Hypercholesterolaemia And Hypertriglyceridaemia

Niacin has been used for the treatment of hypercholesterolemia and hypertriglyceridaemia since the 1950s. Large doses of niacin reduce total cholesterol, LDL-cholesterol, triglycerides and lipoprotein (a) levels and also markedly raise HDL-cholesterol C levels (lllingworth et al 1994). Considering these factors are also predictive of cardiovascular events, niacin is used to reduce overall risk of cardiovascular disease (Canner et al 1986). According to a recent meta-analysis effects on LDL-© 2007 Elsevier Australia

cholesterol and triglycerides appear to be more significant in females especially at doses > 1 500 mg/day (Goldberg 2004).

Extended-release niacin (nicotinic acid) has been evaluated in at least four randomised, placebo-controlled trials, with the most efficacious results occurring at doses of 1 500-2000 mg/day (Goldberg 1998, Grundy 2002, Guyton et al 2000, Morgan et al 2003). Results were dose- and time-dependent, with trials ranging in length from 4 to 16 weeks. At the 1500 and 2000 mg doses, reductions were noted in total cholesterol (-7 to -12.1 %); total cholesterol to HDL-C ratio (-17 to -22%); LDL-cholesterol (0 to -7%); triglycerides (-16 to -36%); and lipoprotein (a) (-7 to -23.6%). One trial noted a particular decrease in the smaller, more atherogenic, dense LDL particles and an increase in the larger cardioprotective HDL particles (Morgan et al 2003). HDL-cholesterol increased by 21-25.8% and apolipoprotein A-l levels were reported in one study to be increased 9-11% (Guyton et al 2000). The main side-effects reported included flushing, a 5% increase in fasting blood glucose, pruritis and rash (Goldberg 1998).

A 2002 review suggests that niacin is the 'only agent currently available that favourably affects all components of the lipid profile to a significant degree' and has the greatest effect on HDL levels (Pieper 2002).

Niacin may also be combined with chromium (Bolkent et al 2004, Shara et al 2005, Yanardag et al 2005) or phytosterols (Yeganeh et al 2005) for synergistic effects.

Clinical note— Major lipids affecting cardiovascular disease risk

Cardiovascular risk is predicted by a number of factors; however, the major lipids involved are LDL-cholesterol lipoprotein (a), triglycerides and HDL-cholesterol. Furthermore, LDL particle size and number are associated with different levels of atherogenicity.

A reduction in HDL-cholesterol and an increase in triglycerides and LDL-cholesterol has been associated with an increased risk of cardiovascular disease, whereas high HDL-cholesterol is protective against atherosclerosis and is inversely related to risk of early coronary heart disease (Packard et al 2002). Its cardioprotective properties appear to be due to its involvement in processes such as reverse cholesterol transport and inhibition of LDL-cholesterol oxidation (Kwiterovich 2000). The potential for regression of atherosclerosis has been suggested due to the ability of niacin to affect reverse cholesterol transport out of vessel walls (Rubic et al 2004).

Furthermore, the LDL phenotype B, characterised by small, dense LDL particles, is associated with increased atherogenicity than phenotype A and niacin increases LDL © 2007 Elsevier Australia

particle size from small LDL to the less atherogenic, large LDL subclasses (Morgan et al 2004). The frequency of the LDL phenotype B increases as HDL's decrease and triglycerides increase.

Lipoprotein (a) has been identified as an independent risk factor for premature coronary artery disease and aggravates the atherogenic effect of diabetes mellitus (Wassef 1999).

A 2002 review highlights the ability of niacin to effectively lower triglycerides, raise HDL-cholesterol, and shift LDL particles to the less atherogenic phenotype A, all important factors that reduce the risk of cardiovascular disease (Ito 2002).

Combined therapy: statins and niacin Although monotherapy with statin drugs (HMG-CoA reductase inhibitors) cause significant reductions in LDL-cholesterol, they provide only modest improvements in triglycerides and HDL-cholesterol. Niacin, on the other hand, provides significant reduction of triglycerides and enhancement of HDL-cholesterol levels, although reductions in LDL-cholesterol are less significant. As a result, combinations of these lipid-modifying agents will better address lipid abnormalities and improve clinical outcomes (Ito 2002, Levy & Pearson 2005).

In practice, the concurrent use of niacin with a statin has demonstrated improved outcomes in patients for whom monotherapy was unable to achieve adequate lipid control (Gardner et al 1997, Guyton & Capuzzi 1998). The combination may also slow the progression of atherosclerosis in individuals with known coronary heart disease and moderately low HDL-cholesterol (Taylor et al 2004).

Numerous studies exist to support the safe and effective use of extended-release niacin with lovastatin (Armstrong et al 2004, Bays et al 2003, Rubenfire 2004), simvastatin (Kaur et al 2004, Zhao et al 2004), pravastatin (Gardner et al 1997), and rosuvastatin (Capuzzi et al 2003).

Lovastatin plus extended-release niacin is comparable to atorvastatin and more effective than simvastatin in reducing LDL-cholesterol, more effective in increasing HDL-cholesterol and provides greater global improvements in non-HDL-cholesterol, triglycerides, and lipoprotein-a (Bays et al 2003). The combination is associated with good compliance and safety (Rubenfire 2004) and may also be less costly than simvastatin (Armstrong et al 2004).

In a clinical trial of diabetic patients, the addition of niacin 500 mg three times daily to pravastatin 20 mg resulted in a significant lowering of LDL-cholesterol compared with pravastatin monotherapy. Furthermore, improvements in lipid profile were gained without compromising glycaemic control (Gardner et al 1997). In a separate trial of simvastatin plus niacin among people with diabetes, glycaemic

control Initially declined mildly but returned to pretreatment levels at 8 months and remained stable for the remainder of the study (Zhao et al 2004).

As early studies indicated a potential for myopathy, rhabdomyolysis and hepatotoxicity, use of the sustained-release form of niacin in combination with statins is controversial. Although current trials tend to focus on the safer extended-release form, liver function should be monitored and patients observed for symptoms of myopathy (Guyton & Capuzzi 1998).

Low-dose niacin therapy (50 mg twice daily) in combination with statins for 3 months may also significantly increase HDL-cholesterol, while avoiding the side-effects commonly associated with higher doses (Wink et al 2002).

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