NICOTINIC ACID — Nicotinic acid is available in several formulations that include immediate-release (crystalline) and sustained release formulations such as Niacor® and Niaspan®. Nicotinic acid and nicotinamide are the two common forms of the vitamin most often referred to as niacin. (See "Overview of water-soluble vitamins", section on vitamin B3.) Nicotinic acid has a variety of effects on lipid metabolism (show figure 2):
It inhibits the hepatic production of VLDL and consequently its metabolite LDL [8].
It raises HDL levels by as much as 30 to 35 percent, both by reducing lipid transfer of cholesterol from HDL to VLDL and by delaying HDL clearance [8,9].
Another favorable property of nicotinic acid is a reduction in plasma fibrinogen levels [10].
Preparations — The content of over-the-counter (OTC) preparations of niacin are not federally regulated in the US [11]. OTC preparations that are marketed as causing "no flush" may have no free nicotinic acid and are ineffective in treating dyslipidemia, while some formulations of sustained-release OTC niacin have been associated with an increased risk of hepatotoxicity (see below); Slo-Niacin and perhaps Enduracin appear to be relatively safe. The sustained-release prescription brand Niaspan appears to be safe and effective although it is more expensive. OTC immediate-release niacin preparations are inexpensive, contain a full amount of free nicotinic acid, and are safer than most sustained-release preparations.
Uses — Nicotinic acid is effective in patients with hypercholesterolemia and in combined hyperlipidemia associated with normal and low levels of HDL cholesterol (hypoalphalipoproteinemia) [8,9,12]. The HDL raising properties of nicotinic acid occur with dosages as low as 1 to 1.5 g/day [12]. In contrast, the VLDL and LDL lowering effects are typically seen with higher doses (3 g/day) [8,9]. In one study, for example, nicotinic acid in a dose of 500 mg TID raised HDL cholesterol by 20 percent but reduced LDL cholesterol by only 5 percent. In comparison, a higher dose of 1.5 g TID produced more prominent changes of 33 percent (HDL elevation) and 23 percent (LDL reduction). At higher doses, nicotinic acid can also lower lipoprotein (a) levels by as much as 35 percent [9].
Additional LDL lowering can be attained by the addition of a bile acid sequestrant and/or HMG CoA reductase inhibitor (statin). In one study of 269 patients, the reduction of total and LDL cholesterol with sustained release niacin was 11 and 18 percent, respectively, compared with 23 and 32 percent, respectively, in those taking a combination of niacin and a statin [13]. A combination tablet with extended release niacin and lovastatin is now available and may help with compliance in patients who are already on a stable dose of both drugs [14].
Therapy with crystalline nicotinic acid is initiated at 100 mg three times daily and gradually increased to the targeted dosage as tolerated [12]. Pretreatment with aspirin 30 minutes prior to dosing can minimize flushing and other prostaglandin-mediated side effects noted below. This adverse reaction often diminishes in seven to 10 days. Nicotinic acid is better tolerated when ingested with food, which minimizes gastrointestinal side effects.
Niaspan® is a controlled release formulation of nicotinic acid that is administered once daily. Niaspan® is initiated at a dose of 500 mg nightly for one month and the dosage is titrated to 1000 mg. The standard dosage of Niaspan® is 1 to 2 grams nightly. It is advised that the medication be given with a night-time snack, but our experience suggests improved tolerability with dosing after the evening meal.
Side effects — The use of nicotinic acid is often limited by poor tolerability. At standard doses (1.5 to 4.5 g/day), flushing occurs in 80 percent of patients taking the crystalline preparation, and pruritus, paresthesias, and nausea each occur in about 20 percent [9].
Flushing appears to be less common with controlled release Niaspan®. In one study of 269 patients receiving a median dose of 2000 mg/day for 48 weeks, 4.8 percent discontinued the drug because of flushing [13]. In another report in which both formulations were given in a dose of 1500 mg/day for four months, Niaspan® was accompanied by fewer flushing episodes per month (1.9 versus 8.6) [15].
Elevations in hepatocellular enzymes are also common with nicotinic acid and may lead to severe hepatotoxicity, jaundice, and fulminant hepatitis. The onset of hepatocellular injury is not predictable; therefore regular monitoring of biochemical studies is mandatory. Crystalline niacin is preferred to most sustained-release preparations, since the former is associated with a greater hypolipidemic effect and seemingly less hepatotoxicity (show figure 3) [12,16]. An exception may be extended release Niaspan®, which has been found to minimally raise transaminases in clinical trials, but not cause significant hepatotoxicity [17].
Other important problems with nicotinic acid include [12]:
Nicotinic acid causes insulin resistance. As a result, hyperglycemia may develop in susceptible patients and the glycemic state may be worsened in those already being treated for overt diabetes mellitus [18]. This effect appears to be greatest with some extended release preparations, and minimized with crystalline niacin and perhaps Niaspan®. (See "Treatment of dyslipidemia in diabetes mellitus").
Nicotinic acid can induce hyperuricemia and precipitate acute gouty arthritis; it should therefore be avoided in any patient with a history of gout.
Nicotinic acid can produce hypotension in subjects treated with vasodilators, and can exacerbate unstable angina pectoris [19].
Nicotinic acid causes a dose-dependent elevation in plasma homocysteine levels that may negate its favorable effects on the lipid profile in certain subsets of patients [20]. Thus, after nicotinic acid is titrated to a stable maintenance dose, homocysteine levels should be measured. While many investigators would recommend therapy when homocysteine levels exceed 15 µmol/L, the efficacy of this approach remains uncertain and clinical trials are now ongoing to address this issue. (See "Overview of homocysteine").
