Genetic risk factors for statin myopathy found; coenzyme Q10, carnitine supplements might help

Janis Kelly

October 22, 2004

Oct 22, 2004

San Antonio, TX - Statins are increasingly important in rheumatology as clinicians work out ways to reduce the high risk of cardiovascular disease associated with rheumatoid arthritis (RA) and other rheumatoid conditions. Serious myopathies have been reported in only 0.1% to 0.2% of patients treated with statins, but milder myalgias have been reported in up to 6% of patients. Presentations at the American College of Rheumatology 2004 meeting point to several genetic risk factors that may trigger myopathies in susceptible patients.


Many with myopathies have multiple genetic changes

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 [ 1 ].

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.

"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 among patients who suffer from statin myopathies than would be expected in the general population. Furthermore, since manifesting carriers for metabolic myopathies exist, 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 1 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 associated 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, carnitine may be involved

Nearly half of the samples analyzed had coenzyme Q10 (ubiquinone) levels 2 to 4 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 2 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 [ 2 ]. 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"[ 3 ].

"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."

 

 

Sources

1. Vladutiu G, Isackson P, Wortmann R. Metabolic muscle disorders and cholesterol-lowering drugs. American College of Rheumatology 2004 meeting, October 16-21, 2004; San Antonio, TX; Abstract 1784.

2. US Patent 4 933 165. June 12, 1990. Coenzyme Q.sub.10 with HMG-CoA reductase inhibitors. A pharmaceutical composition and method of counteracting HMG-CoA reductase inhibitor-associated myopathy is disclosed. The method comprises the adjunct administration of an effective amount of an HMG-CoA reductase inhibitor and an effective amount of coenzyme Q.sub.10. Inventors: Brown MS (Dallas, TX). Assignee: Merck & Co Inc (Rahway, NJ).

3. US Patent 4 929 437. May 29, 1990. Coenzyme Q sub 10 with HMG-CoA reductase inhibitors. A pharmaceutical composition and method of counteracting HMG-CoA reductase inhibitor-associated elevated transaminase levels is disclosed. The method comprises the adjunct administration of an effective amount of an HMG-CoA reductase inhibitor and an effective amount of coenzyme Q sub10. Inventors: Tobert JA (Maplewood, NJ). Assignee: Merck & Co Inc (Rahway, NJ).

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