Atorvastatin

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

StatinsIn 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 preventionASCOT-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 preventionPost-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].