The comparative effects of the major classes of lipid regulating drugs are illustrated in table 1. Statins provide the most effective means of lowering LDL cholesterol, nicotinic acid of raising HDL cholesterol, and fibrates (exemplified by gemfibrozil) of lowering triglyceride. Ezetimibe is relatively ineffective in lowering LDL when given as monotherapy but looks set to displace bile acid sequestrants as an adjunct to statins in the treatment of severe hypercholesterolaemia, being much easier to administer and with fewer side effects.
Table 1 Comparative effects of lipid regulating drugs
The introduction into clinical practice of statins has revolutionised the management of dyslipidaemia and the treatment and prevention of CVD. These drugs competitively inhibit HMG-CoA reductase, thereby reducing cholesterol synthesis in the liver, which leads to an increased expression of hepatic LDL receptors and greater uptake of LDL cholesterol from plasma. Production of very low density lipoprotein (VLDL), the precursor of LDL, is decreased, the net effect being dose dependent reductions in LDL cholesterol of 20–60%, accompanied by lesser reductions in plasma triglyceride and a small rise in HDL cholesterol.
Until recently atorvastatin was the most effective statin available for decreasing LDL when given in doses of 10–80 mg daily. Furthermore, the higher dose was shown to decrease serum triglycerides by 45% in individuals with hypertriglyceridaemia. However, rosuvastatin, which was recently launched in the UK, is even more effective than atorvastatin in lowering LDL cholesterol over its licensed dose range of 10–40 mg, although there was no significant difference between rosuvastatin 40 mg and atorvastatin 80 mg in this respect (fig 2).14
Figure 2 Comparative LDL lowering efficacy of rosuvastatin, atorvastatin, simvastatin, and pravastatin. Graph based on data of Jones and colleagues.14
The extent to which LDL cholesterol should be lowered to obtain maximum benefit has yet to be established. A recent analysis which includes the results of HPS showed a strong correlation between the percentage change in serum cholesterol and the logarithmic risk of a CHD event.15
Extrapolation of the regression line suggests that a decrease in total cholesterol of 45%, equivalent to a decrease in LDL cholesterol of about 60%, would halve the risk of CHD. The recently reported results of the REVERSAL16
and PROVE IT17
trials show that decreases in LDL cholesterol of 47–51% on atorvastatin 80 mg/day were of greater benefit in preventing progression of coronary atherosclerosis and reducing cardiovascular events respectively than were decreases of 22–27% on pravastatin 40 mg/day. These findings support “the lower the LDL, the better” concept, but a definitive answer to the question “how low?” will have to await the results of trials not due to be completed until 2005.
The most important adverse effect of statins is myositis, defined as muscle pain plus an increase in creatine phosphokinase (CPK) greater than 10 times the upper limit of normal. Rarely, severe rhabdomyolysis leading to fatal renal damage has occurred and the synthetic HMG-CoA reductase inhibitor, cerivastatin, was recently withdrawn on this account. Other statins have a remarkably good safety record and an analysis of data from over 30 000 patients who had received pravastatin, simvastatin, or lovastatin for a period of five years or more found that the incidence of myositis was only 0.1%, identical to that on placebo. In the HPS the frequency of CK elevations > 10 times the upper limit of normal was 0.09% in patients on simvastatin compared with 0.05% in those on placebo. The likelihood of this complication occurring is dose related and is increased by concomitant treatment with drugs such as cyclosporine, which inhibit the cytochrome P450 3A4 pathway via which most statins are metabolised.
The lipid regulating effect of large doses of nicotinic acid were first described in 1962. Long term follow up of patients who participated in the Coronary Drug Project showed a reduction in total mortality in those taking nicotinic acid during the trial and the drug would be more widely used were it not for its side effects. These include cutaneous flushing, skin rashes, gastrointestinal upsets, hyperuricaemia, hyperglycaemia, and hepatic dysfunction. Sustained release preparations reduce flushing but accentuate the risk of hepatitis.
However, recently an extended release form of nicotinic acid (Niaspan) has been marketed in the UK which seems to be free from this drawback. At the maximum recommended dose of 2 g daily, decreases in LDL cholesterol, triglycerides, and liopoprotein Lp(a) averaged 17%, 35%, and 24%, respectively, whereas HDL cholesterol increased by 26%. Although 30% of those randomised to Niaspan had troublesome side effects, the frequency of abnormal liver function tests was similar to that on placebo.
The lipid regulating properties of fibrates were first described almost 40 years ago. The five compounds marketed in the UK—clofibrate, bezafibrate, fenofibrate, gemfibrozil, and ciprofibrate—are all effective in controlling hypertriglyceridaemia and in raising HDL cholesterol, but vary in their ability to reduce LDL cholesterol, fenofibrate and ciprofibate being the most potent. Clofibrate is now obsolete because it increases the risk of developing gall stones. A rare side effect of fibrates is an acute myositic syndrome similar to that seen with statins, patients with renal impairment being particularly vulnerable.
During the Helsinki heart study, reductions in the incidence of primary CHD events by gemfibrozil were attributable both to the decrease in LDL cholesterol and to the increase in HDL cholesterol, being most pronounced in individuals with triglyceride > 2.3 mmol/l and LDL:HDL cholesterol ratio > 5. Additional evidence of the benefits of gemfibrozil came from the Veterans Affairs high density lipoprotein cholesterol intervention trial, which showed that the drug reduced the risk of secondary events in men with a low HDL cholesterol. More recently, the Bezafibrate infarction prevention trial demonstrated the benefits of bezafibrate in secondary prevention of CHD in hypertriglyceridaemic subjects.
Recently, a specific pathway which mediates the uptake of cholesterol from the lumen into the wall of the small intestine was identified. A novel class of compounds, 2-azetidinone derivatives, has now been shown to interact with this putative cholesterol transporter in the intestinal brush border membrane, thereby inhibiting cholesterol absorption. The first of these cholesterol absorption inhibitors to be licensed is ezetimibe.
Randomised, placebo controlled trials of ezetimibe in hypercholesterolaemic subjects show dose dependent reductions in LDL cholesterol over the range 0.25–10 mg daily. The mean decrease in LDL cholesterol on 10 mg daily was 18.2% which was accompanied by small but significant increases in HDL cholesterol and decreases in serum triglyceride.18
The drug was well tolerated and the frequency of adverse events was similar to that in the placebo group.
Management of dyslipidaemia: key points
- Effective treatment of dyslipidaemia is an important element of strategies to prevent cardiovascular disease in clinical practice
- Current guidelines advocate dietary measures as first line management, including functional foods such as plant sterols or stanols and ω3 fatty acids, with addition of lipid regulating drugs in high risk subjects if target values of cholesterol are not achieved
- The results of the Heart Protection Study suggest that lowering LDL cholesterol reduces risk of CHD and stroke regardless of pre-treatment cholesterol value and age
- Novel lipid regulating drugs include rosuvastatin, currently the most effective statin in terms of LDL lowering, and ezetimibe, a cholesterol absorption inhibitor
- The ability of statins given alone in high doses, or combined with ezetimibe, to lower LDL cholesterol by 55–60% should in theory enable the rate of CHD events to be halved