After statin-induced myopathy: What next?

Motivation: A frequent finding in both the hospital and outpatient setting is the patient with hyperlipidemia and/or coronary artery disease who was on a statin, but had to stop due to side effects, mainly muscle cramps. Some of these patients have been switched to a different statin, are on a lower dose of the same statin, or not on any statin at all. There appears to be no consensus on what comes next. This observation had me running toward the literature wondering what the data shows for best treatment option in patients who have had adverse effects (e.g. myopathies) from statin use.

Papers:
Reinhart KM and Woods AJ. Strategies to preserve the use of statins in patients with previous muscular adverse effects. Am J Health Sys Pharm 2012; 69:291-300.
Robenson, RS. Current overview of statin-induced myopathy. Am J Med 2004;116:408-416.

Background: Statins have a number of adverse effects, the most common being myopathies (usually bilateral leg cramping) that may cause serum elevations of the muscle enzyme creatine kinase (CK). About 10% patients discontinue statins after 1 year and 28% after 4 years and nearly half of these due so because of the adverse effects. An estimated 1 out of 5 people on statins will have some adverse myopathic reaction in their lifetime. The mechanism is not entirely understood, but the most convincing hypothesis is that statins as HMG-CoA reductase inhibitors inhibit the production of mevolonate, a precursor to not only artery-clogging cholesterol but also the "good" cholesterol that supply our cellular membranes. Furthermore, mevalonate is a precursor of ubiquinone (coenzyme Q10) which is a powerful antioxidant, membrane stabilizer, and essential player in the ATP chain that leads to the production of energy that myocytes rely on to do their job.

Methods:
Unfortunately, no large-scale randomized trials have been done to address this issue. Reinhard and Woods conducted the largest literature review on an understudied field that included 16 restrospective studies, and some intereventional (not all randomized or controlled) trials that examined the outcomes of a strategy for the preventon of recurrent statin-associated myalgia.

Results:
Five options were found in the literature: 1) reduced dosing of statin 2) addition of vitamin D or E to statin therapy 3) addition of supplemental coenzyme Q10 to statin therapy 4) red yeast rice as substitution for statin (RYR contains a naturally occuring lovastatin) 5) trial of a different statin. For patients reduced from once daily to once or twice a week regimen of atorvastatin, about 20% were able to significantly lower their statins to reach goal and there was no difference compared to placebo in the incidence of myalgias suggesting that this is a more tolerable, if less effective option. Vitamin E did not show any benefit in reducing myalgias, while vitamin D added to statins showed a mild effect. CoQ added to a statin had conflicting data with some showing significant decrease in myalgias in RCT, and others showing none. RYR had difficult to interpret data mainly because it is a supplement that is not approved by FDA to contain any lovastatin in US (whereas it contained varying degrees of lovastatin in the reviewed studies). Trial of alternative statins showed fairly good results (>90% tolerability in 3 RCTs) when patients were switched from a different statin to an equivalent dose of fluvastatin (80mg), atorvastatin (10-20mg), or rosuvastatin (5-10mg).

Discussion:
Overall, using an alternative statin may be the most tolerable and efficacious option after discontinuance of a previous statin due to adverse effects. It is thought that hydrophilic (water-loving) statins are less likely to cause symptoms as they cannot cross the cell membrane easily through passive diffusion (unlike lipophilic statins). For example, simvastatin is a commonly used lipophilic statin that is known to cause adverse effects whereas rosuvastatin, a hydrophilic drug, is much less likely to do so. Vitamin D or CoQ supplementation may be helpful in patients with mild symptoms and no elevation of creatine kinase. RYR should not be used because it does not include the active ingredient (e.g. lovastatin) when purchased in the US and has previously been shown to contain nephrotoxic additives. These interpretations are very limited given that there has been no head to head studies and the few trials that exist are in relatively small samples with poor controls and ample potential for bias. As a future preventative cardiologist, I must advocate against the discontinuation of statins altogether. The data showing the ability of statins to prevent MI and death from cardiovascular causes even in patients with normal lipid levels is powerful, indeed. The biggest conclusion I can draw is that pragmatic, randomized clinical trials comparing these options are desperately needed.