Niacin: a cardiovascular jewel
Frank nutritional deficiency in humans of the B vitamin niacin (aka nicotinic acid) produces pellagra, a condition with hallmark symptoms including diarrhoea, dermatitis, dementia and, if uncorrected, ultimately death. At the near opposite end of the intake spectrum one observes a striking pharmacological effect: potent alterations in blood lipids with doses in excess of 1g.
Provocatively, pellagra is unaccompanied by dyslipidaemia, indicating that niacin's lipid-modifying effects are unrelated to its classical vitamin/coenzyme substrate role. Additionally, nicotinamide, an essentially bioequivalent to niacin, has no appreciable lipid-modifying effects.
The history of niacin as a lipid-response modifier (LRM) is intriguing. Niacin (in an immediate release form; see below) is the only nutraceutical shown in a controlled clinical trial longer than five years to significantly reduce secondary heart attacks, 1 as well as all-cause mortality. 2 This is contrasted to many naturally occurring bioactives, such as sterols and oat bran, that may reduce cardio-disease risk factors, such as elevated LDL, but have yet to systematically show actual disease-risk reduction.
Despite these findings more than 30 years ago, relatively little recognition has been accorded, arguably due to the unpatentability of niacin by any pharmaceutical company. The most striking aspect of niacin is its unparalleled breadth as an LRM. Indeed, no currently available drug demonstrates such robust abilities in favourably altering virtually all blood lipid risk factors, especially high-density lipoprotein (HDL) cholesterol.3,4 Like many drugs, its mechanism of action remains enigmatic.
The favourable outcome with niacin in the Coronary Drug Project was attained with the use of a rapid/immediate release (IR) niacin solid dosage form. The intense flushing associated with niacin prompted the development of dose forms with prolonged/delayed release profiles. The latest evolutionary step in this regard has been the synthesis of drug antagonists to the prostaglandin receptor that mediates niacin-induced flushing in humans.5
A less-innovative but equally effective approach has been the creation of dosage forms that exploit tableting technology to alter the release profile while maintaining clinical efficacy as an LRM. Two clinically validated modified release forms of niacin are Niaspan (Kos Pharmaceuticals, USA), a prescription drug, and Niamax (Lonza, USA), sold as bulk tablets.
Niaspan has markedly increased undesirable skin-flushing effects than Niamax,6 but has been the subject of a greater number of randomised, controlled clinical trials. In a comparator study of Niaspan against patients who had taken an equal dose of IR niacin, the LRM impact was bioequivalent between the two-dose forms.7
Another no-flush approach is use of a chemically modified, non-natural congener of niacin, inositol hexanicotinate. Inositol, a cyclitol with six potential attachment points for esterification, serves as the axis for the attachment of niacin. This form is completely devoid of skin-flushing activity but exerts anaemic LRM bioactivity, if at all, and lacks any evidence from randomised, controlled trials demonstrating significant elevations in HDL cholesterol.8 Despite the relative absence of efficacy, it continues to be marketed as a 'flush-free' substitute for crystalline, unesterified niacin.
Niacin's roughest edge rests upon an increased risk of hepatotoxicity with pharmacologic doses - greater than 500mg.9 However, IR preparations, or specific modified-release preparations that have undergone clinical assessment for safety (and efficacy), appear safe but still may warrant professional supervision.
An additional concern is niacin's ability to produce or worsen insulin resistance and aggravate blood-glucose control in diabetics.10 The ongoing AIM HIGH trial, with more than 3,000 dyslipidaemic (metabolic syndromelike) subjects with cardiovascular disease being enrolled to assess the efficacy of a statin with or without niacin (Niaspan), will likely provide illumination.
References
1. The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360-81.
2. Canner PL, et al. Fifteen year mortality in Coronary Drug Project patients. Long-term benefits with niacin. J Am Coll Cardiol 1986;81:1245-55.
3. Sirtori CR and Fumagalli R. LDL-cholesterol lowering or HDL-cholesterol raising for cardiovascular prevention. Atherosclerosis 2006;186:1-11.
4. Carlson LA. Nicotinic acid and other therapies for raising high-density lipoprotein. Curr Opin Cardiol 2006;21:336-44.
5. Cheng K, et al. Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans. PNAS 2006;103:6682-7.
6. McCormack PL and Keating GM. Prolonged-release nicotinic acid. A review of its use in the treatment of dyslipidaemia. Drugs 2005;65: 2719-40.
7. Superko HR, et al. Differential effect of two nicotinic acid preparations on low-density lipoprotein subclass distribution in patients classified as low-density lipoprotein pattern A, B,I. Am J Cardiol 2004;94:588-94.
8. Meyers CD, et al. Varying cost and free nicotinic acid content in OTC niacin preparations for dyslipidemia. Ann Intern Med 2003;139:996-1002.
9. Rader JI, et al. Hepatic toxicity of unmodified and time-release preparations of niacin. Am J Med 1992;92:77-81.
10. Ginsberg HN. Niacin in the metabolic syndrome: more risk than benefit? Nature Clin Pract Endocrinol Metab 2006; 2:300-1.
Anthony Almada, MSc, is president and CSO of IMAGINutrition. Respond: [email protected]
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