Niacin, N-3 Fatty Acids and Insulin Resistance
Information source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Metabolic Syndrome; Hypertriglyceridemia
Intervention: omega-3 acid ethyl esters (Drug); extended release niacin (Drug); placebo (Drug); omega-3 acid ethyl esters (Drug); combined treatment (Drug)
Phase: Phase 4
Status: Active, not recruiting
Sponsored by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Official(s) and/or principal investigator(s):
William S Harris, PhD, Principal Investigator, Affiliation: Sanford Research/USD
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.
Official title: Niacin, N-3 Fatty Acids and Insulin Resistance
Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study
Primary outcome: Serum TG and HDL-C
Secondary outcome: Insulin sensitivity, postprandial triglyceridemia, peripheral arterial tonometry
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
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.
Minimum age: 40 Years.
Maximum age: 69 Years.
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
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
Locations and Contacts
Sanford Clinic Clinical Research Services, Sioux Falls, South Dakota 57105, United States
Starting date: October 2007
Ending date: December 2008
Last updated: April 15, 2008