ABSTRACT
The discovery that niacin decreases serum cholesterol was made in 1955.215 In addition to lowering LDL cholesterol and apo B, it also reduces triglycerides and raises HDL cholesterol. To achieve this, it must be used in pharmacological doses that far exceed its physiological requirement as a vitamin. Before the advent of statins, it was prescribed in doses of several grams per day in some clinics.216 It has two major drawbacks. One is the high prevalence of side effects. These include hepatotoxicity,217
unstable glycaemic control in diabetes,218 hyperuricaemia,219 exacerbation of peptic ulcer219 and, rarely, acanthosis nigricans.219 The most frequent and troublesome side effect of niacin, however, is severe flushing, often accompanied by pruritus. This may be ameliorated to some extent by aspirin, because the flushing is prostaglandin mediated. However, it remains the major limitation to the wider use of nicotinic acid, despite its attractive lipid and lipoprotein-modifying properties. The second problem is that the evidence that niacin prevents CVD events, like that for fibrates, looks jaded besides the volume, clarity and consistency of the statin evidence. One problem with niacin in clinical trials is that, though randomization is possible, blinding is not, because of the flushing. There appeared to be benefit in terms of reduced CVD events in an early secondary prevention trial lasting 6 years that translated into an 11% reduction in all-cause mortality during the 9 years after the trial finished.220,221 The only other trial with clinical events as an outcome was another secondary prevention trial in which clofibrate was also prescribed. Although small, a significant decrease in allcause mortality was achieved.222 A meta-analysis that captured many smaller trials using a variety of nicotinic acid preparations, often in combination with other lipid-modifying drugs, suggested that nicotinic acid treatment was associated with a 27% decrease in CHD events.134 Nicotinic acid also has the potential benefit that it increases HDL by more than any other currently available lipid-modifying drug (CETP inhibitors are more effective in this respect – see later)134 and is the only lipid-lowering drug to lower Lp(a).223-225
Understandably, with such potential there have numerous attempts, using a variety of approaches, to make nicotinic acid more tolerable. These have
included chemical derivatization, modified release (to try to reduce fluctuations in its circulating levels, which are associated with flushing) and the development of more effective inhibitors of flushing than aspirin. Until recently most of these were hardly even partially successful, particularly when some derivatives retained only part of the lipid-lowering effect of the parent nicotinic acid. Acipimox retained the triglyceride-lowering effect but had little or no effect on LDL.226
