9/21/2023

Janusmed kön och genus

Janusmed kön och genus – Zocord

Janusmed kön och genus är ett kunskapsstöd som tillhandahåller information om köns- och genusaspekter på läkemedelsbehandling. Kunskapsstödet är avsedd främst för hälso- och sjukvårdspersonal. Texterna är generella och ska inte ses som behandlingsriktlinjer. Det är alltid behandlande läkare som ansvarar för patientens medicinering.

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Simvastatin

Simvastatin

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Produkter

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Ezetimib/Simvastatin 2care4, Ezetimib/Simvastatin Ebb, ......

Ezetimib/Simvastatin 2care4, Ezetimib/Simvastatin Ebb, Ezetimib/Simvastatin Glenmark, Ezetimib/Simvastatin Krka, Ezetimibe/Simvastatin Accord, 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 STADA, Simvastatin SUN, Simvastatin Sandoz, Simvastatin Teva, Simvastatin ratiopharm, Vabadin, Zocord
ATC-koder

C10AA01, C10BA02

C10AA01, C10BA02
Substanser

simvastatin

simvastatin
Sammanfattning

Studier har visat att simvastatin vid sekundärprevention minskar dödlighet och sjuklighet på ett likvärdigt sätt hos kvinnor och män. I en studie på japanska patienter med hyperkolesterolemi fick kvinnor en större kolesterolsänkande effekt av 5 mg simvastatin jämfört med män. En stor registerstudie har visat att män har större risk att drabbas av måttliga till svåra muskelbiverkningar av simvastatin jämfört med kvinnor.

Studier har visat att simvastatin vid sekundärprevention minskar dödlighet och sjuklighet på ett likvärdigt sätt hos kvinnor och män. I en studie på japanska patienter med hyperkolesterolemi fick kvinnor en större kolesterolsänkande effekt av 5 mg simvastatin jämfört med män. En stor registerstudie har visat att män har större risk att drabbas av måttliga till svåra muskelbiverkningar av simvastatin jämfört med kvinnor.
Background

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 am......

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# 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 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]. 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].
Försäljning på recept

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Fler män än kvinnor hämtade ut tabletter innehållande simvastatin (ATC-kod C10AA01) på recept i Sverige år 2018, totalt 216 679 män och 172 300 kvinnor. Det motsvarar 42 respektive 34 personer per tusen invånare. Andelen som hämtat ut läkemedel var högst i åldersgruppen 70 år och äldre hos båda könen. I genomsnitt var tabletter innehållande simvastatin 1,6 gånger vanligare hos män [20].
Referenser

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  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  10. García MJ, Reinoso RF, Sánchez Navarro A, Prous JR. Clinical pharmacokinetics of statins. Methods Find Exp Clin Pharmacol. 2003;25:457-81.

  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.

  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.

  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.

  14. Zocor (simvastatin). DailyMed [www]. U.S. National Library of Medicine. [updated 2019-07-04, cited 2019-08-20].

  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.

  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.

  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.

  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.

  20. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2018 [cited 2019-03-08.]

  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  10. García MJ, Reinoso RF, Sánchez Navarro A, Prous JR. Clinical pharmacokinetics of statins. Methods Find Exp Clin Pharmacol. 2003;25:457-81.
  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.
  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.
  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.
  14. Zocor (simvastatin). DailyMed [www]. U.S. National Library of Medicine. [updated 2019-07-04, cited 2019-08-20].
  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.
  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.
  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.
  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.
  20. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2018 [cited 2019-03-08.]
Uppdaterat

Litteratursökningsdatum: 8/20/2019

Litteratursökningsdatum: 8/20/2019
Se även

Atorvastatin

Rosuvastatin

Pravastatin

Ezetimib