Metabolic Syndrome, Hypertriglyceridemia
Conditions
Keywords
triglycerides, HDL-cholesterol, insulin resistance, omega-3 fatty acids, niacin
Brief summary
This research study is being conducted to test the effects of two drugs on blood lipids (cholesterol and triglycerides) and blood sugar (glucose) levels in patients with diabetes or pre-diabetes (both of which have a condition called insulin-resistance). These products are Niaspan (extended release nicotinic acid) and Omacor (omega-3 acid ethyl esters). We hypothesize that the combination of Niaspan and Omacor will reduce serum triglyceride levels, increase HDL-cholesterol levels and do so without altering glucose levels.
Detailed description
The insulin resistance syndrome (IRS) afflicts approximately 25% of the US adult population. Its principal components include some or all of the following: central obesity, elevated triglyceride levels, decreased high density lipoprotein cholesterol (HDL-C) levels, a preponderance of small, dense low density lipoprotein (LDL) particles, hyperglycemia, hypertension, and increased thrombotic tendency. Subjects with the IRS are at increased risk for type 2 diabetes and/or coronary heart disease (CHD). While lifestyle changes (diet and exercise) often improve many of the manifestations of the IRS, pharmacotherapy is often needed to normalize individual components. In recent studies from our laboratory, niacin and fish oil (n-3 fatty acids, FA) used in combination in insulin resistant individuals led to an expected improved the lipid phenotype (reduced triglycerides, increased HDL-C, and fewer, small, dense LDL particles). What was not expected, however, was that an important marker of adipose tissue insulin resistance - meal-induced suppression of free fatty acid (FFA) flux - would be improved as well. Further, knowing that these agents (given as monotherapy) have been reported to worsen glycemia in diabetic subjects, we were surprised to find no significant deterioration in glycemic control. Further preliminary studies in patients with poorly-controlled type 2 diabetes confirmed the ability of this combination of over-the-counter natural agents to significantly improve the lipid profile without adverse effects on glycemia. Our working hypothesis is that excessive FFA flux from adipose tissue raises serum triglyceride concentrations and leads to other manifestations of the IRS. FFA flux is chronically elevated in insulin resistant subjects due to the insensitivity (i.e., resistance) of their adipocytes to the anti-lipolytic effects of insulin. Released FFA (especially from visceral adipose depots) stimulate hepatic triglyceride synthesis, leading to elevated serum triglyceride levels which subsequently contribute to reduced HDL-C and increased small, dense LDL concentrations. In addition, a high FFA flux can interfere with whole body glucose disposal. If this hypothesis is true, then interventions that improve adipocyte insulin sensitivity may be expected to improve a spectrum of risk factors associated with the insulin resistant state. Since our preliminary studies support this hypothesis, we propose the following four specific aims which will be tested in a 4-arm, randomized, placebo-controlled, double blind trial: Specific Aim 1. To test the hypothesis that n-3 FA and niacin (given singly and in combination) will enhance insulin-mediated suppression of FFA rate of appearance (Ra; a surrogate for adipose tissue insulin sensitivity) in insulin resistant subjects. Specific Aim 2. To test the hypothesis that n-3 FA and niacin (given singly and in combination) will improve insulin sensitivity in insulin resistant subjects. Specific Aim 3. To test the hypothesis that n-3 FA and niacin (given singly and in combination) will reduce VLDL-triglyceride production rates in insulin resistant subjects. Specific Aim 4. To test the hypothesis that n-3 FA and niacin (given singly and in combination) will improve the dyslipidemic profile (i.e., reduce serum triglyceride and small, dense LDL concentrations and elevate HDL-C concentrations) in insulin resistant subjects. At the completion of these studies, we expect to have detailed information on the potential therapeutic efficacy and the kinetic mechanism of action of combined treatment with n-3 FA and niacin. A better understanding of the action of these agents should lead to a clearer appreciation of the relationship between FFA flux and insulin resistance, to more effective therapy for the dyslipidemia of insulin resistance and ultimately to reduced risk for CAD in this burgeoning patient population.
Interventions
4 q qd
2 g qpm
DRUGplacebo
omacor placebo plus niaspan placebo
omega-3 acid ethyl esters 4 g qd and extended release niacin, titrate up to 2 g Qpm
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of South Dakota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 69 Years
Healthy volunteers
No
Inclusion criteria
40 and 69 years of age Male or female (without hormonal cycling as described below) BMI \> 25 Fasting serum triglycerides \> 150 mg/dL Ratio of TG/HDL-C \> 3.5
Exclusion criteria
BMIs \> 40 kg/m2 TG \> 750 mg/dL HDL-C \< 10 mg/dL Presence of other secondary causes of dyslipidemia or hyperglycemia such as hepatic, renal, thyroid or other endocrine diseases History of hypersensitivity to niacin or fish oils History of gout, hepatitis, peptic ulcer or cardiovascular disease Presence of diabetes mellitus, whether controlled by diet or drugs. (We will eliminate subjects with undiagnosed diabetes by screening for fasting glucose \> 126 mg/dL) Use of any dietary supplements providing more than 50 mg of niacin or 100 mg of n-3 FA Use of any herbal preparations or weight-loss products Taking any lipid-lowering drugs for at least four weeks prior to screening for the study Medically-required treatment with nitrates, calcium channel blockers, or adrenergic blocking agents (per the Niaspan package insert) Hemoglobin \< 12 g/dL (owing to the significant amount of blood being drawn) LDL-C \> 145 mg/dL. (This restriction will prevent the randomization of any subject whose LDL-C levels, if assigned to an n-3 FA group, might rise by 10% and thus exceed 160 mg/dL) Known substance abuse Participation in a clinical drug trial anytime during the 30 days prior to screening Anyone whom the investigators judge to be a poor candidate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum TG | 4 months | Change From Baseline to 4 Months in Serum Triglycerides |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Non-HDL-C | baseline and 4 months | Change From Baseline to 4 Months in Serum Non-HDL cholesterol |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from throughout the Sanford Clinic - Clinical Research Services in Sioux Falls by posted advertisements in public places and at sponsored health fairs.
Pre-assignment details
68 subjects willing to participate and qualified were subjected to a 6 week single blind run in period where they were given placebo omega-3 and placebo niacin. Baseline was defined as values and metrics after this run in period.
Participants by arm
| Arm | Count |
|---|---|
| Dual Placebo Dual placebo
placebo: omacor placebo plus niaspan placebo | 17 |
| Niaspan niaspan
extended release niacin: 2 g qpm | 17 |
| Lovaza lovaza
omega-3 acid ethyl esters: 4 q qd
omega-3 acid ethyl esters: 4 g qd | 17 |
| Combined Therapy combined therapy
combined treatment: omega-3 acid ethyl esters 4 g qd and extended release niacin, titrate up to 2 g Qpm | 17 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 2 | 0 | 1 |
Baseline characteristics
| Characteristic | Dual Placebo | Niaspan | Lovaza | Combined Therapy | Total |
|---|---|---|---|---|---|
| Age, Continuous | 45 years | 49 years | 44 years | 48 years | 46 years |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 10 Participants | 8 Participants | 33 Participants |
| Sex: Female, Male Male | 10 Participants | 9 Participants | 7 Participants | 9 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 15 | 0 / 15 | 0 / 17 | 0 / 13 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 0 / 17 | 0 / 13 |
Outcome results
Primary
Serum TG
Change From Baseline to 4 Months in Serum Triglycerides
Time frame: 4 months
Population: Those subjects with complete data baseline to end
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dual Placebo | Serum TG | 233 mg/dl | Standard Deviation 162 |
| Niaspan | Serum TG | 157 mg/dl | Standard Deviation 52 |
| Lovaza | Serum TG | 176 mg/dl | Standard Deviation 63 |
| Combined Therapy | Serum TG | 156 mg/dl | Standard Deviation 56 |
Secondary
Non-HDL-C
Change From Baseline to 4 Months in Serum Non-HDL cholesterol
Time frame: baseline and 4 months
Population: all subjects with pre and post treatment data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dual Placebo | Non-HDL-C | 145 mg/dl | Standard Deviation 23 |
| Niaspan | Non-HDL-C | 155 mg/dl | Standard Deviation 43 |
| Lovaza | Non-HDL-C | 133 mg/dl | Standard Deviation 34 |
| Combined Therapy | Non-HDL-C | 170 mg/dl | Standard Deviation 36 |