Genetic Basis of Statin Myopathy


dr_duane_graveline_m.d._134By Duane Graveline, M.D., M.P.H.

Much of statin myopathy may not be due to toxicity or direct effect of statins but to an underlying genetic predisposition, existing naturally in many people, brought out by the use of statins.

The genetic basis of much of apparent statin myopathy is already well established. McArdle disease with its deficiency of the enzyme, phosphorylase, frequently is first manifest after Statins are initiated.

The same is true of carnitine palmitoyl transferase II deficiency (CPT) where the ability to utilize lipids for energy production is compromised. Both of these conditions result in limited exercise capacity and muscle soreness, which often does not begin until after the third decade.

Statins' collateral damage to CoQ10 synthesis with resulting tiredness, soreness and fatigability from CoQ10 lack, often times is more than sufficient to trigger these underlying metabolic defects. A number of different varieties of both CPT and McArdle disease have been identified just in the past few years indicating that they likely are significantly under-reported.

In addition muscle biopsies from statin-intolerant patients showed that about half had significant qualitative abnormalities in mitochondrial and fatty acid metabolism never suspected until statin drugs were initiated.

In a more recent study of the COQ2 gene of the CoQ10 metabolic pathway, done because of the known association of this gene with severe inherited myopathy, many of the statin intolerance subjects showed a surprising frequency of what is called polymorphism, that is, different varieties of the same gene, leading to decreased exercise capacity never suspected until statins were started. So, much of statin intolerance of the muscle variety appears to be genetically pre-ordained.

Another form of statin associated myopathy is due to impairment of selenoprotein synthesis by statins. The clinical picture of statin myopathies due to selenoprotein deficiency includes muscle aches and pains, weakness and tenderness with easy fatigability. It can vary from mild to very severe - even disabling. CPK is often normal.

The cause appears to be a direct interference of the isopentyl step of the mevalonate pathway by statins. The substrate for this reaction, isopentanyl pyrophosphate IPP, is a direct metabolite of mevalonate; therefore all statins inhibit this reaction.

Estimates as to frequency of these statin intolerances due to inherited myopathies range to 4-7% as greater experience is gained in identifying these cases in the general population. All cause myopathy, adding together the inherited myopathies and the statin caused groups give an expected figure of 7%, which is at tremendous variance with certain recently reported studies.

For instance, a recent systemic overview of randomized clinical trials on risks associated with statin therapy appeared to show no excess of myalgias or CK elevations in patients on statins compared to placebo in 74,000 subjects involved in 35 trials.

Such results are at complete variance with estimates based on known frequency of these genetic contributors to myopathy in the population at large and even with the statin manufacturers' myopathy warnings and they defy explanation.

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor


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