the amount of fat (triglycerides) in the blood while pioglitazone is routinely used to make the body more sensitive to insulin in patients with diabetes. The purpose of this study is to compare the effects of either of these two medications (pioglitazone and fenofibrate) alone or the combination of both on fat accumulation in body (muscle) and inflammation. The amount of fat accumulation in muscle is thought to affect insulin sensitivity. In addition, the changes in the level of proteins produced by fat tissues will be studied in response to the two medications in this study. These proteins are thought to be involved in diabetes and insulin resistance.
These studies are designed to examine fundamental clinical mechanisms underlying the metabolic syndrome and diabetes.
Detailed description
The correlation between obesity, inflammation and ectopic fat accumulation is well recognized; however, the mechanism(s) responsible for obesity induced insulin resistance is not well understood. The investigators will focus on lipotoxicity and inflammation as the link between obesity and insulin resistance. The factors leading to inflammation and ectopic lipid accumulation in obesity and the best intervention to reverse this pathophysiology are not clear. In this study, the investigators will examine inflammation in adipose tissue and muscle lipid mechanism in response to Peroxisome Proliferator Activated Receptors (PPAR) and ligands have synergistic anti-inflammatory effects in adipose tissue and activation of PPAR and decrease muscle lipid oxidation and redistribution of lipid from muscle to adipocytes respectively. The combination of both medications will be particularly effective in reducing inflammation and muscle lipid accumulation.
In this study, IGT subjects will be randomized to treatment with PPAR ligand (fenofibrate), PPAR ligand (pioglitazone) or combination of both for 10 weeks. Baseline studies will include assessment of body composition, insulin sensitivity, muscle and fat biopsies. All studies will be repeated after treatment with fenofibrate, pioglitazone or combination of both.
Specific Aims (SA) are as follows:
SA 1. Insulin sensitivity and Intramyocellular lipid (IMCL) from muscle biopsy specimens will be measured in response to different treatments (PPAR , and combination of both ligands).
SA 2. The rate of fatty acid oxidation and the number of mitochondria in muscle will be measured in response to PPAR ligands.
SA 3. The anti-inflammatory effects of PPAR and ligands will be studied by the measurement of the number of adipose tissue macrophages and the rate of macrophages apoptosis in fat biopsy specimens. In addition, the plasma levels and expression of proinflammatory proteins will be studied in response to different treatment.
SA 4. The rate of SUMOylation of PPAR (a novel mechanism regulating anti-inflammatory effects of PPAR ligands) will be studied in response to PPAR , ligand or combination of both.
These studies are designed to examine fundamental clinical mechanisms underlying the metabolic syndrome and diabetes.
Potential Impact on Veterans Health Care: The national obesity/diabetes epidemic is magnified in the VA, and the cost of caring for these patients is enormous. This study will provide data on the mechanism of action of these drugs, which will improve the investigators' understanding of these drugs, impaired glucose tolerance, and treatment of metabolic syndrome. From the clinical perspective, this study uses drugs to treat patients with IGT, which is rapidly becoming recognized as a "disease" because of its association with coronary artery disease risk factors, and because of its high rate of progression to T2DM. If these drugs were shown to improve the care of patients, then they would eventually be a cost savings to the VA, either by choosing the less expensive drug, or by using the drug that delays the progression of the disease, and improves the care of the patient by preventing complications.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Fenofibrate 145 mg PO QD and Pioglitazone 45 mg PO QD | Other | Drug: Fenofibrate 145mg PO QD, Drug: Pioglitazone 45 mg PO QDTreatment with pioglitazone and fenofibrate in subjects with pre diabetes |
| Fenofibrate 145 mg PO QD | Other | Drug: Fenofibrate 145mg PO QDTreatment with fenofibrate in subjects with pre diabetes |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Impaired glucose tolerance and/or impaired fasting glucose and/or metabolic syndrome
- Age 18-65
- BMI 28-38
Key exclusion criteria (3 listed)
- Renal insufficiency: creatinine.1.4
- Liver disease: ALT.2x normal, congestive heart failure, history of documented coronary artery disease, concomitant use HMG CoA-reductase inhibitors (statins)
- Concurrent use of ASA, steroids and other anti-inflammatory agents
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Fenofibrate 145mg PO QDAlso: TricorSubjects will be randomized to either fenofibrates or combination of both fenofibrate and pioglitazone | Drug | Fenofibrate 145 mg PO QD, Fenofibrate 145 mg PO QD and Pioglitazone 45 mg PO QD |
| Pioglitazone 45 mg PO QDAlso: ActosSubjects will be randomized to either fenofibrate 145 mg PO QD or a combination of both fenofibrate 145 mg PO QD and pioglitazone 45 mg PO QD | Drug | Fenofibrate 145 mg PO QD and Pioglitazone 45 mg PO QD |
Primary outcome
Insulin Sensitivity
Time frame: 3 months
Insulin sensitivity was measure through frequently sampled intravenous glucose tolerance test. Subjects presented to research center fasting. Blood samples were collected at -21, -11, and -1 minutes. At time t=0 initiates the start of the IVGTT and the injection of glucose into the non-sampling arm. The glucose dose was calculated as 11.4g/m2 of body surface area, given as a 50% dextrose solution. This glucose injection was administered over 60 seconds or less. At time t=20 minutes, an insulin dose of 0.04u/kg was administered over 30 seconds. Blood samples were collected at times t=2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 40, 50, 70, 90, 100, 120, 140, 160, and 180. If blood sugar did not return to a steady state the test was continued to t= 210 or t= 240.
1 secondary outcome
IMCL
Time frame: 3 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Jul 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 33210751Ipsen EO, Madsen KS, Chi Y, Pedersen-Bjergaard U, Richter B, Metzendorf MI, Hemmingsen B. Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus. Cochrane Database Syst Rev. 2020 Nov 19;11(11):CD013516. doi: 10.1002/14651858.CD013516.pub2.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Neda Rasouli, MD principal investigator
VA Eastern Colorado Health Care System, Denver
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Fenofibrate 145mg PO QD and Pioglitazone 45 mg PO QD in people with Metabolic Syndrome X and Prediabetic State, run by VA Office of Research and Development at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Jul 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 21 Jul 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Insulin Sensitivity (time frame: 3 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00470262, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jul 2016.