Drug Topics - November 5, 2007 - (Page 31)

31 date combining nicotinic acid with statins, fibrates, and bile acid binding resins and have provided a variety of positive results. In the HDL-Atherosclerosis Treatment Study (HATS), men and women with low HDL-C (35 mg/dl or less in men or 40 mg/dl or less in women) were assessed while receiving combined nicotinic acid and simvastatin. After three years, the primary end points of death from coronary complications, confirmed MI, stroke, or revascularization for worsening ischemic symptoms were 90% lower in the combination treatment arm compared with the placebo arm. Unfortunately, the HATS investigation was not large enough to have monotherapy groups in which to compare the results against. A 28-week study that investigated a combination product, niacin ER/lovastatin, provided a comparison of lipid parameters. The maximum dose of 2,000 mg/40 mg of niacin ER/lovastatin reduced LDL-C by 42%, reduced TG by 44%, and raised HDL-C by 30%. In comparison, 2,000 mg of niacin ER reduced LDL-C by 14%, reduced TG by 31%, and raised HDL-C by 24%, while lovastatin reduced LDL-C by 32%, reduced TG 20%, and raised HDL-C by 6%. The broad array of lipid effects that nicotinic acid provides brings about the question, “Will simply raising HDL-C levels Pharmacologic intervention to raise HDL-C levels provide positive outcomes?” The two most notable lipid paramNicotinic acid. Nicotinic acid (also known as niacin or vita- eters that are altered by nicotinic acid are the decreases in TG and min B3) has a long history of use in the treatment of dyslipi- increases in HDL-C. The magnitude of the HDL-C increase demia. The positive lipid effects of nicotinic acid use were rec- places nicotinic acid at the forefront in a battle to raise “good choognized in 1955. One of the first large randomized trials lesterol.” Despite its variety of beneficial effects on lipid biomarkmeasuring long-term cardiovascular outcomes using nicotinic ers, nicotinic acid has faced an uphill battle. The side-effect proacid was the Coronary Drug Project. The trial, published in the files of the different nicotinic acid formulations have been Journal of the American Medical Association (JAMA), was com- somewhat problematic. The immediate-release formulation is aspleted in 1975 and demonstrated nicotinic acid could reduce sociated with severe flushing and often prompts patients to disnonfatal myocardial infarction (MI) by 27% over a six-year pe- continue therapy. This led to the development of sustainedriod. After absorption, nicotinic acid undergoes enzymatic con- release niacin, which was designed to reduce the flushing side efversion to the active form nicotinamide adenine dinucleotide fect. Yet, the sustained-release formulation introduced a grave risk (NAD) via the NAD coenzyme system. The exact molecular of liver toxicity and for this reason should be avoided. mechanisms by which nicotinic acid and, therefore, NAD, enNiacin ER is the only prescription extended-release formulahances a patient’s lipid profile are not well defined. Some pro- tion. This product releases nicotinic acid contents over a period posed mechanisms include a reduction in the release of free fat- of eight to 12 hours. All formulations of niacin are associated ty acids from adipose tissue and increased activity of the with flushing, and up to 88% of patients report at least one enzyme lipoprotein lipase. More defined actions are derived episode of this adverse effect. The box on this page provides tips from the results of clinical trials utilizing oral nicotinic acid in- for patient counseling on methods to reduce the incidence of dicating positive actions on multiple lipid parameters. These flushing from niacin. The extended-release formulation also pharmacologic actions include: reduces the incidence of liver toxicity compared with the 1. Decreased LDL-C levels (3%-17%) secondary to a decreased sustained-release niacin. The reduced incidence of liver toxicity rate of VLDL production via the liver is in part due to the pharmacokinetics of niacin ER and may also 2. Decreased TG levels (5%-35%) secondary to a decreased rate be in part due to the mandatory slow titration of niacin ER, of VLDL production via the liver starting with the lowest dose of 500 mg. Another pharmacoki3. Increased levels of HDL-C netic issue arises between genders. (10%-26%) as a result of decreased Due to potential pharmacokinetic Methods for patients apoA-I destruction. differences between men and women, to reduce incidence 4. Increased ratio of HDL2 to higher concentrations of nicotinic of flushing with niacin HDL3 acid are found in women when dosed •Take a regular-strength aspirin or ibupro- with niacin ER. Because of this phar5. Reduced levels of lipoprotein (a) fen 30 minutes prior to taking niacin and apoB macokinetic difference, women have •Take the medication at bedtime Since 1975, many more studies better response rates than men at have been performed showing the equivalent niacin dosing. This means •Take the medication with a low-fat snack beneficial effects of nicotinic acid •Prior to medication administration, avoid that, when niacin ER is tolerated, alone and in combination theramen have a greater need to be fully hot beverages, spicy foods, alcohol, hot pies. Trials have been performed to titrated to the maximum dose of showers, or vigorous exercise ed with a 40% reduction in stroke; however, the risk for stroke was increased in patients who heavily consumed alcohol. Currently, ATP III recommends no more than one drink per day in women and no more than two drinks per day in men. For patients who do not drink alcohol, it is not recommended for them to begin routine consumption. Patients who smoke tobacco or use smokeless tobacco have been noted to have low HDL-C levels. In the Framingham Offspring Study, men who smoked had a 4 mg/dl difference in HDL compared with nonsmokers and women smokers had a 6 mg/dl difference. Data suggest that smoking cessation can improve HDL-C levels by as much as 4 mg/dl. Additionally, smoking status is currently a consideration in the Framingham calculation for heart disease. Patients should continue to be encouraged to quit smoking to improve not only HDL-C levels but their overall health status. Encouragement of weight loss is also an important step in improving HDL-C levels, especially in overweight and obese individuals. Once stabilized, HDL-C levels can be improved by 0.35 mg/dl per kg of weight loss. Patients should strive to achieve a normal body mass index (19.5-24.9 kg/m2).

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Drug Topics - November 5, 2007 Contents Latebreakers Latebreakers in Depth Letters Rx Care Community Practice 150 Years of American Pharmacy Hospital Practice Pharmacists at Risk Government and Law High-Density Lipoprotein New Products Advertisers Index Classified Viewpoint

Drug Topics - November 5, 2007

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