PHILADELPHIA — Be alert for potential interactions and side effects when prescribing statins, Dr. Douglas S. Paauw advised at the annual meeting of the American College of Physicians.
Hepatotoxicity and rhabdomyolysis are relatively rare, but myalgias are quite common and often prompt patients to discontinue the drugs, said Dr. Paauw, professor of medicine at the University of Washington, Seattle.
And, although the overall risk of rhabdomyolysis is low, the chance is greater with the addition of other drugs.
In one frequently cited study, rates of toxicity were very low (2% myalgias, 0.4% myositis, and 0.4% hepatotoxicity) among 252 atherosclerotic patients receiving a statin plus gemfibrozil, leading the authors to conclude that the combination could be used safely in high-risk patients (Am. Heart J. 1999;138:151–5).
But those results may not reflect current clinical experience. Pravastatin, which is used less often today, was the statin most commonly used in the study. Simvastatin and lovastatin, both used more often today, are metabolized by a subunit of the cytochrome P450 system that is affected to a greater degree by gemfibrozil than are pravastatin or fluvastatin. Thus, the investigators were using “safer statins” in terms of drug interactions, Dr. Paauw noted.
If it is necessary to use both gemfibrozil and a statin—a common scenario—it's important to document the reason. Also, educate the patient about myalgias and rhabdomyolysis, including the importance of stopping the drug right away when muscle pain starts and then calling the physician afterward—especially if the symptoms occur during weekends or holidays. “I tell patients to stop the drug if there's any question. It's not going to be a problem if they're off the statin for 24 hours.”
Always ask patients about muscle pain, and monitor signs and symptoms at every office visit. There is no set policy about blood monitoring, but it's a good idea to measure creatinine phosphokinase (CPK) levels periodically and any time that symptoms develop, he advised.
Fibrates top a long list of other drugs that can increase statin toxicity, including azole antifungals, niacin, erythromycin/clarithromycin, protease inhibitors, verapamil/diltiazem, and cyclosporine. About half of all severe cases of rhabdomyolysis occur when three or more of these agents are taken together, such as in a patient who is already taking a fibrate plus a statin who is then prescribed erythromycin for 2 weeks.
“It's that third drug that markedly increases the risk,” Dr. Paauw said.
Less attention has been paid to simple muscle pain and weakness. Published data suggest that this side effect occurs in only 1%–5% of patients on statins. “I really believe that that number is higher. In my practice, it's probably 20% at least,” he said.
Indeed, patients will often take themselves off the drug and report that the pain goes away. The problem appears to be both dose- and drug-related.
In one study, muscle cell abnormalities were found on biopsy in patients who had normal CPK levels but who complained of muscle pain (Ann. Intern. Med. 2002;137:581–5). “If a CPK comes back normal, it doesn't tell us that the pain isn't from the statin. It simply tells us that the magnitude of the muscle problem doesn't put them at risk for rhabdomyolysis right now, but they could still be severely debilitated by the pain,” Dr. Paauw said.
Further complicating the picture, statin-induced muscle pain isn't necessarily uniform throughout the body. For example, a patient may complain of severe pain only in the left thigh. Quite often, the pain goes away if you take the patient off the drug. “Take very seriously any pain syndrome in a patient on statins. If you can't find an alternative diagnosis, consider a short drug holiday and see what happens,” he recommended.
Once the pain resolves—typically in 1–2 weeks—you can restart the same statin at a low dose, or try switching to a different one. If the patient still experiences muscle pain after trying two different statins, it may be necessary to consider a different category of lipid-lowering drug.
In contrast to muscle problems, hepatotoxicity appears to be less of an issue with statins than was originally thought. In a retrospective cohort study of 23,000 adult HMO patients who received statins over a 5-year period, just 0.3% had severe transaminitis, defined as an alanine aminotransferase (ALT) level 10 times greater than normal. Of those 62 patients, only 17 had ALT elevation due to the statin, and the problem resolved after stopping the statin in 16 of those 17. Most patients were symptomatic at the time of the elevation, which usually occurred within 4 weeks of starting or changing therapy (Am. J. Med. 2005;118:618–24).