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Sponsored by: |
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) |
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Information provided by: | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) |
ClinicalTrials.gov Identifier: | NCT00286234 |
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.
Condition | Intervention | Phase |
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Metabolic Syndrome Hypertriglyceridemia |
Drug: omega-3 acid ethyl esters Drug: extended release niacin Drug: placebo Drug: combined treatment |
Phase IV |
Study Type: | Interventional |
Study Design: | Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study |
Official Title: | Niacin, N-3 Fatty Acids and Insulin Resistance |
Estimated Enrollment: | 60 |
Study Start Date: | October 2007 |
Estimated Study Completion Date: | December 2008 |
Estimated Primary Completion Date: | August 2008 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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1: Placebo Comparator
Dual placebo
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Drug: placebo
omacor placebo plus niaspan placebo
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2: Experimental
niaspan
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Drug: extended release niacin
2 g qpm
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3: Experimental
lovaza
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Drug: omega-3 acid ethyl esters
4 q qd
Drug: omega-3 acid ethyl esters
4 g qd
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4: Experimental
combined therapy
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Drug: combined treatment
omega-3 acid ethyl esters 4 g qd and extended release niacin, titrate up to 2 g Qpm
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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.
Ages Eligible for Study: | 40 Years to 69 Years |
Genders Eligible for Study: | Both |
Accepts 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
United States, South Dakota | |
Sanford Clinic Clinical Research Services | |
Sioux Falls, South Dakota, United States, 57105 |
Principal Investigator: | William S Harris, PhD | Sanford Research/USD |
Responsible Party: | Sanford Research/USD ( William S. Harris ) |
Study ID Numbers: | DK61486 |
Study First Received: | February 2, 2006 |
Last Updated: | April 15, 2008 |
ClinicalTrials.gov Identifier: | NCT00286234 History of Changes |
Health Authority: | United States: Food and Drug Administration; United States: Federal Government |
triglycerides HDL-cholesterol insulin resistance omega-3 fatty acids niacin |
Antimetabolites Vasodilator Agents Vitamin B Complex Hypertriglyceridemia Hyperlipidemias Metabolic Diseases Niacinamide Antilipemic Agents Trace Elements Cardiovascular Agents Insulin |
Hyperinsulinism Nicotinic Acids Vitamins Micronutrients Insulin Resistance Glucose Metabolism Disorders Metabolic Disorder Niacin Dyslipidemias Lipid Metabolism Disorders |
Antimetabolites Vasodilator Agents Vitamin B Complex Hypertriglyceridemia Hyperlipidemias Metabolic Diseases Disease Molecular Mechanisms of Pharmacological Action Growth Substances Antilipemic Agents Physiological Effects of Drugs Cardiovascular Agents |
Pharmacologic Actions Hyperinsulinism Pathologic Processes Vitamins Therapeutic Uses Syndrome Micronutrients Insulin Resistance Glucose Metabolism Disorders Niacin Dyslipidemias Lipid Metabolism Disorders |