Objectives: To systematically review the evidence on whether statin therapy, commonly used in clinical practice to treat hypercholesterolaemia for primary and secondary prevention of cardiovascular disease, contributes to tendinopathy; and to examine causality according to the Bradford Hill criteria.
Study design: A systematic review of studies examining the relationship between statin therapy and tendinopathy. Included studies were rated based on their methodological quality. A best evidence synthesis was used to summarise the results, and Bradford Hill criteria were used to assess causation.
Data sources: Ovid MEDLINE, CINAHL Plus, PubMed and Embase databases.
Study selection: We included adult human studies published in the English language between January 1966 and October 2015. Study designs eligible for inclusion were randomised controlled trials and cross-sectional, cohort or case–control studies.
Data synthesis: Four studies (three cohort studies and one case–control study) were included, with a mean methodological quality score of 67%. Three studies were deemed high quality. Tendon rupture was the primary outcome in three studies, and rotator cuff disease in the other. All studies found no positive association between statin therapy and tendon rupture for the total study population. There was evidence that simvastatin reduces the risk of tendinopathy.
Conclusion: To date, there is a paucity of evidence to implicate statin therapy as a well established risk factor or causal mechanism for tendon rupture in the general population. There is strong evidence that simvastatin reduces the risk of tendinopathy.
- 1. Walley T, Folino-Gallo P, Stephens P, Van Ganse E. Trends in prescribing and utilization of statins and other lipid lowering drugs across Europe 1997-2003. Br J Clin Pharmacol 2005; 60: 543-551.
- 2. Jackevicius CA, Tu JV, Ross JS, et al. Use of ezetimibe in the United States and Canada. N Engl J Med 2008; 358: 1819-1828.
- 3. Black DM, Bakker-Arkema RG, Nawrocki JW. An overview of the clinical safety profile of atorvastatin (lipitor), a new HMG-CoA reductase inhibitor. Arch Intern Med 1998; 158: 577-584.
- 4. Cham S, Evans MA, Denenberg JO, Golomb BA. Statin-associated muscle-related adverse effects: a case series of 354 patients. Pharmacotherapy 2010; 30: 541-553.
- 5. Desai CS, Martin SS, Blumenthal RS. Non-cardiovascular effects associated with statins. BMJ 2014; 349: g3743.
- 6. Hoffman KB, Kraus C, Dimbil M, Golomb BA. A survey of the FDA’s AERS database regarding muscle and tendon adverse events linked to the statin drug class. PLoS One 2012; 7: e42866.
- 7. Marie I, Delafenetre H, Massy N, et al. Tendinous disorders attributed to statins: a study on ninety-six spontaneous reports in the period 1990–2005 and review of the literature. Arthritis Rheum 2008; 59: 367-372.
- 8. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339: b2700.
- 9. Lievense A, Bierma-Zeinstra S, Verhagen A, et al. Influence of work on the development of osteoarthritis of the hip: a systematic review. J Rheumatol 2001; 28: 2520-2528.
- 10. Lievense AM, Bierma-Zeinstra SM, Verhagen AP, et al. Influence of obesity on the development of osteoarthritis of the hip: a systematic review. Rheumatology (Oxford) 2002; 41: 1155-1162.
- 11. Kim SY, Park JE, Lee YJ, et al. Testing a tool for assessing the risk of bias for nonrandomized studies showed moderate reliability and promising validity. J Clin Epidemiol 2013; 66: 408-414.
- 12. Hill A. The environment and disease: association or causation? Proc R Soc Med 1965; 58: 295-300.
- 13. Lin TT, Lin CH, Chang CL, et al. The effect of diabetes, hyperlipidemia, and statins on the development of rotator cuff disease: a nationwide, 11-year, longitudinal, population-based follow-up study. Am J Sports Med 2015; 43: 2126-2132.
- 14. Beri A, Dwamena FC, Dwamena BA. Association between statin therapy and tendon rupture: a case-control study. J Cardiovasc Pharmacol 2009; 53: 401-404.
- 15. Savvidou C, Moreno R. Spontaneous distal biceps tendon ruptures: are they related to statin administration? Hand Surg 2012; 17: 167-171.
- 16. Contractor T, Beri A, Gardiner JC, et al. Is statin use associated with tendon rupture? A population-based retrospective cohort analysis. Am J Ther 2015; 22: 377-381.
- 17. de Oliveira LP, Vieira CP, Da Re Guerra F, et al. Statins induce biochemical changes in the Achilles tendon after chronic treatment. Toxicology 2013; 311: 162-168.
- 18. Ferreira TS, Lanzetti M, Barroso MV, et al. Oxidative stress and inflammation are differentially affected by atorvastatin, pravastatin, rosuvastatin, and simvastatin on lungs from mice exposed to cigarette smoke. Inflammation 2014; 37: 1355-1365.
- 19. Chazerain P, Hayem G, Hamza S, et al. Four cases of tendinopathy in patients on statin therapy. Joint Bone Spine 2001; 68: 430-433.
- 20. Stephenson AL, Wu W, Cortes D, Rochon PA. Tendon injury and fluoroquinolone use: a systematic review. Drug Saf 2013; 36: 709-721.
- 21. Carmont MR, Highland AM, Blundell CM, Davies MB. Simultaneous bilateral Achilles tendon ruptures associated with statin medication despite regular rock climbing exercise. Phys Ther Sport 2009; 10: 150-152.
- 22. Rubin G, Haddad E, Ben-Haim T, et al. Bilateral, simultaneous rupture of the quadriceps tendon associated with simvastatin. Isr Med Assoc J 2011; 13: 185-186.
- 23. Celik EC, Ozbaydar M, Ofluoglu D, Demircay E. Simultaneous and spontaneous bilateral quadriceps tendons rupture. Am J Phys Med Rehabil 2012; 91: 631-634.
- 24. Ganske CM, Horning KK. Levofloxacin-induced tendinopathy of the hip. Ann Pharmacother 2012; 46: e13.
- 25. Nesselroade RD, Nickels LC. Ultrasound diagnosis of bilateral quadriceps tendon rupture after statin use. West J Emerg Med 2010; 11: 306-309.
- 26. Lehtonen A, Makela P, Viikari J, Virtama P. Achilles tendon thickness in hypercholesterolaemia. Ann Clin Res 1981; 13: 39-44.
- 27. Civeira F, Castillo JJ, Calvo C, et al. [Achilles tendon size by high resolution sonography in healthy population. Relationship with lipid levels] [Spanish]. Med Clin (Barc) 1998; 111: 41-44.
- 28. Ames PR, Longo UG, Denaro V, Maffulli N. Achilles tendon problems: not just an orthopaedic issue. Disabil Rehabil 2008; 30: 1646-1650.
- 29. Abate M, Schiavone C, Salini V, Andia I. Occurrence of tendon pathologies in metabolic disorders. Rheumatology (Oxford) 2013; 52: 599-608.
- 30. Schmidt HH, Hill S, Makariou EV, et al. Relation of cholesterol-year score to severity of calcific atherosclerosis and tissue deposition in homozygous familial hypercholesterolemia. Am J Cardiol 1996; 77: 575-580.
- 31. Murano S, Shinomiya M, Shirai K, et al. Characteristic features of long-living patients with familial hypercholesterolemia in Japan. J Am Geriatr Soc 1993; 41: 253-257.
- 32. Haacke H, Parwaresch MR. Spontaneous rupture of the Achilles tendon - a sign of hyperlipoproteinaemia (HLP) type II. Klin Wochenschr 1979; 57: 397-400.
- 33. Ozgurtas T, Yildiz C, Serdar M, et al. Is high concentration of serum lipids a risk factor for Achilles tendon rupture? Clin Chim Acta 2003; 331: 25-28.
- 34. Tsouli SG, Xydis V, Argyropoulou MI, et al. Regression of Achilles tendon thickness after statin treatment in patients with familial hypercholesterolemia: an ultrasonographic study. Atherosclerosis 2009; 205: 151-155.
- 35. Dodds WN, Burry HC. The relationship between Achilles tendon rupture and serum uric acid level. Injury 1984; 16: 94-95.
- 36. Zakaria MH, Davis WA, Davis TM. Incidence and predictors of hospitalization for tendon rupture in type 2 diabetes: the Fremantle Diabetes Study. Diabet Med 2014; 31: 425-430.
Publication of your online response is subject to the Medical Journal of Australia's editorial discretion. You will be notified by email within five working days should your response be accepted.