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Rosuvastatin

Classification: A

Drug products: Crestor, Crestor®, Rosuvastatin Accord, Rosuvastatin Glenmark, Rosuvastatin Krka d.d., Rosuvastatin Medical Valley, Rosuvastatin Mylan, Rosuvastatin Orion, Rosuvastatin Sandoz, Rosuvastatin STADA, Rosuvastatin Teva, Visacor

ATC code: C10AA07

Substances: rosuvastatin, rosuvastatin calcium

Summary

Studies have shown similar effect of rosuvastatin in men and women.

A large register-based study has shown men and women to have similar risk of moderate to serious muscular adverse effects.

Additional information

Pharmacokinetics and dosing

Several studies have found no sex differences in rosuvastatin pharmacokinetics [8-10]. However, a small Chinese study (6 men, 6 women), found a 5% lower AUC and 6.5% lower mean Cmax in men compared to women [11].  Since no sex differences have been found for rosuvastatin pharmacokinetics [2-4], no dose adjustments based on patient’s sex are needed.

Effects

Statins

In general, randomized controlled trials of statins  have only conducted subgroup analyses to detect potential sex differences in efficacy.

Meta-analyses conclude that statin treatment is similarly effective for secondary prevention of cardiovascular events in both men and women, although there was no benefit in mortality among women [1-3]. However, meta-analyses on the effects of statin treatment as primary prevention in women report conflicting conclusions [1, 2, 4]. Underrepresentation of women in clinical trials and lower incidence rates in women may have contributed to these conflicting results.

A meta-analysis including both primary and secondary prevention trials (in total 54 160 men, 17 818 women) concluded that statins (atorvastatin, pravastatin, simvastatin, lovastatin) reduced the risk of cardiovascular events in both men and women. Men, but not women, had a significant decrease in mortality, myocardial infarction, and stroke. It was suggested that women may have derived their benefits from a decrease in the prevalence of unstable angina  in need for revascularization [5]. However, this study did not perform separated analyses for primary and secondary prevention.

Two other meta-analyses (141 235 patients and 174 149 patients respectively, on average 73% men in both) found similar beneficial effects of statin treatment (atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin) in both primary and secondary prevention in men and women [1, 2]. Another smaller meta-analysis (in total 30 194 men, 19 052 women) conclude that primary prevention with statins (atorvastatin, lovastatin, pravastatin, simvastatin) reduce the risk of coronary heart disease events only in men. The risk of total mortality was not reduced in men or women [4]. A meta-analysis including only secondary prevention trials (in total 34 294 men, 8897 women) concluded that statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) were similarly effective as prevention of cardiovascular events in both men and women, however there was no benefit  on stroke or all-cause mortality in women [3].

Results from the VOYAGER meta-analysis (17 897 men, 13 662 women) showed that statins (atorvastatin, simvastatin, rosuvastatin) reduced concentrations of LDL and non-HDL and increased concentrations of HDL dose-dependently in both men and women of all ages, with largest reductions in women aged ≥70 years [6]. 

Specific for rosuvastatin

Primary prevention: In the JUPITER trial (11001 men, 6801 women), rosuvastatin treatment (20 mg/day) of healthy individuals with elevated high sensitivity CRP and normal LDL cholesterol resulted in similar risk reductions in cardiovascular disease events in both men and women. However, women had greater reduction in revascularization/unstable angina and men had greater reduction in stroke. Subgroup analysis suggested that women with a family history of premature coronary disease may benefit more from rosuvastatin therapy than those without [12, 13].The efficacy of rosuvastatin 40 mg on changes in carotid intima-media thickness (CIMT) wereas measured in the randomized, placebo-controlled METEOR trial. Results show that rosuvastatin slowed progression of maximum CIMT over 2 years and results were consistent in men and women [14].

Secondary prevention: The CORONA trial included patients with systolic heart failure (EF<40%), due to ischemic heart disease (3831 men, 1180 women). In this trial, rosuvastatin did not reduce death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, in patients with systolic heart failure. Rosuvastatin did reduce the number of cardiovascular hospitalizations. The treatment effect was similar in men and women [15].

Adverse effects

In the JUPITER trial, rates of muscle disorders or myopathy were similar in men and women regardless of treatment assignment [12, 13].

In a large register-based cohort study (121 148 men, 104 744 women), the risk of moderate to serious myopathy was higher in men than in women for lipophilic statins such as simvastatin and atorvastatin. However, for the hydrophilic statins such as rosuvastatin and pravastatin there were no sex differences in the risk of moderate to serious myopathy. Adjusted hazard ratio for rosuvastatin-induced myopathy was 4.2 in men vs. 5.4 in women [16].

Most large pivotal studies, even recent ones, have not performed relevant sex-analyses of side effects [17].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

A significant association between statin therapy and decreased risk of overall fractures has been found for men but not for women [18].

A meta-analysis of controlled clinical trials (413 men, 480 women) report that among hyperlipidemic patients who receive long-term rosuvastatin treatment (10 mg/day for ≥96 weeks), GFR was unchanged regardless of patient’s sex. This suggests that rosuvastatin may arrest the progression of renal disease [19]. A meta-analysis of adherence to statin treatment report that women (OR 1.10) and non-white patients (OR 1.53) were more likely to be non-adherent to their statin treatment. Non-adherence measured by self-report data demonstrated higher rates for women (OR 1.20) compared with data based on pharmacy-claims (OR 1.10) [7].

Updated: 2020-08-28

Date of litterature search: 2019-08-20

References

  1. Kostis WJ, Cheng JQ, Dobrzynski JM, Cabrera J, Kostis JB. Meta-analysis of statin effects in women versus men. J Am Coll Cardiol. 2012;59(6):572-82. PubMed
  2. Cholesterol Treatment Trialists' (CTT) Collaboration, Fulcher J, O'Connell R, Voysey M, Emberson J, Blackwell L et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet. 2015;385(9976):1397-405. PubMed
  3. Gutierrez J, Ramirez G, Rundek T, Sacco RL. Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis. Arch Intern Med. 2012;172(12):909-19. PubMed
  4. Petretta M, Costanzo P, Perrone-Filardi P, Chiariello M. Impact of gender in primary prevention of coronary heart disease with statin therapy: a meta-analysis. Int J Cardiol. 2010;138(1):25-31. PubMed
  5. Dale KM, Coleman CI, Shah SA, Patel AA, Kluger J, White CM. Impact of gender on statin efficacy. Curr Med Res Opin. 2007;23(3):565-74. PubMed
  6. Karlson BW, Palmer MK, Nicholls SJ, Barter PJ, Lundman P. Effects of age, gender and statin dose on lipid levels: Results from the VOYAGER meta-analysis database. Atherosclerosis. 2017;265(1):54-59. PubMed
  7. Lewey J, Shrank WH, Bowry AD, Kilabuk E, Brennan TA, Choudhry NK. Gender and racial disparities in adherence to statin therapy: a meta-analysis. Am Heart J. 2013;165(5):665-78, 678e1. PubMed
  8. Martin PD, Dane AL, Nwose OM, Schneck DW, Warwick MJ. No effect of age or gender on the pharmacokinetics of rosuvastatin: a new HMG-CoA reductase inhibitor. J Clin Pharmacol. 2002;42:1116-21. PubMed
  9. Li Y, Jiang X, Lan K, Zhang R, Li X, Jiang Q. Pharmacokinetic properties of rosuvastatin after single-dose, oral administration in Chinese volunteers: a randomized, open-label, three-way crossover study. Clin Ther. 2007;29:2194-203. PubMed
  10. Zhou Q, Ruan ZR, Yuan H, Xu DH, Zeng S. ABCB1 gene polymorphisms, ABCB1 haplotypes and ABCG2 c421c > A are determinants of inter-subject variability in rosuvastatin pharmacokinetics. Pharmazie. 2013;68:129-34. PubMed
  11. Li Y, Jiang X, Lan K, Jiang Q. Comparative single- and multiple-dose pharmacokinetics of rosuvastatin following oral administration in Chinese volunteers. Eur J Drug Metab Pharmacokinet. 2009;34:221-7. PubMed
  12. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-207. PubMed
  13. Mora S, Glynn RJ, Hsia J, MacFadyen JG, Genest J, Ridker PM. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation. 2010;121:1069-77. PubMed
  14. Crouse JR, Raichlen JS, Riley WA, Evans GW, Palmer MK, O'Leary DH et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA. 2007;297:1344-53. PubMed
  15. Kjekshus J, Apetrei E, Barrios V, Böhm M, Cleland JG, Cornel JH et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:2248-61. PubMed
  16. Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ. 2010;340:c2197. PubMed
  17. Finegold JA, Manisty CH, Goldacre B, Barron AJ, Francis DP. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. Eur J Prev Cardiol. 2014;21:464-74. PubMed
  18. An T, Hao J, Sun S, Li R, Yang M, Cheng G et al. Efficacy of statins for osteoporosis: a systematic review and meta-analysis. Osteoporos Int. 2017;28(1):47-57. PubMed
  19. Vidt DG, Cressman MD, Harris S, Pears JS, Hutchinson HG. Rosuvastatin-induced arrest in progression of renal disease. Cardiology. 2004;102:52-60. PubMed
  20. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2018 [cited 2019-03-08.] länk

Authors: Linnéa Karlsson Lind

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson