BMJ  2006;332 (6 May), doi:10.1136/bmj.332.7549.0-e

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Statins rarely cause serious side effects

Research question Are statins safe?

Answer Yes. Serious side effects such as rhabdomyolysis, myopathy, and peripheral neuropathy are rare. There's little or no evidence that statins cause liver disease, renal disease, or cognitive decline

Why did the authors do the study? Statins are widely used and are generally considered safe. But well documented concerns over two drugs in this class—cerivastatin and rosuvastatin—prompted these authors to review the published safety data on all statins. Cerivastatin was withdrawn from the market in 2001.

What did they do? They systematically searched for data on the side effects of any statin from four sources: randomised controlled trials, cohort studies, voluntary notifications to regulatory authorities, and case reports. They combined data where possible to estimate the risks of muscle disease (rhabdomyolysis, myopathy), liver disease, renal disease, and neurological disease associated with taking statins. They estimated the class effect, the effects of individual statins, and any additional risks associated with combining statins with other drugs, especially the fibrate gemfibrozil.

What did they find? The estimated incidence of rhabdomyolysis was 3.4 (95% CI 1.6 to 6.5) per 100 000 person years of treatment with any statin other than cerivastatin. This estimate was based on two large cohort studies and 20 randomised controlled trials. Combining a statin with gemfibrozil resulted in a 10-fold increase in the risk of rhabdomyolysis. Drugs metabolised by cytochrome P450, such as simvastatin and atorvastatin, were slightly more likely than other statins to cause rhabdomyolysis (4.2 per 100 000 person years), particularly when combined with a fibrate. Rosuvastatin had the weakest safety data.

Statins were also associated (rarely) with myopathy (11 per 100 000 person years), and peripheral neuropathy (12 per 100 000 person years estimated from four cohort studies and case reports), but the authors found no convincing evidence of a link with hepatobiliary problems including liver failure. Data from three randomised trials and the adverse events reporting system of the US Food and Drug Administration, suggest that the risk of liver failure associated with statins is about 0.5 per 100 000 person years of treatment, which is no greater than the risk in the general population. These authors found no evidence at all that statins damage renal function or accelerate cognitive decline in older people.

What does it mean? Simvastatin, atorvastatin, lovastatin, pravastatin, and fluvastatin are widely used and seem safe. Serious side effects can occur but are rare. The well established benefits of these drugs outweigh the risks. Rosuvastatin has the weakest safety record simply because few data have been published on this statin.

Most cases of rhabdomyolysis in this study were associated with drug interactions, usually between simvastatin, lovastatin, or atorvastatin and another drug metabolised by cytochrome P450, such as erythromycin or azole antifungal drugs. In a fifth of rhabdomyolysis cases, the patient was taking a statin and a fibrate (usually gemfibrozil). The authors conclude that many cases could be prevented by avoiding these kinds of interactions.

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Law M, et al. Statin safety: a systematic review. Am J Cardiol 2006;97(suppl): 52-60C

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