Statin Safety in Perspective - Maximising the Risk:Benefit

Marc Evans

Disclosures

Br J Cardiol. 2004;11(6) 

In This Article

Risks of Statins

Overall, the statin class of drugs has a good safety profile and is well tolerated. The withdrawal of cerivastatin, however, led to questions regarding the safety of statins and, as with all drugs, the safety profile of statins must be evaluated relative to their clinical benefits.

The overall adverse event rate associated with statin therapy is low, with the most common side effects reported being headaches, gastrointestinal disturbance and myalgia.[17] Based on data from the rosuvastatin pre-registration clinical trial package, which reviewed the key currently available statins in the UK (simvastatin, atorvastatin, pravastatin, and rosuvastatin), statins have equivalent adverse event withdrawal rates of approximately 3% (figure 3).[18]

Adverse event withdrawal rates of statins.

However, as with most drugs, statins exhibit a dose-related adverse events (AEs) profile.[18] One of the most common side effects associated with statin therapy relates to muscle toxicity and myopathy. It is important to appreciate that there is a distinct classification of muscle AE, ranging from mild myopathy to frank rhabdomyolysis. Furthermore, rhabdomyolysis and myositis have a strict clinical definition ( Table 2 ).[19]

The total reported incidence of statin-associated myotoxicity ranges from between 1-7%[19] and is a function of dose rather than LDL-C reduction.[18] This dose-related effect has been demonstrated across the statin class (figure 4)[18] and was further supported in the A to Z trial which demonstrated higher rates of side effects with simvastatin 80 mg.[20]

Myopathy in association with statins is dose-related.

Myalgia is the most common side effect with statins while rhabdomyolysis and myositis, the most serious of muscle AEs, account for less than 0.1% of all statin-related AEs, with comparable reporting rates across currently available statins.[21] Cerivastatin was a lipophilic enantiomeric agent with a dual excretory pathway (2C8 and 3A4). The pre-marketing data showed increased rates of myotoxicity, particularly at higher doses, while the post-marketing data revealed the incidence of myotoxicity was greater than ten times that of other statins. The majority of cases of rhabdomyolysis occurred with the 0.8 mg dose and there was a particularly high incidence associated with the use of cerivastatin in combination with gemfibrozil.

The frequency of rhabdomyolysis reported with the currently available statins is less than one in 100,000 and is comparable for simvastatin, atorvastatin, rosuvastatin, pravastatin, fluvastatin and lovastatin.[21,22] Deaths due to rhabdomyolysis are very rare (<1:1,000,000.) The reported rate of deaths due to rhabdomyolyis as a function of cerivastatin therapy were many fold greater than seen with other agents ( Table 3 ). Indeed, Staffa reported that after 9.8 million prescriptions in the US there were 31 cases of fatal rhabdomyolysis reported.[23] Since the withdrawal of cerivastatin, rosuvastatin has been launched and, to date, there have been in excess of 10 million prescriptions with no fatal cases of rhabdomyolysis reported (AstraZeneca, data on file).

In summary, whilst rhabdomyolysis may be serious and life-threatening, it is very rare in relation to currently available statin therapy. When it does occur, it is most commonly in the context of predisposing risk factors, such as trauma, major surgery, hypothyroidism, liver failure, renal failure and concomitant drug therapy such as amiodarone.[18]

Mild proteinuria has recently been identified in patients treated with all statin therapy,[24] although this is generally transient and reversible. Furthermore, the finding of mild proteinuria is not predictive of any acute or progressive change in renal function or suggestive that statin therapy is associated with deteriorating renal function. In fact, statin therapy, potentially through improvements in vascular function, has been shown to improve glomerular filtration rates.[24]

The excreted urine proteins appear to be mainly low molecular weight proteins, indicating a specific effect on proximal tubular protein reabsorption. In recent in vitro studies, various statins decreased protein reabsorption in an opossum kidney cell line derived from proximal tubules[25] and human tubular kidney cells.[26] This effect was associated with inhibition of 3-HMG CoA reductase and was reversed by adding mevalonate (the product of 3-HMG-CoA reductase) and geranylgeranyl pyrophosphate (a mevalonate product involved in protein prenylation), suggesting a potential pharmacologic mechanism for the tubular proteinuria seen with statin therapy.[26]

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