Metabolic Syndrome
Conditions
Keywords
Inflammation, Visceral adiposity, TNF, Adiponectin, glucose tolerance, endothelial function, metabolic syndrome
Brief summary
This study will investigate whether etanercept will result in improved inflammatory indices, glucose tolerance and endothelial function in patients with the metabolic syndrome.
Detailed description
Metabolic syndrome is an increasingly prevalent disorder associated with elevated risks of type II DM (diabetes mellitus) and cardiovascular morbidity and mortality. A subclinical inflammatory state is thought to contribute to the pathophysiology of metabolic syndrome, insulin resistance, and coronary artery disease (CAD). Tumor Necrosis Factor (TNF) -alpha is an inflammatory cytokine that is increased in a spectrum of inflammatory diseases as well as in insulin resistance. TNF-alpha antagonists are clinically effective in the inflammation of arthritides, and have recently been shown by our group to decrease inflammatory cardiovascular risk markers in metabolic syndrome. Data suggests that adiponectin, a recently discovered adipocytokine that may protect against the development of insulin resistance and atherosclerosis, may be downregulated by TNF-alpha. In addition, population based studies have shown that those with the highest levels of TNF-alpha have an increased relative risk of cardiovascular morbidity while rheumatoid arthritis patients treated with TNF-alpha blockade appear protected from cardiovascular disease. We will perform a 6-month study in which we will administer etanercept, a TNF-alpha receptor fusion protein, to subjects with metabolic syndrome to investigate its effect on surrogate markers of cardiovascular disease, including inflammatory markers, adiponectin and glucose tolerance and endothelial function. The results of the proposed study will have broad implications regarding the physiological role of TNF-alpha on the inflammatory cascade, cardiovascular indices and endothelial function.
Interventions
DRUGPlacebo
50 mg one syringe sc 2x per week for three months followed by 50 mg one syringe sc 1X per week for three months
DRUGEtanercept
50 mg one syringe sc 2X per week for three months followed by 50 mg one syringe sc 1X per week for three months
Sponsors
Amgen
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. Hyperinsulinemia in the upper quartile of the non-diabetic population defined as \>= 10 mU/mL (based on Framingham Data, oral communication, James Meigs, MD) or fasting glucose 110-126 mg/dL 2. Plus two of the following: * Abdominal obesity defined by waist hip ratio \> 0.90 for men and \> 0.85 for women and BMI \> 30 kg/m2 * Dyslipidemia including serum triglycerides \>= 150 mg/dl or serum high density lipoprotein (HDL) \< 0.9 mmol/L for men (35 mg/dL) and \< 1.0 mmol/L (39mg/dL) for women * Hypertension defined as blood pressure \>= 140/90 or on medication
Exclusion criteria
1. Age \< 18 or \> 60 years 2. Body mass index (BMI) \< 30 kg/m2 3. Positive tuberculosis (purified protein derivative \[PPD\]) skin test (5mm induration or more) on screening 4. Mycobacterial disease treated less than 6 months. 5. Current or recurrent infection or any underlying condition that may predispose to infection or anyone who has been admitted to the hospital due to bacteremia, pneumonia or any other serious infection. 6. Therapy with glucocorticoid or immunosuppressant at time of recruitment or within past 3 months. 7. Prior or concurrent cyclophosphamide therapy 8. Use of a live vaccine 90 days prior to, or during this study. 9. History of blood dyscrasia including any kind of anemia, thrombocytopenia, pancytopenia. Women with a reversible cause of anemia that has resolved will be eligible. 10. Hemoglobin \< 11 g/dl 11. History of malignancy (except patients with surgically cured basal cell or squamous cell skin cancers who will be eligible) 12. History of organ transplantation 13. HIV-positive status determined by HIV test at screening or known history of any other immuno-suppressing disease. 14. Hepatitis B or hepatitis C infection detected at screening, lupus (SLE), history of multiple sclerosis, transverse myelitis, optic neuritis or epilepsy 15. Patients with known autoimmune or inflammatory conditions (excluding patients with stable, treated hypothyroidism) 16. Severe comorbidities (diabetes mellitus requiring insulin, congestive heart failure (CHF) (EF\<50% at baseline will be exclusionary) of any severity, myocardial infarction (MI), cerebral vascular accident (CVA) or transient ischemic attack (TIA) within 3 months of screening visit, unstable angina pectoris, oxygen-dependent severe pulmonary disease 17. Uncontrolled systolic blood pressure \> 150 mmHg or diastolic blood pressure \> 100 mmHg 18. Fasting blood glucose \> 126 mg/dL 19. Creatinine \> 1.5 20. Current use of insulin, any oral anti-hyperglycemic agents (including insulin sensitizing agents). Initiation of insulin, oral hypoglycemics, or insulin sensitizing agents during the study will result in discontinuation from the study. 21. Initiation of statins, niacin, antihypertensive or fibrate therapy within 6 weeks of the study. Chronic use of fibrates, niacin, or antihypertensives for \> 6 weeks prior to study initiation at a stable dose is not exclusionary, but chronic use of statins for \> 6 months is exclusionary. Initiation of statins, fibrates, niacin or antihypertensive treatments during the study is not exclusionary but will be considered in the analysis (see Protection against risks). 22. Positive pregnancy test or lactating females 23. Women of child-bearing potential not currently using non-hormonal birth control methods including barrier methods (intrauterine device \[IUD\], condoms, diaphragms) or abstinence 24. Subject is currently enrolled in another investigational device or drug trial(s), or subject has received other investigational agent(s) within 28 days of baseline visit. 25. Subjects who have known hypersensitivity to Enbrel or any of its components or who is known to have antibodies to etanercept 26. Concurrent sulfasalazine therapy 27. History of recent alcohol or substance abuse (\< 1 year) 28. Any condition judged by the patient's physician to cause this clinical trial to be detrimental to the patient. 29. History of non-compliance with other therapies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| C-reactive Protein (CRP) | 6 months | As a measure of C-reactive protein (CRP), which is an inflammatory marker, Log10 of the CRP at 6 months is reported |
| Interleukin-6 (IL-6) | 6 months | 6 month value of IL-6 (pg/mL) |
| Adiponectin | 6 months | The ratio of circulating high molecular weight (HMW) adiponectin to total adiponectin ratio (HMW:total Adiponectin) at 6 months is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cardiac Echo Ejection Fraction (EF) | Baseline to 6 months | change in EF (6mo - baseline). Please note that the value given is the absolute change in EF (which has units of percent), not the percent change in the variable. |
| Body Composition | 6 months | 6 month visceral adipose tissue (cm\^2) - cross-sectional area of the visceral adipose tissue at the level of the 4th lumbar vertebrae was measured using single-slice abdominal computed tomography (CT) scan |
| Tumor Necrosis Factor (TNF) Receptor | 6 months | Circulating concentrations of Tumor necrosis factor receptor 2 (TNFR2) at 6 months |
| Glucose Tolerance | 6 months | Fasting glucose (mg/dL) at 6mo |
| Lipid Levels | 6 months | total cholesterol (mg/dL) at 6 months |
| Adipocyte Messenger Ribonucleic Acid (mRNA) Levels of Adipocytokines Including Tumor Necrosis Factor (TNF) -Alpha | 6 months | fold-change in subcutaneous adipose tissue expression of TNF-alpha (mRNA) after 6 months |
| Other Adipocytokines | 6 months | circulating resistin at 6 months |
| Endothelial Function | 6 months | Reactive Hyperemia Index (RHI) using peripheral artery tonometry (using Endo-PAT 2000). Peripheral artery tonometry measures blood flow in the tip of the index finger at baseline and in response to vaso-occlusion (inflated blood pressure cuff). The reactive hyperemia index is an index of vasodilation after occlusion compared to baseline. A higher value indicates better vasoreactivity. As this is a relatively new test, there are no thoroughly validated clinically utilized norms. |
| White Blood Cell (WBC) Count | Baseline to 6 months | Change in WBC during study (WBC at six months minus WBC at baseline) |
Countries
United States
Participant flow
Recruitment details
Recruitment period 12/2006 to 3/2009
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo injections, subcutaneously, twice weekly x 3 months, then once weekly x 3 months | 24 |
| Etanercept Etanercept 50mg subcutaneously twice weekly x 3 months, then once weekly x 3 months | 16 |
| Total | 40 |
Baseline characteristics
| Characteristic | Etanercept | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 24 Participants | 40 Participants |
| Age Continuous | 41 years STANDARD_DEVIATION 9 | 47 years STANDARD_DEVIATION 8 | 45 years STANDARD_DEVIATION 9 |
| Region of Enrollment United States | 16 participants | 24 participants | 40 participants |
| Sex: Female, Male Female | 8 Participants | 12 Participants | 20 Participants |
| Sex: Female, Male Male | 8 Participants | 12 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 24 | 6 / 16 |
| serious Total, serious adverse events | 2 / 24 | 2 / 16 |
Outcome results
Primary
Adiponectin
The ratio of circulating high molecular weight (HMW) adiponectin to total adiponectin ratio (HMW:total Adiponectin) at 6 months is reported.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adiponectin | 0.30 (ratio) | Standard Error 0.08 |
| Etanercept | Adiponectin | 0.40 (ratio) | Standard Error 0.15 |
Comparison: within subject percent changes were calculated for each time point, then repeated measures ANCOVA controlling for age and race performedp-value: 0.02Repeated Measures ANCOVA
Primary
C-reactive Protein (CRP)
As a measure of C-reactive protein (CRP), which is an inflammatory marker, Log10 of the CRP at 6 months is reported
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | C-reactive Protein (CRP) | 0.61 Log10 mg/L | Standard Error 0.06 |
| Etanercept | C-reactive Protein (CRP) | 0.68 Log10 mg/L | Standard Error 0.18 |
Comparison: treatment effect (etanercept vs. placebo) using ANCOVA including baseline CRP, age, and racep-value: 0.2ANCOVA
Primary
Interleukin-6 (IL-6)
6 month value of IL-6 (pg/mL)
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Interleukin-6 (IL-6) | 8.2 pg/mL | Standard Error 1.1 |
| Etanercept | Interleukin-6 (IL-6) | 11.3 pg/mL | Standard Error 2.1 |
Comparison: within subject percent changes calculated for each timepoint and repeated measures ANCOVA controlling for age and race performedp-value: 0.92Repeated Measures ANCOVA
Secondary
Adipocyte Messenger Ribonucleic Acid (mRNA) Levels of Adipocytokines Including Tumor Necrosis Factor (TNF) -Alpha
fold-change in subcutaneous adipose tissue expression of TNF-alpha (mRNA) after 6 months
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adipocyte Messenger Ribonucleic Acid (mRNA) Levels of Adipocytokines Including Tumor Necrosis Factor (TNF) -Alpha | 2.3 fold-change | Standard Error 0.7 |
| Etanercept | Adipocyte Messenger Ribonucleic Acid (mRNA) Levels of Adipocytokines Including Tumor Necrosis Factor (TNF) -Alpha | 1.1 fold-change | Standard Error 0.3 |
Secondary
Body Composition
6 month visceral adipose tissue (cm\^2) - cross-sectional area of the visceral adipose tissue at the level of the 4th lumbar vertebrae was measured using single-slice abdominal computed tomography (CT) scan
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Body Composition | 206 cm^2 | Standard Error 18 |
| Etanercept | Body Composition | 186 cm^2 | Standard Error 14 |
Comparison: ANCOVA controlling for baseline value, age, racep-value: 0.59ANCOVA
Secondary
Cardiac Echo Ejection Fraction (EF)
change in EF (6mo - baseline). Please note that the value given is the absolute change in EF (which has units of percent), not the percent change in the variable.
Time frame: Baseline to 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cardiac Echo Ejection Fraction (EF) | 1.1 percent | Standard Error 0.7 |
| Etanercept | Cardiac Echo Ejection Fraction (EF) | -1.1 percent | Standard Error 1.2 |
p-value: 0.11t-test, 2 sided
Secondary
Endothelial Function
Reactive Hyperemia Index (RHI) using peripheral artery tonometry (using Endo-PAT 2000). Peripheral artery tonometry measures blood flow in the tip of the index finger at baseline and in response to vaso-occlusion (inflated blood pressure cuff). The reactive hyperemia index is an index of vasodilation after occlusion compared to baseline. A higher value indicates better vasoreactivity. As this is a relatively new test, there are no thoroughly validated clinically utilized norms.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Endothelial Function | 1.8 (index) | Standard Error 0.11 |
| Etanercept | Endothelial Function | 2.0 (index) | Standard Error 0.15 |
Comparison: ANCOVA controlling for baseline value, age, racep-value: 0.46ANCOVA
Secondary
Glucose Tolerance
Fasting glucose (mg/dL) at 6mo
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Glucose Tolerance | 95 mg/dL | Standard Error 5 |
| Etanercept | Glucose Tolerance | 91 mg/dL | Standard Error 6 |
Comparison: percent change calculated then repeated measures ANCOVA performed controlling for age and racep-value: 0.02repeated measures ANCOVA
Secondary
Lipid Levels
total cholesterol (mg/dL) at 6 months
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Lipid Levels | 196 mg/dL | Standard Error 9 |
| Etanercept | Lipid Levels | 201 mg/dL | Standard Error 12 |
Comparison: ANCOVA controlling for baseline value, age, and racep-value: 0.55ANCOVA
Secondary
Other Adipocytokines
circulating resistin at 6 months
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Other Adipocytokines | 6.7 ng/mL | Standard Error 0.5 |
| Etanercept | Other Adipocytokines | 8.6 ng/mL | Standard Error 1.1 |
Comparison: within subject percent changes calculated then repeated measures ANCOVA performed controlling for age and racep-value: 0.08Repeated Measures ANCOVA
Secondary
Tumor Necrosis Factor (TNF) Receptor
Circulating concentrations of Tumor necrosis factor receptor 2 (TNFR2) at 6 months
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Tumor Necrosis Factor (TNF) Receptor | 2573 pg/mL | Standard Error 148 |
| Etanercept | Tumor Necrosis Factor (TNF) Receptor | 4518 pg/mL | Standard Error 329 |
Comparison: within subject percent changes calculated then repeated measures ANCOVA controlling for age and race performedp-value: <0.0001Repeated measures ANCOVA
Secondary
White Blood Cell (WBC) Count
Change in WBC during study (WBC at six months minus WBC at baseline)
Time frame: Baseline to 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | White Blood Cell (WBC) Count | -0.17 th/cumm | Standard Error 0.23 |
| Etanercept | White Blood Cell (WBC) Count | -0.04 th/cumm | Standard Error 0.45 |
p-value: 0.78t-test, 2 sided