Niacin (nicotinic acid) lowers lipids by inhibiting very-low-density lipoprotein (VLDL) production in the liver and reducing the level of VLDL that can be converted into low-density lipoprotein (LDL). Niacin can lower LDL cholesterol by 10 to 25 percent and triglyceride levels by 20 to 50 percent, and can raise levels of high density lipoprotein (HDL) cholesterol by 15 to 35 percent. These effects may be even greater in patients with a predominance of small, dense LDL, which has been associated with greater coronary heart disease risk. For these reasons, niacin is considered a useful treatment in patients with mixed dyslipidemia. The adverse effects of immediate-acting niacin preparations, including flushing, itching, gastrointestinal upset and hepatotoxicity, have limited its use. An extended-release form, called Niaspan, was designed to be taken nightly to minimize liver toxicity and other side effects.

Goldberg and associates compared the safety and efficacy of escalating doses of extended-release niacin (from 500 to 3,000 mg per day taken nightly) with placebo in patients with primary hyperlipoproteinemia eating an appropriate diet. One hundred thirty-one men and women from 21 to 75 years of age who met the National Cholesterol Educational Program criteria for treatment and who did not have a serious comorbidity were randomized to receive placebo or extended-release niacin in a double-blind, placebo-controlled manner. The daily niacin dosage was started at 375 mg taken nightly and slowly increased, to a maximum of 3,000 mg per day, at four-week intervals for a total of 25 weeks. Patients were permitted to take 325 mg of aspirin before taking the study medication if they wished to prevent flushing.

Fifty-one patients terminated the study early; 31 of them withdrew for medical reasons (30 and 11 percent in the extended-release niacin and the placebo groups, respectively). One half of the extended-release niacin group dropped out because of flushing or rash. The extended-release niacin therapy resulted in a significant reduction in LDL cholesterol levels and significant increases in HDL levels, beginning with the 500-mg per day dosage and apparent at all subsequent dosage levels. Significant decreases in the triglyceride level occurred in patients taking 1,000 mg per day of the extended-release niacin and were apparent at all subsequent dosage levels. None of these changes occurred in the placebo recipients. A significant decrease in platelet count was noted in patients taking the niacin preparation, but there were no incidents of bleeding or bruising in these patients.

The authors conclude that extended-release niacin taken at bedtime can effectively and safely treat mixed dyslipidemia. The dose response demonstrates a linear effect, with maximal benefit at a dosage of approximately 2,500 mg, although the maximum recommended dosage of extended-release niacin is 2,000 mg. Although some liver toxicity occurred, it was significantly less than that documented with older sustained-release niacin preparations, and there was no evidence of irreversible liver toxicity.

editor's note: The availability of extended-release niacin preparations provides another tool to lower patients' lipid levels. Other studies have confirmed the findings noted above, as well as a lowering of apolipoproteins A, B and E. Flushing occurs more frequently with plain niacin than with the extended-release preparation. Although the frequency of hepatotoxicity represented by hepatic enzyme effects is probably similar with both preparations, the extended-release formulation causes a lower uric acid rise. Taking the extended-release formulation at bedtime may diminish lipolysis and the release of free fatty acids to the liver, limiting the usual diurnal increase in plasma triglycerides. This may result in decreased formation and secretion of triglyceride in the VLDL cholesterol fraction. Once-daily nighttime dosing may also increase compliance. The use of niacin alone or in combination with other lipid-lowering agents, such as statins, has now become an easier option.—r.s.