ReviewGender related differences in treatment and response to statins in primary and secondary cardiovascular prevention: The never-ending debate
Graphical abstract
Introduction
Cardiovascular disease (CVD) continues to be a prominent cause of mortality and morbidity throughout the world despite improvements in diagnosis and management. In the last decade, the mortality in men due to CVD has decreased substantially. The rate of cardiac deaths, primarily caused by coronary artery disease (CAD), is significantly higher in women compared to men (51 vs. 42%) [1]. Nevertheless, women are at lower risk for CVD than men; therefore, women require less urgent CVD prevention treatments, that include lipid-lowering or antiplatelet drugs [2]. In fact, women experience the first event of coronary heart disease (CHD) usually ten years later compared to men. Conversely, the incidence of CVD in women increases considerably for the lack of cardio-protective effect from ovarian hormones after menopause [3].
The pathogenesis of CVD is always multifactorial and is related to well-known risk factors. Changes in traditional cardiovascular (CV) risk factors, such as smoking, hypertension and dyslipidemia, are responsible for more than a 50% reduction in CV mortality in the general population [4]. Unfortunately, the control of these CV risk factors is still insufficient. Lipid abnormalities are the more prevalent risk factors in women, detectable in around 50% of cases [5]. Notably, premenopausal women are less affected by hypertension and have lower lipid levels than men of the same age, while the sex disparity disappears in the elderly [6]. Therefore, the impact of high cholesterol levels is typically observed after menopause but not in pre-menopause, where cholesterol levels can be acceptably elevated [5], [6].
Nowadays, cholesterol lowering agents [7], [8] are a cost-effective strategy to prevent CVD in individuals with high CV risk. Because statins provide the most effective pharmacologic approach to CVD risk reduction, a likely difference in sex-dependent response in CVD reduction and in lipid changes deserves to be deeply examined. However, women are underrepresented in statin trials, challenging the assessment of sex-related disparities in lipid response. The rate of female enrollment spreads from 14% to 69% in statin trials [9] and rarely sex-stratified analysis of outcomes are provided.
Available data indicate that statins are effective in women for secondary CVD prevention. Benefits outweigh disadvantages of statin therapy in those with a high CV risk, while several doubts exist for the primary prevention of women at low-intermediate CV risk.
Thus, the present review summarizes the sex and gender differences in statin use. It raises concerns and updates perspectives towards an evidence-based and sex-tailored prevention of CVD management.
Section snippets
Sex-dependent differences in pharmacology of statins
Statins are essential for the treatment and prevention of CVD. Their CV benefits are not exclusively linked to the lipid-lowering effect. Despite the reduction of low-density lipoprotein cholesterol (LDL-C) levels through the direct inhibition of the 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, statins exert other advantageous and pleiotropic effects that help explaining their effectiveness in CVD prevention and treatment. These effects occur through the modulation of atherosclerosis
Statins’ adverse effects and gender differences
To date, no compelling data support that statins are more harmful for women than for men.
Some statin adverse effects, like skeletal muscle toxic damage and diabetes mellitus (DM), seem to be more common in women. Muscle toxicity is the primary adverse effect of statins [30]. Rhabdomyolysis is a rare side effect, whereas mild myalgia is quite common [31]. However, no standard definition for statin-dependent myotoxicity exists so that its real incidence is difficult to quantify. Although
Statins and CVD prevention trials
Sex-oriented evidence on statins' effectiveness and safety in women are poor [5]. Globally, interventional clinical trials reported improved CV outcomes in both men and women. Nevertheless, a critical and focused assessment of gender differences is mandatory to tailor the prevention strategies of CVD.
Secondary CVD prevention guidelines (Table 1)
The most recent American guidelines recommend high-intensity statin therapy in all individuals with documented atherosclerotic CVD and do not promote a specific LDL-C target as previously required by National Cholesterol Education Panel Adult Treatment Panel III [69] or by the latest European guidelines [70]. Specifically, 2013 ACC/AHA jointly released lipid guidelines recommend high-dose statin therapy (atorvastatin 40–80 mg or rosuvastatin 20–40 mg daily) in men and women aged ≤ 75 years, and
Conclusion
According to guidelines, women should be treated with statins for both primary and secondary CVD prevention, when the benefit outweighs the risk and after an individualized assessment for all patients. Unfortunately, the body of evidence supporting this approach is far to be conclusive.
Specifically, the gender-dependent efficacy of statin therapy in primary prevention is still debated, whereas the benefits of statins are sex-balanced in secondary prevention. Currently, physicians should
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