Incidence of Myopathy with Combined Statin Calcium Blockers Use
abstract & commentary
Synopsis: The overall incidence of myopathy with HMG-CoA reductase inhibitor use is low and augmented by the use of potent P450 system inhibitors but not by calcium blockers.
Source: Gruer PJ, et al. Am J Cardiol 1999;84: 811-815.
Although simvastatin is a well-tolerated effective therapy for preventing coronary events due to the consequences of hyperlipidemia, a generalized myopathy is a rare but well-recognized adverse effect of simvastatin and other hydroxymethylglutarate coenzyme A (HMG-CoA) reductase inhibitors. Since most HMG-CoA reductase inhibitors (simvastatin, lovastatin, atorvastatin, and cerivastatin) are metabolized by the cytochrome P450 system, the incidence of myopathy may be higher with the concomitant use of drugs that inhibit the P450 system. Of most concern is the use of calcium blockers, which are weak inhibitors of P450. Thus, Gruer and colleagues analyzed safety data from two large simvastatin trials (Scandinavian Survival Study and the Heart Protection Study) and post-marketing adverse experience data reported to the U.S. Food and Drug Administration (FDA). Myopathy was defined as unexplained muscle pain or weakness and creatine kinase elevations more than 10 times the upper limit of normal. Rhabdomyolysis cases were included in the term myopathy. Concomitant drugs surveyed included calcium blockers and known potent inhibitors of P450, such as cyclosporine, erythromycin, and ketoconazole. In both of the simvastatin trials, about 30% of the patients were on calcium blockers and there were three cases of myopathy in more than 12,000 patients (0.025%, or 1 case per 10,000 patient years); one of the three was on calcium blockers. The post-marketing FDA data confirmed the hypothesis that myopathy was more common with concomitant use of the potent P450 inhibitors, but not with calcium blockers. Gruer et al conclude that the overall incidence of myopathy with HMG-CoA reductase inhibitor use is low and augmented by the concomitant use of potent P450 system inhibitors, but not by calcium blockers.
Comment by Michael H. Crawford, MD
Ever since the Seldane fiasco, physicians have been alert to drug interactions with the potent P450 inhibitors, but less is known about the weaker inhibitors such as calcium blockers. Thus, this report on the popular HMG-CoA reductase inhibitor simvastatin and calcium blockers is of interest. Although no interaction was seen, it reminds us that simvastatin use with potent P450 inhibitors is a potential problem. Patients on cyclosporine have had no problems reported with low-dose simvastatin (10 mg qd) but higher doses are problematic. If a short course of macrolide antibiotics is necessary, discontinuation of simvastatin or other HMG-CoA reductase inhibitors would be prudent.
Despite these cautions, this report demonstrates that simvastatin-induced myopathy is rare (0.025% incidence). Even in the FDA database, there were only 25 reported cases and 14 were also taking cyclosporine. It has been estimated that more than 20 million people worldwide have been prescribed simvastatin.
The one patient with myopathy in the simvastatin megatrials who was on a calcium blocker was on diltiazen, but the FDA database showed an even distribution of diltiazen and verapamil vs. the dihydroperidine calcium blockers. Thus, the lack of an association between calcium blockers and myopathy in patients on simvastatin cannot be explained by the type of calcium blockers being used.
There are some limitations to this study. First, the number of cases of myopathy is small, which reduces the power of these observations. However, it is unlikely that larger databases exist to address these issues. Second, the mega-trials used a maximum simvastatin dose of 40 mg qd and recently an 80 mg qd maximum dose was approved by the FDA. Third, FDA adverse drug reports probably underestimate the incidence of adverse events and are subject to physician reporting biases that have unpredictable effects. However, adverse event reports in clinical trials are highly accurate. Also, the finding that the potent P450 inhibitors increase the incidence of myopathy suggests that this analysis is robust.
The incidence of myopathy associated with statin therapy may be increased by:
a. cyclosporine.
b. diltiazem.
c. amlodipine.
d. verapamil.
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