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Atorvastatin

Classification: A

Drug products: Atorab, Atorbir, Atorstad, Atorvastad, Atorvastatin 1A Farma, Atorvastatin Accord, Atorvastatin Actavis, Atorvastatin Bluefish, Atorvastatin Ebb, Atorvastatin Krka, Atorvastatin Mylan, Atorvastatin Orifarm, Atorvastatin Orion, Atorvastatin Paranova, Atorvastatin Pfizer, Atorvastatin Sandoz, Atorvastatin SUN, Atorvastatin Teva, Atorvastatin Xiromed, Atozet, Lipistad, Lipitor, Lipitor®, Sortis, Tahor, Tavara, Torvast, Zarator

ATC code: C10AA05, C10BA05

Substances: atorvastatin, atorvastatin calcium, atorvastatin calcium amorphous, atorvastatin calcium isopropanolate, atorvastatin calcium propylene glycol solvate, atorvastatin calcium trihydrate

Summary

Studies have shown that during secondary prevention, atorvastatin reduces the risk of cardiovascular events equally among men and women.

A large registry-based study has shown that men have a greater risk of moderate to severe muscular adverse effects of atorvastatin compared to women. However, smaller studies have not shown any sex difference regarding the presence of muscular adverse effects.

Additional information

Pharmacokinetics and dosing

Sex differences in the pharmacokinetics of atorvastatin was evaluated after administration of single 20 mg tablets to young and elderly men and women (16 men, 16 women). Maximum plasma concentration (Cmax) was 18% higher in women than in men, while AUC was 11% lower in women. The confidence intervals were wide, and no significance analysis was performed. The authors considered the pharmacokinetic sex differences too small to warrant dosage modification [8, 9].

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 atorvastatin

Primary prevention: ASCOT-LLA was a double-blind randomized study of atorvastatin in hypertensive patients with at least three other risk factors for cardiovascular disease. In a subgroup analysis (10305 men, 1942 women), a beneficial effect of atorvastatin 10 mg/day was shown in men, but this effect could not be confirmed in women, possibly due to the low number of events in women [10].

Secondary prevention: Post-hoc and subgroup analyses of pivotal trial data showed that atorvastatin 80 mg/day as secondary prevention reduced cardiovascular events in both men and women [11-13]. It is suggested that men and women may have gained additional benefit through different mechanisms; men had a substantially larger increase in HDL cholesterol and women a significantly greater reduction in triglycerides [12].

Adverse effects

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 HR for atorvastatin-induced myopathy was 6.7 in men vs. 2.9 in women [14]. However, in the prospective placebo-controlled STOMP study (The effects of Statins on Skeletal Muscle Function and Performance) (214 healthy men, 216 healthy women, of different ages), no difference in myalgia was reported between men and women [15]. A post-hoc analysis of the SPARCL study showed no sex differences in adverse events [11].

A significant association between statin therapy and decreased risk of overall fractures has been found for men but not for women [16]. Analyses of serum biomarkers of bone metabolism showed that treatment with simvastatin 40 and 80 mg/day reduced bone-specific alkaline phosphatase (BSAP) in both men and women. Treatment with atorvastatin 20 mg or 40 mg had no effect of BSAP levels in men or women. This suggests that simvastatin but not atorvastatin may have a beneficial effect on bone turnover [17].

Reproductive health issues

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

Other information

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. Gibson DM, Bron NJ, Richens A, Hounslow NJ, Sedman AJ, Whitfield LR. Effect of age and gender on pharmacokinetics of atorvastatin in humans. J Clin Pharmacol. 1996;36:242-6. PubMed
  9. García MJ, Reinoso RF, Sánchez Navarro A, Prous JR. Clinical pharmacokinetics of statins. Methods Find Exp Clin Pharmacol. 2003;25:457-81. PubMed
  10. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-58. PubMed
  11. Goldstein LB, Amarenco P, Lamonte M, Gilbert S, Messig M, Callahan A et al. Relative effects of statin therapy on stroke and cardiovascular events in men and women: secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study. Stroke. 2008;39:2444-8. PubMed
  12. Athyros VG, Kakafika AI, Papageorgiou AA, Paraskevas KI, Tziomalos K, Anagnostis P et al. Effects of statin treatment in men and women with stable coronary heart disease: a subgroup analysis of the GREACE Study. Curr Med Res Opin. 2008;24:1593-9. PubMed
  13. Truong QA, Murphy SA, McCabe CH, Armani A, Cannon CP, TIMI Study Group. Benefit of intensive statin therapy in women: results from PROVE IT-TIMI 22. Circ Cardiovasc Qual Outcomes. 2011;4:328-36. PubMed
  14. Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J et al. Effect of statins on skeletal muscle function. Circulation. 2013;127:96-103. PubMed
  15. 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
  16. 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
  17. Stein EA, Farnier M, Waldstreicher J, Mercuri M, Simvastatin/Atorvastatin Study Group. Effects of statins on biomarkers of bone metabolism: a randomised trial. Nutr Metab Cardiovasc Dis. 2001;11(2):84-7. PubMed
  18. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2018 [cited 2019-03-08.] länk

Authors: Linnéa Karlsson Lind

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson