Niacin, N-3 Fatty Acids and Insulin Resistance
Condition: Metabolic Syndrome; Hypertriglyceridemia
MeSH terms: Metabolic Syndrome; Insulin Resistance; Hypertriglyceridemia
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): omega-3 acid ethyl esters; extended release niacin; placebo; omega-3 acid ethyl esters; combined treatment
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): 4 q qd; 2 g qpm; omacor placebo plus niaspan placebo; 4 g qd; omega-3 acid ethyl esters 4 g qd and extended release niacin, titrate up to 2 g Qpm
Other intervention name(s): lovaza omacor; niaspan; lovaza omacor; lovaza, omacor; niaspan
Intervention MeSH terms: Niacin; Nicotinic Acids
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: triglycerides; HDL-cholesterol; insulin resistance; omega-3 fatty acids; niacin