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Muscle sensitive biomarkers can be used to reveal statin-induced muscle injury
21.12.2006
Large-scale clinical trials have earlier shown that statins are effective and safe cholesterol lowering drugs. However, aggressive treatment with high doses increases the risk of statin-induced muscle injury that in rare occasions can lead to a fatal renal disease (rhabdomyolysis). A study by the VTT Technical Research Centre of Finland and the Tampere University Hospital recently identified muscle sensitive biomarkers that can be used to detect unwanted and potentially toxic statin-induced changes in muscle metabolism. With the help of these biomarkers it is possible to predict statin-induced harmful changes in patients' muscle cells early enough to prevent the onset of toxic events. The findings of this study may also benefit the development of novel cholesterol lowering drugs.
Clinical trials play an important part in the process of developing new
medical products. Many drug candidates fail in the late clinical development
stage due to the drug's toxic side-effects. Indeed, the pharmaceutical
industry is facing extreme challenges to bring effective and safe products on
the market in a timely and cost effective manner. In order to detect
unexpected toxicities in early clinical trial stages new analytical methods
and scientific strategies are needed. Systems biology is a discipline
dedicated to the study of an organism, viewed as an integrated and interacting
network of genes, proteins and biochemical reactions which give rise to life.
Systems biology is one such new scientific strategy that promises better
understanding of disease phenomena and offers better predictive tools for the
drug developers.
An international team led by principal
investigators Dr. Reijo Laaksonen of Tampere University Hospital, Finland; and
Zora Biosciences, Ltd. and Dr. Matej Orešič of VTT Technical Research Centre
of Finland compared in their study two widely used statin drugs in terms of
their effects on muscle metabolism and global plasma lipid profile. By
combining large data sets obtained both from plasma and muscle during statin
treatment Laaksonen and Orešič were able to identify muscle sensitive
biomarkers that can be analyzed from patient’s blood sample. These biomarker
candidates will now be further validated. The researchers expect them to
replace currently used safety measurements both in the clinical use and in
pharmaceutical industry.
In a clinical study that included 37
human subjects on high, yet clinically used, doses of statins (atorvastatin 40
mg/day and simvastain 80 mg/day), Laaksonen and Orešič studied drug effects on
genome wide expression profiles of muscle tissue as well as on global plasma
lipid composition. They revealed that statins at high doses may induce
significant changes in the expression of multiple genes controlling metabolic
and inflammatory pathways in muscle. They were able to pinpoint relevant
biological pathways and to identify plasma lipid biomarker candidates related
to unwanted and potentially toxic statin-induced changes in muscle metabolism.
The
doses of the two studied statins have earlier been considered equivalent in
terms of their lipid lowering potential. Intriguingly, in the study by
Laaksonen and Orešič atorvastatin and simvastatin treatments resulted in very
specific plasma lipid profile changes. Thus, the mass spectrometry based
analysis of global plasma lipid composition offers significant potential for
more appropriate patient dosing. Moreover, it may aid development of specific
lipid lowering agents (such as cholesteryl ester transfer protein inhibitors)
upon the elucidation of the significance of these novel lipid biomarkers.
Reference
R. Laaksonen, M. Katajamaa, H. Päivä, M. Sysi-Aho, L. Saarinen, P. Junni, D.
Lütjohann, J. Smet, R. Van Coster, T. Seppänen-Laakso, T. Lehtimäki, J. Soini,
M. Orešič, A systems biology strategy reveals biological pathways and plasma
biomarker candidates for potentially toxic statin induced changes in muscle,
PLoS ONE 1(1): e97 (2006).
Link
to PLoSONE website presenting the study