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Lipid-regulating drugs

Scientists get closer to finding out why statins cause muscle pain

Chemical conversion of statins could disrupt muscle mitochondria function, leading to pain and weakness.

Researchers suspect that statins disrupt muscle mitochondria function, a possible mode of action of how they cause muscle toxicity. In the image, micrograph of mitochondrion

Source: Bill Longcore / Science Photo Library

Statins in the lactone form can interfere with the mitochondrial pathway involved in the production of energy via adenosine triphosphate, suggests new research

A possible explanation for the adverse muscular effects experienced by a quarter of patients who take statins to reduce cholesterol has been reported by Dutch researchers.

Most statins are prescribed in their pharmacologically active acid form, but are converted to the inactive lactone form by the enzyme uridine 50-diphospho-glucuronosyltransferases (UGTs). In the journal Cell Metabolism[1] on 1 September 2015, researchers report that the highly polymorphic nature of UGTs may further contribute to the differences in conversion rates and ensuing lactone levels between patients.

They found that statins in the lactone form can interfere with the mitochondrial pathway involved in the production of energy via adenosine triphosphate. The Qo binding site of the CIII mitochondrial complex was identified as the target.

In mouse muscle cells, lactones were three times more potent at disrupting mitochondrial function than the acid form, a finding confirmed by analysis of the muscle biopsies of 37 patients suffering from statin-induced myopathies, where there was an 18% reduction in enzyme activity at the CIII mitochondrial complex.

“This research leads to several opportunities to synthesise new classes of cholesterol-lowering drugs without the unwanted muscle effects, as well as the development of new avenues to counteract these effects, both of which we are investigating,” says senior author, Frans Russel, of the Nijmegen Center for Mitochondrial Disorders at the Radboud University Medical Center in the Netherlands.

Dermot Neely, a Heart UK trustee, and co-chairman of the familial hypercholesterolaemia guideline implementation team, says the research is interesting and provides insights into the mechanisms involved in statin-related muscle toxicity.

He points to previous inconclusive research that suggested that more severe muscle problems experienced by a minority of patients may be due to reduced mitochondrial energy production caused by statins.

“Although these studies were carried out in cultured cells, the results appear to show that partially metabolised forms of several statins impair energy production by preventing the binding of CoEnzymeQ10, and cells from patients with a history of statin related myopathy seem more susceptible to this effect.”

He adds: “Understanding of this mechanism may lead to development of strategies to prevent statin-related muscle toxicity in patients at highest risk.”

Klim McPherson, chair of the UK Health Forum and visiting professor of public health epidemiology at the University of Oxford, says: ‘Side effects can only be properly compared by measuring them blindly and routinely, which hardly ever happens in clinical trials designed to compare beneficial outcomes.”

He stresses: “The statin saga is iconic, not only because it highlights the need for clinical data sharing but because it highlights the need for the proper assessment of side effects.”

Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition

Statins and mitochondria 

Source: Tom Schirris

Study looks at how statin-induced muscle pain is linked with mitochondrial complex III inhibition

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2015.20069250

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Supplementary images

  • Researchers suspect that statins disrupt muscle mitochondria function, a possible mode of action of how they cause muscle toxicity. In the image, micrograph of mitochondrion
  • Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition

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