Simvastatin

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 generalRandomized 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

HypercholesterolemiaThe 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 eventsIn 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].