• DOI:10.7326/0003-4819-139-12-200312160-00009
• Corpus ID: 23980567

Varying Cost and Free Nicotinic Acid Content in Over-the-Counter Niacin Preparations for Dyslipidemia

@article{Meyers2003VaryingCA,
  title={Varying Cost and Free Nicotinic Acid Content in Over-the-Counter Niacin Preparations for Dyslipidemia},
  author={Charles Daniel Meyers and Molly C. Carr and Sang Bong Park and John D. Brunzell},
  journal={Annals of Internal Medicine},
  year={2003},
  volume={139},
  pages={996-1002}
}

• C. Meyers, M. C. Carr, +1 author J. Brunzell
• Published 16 December 2003
• Medicine
• Annals of Internal Medicine

Key Summary Points: Types of Niacin Preparations No-flush (inositol hexaniacinate) Most expensive form ($21.70 per month); contains no free nicotinic acid Ineffective lipid lowering in humans; should not be used to treat dyslipidemia Sustained-release Less expensive form ($9.76 per month); contKey ains a full amount of free nicotinic acid Hepatotoxicity associated with several formulations; some brands are safe Immediate-release Least expensive form ($7.10 per month); contains a full amount of free nicotinic acid Used safely for more than 40 years; shown to prevent cardiovascular disease and death The essential role of nicotinic acid in human metabolism was first shown in 1937, when researchers found it prevented pellagra (1). Pellagra, which manifests as the triad of dermatitis, diarrhea, and dementia, is caused by an intracellular deficiency of the cofactor nicotinamide adenine dinucleotide. Nicotinic acid and its amide form, nicotinamide, prevent pellagra, as both are precursors of nicotinamide adenine dinucleotide. Initially called the pellagra-preventing, or PP, vitamins, nicotinic acid and nicotinamide were later classified as vitamin B3. The term niacin (nicotinic acid vitamin) was coined in 1942 and referred to both nicotinic acid and nicotinamide (2). The recommended daily allowance of niacin ranges from 14 to 18 mg (3); because bread and cereal are supplemented with niacin, pellagra is essentially nonexistent in the United States. With the discovery in 1955 that nicotinic acid (but not nicotinamide) in daily doses of 1000 to 4000 mg reduced total cholesterol level in hyperlipidemic persons (4), it became the first agent used to treat dyslipidemia (5). Although how nicotinic acid lowers lipid levels remains unclear, it improves the clinical lipid profile in several ways: Total triglyceride levels are reduced by 20% to 50% (6, 7); low-density lipoprotein (LDL) cholesterol levels are reduced by 10% to 25% (6, 7), including a preferential decrease in the more atherogenic population of small dense LDL (8); high-density lipoprotein (HDL) cholesterol levels are increased by 10% to 30%, with a preferential increase in the more atheroprotective HDL-2 subclass (9, 10); and lipoprotein(a) levels are lowered by 10% to 30% (11, 12). Such broad-ranging effects make nicotinic acid an effective tool in the treatment of most lipid disorders, including dyslipidemia of the metabolic syndrome (13). Nicotinic acid was also the first lipid-lowering medication to significantly reduce cardiovascular events in at-risk patients. The Coronary Drug Project (1969 to 1975), a randomized, placebo-controlled trial of 3908 men, showed that 6 years of nicotinic acid therapy reduced the occurrence of nonfatal myocardial infarction compared with placebo (14). After 9 more years of follow-up, patients receiving nicotinic acid also had an 11% reduction in all-cause mortality compared with those receiving placebo (15). More recent data have shown that nicotinic acid combined with a bile-acid sequestrant (16, 17) or a statin (18) causes angiographic regression of atherosclerosis and reduces clinical cardiovascular events. Despite the versatility of nicotinic acid in treating a range of lipid disorders and the compelling clinical evidence of mortality reduction, this medication has not become a first-line treatment. One reason for its underuse is the side effects. After administration of nicotinic acid in doses as low as 100 mg, cutaneous symptoms, including redness, itching, burning, and paresthesias, occur (19). This niacin flush begins as soon as 10 to 15 minutes after ingestion and lasts 30 to 60 minutes. The flushing is thought to be most intense when levels of free nicotinic acid are increasing in the serum (20). Fortunately, both the frequency and severity of flushing episodes decrease with repeated doses of nicotinic acid. Although many patients stop flushing within 1 week of initiating therapy, this side effect has contributed to discontinuance rates higher than 40% in some clinical series (21). Other less common but serious side effects include hepatotoxicity (22), insulin resistance and hyperglycemia (23), and hyperuricemia (24). A second reason for the underuse of nicotinic acid is confusion about the many prescription and over-the-counter preparations marketed as niacin. Niacin is classified as a dietary supplement, and therefore the production and marketing are not strictly regulated by the U.S. Food and Drug Administration (FDA). Without FDA regulation, over-the-counter niacin preparations are readily available and inexpensive, but the free nicotinic acid content is not guaranteed. Scores of companies sell hundreds of niacin products differing in name, appearance, formulation, dose, and cost. To add to the confusion, nicotinamide is also marketed as niacin, even though it has no lipid-lowering effects (4). The dizzying array of over-the-counter niacin products makes it difficult to know which preparations actually contain free nicotinic acid and might be efficacious in treating dyslipidemia. Over the last several years, patients have been referred to the University of Washington Medical Center Lipid Clinic in Seattle, Washington, because of apparent failure to respond to over-the-counter niacin therapy. In reviewing these cases, we became suspicious that some over-the-counter niacin products did not contain free nicotinic acid. This study was designed to evaluate 3 aspects of over-the-counter niacin preparations: 1) What types of over-the-counter niacin preparation are generally available? 2) What are the costs of the various over-the-counter niacin preparations? 3) What is the content of free nicotinic acid in these over-the-counter niacin preparations? Methods Procurement of Niacin Preparations Over-the-counter niacin preparations are divided into 3 categories: immediate release, sustained release, and no flush. Immediate-release niacin preparations are absorbed within 1 hour of ingestion and are marketed as immediate-release, crystalline, or plain niacin. Sustained-release preparations are absorbed slowly over several hours and are marketed as sustained-release, controlled-release, or timed-release niacin. No-flush niacin is marketed as no-flush, zero-flush, or flush-free niacin. We studied 10 brands each of immediate-release and no-flush niacin and 9 brands of sustained-release niacin, for a total of 29 preparations. Commonly used brands of niacin were identified in 2 ways. First, we sent an informal e-mail survey to clinical lipidologists in the United States, asking which niacin brands they typically recommended to their patients. Second, after consulting national sales figures, we identified top-selling over-the-counter niacin brands. The niacin preparations were purchased at local health food stores and pharmacies as well as from Internet-based vitamin supply companies. We studied only preparations advertised as containing 500 mg of niacin. We did not test niacin preparations labeled nicotinamide or niacinamide, nor did we evaluate prescription brands of niacin. Cost Analysis We recorded the retail purchase price to the investigator for each niacin preparation. Then we calculated the cost of each preparation from the purchase price and expressed it as U.S. dollars per milligram. The cost of a month's supply of niacin therapy (at a dose of 2000 mg/d, the maximum recommended dosage for sustained-release niacin preparations) was calculated as follows: monthly cost = ($/mg) (2000 mg/d) (30 d/mo). Measurement of Free Nicotinic Acid We analyzed in duplicate the free nicotinic acid content of each niacin preparation as follows. Individual niacin pills (tablets or capsules) were weighed and then ground to a fine powder. One mg of the resulting powder was dissolved in 1 mL of water and filtered through a syringe nylon filter to yield a sample solution of 1 mg/mL. An aliquot (100 L) of the sample solution was combined with 50 L of 6-methyl nicotinic acid in water (1 mg/mL) and 850 L of high-performance liquid chromatography (HPLC) mobile phase to yield 1 mL in final volume. This mixture was then transferred to an autosampler vial and analyzed by HPLC. We did the chromatographic separation as previously described by Miyauchi, with minor modifications (25). In brief, we performed HPLC using an HP 1050 LC system (Hewlett Packard, Wilmington, Delaware) equipped with an ultraviolet detector at 245 nm. Separation was achieved on a Microsorb-mv C18 column (Rainin, Oakland, California) using an isocratic elution with 93% of 10-mmol sodium phosphate per L and 7% of acetonitrile containing 10 mmol of octane sulfonate per L (pH, 2.1). The mobile phase was delivered at 1 mL/min. We estimated the free nicotinic acid content in each solubilized aliquot from a calibration curve that was constructed using a known nicotinic acid standard. We calculated the total nicotinic acid content in each preparation by multiplying the amount of free nicotinic acid measured in the 1-mg sample aliquots by the total weight of the individual sample pill. We noted the expiration dates of each product, and all analyses took place well before the expiration dates. Statistical Analysis We used Prism statistical software (GraphPad Software, San Diego, California) for data compilation and statistical analysis. We calculated monthly cost and free nicotinic acid content as described and compared them using the unpaired Student t-test, with a P value for statistical significance set at less than 0.05. All data are presented as means ( SE). Data Synthesis Cost of Niacin Preparations We analyzed 29 over-the-counter niacin preparations (Table). We purchased 16 niacin preparations from health food stores and pharmacies and 13 preparations from Internet-based suppliers. The average cost of niacin samples purchased from health food stores or pharmacies compared with the cost of those purchased over the Internet did not differ (data not shown). Table. Over-the-Counter Niacin