• Services
  • Surgical Weight Control
  • Joint Replacement
  • Edwards Comprehensive Cancer Center
  • Family Medical Centers
  • Mother & Baby Health
  • Emergency / Trauma Services
  • Complete A-Z list
• News & Events
  • What's New
  • Magazine Highlights
  • Calendar of Events
  • Newsbreaks
  • Newsletters
• Patients & Visitors
  • Patients & Visitors - Main
  • Rights & Responsibilities
  • Advance Directives
  • Shuttle Service & Valet Parking
  • Billing & Financial Information
  • Find a Physician
• For Physicians
  • For Physicians - Main
  • HealthNet Aeromedical
  • Patient Transfer Center
  • Patient Scheduling & Referral
• Employment
  • Employment - Main
  • Current Openings
  • Hospital Ancillary Credentialing
  • Employee Assistance
• Special Features
  • CHH eCards
  • Interactive Health Tools
  • Speakers Bureau
  • 360° Views
  • Photo Gallery
  • Online Nursery
  • Physician Directory
• Facilities & Projects
  • North Patient Tower

Niacin for Dyslipidemia: Safety Versus Efficacy

Niacin (nicotinic acid) is a water-soluble vitamin with clinically important effects on lipids and lipo-proteins. The attractiveness of niacin is counter-balanced by poor tolerance with standard formulations mostly in the form of flushing or other cutaneous reactions.

Niacin is commercially available as immediate-release (IR) and extended-release (ER) form-ulations. Most of these products are available over the counter and have neither undergone review by the Food and Drug Administration (FDA) nor received approval as lipid-altering agents. Two IR products, [Niacor (Upsher-Smith) and Nicolar (Aventis)] have FDA-approved labeling for use as lipid-altering therapies. IR niacin products are quickly absorbed, with peak serum levels attained within thirty to sixty minutes. ER niacin products, also referred to as timed release, controlled release, or sustained release (SR), maintain serum niacin levels by retarding its absorption through such techniques as tight tablet compression, combination with an inert resinous base, bonding to a carrier molecule, or formulation in a polygel, waxy, or plastic matrix. Dissolution times of ER products are variable, even within manufacturing lots of the same product, but often exceed twelve hours. The pharmacokinetics of ER niacin products are relatively complex and depend on the particular formulation tested. One ER niacin product, Niaspan (Kos Pharmaceuticals), has FDA-approved labeling for use in dyslipidemia; other ER niacin products are sold over the counter as dietary supplements. Niaspan has a dissolution time of eight to twelve hours, intermediate between the IR and most other ER niacin products.

The major therapeutic action of niacin is to decrease normal mobilization of free fatty acids from adipose tissue, which leads to prominent reductions in triglycerides and very-low-density-lipoprotein (VLDL) cholesterol synthesis and hepatic secretion of smaller VLDL cholesterol particles that contain less triglycerides. Niacin increases HDL by recirculating these cells by reverse cholesterol transport through the liver.

Niacin undergoes hepatic detoxification by conjugation with glycine, forming nicotinuric acid, which is then excreted in the urine along with unchanged niacin. The other pathway involves the generation of nicotinamide, which is then metabolized to a variety of pyrimidine breakdown products.

Cutaneous flushing, an uncomfortable sensation of warmth, reddening, itching, or tingling, is produced by dilation of the small subcutaneous blood vessels. It occurs most often on the upper body, affects almost all users initially, and leads to discontinuation in ten to fifty percent of patients. The frequency of flushing is related to the rate of gastrointestinal absorption; ER niacin products were developed to circumvent this problem.

While ER products are associated with less flushing, they have caused hepatotoxicity. In a randomized, double-blind, escalating-dosage study comparing IR and ER niacin, none of the ER niacin-treated patient experienced flushing, but three fourths had to be withdraw from the trial, mostly because their transaminase levels had increased to values greater than three times the upper limit of normal; many patients had symptoms of hepatic dysfunction. Conversely, about fifty percent of patients treated with IR niacin had flushing, but none of these patients had significant changes in transaminase levels. When Niaspan was compared with IR niacin, it was shown to produce significantly less flushing and no increase in transaminases for the doses used.

These contrasting adverse-effect profiles ? flushing with IR niacin and hepatotoxicity with most ER preparations ? are related to two metabolic pathways. The conjugation pathway leads to prostaglandin-mediated vasodilation, while the nicotin-amide pathway results in hepatotoxicity, as denoted in Figure 1. This is why IR niacin readily causes flushing and ER niacin causes hepato-toxicity, especially at doses exceeding two grams per day.

Another important adverse effect associated with niacin therapy is hyperglycemia. Hyperglycemia does not occur in all patients who receive niacin, and the average change in fasting glucose levels in any population of subjects participating in controlled clinical trials is typically modest and transient.

IR niacin increases HDL cholesterol levels by fifteen to thirty-five percent, lowers LDL cholesterol by five to twenty-five percent and decreases triglyceride levels by twenty to fifty percent. Administering niacin in dosages of less than two grams per day produces near maximal effects on HDL cholesterol and triglyceride levels without the adverse reactions associated with higher doses. ER niacin is generally less effective at altering triglyceride and HDL cholesterol levels. The LDL cholesterol reduction associated with these pro-ducts is generally comparable to IR niacin. When using ER niacin products with a greater than twelve hour absorption period, some of the LDL cholesterol lowering effect may be due to a hepatotoxic effect (the more hepatic dysfunction is produced by niacin, the less cholesterol is produced and the lower the circulating LDL cholesterol levels). Unlike other ER products, Niaspan produces about the same changes in all lipid measures as IR niacin at the same daily dosages. Niaspan?s eight to twelve hour duration of action, when given at bedtime, reduces the awareness of flushing.

IR niacin should be initiated with small divided doses (e.g., 50mg to 100mg two or three times daily for the first week) and taken with meals. The dose should be increased slowly over several weeks to achieve treatment goals. The usual daily dose of IR niacin is 1.5g to 3g. The maximum recommended dose is typically 4.5g daily.

ER niacin should be initiated at 500 mg at bedtime with a snack for one month and then increased to 1g for one month. At this time the dose can be further titrated upward by 500 mg increments at a minimum of one-month intervals according to patient response. A maximum daily dose of 2g should not be exceeded.

IR niacin has long been used in the management of patients with dyslipidemia. Although its major limitation is the frequency of flushing, this adverse effect is often temporary and can be minimized by dividing doses, administering the drug with food, or pretreating patients with aspirin. ER niacin products cause less flushing, but those with an absorption period that exceeds twelve hours have been associated with hepatotoxicity. Liver injury is usually mild and reversible but can occasionally lead to fulminant hepatic failure, especially when daily doses exceed 2 grams. ER niacin is also less effective in lowering triglyceride and raising HDL cholesterol levels compared with IR niacin. Niaspan provides a dissolution time that is between IR and non-prescription ER niacin and is better tolerated. Its marketing has been approved by the FDA for the treatment of adult dyslipidemia, and it is available by prescription only. It has similar efficacy to IR niacin, but produces less flushing and has a low risk of causing hepatotoxicity.