22 July 2009

Niacin and Hyperlipidemia

NIACIN FOR HIGH CHOLESTEROL
The recommended daily intake for niacin, or vitamin B3, is only 14 mg for women and 16 mg for men with a tolerable upper intake level of 35mg (1). Nutrition professionals should also be aware that niacin, as nicotinic acid (not nicotinamide), has also been used in much larger doses—up to 6 g per day—for decades as a treatment for hyperlipidemia (1). Note that nicotinic acid is available as a dietary supplement.

Use as a Drug
High-dose niacin, in fact, was the first-ever lipid-modifying drug treatment. It helps increase HDL cholesterol while lowering total serum cholesterol, triglycerides and LDL cholesterol (2). After initial discovery in the 1950s and research in the ‘70s, it was found that niacin helped prevent myocardial infarction and reduced risk of death from myocardial infarction when used in doses of 3 g daily (2;3).

The mechanism of high-dose nicotinic acid is broad and unique. It inhibits lipolysis in adipose tissue decreasing free fatty plasma levels within minutes (1;2). Within a few hours it inhibits the liver’s synthesis of triglycerides reducing overall triglycerides in plasma (1;2). And, although it’s unclear just how, after only a few days it lowers LDL and increases HDL cholesterol (1;2).

Unpleasant Side Effects
Although an effective treatment and cost effective, the unpleasant side effects of high-dose niacin have kept many patients from adopting niacin as a regular drug treatment (2). By the 1980s, statins were on the market and greater in popularity (2). Still, niacin continues to present potential.

The main side effect is vasodilation, which includes flushing and redness like a temporary sunburn-like sensation (1;2). This is harmless, but bothersome (2). It is mediated partly by release of histamine; thus, an aspirin or COX inhibitors can reduce the response (1;2).

Precautions
Other side effects can include gastrointestinal problems like heartburn, elevated plasma glucose concentration, and hyperuricemia that can lead to gout since niacin competes with uric acid for excretion (1). Most worrisome is possible hepatotoxicity, which can go as far as obstructing bile flow, hepatitis or liver failure (1).

Newer forms of extended-release niacin, such as Niaspan from Abbot, are reported to have fewer side effects and no hepatotoxicity (2). This is significant for re-establishing niacin as the preferred, cost-effective treatment in comparison to other drugs. Newer studies are now researching niacin’s effectiveness in comparison to or in combination with other lipid- and cholesterol-lowering drugs (3). See "Research Summary and Critique" below.

Niacin is available in immediate-release (IR), sustained-release (SR), and extended-release (ER) (Niaspan) (4). They all differ in effectiveness, side effects and safety. Flushing is seen most with IR, hepatotoxicity is mostly noted with SR (4). The hepatotoxicity has to do with absorption rate (4). ER apparently allows absorption to be "intermediate" in comparison to IR and SR (4). In conclusion, avoid SR niacin!

Reference List

1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.

2. E T Bodor and S Offermanns. Nicotinic acid: an old drug with a promising future. Br J Pharmacol. 2008 March; 153(S1): S68–S75. Published online 2007 November 26. doi: 10.1038/sj.bjp.0707528. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18037924.

3. Guyton JR, Blazing MA, Hagar J, Kashyap ML, Knopp RH, McKenney JM, Nash DT, Nash SD. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Arch Intern Med. 2000 Apr 24;160(8):1177-84. Available at: http://archinte.ama-assn.org/cgi/content/full/160/8/1177#TABLEIOI90276T3

4. Pieper JA. Understanding niacin formulations. Am J Manag Care 2002;8:S308-S314.


RESEARCH SUMMARY AND CRITIQUE
One randomized, double-blind human clinical study in 2000 made a direct comparison using Niaspan and gemfibrozil.

Full reference: Guyton JR, Blazing MA, Hagar J, Kashyap ML, Knopp RH, McKenney JM, Nash DT, Nash SD. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Arch Intern Med. 2000 Apr 24;160(8):1177-84. Available at: http://archinte.ama-assn.org/cgi/content/full/160/8/1177#TABLEIOI90276T3

Purpose of Study: To compare effects of Niaspan with gemfibrozil, a lipid-lowering drug from a class called fibrates. Commercially, gemfibrozil goes by names of Lopid, Jezil and Gen-Fibro.

Type of study: Randomized, double-blind human clinical study.

Methods: Patients exhibiting factors for hypercholesterolemia and atherosclerosis were given Niaspan at doses increased sequentially from 1g to 2 g before bedtime and 80 or gemfibrozil at 600 mg given twice daily. Of 173 patients, 72 of 88 given Niaspan and 68 of 85 given gemfibrozil completed the study.

Percentage change from baseline was provided through analysis of blood samples collected after 12-hour fasts. They provided measurements for total cholesterol, HDL cholesterol, LDL cholesterol, lipoprotein levels, total triglycerides and fibrinogen levels.

Exclusions included most diabetics (not with normal-range fasting glucose), patients on blood thinners, patients with active gout as well as those with other serious illnesses and/or abnormalities.

The patients were men and women between ages 21 and 75 years. All were counseled by a National Cholesterol Education Program.

Results Summary: Niaspan increased HDL cholesterol twice as much as gemfibrozil and had better results in improving LDL cholesterol while lowering levels of fibrinogen (protein involved in clotting). The gemfibrozil had greater effects at lowering triglycerides, but increased LDL cholesterol.

Much more Niaspan flushing responses (78% compared to 10%) were observed in comparison to gemfibrozil; however, dyspepsia was observed more often in patients taking gemfibrozil.

Critique of Research Design: The study was well-designed and included appropriate measurements to determine biological response to treatment. The exclusions were appropriate in nature. The support of a pharmaceutical company for the study hinted at a natural bias that could be noted since there was no discussion given by the authors of this study regarding possible confounding variables. The flushing responses clearly indicate that the patients would have known what they were taking, which may have affected results. Also, dietary factors were not noted in the study. There was conversation seeming out of place about the possible use of both drugs for complementary treatment, which would need further research.

Nutritional Implications and Implications for Future Study: Nutrition professionals should have a thorough understanding of its uses and possible side effects when used as a drug for hypercholesterolemia. Because niacin is a vitamin found in many foods, further research should also review the potential role of diet along with niacin treatment.

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