Curr Cardiol Rep (2015) 17:52 DOI 10.1007/s11886-015-0609-5
LIPID ABNORMALITIES AND CARDIOVASCULAR PREVENTION (G DE BACKER, SECTION EDITOR)
Dyslipidemia and Cardiovascular Disease in Women Renata Cífková 1 & Alena Krajčoviechová 1
# Springer Science+Business Media New York 2015
Abstract Cardiovascular disease is the major cause of death in women in developed countries. Dyslipidemia is highly prevalent in women, particularly after the menopause. Elevated low-density lipoprotein cholesterol (LDL-C) has been identified as the key lipid parameter in both genders whereas HDL-cholesterol and triglycerides have been more closely associated, in some studies, with cardiovascular risk in women. Menopause has been shown to be associated with an increase in total and LDL-cholesterol and a decrease in HDLcholesterol (predominantly in the HDL2 subfraction). Despite its beneficial effects on the lipid profile, hormone replacement therapy is not recommended for primary or secondary prevention of cardiovascular disease in women. The latest metaanalysis of statin trials with gender-specific outcomes showed a similar benefit in women and men. The addition of ezetimibe to simvastatin in patients with acute coronary syndromes showed a further reduction of the primary endpoint in both genders. While there are no gender-related differences in drug treatment of dyslipidemia, current guidelines, to avoid overtreatment, strongly suggest risk estimation before initiating lipid-lowering treatment in women without manifest cardiovascular disease. Keywords Coronary heart disease . Stroke . Cardiovascular risk factors . Lipid-lowering drugs . Oral contraception . Menopause This article is part of the Topical Collection on Lipid Abnormalities and Cardiovascular Prevention * Renata Cífková [email protected] Alena Krajčoviechová [email protected] 1
Center for Cardiovascular Prevention, Charles University in Prague, First Faculty of Medicine and Thomayer Hospital, Videnska 800, 140 59 Prague 4, Czech Republic
Introduction Cardiovascular disease (CVD) is the leading cause of death among women in developed countries. The proportion of deaths due to CVD is greater in women than in men, currently accounting for 51 % of all deaths in females and 42 % in males in Europe [1•]. In the USA in 2010, CVD caused more deaths in females than in males regardless of race or ethnicity [2]. About half of cardiovascular deaths results from coronary heart disease (CHD). The first presentation of CHD occurs 10 years later among women than among men and, most commonly, after menopause [3]. It was assumed that this age difference reflects premenopausal protection from the development of atherosclerotic CHD afforded by circulating estrogen, which is markedly reduced at menopause. However, estrogen replacement after menopause does not prevent cardiovascular events in females [4] and is not recommended by the current guidelines [5]. The gender difference in CVD risk is smaller in females with diabetes; the reason for this has not been fully explained [6•]. Women are more likely than men to die from their first myocardial infarction thus underlining the importance of primary prevention [7]. Women surviving their first coronary event have approximately double the chance of subsequently developing heart failure or experience a recurrent coronary event [2]. Women have a higher lifetime risk of stroke than men. In individuals aged 55–70 years, the Framingham Heart Study showed a lifetime risk of stroke of 20–21 % for women and 14–17 % for men [8]. Cardiovascular morbidity and mortality differ substantially within Europe as well as within the USA. There is a strong west-east gradient in CVD mortality in Canada, USA, and Europe [2, 9, 10]. In addition to that, there is a north-south gradient in the USA and Europe [2, 10]. Mortality rates continue to fall in most developed countries with the magnitude of changes varying substantially among countries. Generally, the decline in CVD mortality in females is slower [11] or delayed [2].
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Cardiovascular Risk Factors in Women Three risk factors in particular—dyslipidemia, smoking, and hypertension, or a combination of these—are responsible for more than 75 % of all CVDs worldwide [12]. The risk factors such as hypertension and smoking in women are similar to those found in men; however, smoking in women is associated with a higher relative risk than in men [13, 14]. This could be explained by differences in nicotine metabolism, which is faster in women, particularly in those taking oral contraceptives (OCs) [15]. Elevated low-density lipoprotein cholesterol (LDL-C) has been identified as the key lipid parameter [16, 17] in both genders whereas other lipids and lipoproteins have been shown to be especially potent risk predictors in women. Prevalence of dyslipidemia depends on its definition, which is not uniform, and on the study population. Crosssectional population studies in the USA have shown that about 20 % of women have total cholesterol >6.2 mmol/l (240 mg/ dl). However, the decision to initiate lipid-lowering treatment is not dependent on absolute values of lipid parameters unless they are severely elevated (suspected familiar hypercholesterolemia), but on total cardiovascular risk estimation [10, 18, 19••]. The decision to treat in patients at lower CVD risk should be based on clinical judgment, preferences of informed patients, additional factors, and, in patients aged over 75 years, on comorbidities and anticipated longevity. Hypertriglyceridemia has been identified as a significant independent CVD risk factor; however, the association seems not to be as strong as that for hypercholesterolemia [20]. This risk association is established more strongly for moderate than for severe hypertriglyceridemia; this seems to be particularly true for women, where, for example, in the Lipid Research Clinics Follow-up Study, triglycerides >2.25 mmol/l (200 mg/ dl) were associated with increased CVD mortality [21].
Gender Differences in Lipids The first gender differences in lipids could be detected at puberty when high-density lipoprotein (HDL)-cholesterol decreases in boys while not changing in girls. HDL particles are larger in girls than in boys even after correction for HDL-cholesterol levels [22]. Low-density lipoprotein (LDL)-cholesterol levels are about the same in both genders in childhood and adolescence, but girls have larger mean LDL particle size, and smaller mean very low density lipoprotein (VLDL) particle size than boys [23]. These gender-related changes in lipoproteins in childhood and adolescents have been suggested to be partly responsible for the lower cardiovascular risk of premenopausal women compared with men of similar age. Throughout their middle age, women have lower total, LDL-, and non-HDL-cholesterol. In older age, all these
parameters are higher in women with a crossover around menopause [24]; however, LDL particle number remains lower in women throughout their lifespan [25]. Some authors have reported an increase in lipoprotein a [Lp (a)] with age in women in a similar way as in LDL-cholesterol [26]. However, the Framingham Offspring Study analyzing 736 premenopausal and 647 postmenopausal women found a 19 % difference between the groups. After controlling for age, Lp (a) levels in postmenopausal women were still higher (8 %), but this difference was no longer statistically significant [27]. Apolipoprotein B and triglycerides were reported to be increased in postmenopausal women compared with premenopausal ones [28] suggesting that regulation of plasma triglycerides may deteriorate with the decrease of endogenous estrogens [29]. There are also gender differences in the postprandial triglyceride response [30]. While young women have a better response to fatty meals compared with age-matched men [31, 32], this advantage is lost after menopause, with a similar response to fatty meals in both genders [33].
Effects of Hormones on Lipids There is a need to distinguish between endogenous hormone levels and exogenous administration of hormones. Fluctuations in lipoprotein levels have been seen in different phases of the menstrual cycle, but the type and degree of changes are reported differently in various studies [34]. The route of administration, dose, and type of exogenous estrogen and progestin are critical in the lipoprotein response. Oral Contraception Use of OCs is associated with variable changes of lipoproteins further complicated by changes in plasma volume during the menstrual cycle. The estrogen component in OCs increases HDL-cholesterol, HDL2, and triglycerides while decreasing LDL-cholesterol [35]. On the other hand, the progesterone component of OCs has been shown to have opposite effects on lipoproteins. Once OCs are withdrawn, the levels of lipoproteins appear to return to pre-treatment values. Administration of OCs has been consistently shown to be associated with increased risk for venous thromboembolism. The risk of myocardial infarction (MI) with combined OCs has been intensively studied and is controversial. Earlier prospective studies consistently showed an increased risk of acute MI among women who use OCs, and particularly in OC users who smoke, and extended this observation to past smokers on OCs [36]. Two case-control studies with second- and thirdgeneration OCs showed conflicting results [37, 38]. In a large population Swedish prospective study with most of the current OC users taking low-dose estrogen and second- or thirdgeneration progestins, OC use was not associated with an
Curr Cardiol Rep (2015) 17:52
increased risk of MI [39]. Data from observational studies with progestogen-only OCs suggest no increase in MI risk [40]. There is convincing evidence that OC users have about a twofold increased risk of stroke over non-users [41–43]. There are no cardiovascular outcome data available for the newest-generation hormonal contraception formulations developed for non-oral (injectable, topical, and vaginal) routes. However, transdermal patches and vaginal rings have been found to be associated with an increased risk of venous thrombosis [44]. Although the incidence of MI and ischemic stroke is low in the age group of OC users, the absolute risk of OCs is small but has important implications for women’s health since 80 % of women of childbearing age in Western Europe and in the USA can be considered ever-OC users [45]. Current recommendations suggest that OCs should be selected and initiated by weighing the risks and benefits for the individual patient [46]. Blood pressure should be measured on a regular basis [47]. Women aged 35 years and older should be assessed for cardiovascular risk factors. Oral contraceptives should not be used in women with uncontrolled hypertension. Discontinuation of combined OCs in women with hypertension may improve their blood pressure [48]. In women who smoke and are over the age of 35, OCs should be prescribed with caution [49]. Pregnancy Pregnancy is associated with an increase in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides, presumably induced by hormonal changes during pregnancy. After pregnancy, HDL-cholesterol decreases to lower than preconception values. In the Coronary Artery Risk Development in Young Adults (CARDIA) Study, first pregnancy in particular was associated with adverse changes in HDL-cholesterol (mainly a decrease in the HDL2 subfraction) [50]. Parous women tend to have lower HDL-cholesterol than nulliparous ones [51]. Menopause Cross-sectional studies have consistently shown deterioration of lipoproteins in postmenopausal women compared with their premenopausal counterparts. Longitudinal studies usually report smaller changes in lipoproteins around menopause [52]. Total cholesterol increases in women at the time of menopause, both natural and surgically induced [53]. Initial stages of menopausal transition are associated with changes in LDL composition, i.e., a shift toward smaller, denser LDL particles, which are considered more atherogenic [54], whereas an increase in LDL-cholesterol levels follows at later stages. Changes in HDL-cholesterol levels are usually small (a small
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decrease) with a predominant decrease in the HDL 2 subfraction [55]. Postmenopausal Hormone Replacement Therapy There is huge heterogeneity in the lipoprotein response to hormone replacement therapy (HRT). This may be due to the differences in HRT composition, doses, dosing regimen (continuous vs. cyclic), route of administration, compliance with the regimen, hormonal status before HRT, dietary variations, and differences in baseline lipoprotein profile as well as differences in the apolipoprotein E phenotype (with the E2/E2 or E2/E3 phenotypes showing the greatest total cholesterol and LDL-cholesterol reduction) [56]. Estrogen/progestin oral HRT has been reported to induce small decreases in total and LDL-cholesterol [57, 58]. In the Postmenopausal Estrogen/Progestin Investigators (PEPI) trial, the greatest increase in HDL-cholesterol was seen with oral administration of conjugated equine estrogen (CEE) alone. The HDL-cholesterol increase was attenuated in women treated with a combination of CEE and progestin (least with micronized progestin and most with medroxyprogesterone acetate, MPA). All hormonal regimens tested in the PEPI trial were associated with a small increase in triglycerides, although hypertriglyceridemia at baseline was an exclusion criterion. Similarly, there was a decrease in Lp (a) in all active treatment study arms by 20–25 %. Transdermal estrogen therapy is generally believed to be lipid-neutral. A 2-year study showed that transdermal 17-β estradiol was associated with a decrease in total and LDLcholesterol but no significant changes in HDL-cholesterol or triglyceride levels [59]. Most HRT studies showed adverse changes in LDL particle size [60, 61]. Generally, despite the predominantly beneficial changes in the lipid profile documented with HRT, no benefit in reducing the number of CVD events has been shown by large clinical trials with HRT. Therefore, hormone therapy and selective estrogen receptor modulators (SERMs) should not be used for primary or secondary prevention of CVD in women [5, 62•]. Some authors feel that HRT may be considered with caution for the treatment of severe menopausal symptoms for a limited period of time (no longer than 2 years).
Lipids and Risk of Coronary Heart Disease in Women A number of observational studies including the Framingham Heart Study showed a close relationship between total and LDL-cholesterol and CHD risk [63], and a strong inverse relation between HDL-cholesterol and CHD in both sexes [64]. Cohort studies have suggested a 3 % decrease in CHD
52
Curr Cardiol Rep (2015) 17:52
Page 4 of 10
risk for each 1 % reduction in total cholesterol [65]. Some evidence suggests that HDL-cholesterol and triglyceride concentrations play a larger role in CHD risk in women [21, 66]. In observational epidemiologic studies, an increase of 0.03 mmol (1 mg/dl) in HDL-cholesterol was associated with a 3 % decrease in CHD risk in women compared with only a 2 % decrease in CHD risk in men [67]. Inclusion of HDL-cholesterol in risk stratification by SCORE resulted in a modest but significant improvement in risk estimation and in net reclassification index; this may be particularly useful in women from high-risk countries and in individuals with unusually high or low HDL-cholesterol levels [68]. The role of triglycerides as a risk factor for CHD is still debated. A meta-analysis of 17 population-based prospective studies by Hokanson and Austin [69] showed the univariate relative risk (RR) for triglycerides was 1.32 (95 % confidence interval (CI) 1.26–1.39) for men and 1.76 (95 % CI 1.50– 2.07) for women. After adjustment for HDL-cholesterol and several risk factors, the RR for triglycerides was attenuated to 1.14 (95 % CI 1.05–1.28) and 1.37 (95 % CI 1.13–1.66), respectively, suggesting that triglyceride concentrations are two times as strongly associated with CHD risk in women. An updated meta-analysis of additional prospective studies in Western populations (262,525 participants and 10,158 CHD events) showed a similar impact of triglycerides on CHD risk in both genders [20]. Another important finding from this meta-analysis was that there were no major differences in the strength of this relation to CHD incidence in fasting versus non-fasting triglyceride levels. The same finding was reported by the Women’s Health Study [70]. Only a few studies have examined the relationship between CHD risk and LDL particle size in women. It seems that smaller average LDL particle size and LDL pattern B may be a better predictor of CHD in younger women [71, 72]. The Framingham Heart Study found a strong relationship between Lp (a) levels in women and risk of myocardial infarction [73].
Lipids and the Risk of Stroke The association between cholesterol levels and the risk of stroke continues to be controversial. This may be partly due to the fact that earlier studies did not differentiate between ischemic and hemorrhagic stroke. Most epidemiological studies show that elevated cholesterol increases the risk of ischemic stroke accounting for more than 80 % of all strokes. In a meta-analysis of individual data from 61 prospective studies, total cholesterol was weakly positively associated with ischemic and total stroke mortality in early middle age (40– 59 years), a finding that could be largely or wholly accounted for by the association of cholesterol with blood pressure. A
positive relationship was found only in middle age and in individuals with below-average blood pressure, of advanced age (70–79 years), and, particularly, in those with systolic blood pressure >145 mmHg. By contrast, total cholesterol was inversely related to hemorrhagic and total stroke mortality [74]. On the other hand, there is conclusive evidence from randomized trials that statins substantially reduce not only coronary events but also stroke [75].
Management of Dyslipidemia in Women In early clinical studies in dyslipidemia, women were not routinely included or were frequently underrepresented, the latter being a problem that has persisted to date [76, 77]. Lifestyle Changes The most recent guidelines for the prevention of CVD in women (2011 update) [62] suggest lifestyle modifications as the initial treatment for women with dyslipidemia. These include abstention from smoking, avoidance of secondhand smoking or smoking cessation. A minimum of 30 min of moderate physical activity is recommended on most and preferably on all days of the week. Women should consume a diet rich in fruits and vegetables; choose whole-grain high-fiber foods; consume fish, especially oily fish, at least two times a week; limit intake of saturated fat to
LIPID ABNORMALITIES AND CARDIOVASCULAR PREVENTION (G DE BACKER, SECTION EDITOR)
Dyslipidemia and Cardiovascular Disease in Women Renata Cífková 1 & Alena Krajčoviechová 1
# Springer Science+Business Media New York 2015
Abstract Cardiovascular disease is the major cause of death in women in developed countries. Dyslipidemia is highly prevalent in women, particularly after the menopause. Elevated low-density lipoprotein cholesterol (LDL-C) has been identified as the key lipid parameter in both genders whereas HDL-cholesterol and triglycerides have been more closely associated, in some studies, with cardiovascular risk in women. Menopause has been shown to be associated with an increase in total and LDL-cholesterol and a decrease in HDLcholesterol (predominantly in the HDL2 subfraction). Despite its beneficial effects on the lipid profile, hormone replacement therapy is not recommended for primary or secondary prevention of cardiovascular disease in women. The latest metaanalysis of statin trials with gender-specific outcomes showed a similar benefit in women and men. The addition of ezetimibe to simvastatin in patients with acute coronary syndromes showed a further reduction of the primary endpoint in both genders. While there are no gender-related differences in drug treatment of dyslipidemia, current guidelines, to avoid overtreatment, strongly suggest risk estimation before initiating lipid-lowering treatment in women without manifest cardiovascular disease. Keywords Coronary heart disease . Stroke . Cardiovascular risk factors . Lipid-lowering drugs . Oral contraception . Menopause This article is part of the Topical Collection on Lipid Abnormalities and Cardiovascular Prevention * Renata Cífková [email protected] Alena Krajčoviechová [email protected] 1
Center for Cardiovascular Prevention, Charles University in Prague, First Faculty of Medicine and Thomayer Hospital, Videnska 800, 140 59 Prague 4, Czech Republic
Introduction Cardiovascular disease (CVD) is the leading cause of death among women in developed countries. The proportion of deaths due to CVD is greater in women than in men, currently accounting for 51 % of all deaths in females and 42 % in males in Europe [1•]. In the USA in 2010, CVD caused more deaths in females than in males regardless of race or ethnicity [2]. About half of cardiovascular deaths results from coronary heart disease (CHD). The first presentation of CHD occurs 10 years later among women than among men and, most commonly, after menopause [3]. It was assumed that this age difference reflects premenopausal protection from the development of atherosclerotic CHD afforded by circulating estrogen, which is markedly reduced at menopause. However, estrogen replacement after menopause does not prevent cardiovascular events in females [4] and is not recommended by the current guidelines [5]. The gender difference in CVD risk is smaller in females with diabetes; the reason for this has not been fully explained [6•]. Women are more likely than men to die from their first myocardial infarction thus underlining the importance of primary prevention [7]. Women surviving their first coronary event have approximately double the chance of subsequently developing heart failure or experience a recurrent coronary event [2]. Women have a higher lifetime risk of stroke than men. In individuals aged 55–70 years, the Framingham Heart Study showed a lifetime risk of stroke of 20–21 % for women and 14–17 % for men [8]. Cardiovascular morbidity and mortality differ substantially within Europe as well as within the USA. There is a strong west-east gradient in CVD mortality in Canada, USA, and Europe [2, 9, 10]. In addition to that, there is a north-south gradient in the USA and Europe [2, 10]. Mortality rates continue to fall in most developed countries with the magnitude of changes varying substantially among countries. Generally, the decline in CVD mortality in females is slower [11] or delayed [2].
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Page 2 of 10
Cardiovascular Risk Factors in Women Three risk factors in particular—dyslipidemia, smoking, and hypertension, or a combination of these—are responsible for more than 75 % of all CVDs worldwide [12]. The risk factors such as hypertension and smoking in women are similar to those found in men; however, smoking in women is associated with a higher relative risk than in men [13, 14]. This could be explained by differences in nicotine metabolism, which is faster in women, particularly in those taking oral contraceptives (OCs) [15]. Elevated low-density lipoprotein cholesterol (LDL-C) has been identified as the key lipid parameter [16, 17] in both genders whereas other lipids and lipoproteins have been shown to be especially potent risk predictors in women. Prevalence of dyslipidemia depends on its definition, which is not uniform, and on the study population. Crosssectional population studies in the USA have shown that about 20 % of women have total cholesterol >6.2 mmol/l (240 mg/ dl). However, the decision to initiate lipid-lowering treatment is not dependent on absolute values of lipid parameters unless they are severely elevated (suspected familiar hypercholesterolemia), but on total cardiovascular risk estimation [10, 18, 19••]. The decision to treat in patients at lower CVD risk should be based on clinical judgment, preferences of informed patients, additional factors, and, in patients aged over 75 years, on comorbidities and anticipated longevity. Hypertriglyceridemia has been identified as a significant independent CVD risk factor; however, the association seems not to be as strong as that for hypercholesterolemia [20]. This risk association is established more strongly for moderate than for severe hypertriglyceridemia; this seems to be particularly true for women, where, for example, in the Lipid Research Clinics Follow-up Study, triglycerides >2.25 mmol/l (200 mg/ dl) were associated with increased CVD mortality [21].
Gender Differences in Lipids The first gender differences in lipids could be detected at puberty when high-density lipoprotein (HDL)-cholesterol decreases in boys while not changing in girls. HDL particles are larger in girls than in boys even after correction for HDL-cholesterol levels [22]. Low-density lipoprotein (LDL)-cholesterol levels are about the same in both genders in childhood and adolescence, but girls have larger mean LDL particle size, and smaller mean very low density lipoprotein (VLDL) particle size than boys [23]. These gender-related changes in lipoproteins in childhood and adolescents have been suggested to be partly responsible for the lower cardiovascular risk of premenopausal women compared with men of similar age. Throughout their middle age, women have lower total, LDL-, and non-HDL-cholesterol. In older age, all these
parameters are higher in women with a crossover around menopause [24]; however, LDL particle number remains lower in women throughout their lifespan [25]. Some authors have reported an increase in lipoprotein a [Lp (a)] with age in women in a similar way as in LDL-cholesterol [26]. However, the Framingham Offspring Study analyzing 736 premenopausal and 647 postmenopausal women found a 19 % difference between the groups. After controlling for age, Lp (a) levels in postmenopausal women were still higher (8 %), but this difference was no longer statistically significant [27]. Apolipoprotein B and triglycerides were reported to be increased in postmenopausal women compared with premenopausal ones [28] suggesting that regulation of plasma triglycerides may deteriorate with the decrease of endogenous estrogens [29]. There are also gender differences in the postprandial triglyceride response [30]. While young women have a better response to fatty meals compared with age-matched men [31, 32], this advantage is lost after menopause, with a similar response to fatty meals in both genders [33].
Effects of Hormones on Lipids There is a need to distinguish between endogenous hormone levels and exogenous administration of hormones. Fluctuations in lipoprotein levels have been seen in different phases of the menstrual cycle, but the type and degree of changes are reported differently in various studies [34]. The route of administration, dose, and type of exogenous estrogen and progestin are critical in the lipoprotein response. Oral Contraception Use of OCs is associated with variable changes of lipoproteins further complicated by changes in plasma volume during the menstrual cycle. The estrogen component in OCs increases HDL-cholesterol, HDL2, and triglycerides while decreasing LDL-cholesterol [35]. On the other hand, the progesterone component of OCs has been shown to have opposite effects on lipoproteins. Once OCs are withdrawn, the levels of lipoproteins appear to return to pre-treatment values. Administration of OCs has been consistently shown to be associated with increased risk for venous thromboembolism. The risk of myocardial infarction (MI) with combined OCs has been intensively studied and is controversial. Earlier prospective studies consistently showed an increased risk of acute MI among women who use OCs, and particularly in OC users who smoke, and extended this observation to past smokers on OCs [36]. Two case-control studies with second- and thirdgeneration OCs showed conflicting results [37, 38]. In a large population Swedish prospective study with most of the current OC users taking low-dose estrogen and second- or thirdgeneration progestins, OC use was not associated with an
Curr Cardiol Rep (2015) 17:52
increased risk of MI [39]. Data from observational studies with progestogen-only OCs suggest no increase in MI risk [40]. There is convincing evidence that OC users have about a twofold increased risk of stroke over non-users [41–43]. There are no cardiovascular outcome data available for the newest-generation hormonal contraception formulations developed for non-oral (injectable, topical, and vaginal) routes. However, transdermal patches and vaginal rings have been found to be associated with an increased risk of venous thrombosis [44]. Although the incidence of MI and ischemic stroke is low in the age group of OC users, the absolute risk of OCs is small but has important implications for women’s health since 80 % of women of childbearing age in Western Europe and in the USA can be considered ever-OC users [45]. Current recommendations suggest that OCs should be selected and initiated by weighing the risks and benefits for the individual patient [46]. Blood pressure should be measured on a regular basis [47]. Women aged 35 years and older should be assessed for cardiovascular risk factors. Oral contraceptives should not be used in women with uncontrolled hypertension. Discontinuation of combined OCs in women with hypertension may improve their blood pressure [48]. In women who smoke and are over the age of 35, OCs should be prescribed with caution [49]. Pregnancy Pregnancy is associated with an increase in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides, presumably induced by hormonal changes during pregnancy. After pregnancy, HDL-cholesterol decreases to lower than preconception values. In the Coronary Artery Risk Development in Young Adults (CARDIA) Study, first pregnancy in particular was associated with adverse changes in HDL-cholesterol (mainly a decrease in the HDL2 subfraction) [50]. Parous women tend to have lower HDL-cholesterol than nulliparous ones [51]. Menopause Cross-sectional studies have consistently shown deterioration of lipoproteins in postmenopausal women compared with their premenopausal counterparts. Longitudinal studies usually report smaller changes in lipoproteins around menopause [52]. Total cholesterol increases in women at the time of menopause, both natural and surgically induced [53]. Initial stages of menopausal transition are associated with changes in LDL composition, i.e., a shift toward smaller, denser LDL particles, which are considered more atherogenic [54], whereas an increase in LDL-cholesterol levels follows at later stages. Changes in HDL-cholesterol levels are usually small (a small
Page 3 of 10 52
decrease) with a predominant decrease in the HDL 2 subfraction [55]. Postmenopausal Hormone Replacement Therapy There is huge heterogeneity in the lipoprotein response to hormone replacement therapy (HRT). This may be due to the differences in HRT composition, doses, dosing regimen (continuous vs. cyclic), route of administration, compliance with the regimen, hormonal status before HRT, dietary variations, and differences in baseline lipoprotein profile as well as differences in the apolipoprotein E phenotype (with the E2/E2 or E2/E3 phenotypes showing the greatest total cholesterol and LDL-cholesterol reduction) [56]. Estrogen/progestin oral HRT has been reported to induce small decreases in total and LDL-cholesterol [57, 58]. In the Postmenopausal Estrogen/Progestin Investigators (PEPI) trial, the greatest increase in HDL-cholesterol was seen with oral administration of conjugated equine estrogen (CEE) alone. The HDL-cholesterol increase was attenuated in women treated with a combination of CEE and progestin (least with micronized progestin and most with medroxyprogesterone acetate, MPA). All hormonal regimens tested in the PEPI trial were associated with a small increase in triglycerides, although hypertriglyceridemia at baseline was an exclusion criterion. Similarly, there was a decrease in Lp (a) in all active treatment study arms by 20–25 %. Transdermal estrogen therapy is generally believed to be lipid-neutral. A 2-year study showed that transdermal 17-β estradiol was associated with a decrease in total and LDLcholesterol but no significant changes in HDL-cholesterol or triglyceride levels [59]. Most HRT studies showed adverse changes in LDL particle size [60, 61]. Generally, despite the predominantly beneficial changes in the lipid profile documented with HRT, no benefit in reducing the number of CVD events has been shown by large clinical trials with HRT. Therefore, hormone therapy and selective estrogen receptor modulators (SERMs) should not be used for primary or secondary prevention of CVD in women [5, 62•]. Some authors feel that HRT may be considered with caution for the treatment of severe menopausal symptoms for a limited period of time (no longer than 2 years).
Lipids and Risk of Coronary Heart Disease in Women A number of observational studies including the Framingham Heart Study showed a close relationship between total and LDL-cholesterol and CHD risk [63], and a strong inverse relation between HDL-cholesterol and CHD in both sexes [64]. Cohort studies have suggested a 3 % decrease in CHD
52
Curr Cardiol Rep (2015) 17:52
Page 4 of 10
risk for each 1 % reduction in total cholesterol [65]. Some evidence suggests that HDL-cholesterol and triglyceride concentrations play a larger role in CHD risk in women [21, 66]. In observational epidemiologic studies, an increase of 0.03 mmol (1 mg/dl) in HDL-cholesterol was associated with a 3 % decrease in CHD risk in women compared with only a 2 % decrease in CHD risk in men [67]. Inclusion of HDL-cholesterol in risk stratification by SCORE resulted in a modest but significant improvement in risk estimation and in net reclassification index; this may be particularly useful in women from high-risk countries and in individuals with unusually high or low HDL-cholesterol levels [68]. The role of triglycerides as a risk factor for CHD is still debated. A meta-analysis of 17 population-based prospective studies by Hokanson and Austin [69] showed the univariate relative risk (RR) for triglycerides was 1.32 (95 % confidence interval (CI) 1.26–1.39) for men and 1.76 (95 % CI 1.50– 2.07) for women. After adjustment for HDL-cholesterol and several risk factors, the RR for triglycerides was attenuated to 1.14 (95 % CI 1.05–1.28) and 1.37 (95 % CI 1.13–1.66), respectively, suggesting that triglyceride concentrations are two times as strongly associated with CHD risk in women. An updated meta-analysis of additional prospective studies in Western populations (262,525 participants and 10,158 CHD events) showed a similar impact of triglycerides on CHD risk in both genders [20]. Another important finding from this meta-analysis was that there were no major differences in the strength of this relation to CHD incidence in fasting versus non-fasting triglyceride levels. The same finding was reported by the Women’s Health Study [70]. Only a few studies have examined the relationship between CHD risk and LDL particle size in women. It seems that smaller average LDL particle size and LDL pattern B may be a better predictor of CHD in younger women [71, 72]. The Framingham Heart Study found a strong relationship between Lp (a) levels in women and risk of myocardial infarction [73].
Lipids and the Risk of Stroke The association between cholesterol levels and the risk of stroke continues to be controversial. This may be partly due to the fact that earlier studies did not differentiate between ischemic and hemorrhagic stroke. Most epidemiological studies show that elevated cholesterol increases the risk of ischemic stroke accounting for more than 80 % of all strokes. In a meta-analysis of individual data from 61 prospective studies, total cholesterol was weakly positively associated with ischemic and total stroke mortality in early middle age (40– 59 years), a finding that could be largely or wholly accounted for by the association of cholesterol with blood pressure. A
positive relationship was found only in middle age and in individuals with below-average blood pressure, of advanced age (70–79 years), and, particularly, in those with systolic blood pressure >145 mmHg. By contrast, total cholesterol was inversely related to hemorrhagic and total stroke mortality [74]. On the other hand, there is conclusive evidence from randomized trials that statins substantially reduce not only coronary events but also stroke [75].
Management of Dyslipidemia in Women In early clinical studies in dyslipidemia, women were not routinely included or were frequently underrepresented, the latter being a problem that has persisted to date [76, 77]. Lifestyle Changes The most recent guidelines for the prevention of CVD in women (2011 update) [62] suggest lifestyle modifications as the initial treatment for women with dyslipidemia. These include abstention from smoking, avoidance of secondhand smoking or smoking cessation. A minimum of 30 min of moderate physical activity is recommended on most and preferably on all days of the week. Women should consume a diet rich in fruits and vegetables; choose whole-grain high-fiber foods; consume fish, especially oily fish, at least two times a week; limit intake of saturated fat to
