Statin Myopathy and CPT deficiencies

San Antonio, TX - New research presented at the American College of
Rheumatology 2004 meeting points to several genetic risk factors that
may trigger myopathies in susceptible patients.

Dr Robert Wortmann (University of Oklahoma College of Medicine, Tulsa)
reported that muscle biopsies or tests of blood samples from more than
100 patients who developed statin myopathies showed that such patients
are 11 times more likely to be heterozygous carriers for carnitine
palmitoyltransferase (CPT) II deficiency and 20 times more likely to be
carriers for McArdle's disease (glycogen storage disease Type V) and
have 4 times the usual rate of myoadenylate deaminase deficiency.

"Patients with statin-induced myopathies are at increased risk for
having underlying metabolic muscle diseases and, in some cases, carrier
status alone appears to contribute to the increased risk," Wortmann
said.

"We hypothesized that the prevalence of combined or single inherited
metabolic gene defects would be higher than expected from the general
population among patients who suffer from statin myopathies.
Furthermore, we expected that symptoms in carriers may also be
triggered by statins," Wortmann said. "People with these defects are
usually asymptomatic until forced to depend on the metabolic pathway
with the defect in it."

The cholesterol-lowering drugs are thought to cause that type of
metabolic shift. "We think the downstream metabolic changes from
blocking cholesterol may trigger the myopathies in susceptible
individuals because they alter components the cell needs to manage
energy," Wortmann said.

Wortmann and colleagues analyzed muscle biopsy and/or blood samples
from 132 patients who presented with statin myopathies. "Thirty-six
percent of patients had at least one genetic abnormality, and 30% had
multiple abnormalities," Wortmann said. More than half of the muscle
biopsies evaluated for CPT II activity also had a secondary deficiency,
31% had carnitine abnormalities, and one third had lipid-storage
abnormalities.

Although plasma creatine kinase (CK) elevations have been
--------ociated with statin-related problems, Wortmann said that this
is not always the case. He found that 75% of patients with a 10-fold
elevation of plasma CK had evidence for a defined underlying metabolic
myopathy but that some affected individuals had normal plasma CK.

Coenzyme Q10 and possibly Carnitine supplementation may help

Nearly half of the samples analyzed had coenzyme Q10 (ubiquinone)
levels two to four standard deviations below normal. Statins inhibit
the enzyme HMG-CoA reductase before the final formation of cholesterol
in the mevalonate pathway, and this same pathway is used to synthesize
coenzyme Q10.

The result can be a deficit in the amount of coenzyme Q10 needed for
optimal heart and skeletal muscle function. The link between statin use
and reduction in coenzyme Q10 levels has also been well studied by drug
developers, and in fact two patents were issued to Merck in 1990 for
combination statin/coenzyme Q10 formulations. One was meant "to
counteract HMG-CoA-reductase-inhibitor associated skeletal muscle
myopathy." The other was for "counteracting HMG-CoA-reductase-inhibitor
associated elevated transaminase levels" through "the adjunct
administration of an effective amount of a HMG-CoA reductase inhibitor
and an effective amount of coenzyme Q10."

"In addition to coenzyme Q10 supplementation, which has been
recommended for treatment of statin myopathy and which some patients do
respond to, these data provide a rationale for consideration of the use
of carnitine in these patients," Wortmann said. "For patients who do
not respond to coenzyme Q10, I would suggest the use of carnitine."

Definitions:

Myopathies are inflammatory and non-inflammatory diseases of muscle.

Myopathy refers to any disorder of the muscles.

Statin Myopathy refers to a myopathy caused by any statin drug.

Statin drug is a prescription medication that lowers blood cholesterol
levels by inhibiting HMG-CoA reductase.