Skip to main content
SpringerLink
Log in

Oxidation Injury in Patients Receiving HMG-CoA Reductase Inhibitors

Occurrence in Patients Without Enzyme Elevation or Myopathy

  • Original Research Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Background: Myopathy in its severe forms including rhabdomyolysis is a very rare adverse effect occurring during monotherapy with the HMG-CoA reductase inhibitors (‘statins’) and is associated with pronounced signs of oxidation injury. This has been found at a local (muscle) as well as at a systemic level (blood). Several lines of evidence indicate that even mild forms of myopathy during statin treatment may be associated with in vivo oxidation injury. In contrast, statin therapy has been shown to be associated with a decrease in oxidation injury.

Objective: The aim of this study was to investigate whether patients with heterozygous familial hypercholesterolaemia who did not exhibit any symptoms or abnormalities in safety parameters during 6 months of treatment with various statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) did exhibit a change in oxidation injury as assessed by the isoprostane levels.

Methods: Blood (plasma and serum) as well as urine was tested before and 1, 3 and 6 months after starting statin therapy.

Results: Out of 111 treated patients (63 males, 48 females; aged 19 to 58 years) who did not experience any adverse effects during statin treatment, 11 (seven males, four females; aged 24 to 51 years) showed a pronounced increase in 8-epi-prostaglandin (PG) F2α in all the compartments examined. In the remaining 100 patients (56 males, 44 females; aged 19 to 58 years) there was either no change in or even an apparent decrease in 8-epi-PGF2α. This increase was monitored with all the statins administered. If elevated, the increase in 8-epi-PGF2α remained without change throughout the entire follow-up period. No sex difference or differential response between smokers and nonsmokers was observed.

Discussion: These findings indicate that in the absence of other clinically observable adverse effects, in some of the patients, for an as yet unknown reason, statin therapy may be associated with increased oxidation injury. The fact that changing to another statin is apparently not necessarily associated with an identical response raises the question of a specific predisposition for certain compounds in a given patient. These data add a further piece of evidence that mild adverse effects of statins that are difficult to assess might be much more prevalent than widely considered. The clinical relevance and consequence of these findings still remains to be assessed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III
Table IV

Similar content being viewed by others

References

  1. Sinzinger H, Wolfram R, Peskar BA. Muscular side effects of statins. J Cardiovasc Pharmacol 2002; 40: 163–71

    Article  PubMed  CAS  Google Scholar 

  2. Sinzinger H. Two different types of exercise-induced muscle pain without myopathy and CK-elevation during HMG-Coenzyme-A-reductase inhibitor treatment. Atherosclerosis 1999; 143: 459–60

    Article  PubMed  CAS  Google Scholar 

  3. Bargossi AM, Grossi G, Fioletta PL, et al. Exogenous CoQ10 supplementation prevents plasma ubiquinone reduction induced by HMG-CoA reductase inhibitors. Mol Aspects Med 1994; 15: 187–93

    Article  Google Scholar 

  4. Mohr D, Bowry VW, Stocker R. Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoprotein to the initiation of lipid peroxidation. Biochim Biophys Acta 1992; 1126: 247–54

    Article  PubMed  CAS  Google Scholar 

  5. MacDonald JS. Effects of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase on serum lipoproteins. Am J Cardiol 1988; 62: 16–27

    Article  Google Scholar 

  6. Dujovne CA. New lipid lowering drugs and new effects of old drugs. Curr Opin Lipidol 1997; 8: 362–8

    Article  PubMed  CAS  Google Scholar 

  7. Oguogho A, Sinzinger H. Isoprostanes in atherosclerosis. J Physiol Pharmacol 2000; 51: 673–82

    PubMed  CAS  Google Scholar 

  8. Sinzinger H. Does vitamin E beneficially affect muscle pains during HMG-Co-enzyme-A reductase inhibitors without CK-elevation? Atherosclerosis 2000; 149: 225

    Article  PubMed  CAS  Google Scholar 

  9. Holt S, Reeder B, Wilson M, et al. Increased lipid peroxidation in patients with rhabdomyolysis. Lancet 1999; 353: 358–9

    Google Scholar 

  10. Sinzinger H, Lupattelli G, Chehne F. Increased lipid peroxidation in a patient with CK elevation and muscle pain during statin therapy. Atherosclerosis 2000; 153: 255–6

    Article  PubMed  CAS  Google Scholar 

  11. Sinzinger H, Lupattelli G, Chehne F. Increased isoprostane 8-epi-PGF2α in statin-induced myopathy. In: Samuelsson B, Paolotti R, Folco PC, editors. Advances in prostaglandin and leukotriene research. Dordrecht, The Netherlands: Kluwer Academics Publ., 2001: 197–9

    Google Scholar 

  12. Oguogho A, Mehrabi M, Sinzinger H. Increased plasma, serum and urinary 8-epi-prostaglandin F2α in heterozygous hypercholesterolemia. Wr klin Wschr 1999; 111: 113–8

    CAS  Google Scholar 

  13. Bliznakov E, Wilkins DJ. Biochemical and clinical consequences of inhibiting coenzyme Q10 biosynthesis by lipid-lowering HMG-CoA reductase inhibitors (statins): a critical overview. Adv Ther 1998; 15: 218–28

    CAS  Google Scholar 

  14. Kontush A, Reich A, Baum K, et al. Plasma ubiquinol-10 is decreased in patients with hyperlipidemia. Atherosclerosis 1997; 129: 119–26

    Article  PubMed  CAS  Google Scholar 

  15. Crane FL, Hatefi Y, Lester RL, et al. Isolation of a quinone from beef heart mitochondria. Biochim Biophys Acta 1957; 25: 220–1

    Article  PubMed  CAS  Google Scholar 

  16. Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci U S A 1990; 87: 8931–4

    Article  PubMed  CAS  Google Scholar 

  17. Watts GF, Castelluccio C, Riceevans C, et al. Plasma coenzyme Q (ubiquinone) concentration in patients treated with simvastatin. J Clin Pathol 1995; 46: 1055–7

    Article  Google Scholar 

  18. Ghirlanda G, Oradei A, Manto A, et al. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol 1993; 33: 226–9

    PubMed  CAS  Google Scholar 

  19. Morrow JD, Robert II LJ. The isoprostanes: current knowledge and direction of future research. Biochem Pharmacol 1996; 51: 1–9

    Article  PubMed  CAS  Google Scholar 

  20. Gopaul NK, Nourous-Zadeh J, Molect AI, et al. Formation of PGF2-isoprostanes during oxidative modification of low-density lipoprotein. Biochem Biophys Res Commun 1994; 200: 338–43

    Article  PubMed  CAS  Google Scholar 

  21. Mehrabi MR, Ekmeckioglu C, Tatzber F, et al. The isoprostane 8-epi-PGF2α is accumulated in coronary arteries isolated from patients with coronary heart disease. J Cardiovasc Res 1999; 43: 492–9

    Article  CAS  Google Scholar 

  22. Oguogho A, Karanikas G, Kritz H, et al. 6-oxo-PGF1α and 8-epi-PGF2α in human atherosclerotic vascular tissue. Prostaglandins Leukot Essent Fatty Acids 1999; 60: 129–34

    Article  PubMed  CAS  Google Scholar 

  23. Pratico D, Luliano L, Spagnoli L, et al. Monocytes in human atherosclerotic plaque contain high levels of 8-epi-PGF2α: an index of oxidative stress in vivo [abstract]. Circulation 1996; 94: 277

    Google Scholar 

  24. Helmersson J, Basu S. F2-isoprostane excretion rate and diurnal variation in human urine. Prostaglandins Leukot Essent Fatty Acids 1999; 61: 203–5

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript. Fahdi Chehne was on leave from the University of Aleppo, Syrian Arabic Republic (SAR) when this study was undertaken. The valuable help of Eva Unger in preparing and typing the manuscript is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Wilhelm Auerswald Atherosclerosis Research Group (ASF) Vienna, Nadlergasse 1, Vienna, A-1090, Austria

    Helmut Sinzinger

  2. Department of Nuclear Medicine, University of Vienna, Vienna, Austria

    Helmut Sinzinger & Fahdi Chehne

  3. Department of Internal Medicine, University of Perugia, Perugia, Italy

    Graziana Lupattelli

Authors
  1. Helmut Sinzinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fahdi Chehne
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Graziana Lupattelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helmut Sinzinger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sinzinger, H., Chehne, F. & Lupattelli, G. Oxidation Injury in Patients Receiving HMG-CoA Reductase Inhibitors. Drug-Safety 25, 877–883 (2002). https://doi.org/10.2165/00002018-200225120-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-200225120-00005

Keywords

Search

Navigation