Statin Potency Linked With Muscle Weakness

Nancy A. Melville

August 22, 2012

August 22, 2012 — Muscle weakness, a known adverse effect (AE) of cholesterol-lowering statin drugs, varies significantly between drugs within the class according to their potency, as reported in a study published online August 22 in PLoS ONE.

A team of researchers led by Beatrice A. Golomb, MD, PhD, from the University of California, San Diego, referenced data from the US Food and Drug AE Reporting System (AERS) between July 2005 and March 2011 to evaluate all case reports of muscle-related AEs associated with the most commonly used statins and, when available, generic forms of the drugs.

They found that among 147,789 reports, with the exception of fluvastatin, the relative risk for reported muscle problems corresponded with the individual drugs' per milligram level of low-density lipoprotein–lowering potency.

The highest risk was consistently associated with rosuvastatin (Crestor, AstraZeneca), which is the strongest statin, followed by atorvastatin (Lipitor, Pfizer) and simvastatin (Zocor, Merck), which are next in terms of potency. The latter 2 statins had rates of muscle-related AEs that were 55% and 26% as high as rosuvastatin, respectively.

Pravastatin (Pravachol, Bristol-Myers Squibb) and lovastatin (Mevacor, Merck), the statins next lowest in potency, had the lowest muscle-related AEs, at rates 17% and 7.5% that of rosuvastatin, respectively.

Fluvastatin: An Exception to the Rule

Fluvastatin (Lescol, Novartis), which has the lowest potency of the group, was an exception to the trend, showing the second-highest level of risk: 74% as high as rosuvastatin.

The finding on fluvastatin corroborates data from an earlier study, and the authors of the current trial speculate that the drug's less frequent use may explain the discrepancy.

"We think a likely reason is that fluvastatin, which is far less frequently prescribed than other statins, may be primarily reserved by physicians for patients who have failed to tolerate other statins," the authors note. "Disproportionate use in statin non-tolerators may produce higher apparent adverse effect rates (indeed, use of fluvastatin 80mg for those intolerant to other statins is advised by some)."

The drug may also be used more selectively than the others and be more susceptible to drug interactions or heightened toxicity, the authors add. They suggest further studies to evaluate fluvastatin head-to-head with other agents.

Rosuvastatin, meanwhile, has a pharmacokinetic profile that is typically considered to be stronger than other statins, using common drug clearance pathways that are usually not involved in adverse drug interactions.

However, the new findings underscore that potency can play a key role.

"Higher potency agents, and rosuvastatin in particular, were associated with elevated relative risk of adverse events," the authors write. "This finding has important implications for statin treatment decisions in general, and particularly with regard to patients who have already experienced muscle-related adverse events from statin therapy."

Overall, muscle-related AEs have been shown to occur in as many as 10% to 15% of all statin users, and Dr. Golomb says even that figure is likely an underestimate.

"Only a fraction of adverse effects are reported to the [US Food and Drug Administration], and a range of factors can influence reporting rates and accuracy of this information," Dr. Golomb said in a university news release. "However, findings from this study align with — and extend — other forms of evidence."

Risk–Benefit Analysis Requires Postmarket Surveillance

The authors add that the study underscores the need to analyze postapproval data beyond randomized clinical trials to better evaluate drugs' AEs as they emerge in real-world settings.

"Surveillance of post-marketing AEs is of vital importance to understand real-world AEs and reporting differences between individual statin drugs," they write, adding that postmarketing surveillance is not intended to replace randomized clinical trials, which are "disadvantaged in adverse event detection."

"[C]ase reports and postmarketing surveillance are commonly responsible for the first identification of important adverse events, including those that ultimately lead to regulatory actions...and product withdrawals," the authors write. RCTs and postmarket surveillance both serve necessary and important roles. Each method "complements the other to extend the understanding of drug benefits versus risks."

Limitations of the current analysis include limitations inherent to the AERS database, including potential input errors as well as lack of assessment for bias. In addition, dose data were not available, and there may have been disproportionate reporting of adverse events for rosuvastatin because it was the newest statin on the market.

The authors have disclosed no relevant financial relationships.

PLOS One. Published online August 22, 2012.

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