I searched PubMed for publications between 1985 and 2006, using search terms including “safety of statins”, “myopathy”, “rhabdomyolysis”, “hepatotoxicity”, “safety”, and “randomized” in various combinations and with individual statin names. I concentrated on larger randomised studies but referenced smaller-scale studies, observational studies, and other reviews where appropriate. I also searched the reference lists of articles identified by this search strategy and selected those judged
ReviewThe safety of statins in clinical practice
Introduction
The statins are a widely used group of cholesterol-lowering agents that act by inhibiting the enzyme 3-hydroxy 3-methylglutaryl CoA (HMG CoA) reductase, which catalyses the rate-limiting step in cholesterol biosynthesis.1, 2 Since statins were first approved in 1987, their ability to reduce the risks of vascular death, non-fatal myocardial infarction, stroke, and the need for arterial revascularisation procedures has been shown by several large, high-quality randomised trials.3
In these trials, the extent of risk reduction was judged to be directly proportional to the degree to which LDL (low-density lipoprotein) cholesterol was lowered consistent with this being the main mechanism.3, 4 As a consequence, and because of the additional benefit shown with more intensive statin therapy,5, 6, 7 there has been a trend toward using higher doses of statin. Furthermore, cholesterol-lowering is now recommended for a wide range of people at cardiovascular risk, including those with average and below-average lipid levels.8, 9 This change is leading to increased statin use and to the use of more intensive regimens. Hence, the safety of this group of drugs is of considerable importance.
Six statins are available in most parts of the world: lovastatin (first licensed in 1987 but not available in the UK), simvastatin (1988), pravastatin (1991), fluvastatin (1994), atorvastatin (1997), rosuvastatin (2003), and pitavastatin10, 11 (2003—available in Japan and India only) (table 1). Cerivastatin was approved in 1998 but then withdrawn in 2001 because of a high risk of rhabdomyolysis.12
This Review will examine two aspects of statin safety: the safety of achieving and maintaining low levels of total and LDL cholesterol; and the specific safety of the available statins at different doses. The adverse effects on muscle and on liver enzymes generally apply to all statins, but other aspects of safety (or the propensity for these adverse effects) should not automatically be extrapolated from one statin to another. This Review concentrates on safety information derived from randomised trials of specific statins, taking account of reports of spontaneous adverse effects and other sources of safety data.13, 14 Controlled randomised trials avoid the bias inherent in spontaneous reporting of adverse effects or retrospective study designs, and are therefore the most appropriate means of assessing common adverse effects. Although such trials might exclude some vulnerable individuals, a follow-up of 5–6 years allows time for participants to become at risk, and therefore provide valuable safety information. In contrast, observational studies without a control group are less informative about common symptoms15 but, along with other sources of data, remain important for detection of rare side-effects.14
In this Review, “standard dose” refers to the commonly prescribed daily doses which typically reduce LDL cholesterol by 30–45% (ie, atorvastatin 10–20 mg, fluvastatin 40–80 mg, lovastatin 40 mg, pravastatin 40 mg, rosuvastatin 10 mg, and simvastatin 20–40 mg).
All statins competitively inhibit the rate-limiting enzyme HMG CoA reductase in the metabolic pathway of cholesterol biosynthesis.16 They therefore reduce the concentration of downstream metabolic by-products including mevalonate,17 which in turn leads to increased expression of LDL receptors on hepatocytes, and to increased uptake of LDL cholesterol from the circulation.16 Statins also tend to reduce the production of apolipoprotein B, leading to reduced VLDL (very low density lipoprotein) secretion from the liver.18 Statins have qualitatively similar effects on lipid levels, but their efficacy in lowering LDL cholesterol varies (table 1).
Statins are metabolised in the liver; detailed discussion of their metabolism and mechanisms of drug interactions can be found elsewhere.19, 20 Statins that are metabolised predominantly by the cytochrome P-450 system can interact with other drugs, some of which involve commonly prescribed drugs (table 1 and panel).21 Statins also vary in their propensity to cause drug interactions through other mechanisms (eg, by blocking organic anion transporter peptides);20, 22 genetic polymorphisms within these systems also affect drug disposition and the likelihood of interactions. Prescribing information should therefore be routinely consulted when drug interactions are possible.
Section snippets
Maintaining very low cholesterol levels
Observational cohort studies have consistently shown that people with low total cholesterol levels (eg, <4·0 mmol/L) are at a higher risk of subsequent death from cancers, respiratory causes, haemorrhagic stroke, and non-medical causes of death than are people with higher baseline cholesterol levels.23, 24 Some of these associations can be explained by reverse causality (eg, cancer-reducing cholesterol levels while increasing risk of subsequent death), but concerns remain that low total
Specific adverse effects of statins
The only well-documented, consistent adverse effects associated with statins are muscle toxicity, including myopathy and rhabdomyolysis, and effects on liver enzymes.1 Many other possible side-effects are listed in the product information, but given the lack of confirmatory evidence from large controlled randomised trials, these are likely to be either rare or not truly caused by statin treatment (at least at standard doses). However, there is only limited safety information available about
Effects of statins on the liver
Since the first introduction of statins it has been clear that a small percentage of patients experience an increase in liver enzymes (in particular, alanine and aspartate transaminases).1 Typically, with standard doses, little or no effect is seen on gamma glutamyl transferase, alkaline phosphatase, or bilirubin.52 Abnormalities in concentrations of these indicators of liver function should prompt further investigation of liver dysfunction.40 The increases in transaminases with statins are
Other adverse effects at high statin doses
Other treatment-related, non-serious adverse events have been reported with atorvastatin 80 mg daily in trials where it has been compared with lower statin doses5, 6 or simvastatin 80 mg.73 In particular, gastrointestinal effects such as diarrhoea, abdominal pain, or nausea. These effects were not reported in the trial comparing simvastatin 80 mg with 20 mg daily;36 no comparable large-scale randomised or long-term data exist for rosuvastatin at similarly potent doses.
Alcohol
Most large randomised trials excluded people with excessive alcohol intake from participation, making assessment of the safety of statins in these people difficult. Nevertheless, there is no clear evidence that statin myopathy is more common among those consuming large amounts of alcohol, although excess alcohol intake is a risk factor for rhabdomyolysis induced by pressure necrosis.79, 80 In the Heart Protection Study,81 no upper limit for alcohol intake was imposed provided that liver
Other possible effects of statins
Despite concerns about a variety of possible adverse effects of statins (including causing lens opacities,102 sleep disturbance,103, 104 mood disorders,105, 106 dementias,107 and peripheral neuropathy108, 109), data from controlled randomised comparisons have not confirmed any of these adverse effects.110, 111, 112, 113, 114 For example, in the largest of the studies suggesting that statins may cause peripheral neuropathy, a relative risk of 3·7 (95% CI 1·8–7·6) was reported in association with
Conclusion
Statins are a well-tolerated and extensively studied group of drugs. Their proven impact on cardiovascular disease risk has been driving their widespread use. With a few caveats, and while awaiting good-quality randomised data for the newer drugs, statins seem to be a remarkably safe group of drugs when used at their usual doses. The recognised adverse effects, most importantly myopathy and rhabdomyolysis, are rare and, as with most drugs, increase with higher doses. Muscle pain is common in
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