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Simvastatin

Classification: A

Drug products: Ezetimib/Simvastatin Krka, Inegy®, Simidon, Simvastatin Actavis, Simvastatin Arrow, Simvastatin Bluefish, Simvastatin Brown, Simvastatin Ebb, Simvastatin Krka, Simvastatin Mylan, Simvastatin Nycomed, Simvastatin Orifarm, Simvastatin Orion, Simvastatin Pensa, Simvastatin ratiopharm, Simvastatin Sandoz, Simvastatin STADA®, Simvastatin SUN, Simvastatin Teva, Vabadin, Zocord®

ATC code: C10AA01, C10BA02

Substances: simvastatin

Summary

Studies show that simvastatin as secondary prevention decreases mortality and morbidity equally in men and women.

In a study on Japanese patients with hypercholesterolemia, women had a greater cholesterol lowering effect of 5 mg simvastatin than men.

A large registry-based study has shown that men have a greater risk of moderate to severe muscular adverse effects of simvastatin compared to women.

Additional information

Pharmacokinetics and dosing

The influence of the individual’s sex on the plasma profile of simvastatin (40 mg/day) has been investigated following multiple doses in young (9 men, 9 women) and elderly patients (7 men, 9 women) with hypercholesterolemia. Mean steady-state plasma concentrations of active and total simvastatin were 20-50% higher in women than in men [8] . However, an open-label single-dose study in healthy Chinese patients (6 men, 6 women) found no sex difference in the pharmacokinetics of simvastatin when evaluated as an ezetimibe/simvastatin combination tablet [9][3]. Although sex differences in pharmacokinetics of simvastatin have been described, no dosage adjustment based on individual’s sex is considered necessary [8, 10].

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 simvastatin

Hypercholesterolemia: The effect of simvastatin on cholesterol levels was evaluated in an open multicenter study (342 men, 253 women). Patients with hypercholesterolemia received simvastatin 10-40 mg once daily for 18 weeks. The reduction in LDL cholesterol was similar in women and men [11]. However, in a study in Japanese patients (71 men, 191 women), simvastatin 5 mg/day (the initial dose in Japan) was given to patients with hypercholesterolemia for 12 months. The percentage changes in TC (total cholesterol) and LDL-C (low-density lipoprotein cholesterol) levels were greater in women than in men. These results suggest that the rate of decrease in TC and LDL-C levels might be higher in women, irrespective of the baseline level, and that the response to simvastatin treatment might be greater in women [12]. Another Japanese study (12575 men, 27013 women) showed that among hypercholesterolemic patients taking simvastatin, the incidence of coronary events was 60% lower in women than in men. An observation in this study is that 44% of the men were smokers compared to 4% of the women. The relationship of serum TC and LDL-C concentrations to coronary events was similar in men and women [13].

Secondary prevention of cardiovascular events: In patients with atherosclerotic coronary artery disease, risk reductions with simvastatin have shown to be similar in men and women [14]. The 4S study (3617 men, 827 women) showed that simvastatin reduced the risk of major coronary events in women to the same extent as in men [15]. Also, the HPS trial (15454 men, 5082 women) showed a substantial benefit of adding 40 mg simvastatin daily to existing treatment in patients with coronary artery disease, other arterial disease or diabetes, in women as well as in men. In the HPS study, differences between sexes was a primary outcome and pre-specified power calculations were performed [16]. In most other studies sex differences were assessed in subgroup analyses.

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 hazard ratio for simvastatin-induced myopathy was 6.14 in men vs. 3.03 in women [17].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (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].A significant association between statin therapy and decreased risk of overall fractures has been found for men but not for women [18]. 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 [19].

Updated: 2019-12-09

Date of litterature search: 2019-08-20

References

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  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
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  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. Cheng H, Rogers JD, Sweany AE, Dobrinska MR, Stein EA, Tate AC et al. Influence of age and gender on the plasma profiles of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitory activity following multiple doses of lovastatin and simvastatin. Pharm Res. 1992;9:1629-33. PubMed
  9. Chu NN, Chen WL, Xu HR, Li XN. Pharmacokinetics and safety of ezetimibe/simvastatin combination tablet: an open-label, single-dose study in healthy Chinese subjects. Clin Drug Investig. 2012;32:791-8. PubMed
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  11. Simons LA. Simvastatin in severe primary hypercholesterolemia: efficacy, safety, and tolerability in 595 patients over 18 weeks The Principal Investigators. Clin Cardiol. 1993;16:317-22. PubMed
  12. Nakajima K. Sex-related differences in response of plasma lipids to simvastatin: the Saitama Postmenopausal Lipid Intervention Study S-POLIS Group. Clin Ther. 1999;21:2047-57. PubMed
  13. Sasaki J, Kita T, Mabuchi H, Matsuzaki M, Matsuzawa Y, Nakaya N et al. Gender difference in coronary events in relation to risk factors in Japanese hypercholesterolemic patients treated with low-dose simvastatin. Circ J. 2006;70:810-4. PubMed
  14. Zocor (simvastatin). DailyMed [www]. U.S. National Library of Medicine. [updated 2019-07-04, cited 2019-08-20]. länk
  15. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.
  16. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22. PubMed
  17. 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
  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. 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
  20. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2018 [cited 2019-03-08.] länk

Authors: Linnéa Karlsson Lind

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson