Assessing the statins
Eve Hurley, Senior Editor, Australian Medicines Handbook, Adelaide

Summary

`Statins' are the first-line drug treatment if a low-fat diet and exercise do not correct hypercholesterolaemia. Clinical trials show that people at the highest risk of cardiovascular events, those with hypercholesterolaemia and ischaemic heart disease, benefit the most from treatment. The evidence for secondary prevention is much stronger than the evidence for primary prevention.Although these drugs share their mechanism of action, differences in metabolism, routes of elimination and effect on plasma lipids have been identified. Differences in non-lipid effects are also postulated. The clinical importance of these different characteristics has yet to be established.

Key words: antilipidaemic drugs, coronary disease, hypercholesterolaemia.

Aust Prescr 1999;22:114-7

Introduction
The `statins' are a group of drugs which suppress cholesterol synthesis by inhibiting the enzyme HMG CoA reductase.1 Prescribers now have a choice of five statins (simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin) for treating hypercholesterolaemia.

Statins are the most effective drugs for lowering LDL cholesterol. They are less effective than gemfibrozil and nicotinic acid at reducing triglyceride and increasing HDL cholesterol concentrations. The first-line treatment for hypercholesterolaemia is a low-fat diet and exercise, but a statin may need to be added if the cholesterol remains too high.

Although statins share their mechanism of action, there are differences in their pharmacokinetics and their effect on plasma lipids (Table 1). They are all metabolised in the liver via the cytochrome P450 enzyme system (which has implications for drug interactions). Some statins have active metabolites. The statins differ in their half-life and the duration of HMG CoA reductase inhibition probably varies. Unfortunately, useful comparisons cannot be made as pharmacokinetic data for statins and their metabolites are incomplete.

Table 1

Comparative features of statins

simvastatin pravastatin fluvastatin cerivastatin atorvastatin Comments
Source derived from Aspergillus derived from Aspergillus synthetic synthetic synthetic simvastatin and pravastatin have similar chemical structures
Dose range 10-80 mg 20-40 mg 20-80 mg 300 microgram 10-80 mg
Effect on lipids /upload/issue_files/down.gif TC 15-36% /upload/issue_files/down.gif TC 11-28% /upload/issue_files/down.gif TC 15-21% /upload/issue_files/down.gif TC 22% /upload/issue_files/down.gif TC 20-45% atorvastatin - greatest effect on LDL and triglyceride
/upload/issue_files/down.gif LDL 28-47% /upload/issue_files/down.gif LDL 19-35% /upload/issue_files/down.gif LDL 19-31% /upload/issue_files/down.gifLDL 30% /upload/issue_files/down.gif LDL 38-54%
/upload/issue_files/up.gif HDL 5-13% /upload/issue_files/up.gif HDL 4-10% /upload/issue_files/up.gif HDL 2-10% /upload/issue_files/up.gif HDL 4-8% /upload/issue_files/down.gif HDL 3-/upload/issue_files/up.gif7%
/upload/issue_files/down.gif TG 1-36% /upload/issue_files/down.gif TG 4-24% /upload/issue_files/down.gif TG 1-12% /upload/issue_files/down.gif TG 17% /upload/issue_files/down.gif TG 16-46%
Renal excretion 13% 47% 6% 24-30% <2% renal impairment - adverse effects may be more frequent. Cerivastatin and pravastatin may need lower dosage
Hepatic metabolic isoenzymes CYP450 3A4 CYP450 3A4 CYP450 2C9 CYP450 3A4 CYP450 3A4 most metabolised via same cytochrome P450 isoenzymes
CYP450 2C9 CYP450 3C8
CYP450 2D6
Proven prevention of coronary events yes - in angina or history of myocardial infarction yes - in patients with, or high risk populations without, prior myocardial infarction no no no long-term studies with clinical endpoints lacking for newer drugs

TC = total cholesterol, LDL = low density lipoprotein cholesterol, HDL = high density lipoprotein cholesterol, TG = triglyceride

Effect on lipoproteins
Statins have broadly similar effects on plasma lipids (Table 1). Atorvastatin causes the greatest reduction in LDL cholesterol and triglyceride concentrations, but it is unknown if this results in additional benefits in coronary morbidity and mortality.

Fluvastatin may be slightly less effective in lowering cholesterol concentrations than other statins. However, as lipoprotein reductions are comparable to those achieved with other statins in the large coronary heart disease prevention studies, it seems reasonable to assume that fluvastatin has similar benefits. Cerivastatin is active at a much smaller dosage (micrograms rather than milligrams), but offers no advantage in terms of improved efficacy.

The reduction of triglyceride concentration depends upon baseline concentrations and the dose and LDL lowering efficacy of the statin. Where triglycerides are mildly elevated, all the statins produce reductions of about 12%. Further study is required to determine the effectiveness of statins (other than atorvastatin) in patients with moderate to severe hypertriglyceridaemia. The greatest reductions are achieved using atorvastatin in patients with high baseline triglyceride concentrations.

Non-lipid effects
There is considerable debate about differences in the non-lipid properties of individual statins which may contribute to their beneficial effects on clinical events. Non-lipid mechanisms may modify endothelial function, atherosclerotic plaque stability, inflammatory responses and thrombus formation.2 To what extent such properties are truly independent of the effect on lipoproteins is uncertain. The clinical relevance of these effects is yet to be determined.

Drug interactions
Statins have the potential to interact with drugs which are metabolised by the same metabolic pathways. As different isoforms of cytochrome P450 metabolise individual statins (Table 1), there could be differences in the pattern and severity of interactions. However, as appropriate studies are not available, meaningful comparisons between statins are not possible. Consequently, the approved product information for individual statins also includes interactions described for other drugs from the class, interactions which are not important clinically, and others that are based on isolated case reports.

There are few important interactions. The incidence of myopathy and rhabdomyolysis is increased by concurrent treatment with gemfibrozil, or nicotinic acid. Drugs which inhibit hepatic enzymes (especially CYP450 3A4), such as cyclosporin, itraconazole, ketoconazole and erythromycin, are also associated with an increased risk of myopathy in patients taking statins.

Simvastatin appears to be more likely to increase the anticoagulant effect of warfarin. However, isolated case reports implicating newer statins justify regular monitoring when they are prescribed for patients taking warfarin.

Dose response
In reducing elevated plasma LDL cholesterol concentrations, all statins produce a non-linear dose response curve that reaches a plateau. More than 80% of the LDL lowering effect of a statin is achieved with 50% of the maximum dose. For example, in a patient with an initial LDL cholesterol concentration of 7 mmol/L, a mid-range dose of a statin could be expected to reduce LDL to 4.6 mmol/L, but the maximum dose may give only an additional reduction of 0.4 mmol/L, resulting in a concentration of 4.2 mmol/L.

Combining treatment with low-dose resin, e.g. cholestyramine, can reduce LDL cholesterol by a further 20% (reducing LDL from 4.6 to 3.7 mmol/L in the example above). This is particularly useful in patients with familial hypercholesterolaemia.

Safety
Statins are generally well tolerated and serious adverse effects such as myopathy, rhabdomyolysis and hepatitis are rare. The risk of myopathy may be increased by high doses or the presence of renal impairment. Currently, there are no discernible differences between the statins in the range or severity of adverse effects, but experience is limited especially with cerivastatin and atorvastatin. As lipid-lowering treatment may continue for 50 years, long-term safety remains unproven.

Benefits of statins
Elevated concentrations of LDL cholesterol, total cholesterol, triglyceride or low concentrations of HDL cholesterol are risk factors for coronary heart disease. The anticipated benefits of treatment are a reduction in the incidence of cardiac events and mortality in patients with (secondary prevention) and without (primary prevention) ischaemic heart disease.

Four major studies have been published about the statins available in Australia. To compare benefits between studies, data for key outcomes are expressed as the absolute risk reduction from treatment and the estimate of the number of people who need to be treated to prevent one event.

Table 2

Secondary prevention

Lipids (change from baseline)* All-cause mortality Major coronary events Revascularisation Stroke or TIA

Scandinavian Simvastatin Survival Study (4S)3

Subjects: 4444 (82% men) aged 35-70; post myocardial infarction or angina and TC 5.5-8.0 mmol/L.
Treatment: simvastatin 20-40 mg/day or placebo; median follow-up 5.4 years

/upload/issue_files/down.gif TC 25% ARR - 3.5% ARR - 8.6% ARR - 5.9% ARR - 1.5%
/upload/issue_files/down.gif LDL 35% NNT for 5 years NNT for 5 years NNT for 5 years NNT for 5 years

/upload/issue_files/up.gif HDL 8%

to prevent 1 death -29 to prevent 1 event -12 to prevent 1 procedure -17 to prevent 1 event -65

Cholesterol and Recurrent Events (CARE) study4,6

Subjects: 4159 (86% men) aged 21-75; post myocardial infarction TC <6.2 mmol/L, LDL 3-4.5 mmol/L.
Treatment: pravastatin 40 mg/day or placebo for 5 years

/upload/issue_files/down.gif TC 20% ARR - 0.8% ARR - 3.0% ARR - 4.7% ARR - 1.2%
/upload/issue_files/down.gif LDL 32% NNT for 5 years NNT for 5 years NNT for 5 years NNT for 5 years
/upload/issue_files/up.gif HDL 5% to prevent 1 death -125 to prevent 1 event -33 to prevent 1 procedure -21 to prevent 1 stroke -86

Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study5

Subjects: 9014 (83% men) aged 31-75; post myocardial infarction or unstable angina and TC 4.0-7.0 mmol/L, TG <5 mmol/L.
Treatment: pravastatin 40 mg/day or placebo for 6 years

/upload/issue_files/down.gif TC 18% ARR - 3.0% ARR - 3.5% ARR - 2.7% ARR - 0.8%
/upload/issue_files/down.gif LDL 25% NNT for 6 years to prevent NNT for 6 years to prevent NNT for 6 years to prevent NNT for 6 years to prevent
/upload/issue_files/up.gif HDL 5% 1 death -33 1 event -28 1 procedure -36 1 stroke -127

* LIPID study (compared to control), ARR = absolute risk reduction, NNT = number needed to treat

Table 3

Primary prevention

Lipids (change from baseline)* All-cause mortality Major coronary events Revascularisation Stroke

West of Scotland Coronary Prevention Study (WOSCOPS)7

Subjects: 6595 men aged 45-64; high risk population with no previous myocardial infarction and TC >6.5 mmol/L
Treatment: pravastatin 40 mg/day or placebo for an average of 5 years

/upload/issue_files/down.gif TC 20% Absolute risk Absolute risk Absolute risk Absolute risk
/upload/issue_files/down.gif LDL 26% reduction - 0.9% reduction - 2.2% reduction - 0.9% reduction - 0.15%
/upload/issue_files/down.gif TG 12% Not significant Number needed to treat for 5 years to prevent 1 event - 44 Number needed to treat for 5 years to prevent 1 procedure - 113 Not significant
/upload/issue_files/up.gif HDL 5%

Secondary prevention
The 4S3, CARE4 and LIPID5 studies (Table 2) provide evidence that statins can reduce coronary events, the need for revascularisation (coronary surgery or angioplasty), stroke and all-cause mortality in patients with a history of angina or acute myocardial infarction. The larger estimated benefit from the 4S study may be because it included patients with higher cholesterol concentrations; the average baseline LDL cholesterol was 4.87 mmol/L in 4S, while the upper limit for inclusion in the CARE trial was 4.5 mmol/L. The LIPID study (Table 2), which encompasses a broad range of initial cholesterol concentrations, shows a trend for patients with higher baseline cholesterol concentrations to derive the greatest benefit from statin treatment. The CARE study included stroke as a secondary endpoint in patients receiving pravastatin after myocardial infarction. It found the risk of stroke was significantly reduced only in patients without a prior history of stroke.6

Primary prevention
The WOSCOP study has shown that statins can prevent coronary events in men with no history of myocardial infarction.7 However, the West of Scotland has one of the highest rates of death due to ischaemic heart disease in the world, and this study (Table 3) included many men at high risk of coronary events (5% had angina, 8% ECG abnormality, 15% hypertension and 44% were current smokers). Would a similar study in Australian men produce such beneficial results?

A U.S. study in generally healthy men and women with average cholesterol concentrations (AFCAPS/TexCAPS)8 shows that lovastatin (related chemically to pravastatin and simvastatin) can significantly reduce the risk of first major coronary events (ARR 2.0%) in low-risk patients.

Further analyses of these studies may identify groups of people with a higher risk of CHD who may benefit from treatment. (See also `Sheffield tables for primary prevention of coronary heart disease - an alternative approach.' Aust Prescr 1998;21:98-9.)

Conclusion
There are now five different statins available in Australia. They have similar pharmacology, and range and severity of adverse effects. All statins have established efficacy in terms of beneficial effect on plasma lipid profiles (a surrogate marker for cardiovascular disease). While the effectiveness of all statins in preventing cardiovascular events may be anticipated, because of their effect on lipids, beneficial outcomes have only been confirmed for two, structurally similar, statins (pravastatin and simvastatin).

Comparing the benefits seen in the four major studies, it is clear that the likelihood of benefit is much greater for secondary prevention than for primary prevention. For patients with existing coronary heart disease, those with high cholesterol concentrations are most likely to benefit from treatment with a statin.

References

1 . Fidge NH. Lipid-lowering drugs - mechanisms of action. Aust Prescr 1990;13:73-7.

2 . Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA 1998;279: 1643-50.

3 . Pedersen TR. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S). Lancet 1994;344:1383-9.

4 . Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-9.

5 . The long-term intervention with pravastatin in ischaemic disease (LIPID) study group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-57.

6 . Plehn JF, Davis BR, Sacks FM, Rouleau JL, Pfeffer MA, Bernstein V, et al. Reduction of stroke incidence after myocardial infarction with pravastatin: the cholesterol and recurrent events (CARE) study. Circulation 1999;99:216-23.

7 . Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301-7.

8 . Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. JAMA 1998;279:1615-22.

FURTHER READING

Tonkin AM, Ryan EW. The role of HMG CoA reductase inhibitors after myocardial infarction. Aust Prescr 1998;21:86-7.

Australian Medicines Handbook. Dyslipidemia. In: Australian Medicines Handbook. 1st ed. Adelaide: Australian Medicines Handbook Pty. Ltd.; 1998. p.6-74 - 6-75.

Furberg CD. Natural statins and stroke risk. [editorial] Circulation 1999;99:185-8.

Self-test questions

The following statements are either true or false (click here for the answers)

1. Atorvastatin has less effect on triglyceride concentrations than the other statins.

2. The statins are more effective in secondary prevention than they are in the primary prevention of myocardial infarction.



First published online: October 1999