After 20 Years of Use, We Still Don't Know How Statins Cause Myopathy

Last week, the FDA released its warning about an increased risk of myopathy with high-dose simvastatin (Zocor; Merck). The warning is based on a review of preliminary safety data from the SEARCH trial and "other sources." The data show that, while the risk of myopathy is considerably higher with high-dose simvastatin (vs low-dose simvastatin), it is still relatively uncommon (<1%).

The agency also reemphasized several warnings about the heightened risk of myopathy with simvastatin specifically and statins (or HMG CoA reductase inhibitors) generally. These warnings include the use of concomitant drugs that inhibit the CYP3A4 enzyme and thereby increase the concentrations of some statins—namely atorvastatin (Lipitor; Pfizer), lovastatin (Mevacor; Merck), and simvastatin.

In fact, statins have been recognized to increase with risk of myopathy and rhabdo (typically in a dose-dependent fashion) since the Dawn of Statins in the mid-1980s (beginning with Mevacor).** Yet, despite more than 20 years of clinical experience with statins (and squillions of dispensed prescriptions), we still don't know exactly how statins can cause myopathy.

The mystery necessitates a shortish, painful trip down Biochemistry Lane.

According to a literature review (see, for instance, here), the leading hypothesis implicates the statin-induced depletion of isoprenylated proteins that are products of the cholesterol-producing HMG CoA-reductase pathway. Depletion of these isoprenylated proteins, or isoprenoids, may lead to high levels of calcium in muscle cells, which activate mitochondria-triggered apotosis.

Now: Must read People magazine.

* Muscle breakdown with high creatine kinase (CK) levels (generally 10 or more times the upper limit of normal). The big risk with rhabdomyolosis is myoglobin-induced renal failure.

** Bayer's cerivastatin (Baycol) was famously recalled from the worldwide market in 2001 owing to an increased risk of rhabdomyolysis (especially when compared with other marketed statins). According to Law and Rudnicka, the incidence of statin-induced rhabdo (excluding Baycol-induced rhabdo), is 3.4 per 100,000 person-years of treatment; the fatality rate of rhabdo is about 10%.

Image of right quadriceps muscles from Gray's Anatomy (1918).