Dyslipidemia in Women: Do They Need Separate Guidelines?

INTRODUCTION

In women, cardiovascular disease (CVD) is one of the major causes of death in USA,^[1] as well as in other countries like South Asia (India, Pakistan, Bangladesh, Sri Lanka, Maldives, and Bhutan).^[2] Along with traditional risk factors such as diabetes, hypertension, smoking, and dyslipidemia, the presence of gender-specific risk factors, including hormonal changes, contributes to CVD.^[3,4] Some of the gender-specific conditions include early menarche and menopause, polycystic ovarian syndrome (PCOS), pregnancy-induced hypertension (PIH), gestational diabetes mellitus (GDM), and presence of inflammatory comorbidities (rheumatoid and systemic lupus erythematosus [SLE]). Further, women in general have longer life expectancy (compared to men), leaving greater lifetime risk for cardiovascular (CV) disorders.^[5] The INTER HEART study has shown that dyslipidemia is a greater population attributable risk factor than other modifiable risk factors (like hypertension). Thus, need for evaluating presence of dyslipidaemia in general and women in particular for effective prevention of CVD. Over the last few decades, the incidence and prevalence of dyslipidemia have increased in women. National Health and Nutrition Examination Survey (NHANES)^[6] conducted between 2015 and 2018 revealed that 40% women have total cholesterol (TC) of >200 mg/dL, 12.1% (15.8 million) have TC of >240 mg/dL, and 8.5% (10.3 millions) have high-density lipoprotein (HDL)-C <40 mg/dL. Further analysis of data suggests that TC level is similar for women and men under the age of 35 years and significant number of them have less TC than their male counterparts.^[7] On the contrary, over the age of 50 years, women had higher rates of elevated TC and low-density lipoprotein (LDL)-C, reversal of the trend as compared to values at a younger age (40 years). Further, the impact of these risk factors has differential effects in each biological sex in the development of vascular disease.^[8] For example, the metabolic syndrome, diabetes mellitus (DM), and smoking have a worse effect on CV disease manifestation in women compared to men.^[9-11] Dyslipidemia has racial and ethic influence, with Mexican and Filipino women having a higher prevalence.^[12] Asian Indian and Mexican women are found to have lower concentrations of HDL-C and increased prevalence of hypertriglyceridemia. Overall, Asian Indians, Filipinos, and Vietnamese women are found to have high TG, high LDL-C, and low HDL.^[13] The prevalence of elevated lipoprotein (a) (LP(a)) – highly atherogenic, pro-inflammatory, and prothrombotic – varies by race, ethnicity but is equally distributed among men and women [Figure 1].

Close

Figure 1:

Ideal levels of lipids. (LDL-C/LDLC: Low-Density Lipoprotein Cholesterol, TG: Triglycerides, ApoB: Apolipoprotein B.)

Export to PPT

Dyslipidemia in women differs from that of men but also varies during different stages of life including hormonal changes throughout the menstrual cycle.^[14] Menstrual cycle has a follicular phase and a luteal phase. During the follicular phase, TC and LDL-C levels are higher due to the high estrogen effect. The levels decline during the luteal phase due to rising progesterone. In one study, TC increased by 9.2% during the follicular phase. In women on the oral contraceptive (OC) pill, the TC and triglyceride (TG) are higher compared to those who are not using the OC pill.^[15,16] Pregnancy is characterized by an anabolic state where the body stores fat for the fetus. Insulin resistance is also increased during pregnancy. Hormonal changes in pregnancy lead to increased production of lipids with TC level increasing by 50% and a twofold increase in TG levels.^[17] These lipid changes during pregnancy peak at delivery and return to baseline in few weeks to a month. Maternal supraphysiologic hyperlipidemia (TC and TG levels exceeding the 90^th percentile – generally >250 mg/dL) leads to increased risk of adverse maternal and fetal outcomes. Hyperlipidemia has both short-term adverse effects such as increased risk of GDM, pre-eclampsia, and preterm deliveries but also confers a 1.8–4 fold greater CV risk for these mothers in later life. The ideal time for screening women would be before conception as levels will be higher during pregnancy. A lipid profile can be obtained at the first obstetric visit if not done earlier. After delivery, women maintain elevated TG and TC to meet lactation needs which seems as a physiologic mechanism for excretion of lipids. Breastfeeding increases HDL-C in mothers with no effect on LDL-C and TG but results in CV benefit later in life.

CV risk for women changes with the onset of menopause, usually by the age of 50 years, with changes in lipid profile and metabolic profile, and is mediated by less estrogen.^[18] The lipid changes include increased LDL-C, TG, and LP(a), with a decrease in HDL-C. The metabolic changes include increased visceral fat in the abdomen with higher insulin resistance and endothelial dysfunction. Hormonal replacement therapy to improve CV outcome has been ineffective, as shown by multiple studies. Patient and provider assessment of lipid management dataset^[19] showed that women are under-screened and under-treated as compared to men among those suspected for dyslipidemia. Women are less likely to be offered statin therapy and appropriate intensification to target lipid levels. This bias in treatment in women also occurs with other comorbidities like hypertension and diabetes which contribute to higher ASCVD risk with its attendant morbidity and mortality. Historically, women comprise only about 24–29% of subjects in lipid-lowering trials. This skewed gender ratio in lipid trials is attributed to the late onset of CV disease in women and exclusion of women of childbearing age in most drug trials (as per protocol), poor tolerance of statins by women, and more likelihood to discontinue drug therapy. For a better understanding of lipid-lowering drugs, trials should include more women of different ethnicities and races as the pathophysiology of dyslipidemia in women is influenced more by hormones compared to men. Furthermore, women have higher CYP3A4 activity, leading to increased metabolism and hepatic clearance of drugs.

DYSLIPIDEMIA MANAGEMENT

The management of dyslipidemia starts with risk stratification for the occurrence of atherosclerotic cardiovascular disease (ASCVD) in the future. The ASCVD in India occurs a decade earlier compared to the Western population, despite having lower LDL-C.^[20] The earlier age of onset of ASCVD in Indians emphasizes the importance of evaluating lifetime risk (rather than 10-year risk) as age has an overriding influence on the estimated risk using equations proposed by ACC/AHA and ESC organisations. The estimated risk of ASCVD is influenced not only by conventional risk factors (modifiable and non-modifiable) but also by risk “enhancers’’ (risk modifiers). These ASCVD risk calculators not only consider risk factors but also the presence of clinical vascular diseases, in addition to the presence of sub-clinical atheromatous disease (like CT-coronary artery calcium, carotid atheroma). Lipid targets are basically intended to prevent the occurrence, progression, and rarely regression of atheroma, thus mitigating the risk of clinical disease.

Concept of “cholesterol years’’^[20] has been proposed (like – cigarette pack years) to emphasize the importance of cholesterol burden over the years as a predictor of ASCVD. Higher the cholesterol burdens the earlier and more severe atheroma manifestation. Cholesterol years (LDL-C in mg/dL × age in years) estimates the lifetime risk of ASCVD, with a postulated threshold of 7 G- years above which is high probability of ASCVD. Thus, the earlier the therapy and more intensive the therapy, the latter is onset of ASCVD. “Hit early and hit hard’’ is one proposition to prevent ASCVD in the population, including women.

Estimation of future risk of cardiovascular events is necessary for guiding the therapy. Higher the ASCVD risk, the more intense is the lipid lowering therapy. Primary target is LDL-C level, non HDL-C is a co-primary target and Apolipoprotein B (ApoB) is secondary target (as per LAI guidelines-2023)^[20]. In Indian population, large scale studies that are conducted over a long term regarding the relationship between observed risk factors and incident ASCVD events are not available. Of the available risk prediction scores (for the Western population), the QRISK-3 performs better than pooled cohort equations in predicting ASCVD events in Indian population. LAI has attempted to classify ASCVD risk into low, moderate, high, very high, and extreme categories and suggested lipid targets accordingly. They used parameters such as risk factors, risk modifiers, lipid values, subclinical atheroma, and effect of therapy on ASCVD events and clinical CV disease.^[21] Until we have dedicated, validated Indian specific equations for prediction of ASCVD, guidelines formulated by LAI is useful for therapeutic targets of Indian patients [Figure 2].

Close

Figure 2:

Classification of ASCVD risk.

Export to PPT

Screening for lipid disorders before pregnancy can help to identify women at risk for ASCVD and provide an opportunity for optimal maternal and fetal outcomes, with appropriate interventions. ACC - AHA 2018 guidelines recommend screening starting at age 20 for all adults including women of reproductive age, more so in women at risk for pre-mature ASCVD.^[21] Management of dyslipidemia in females during their reproductive period and pregnancy is no different, except to consider possible adverse effects on the fetus as drugs cross the placenta into fetal circulation. Therapy starts with dietary control, physical activity, and pharmacotherapy. Familial hypercholesterolemia (FH) and the presence of ASCVD during pregnancy are high-risk conditions that demand aggressive therapy.

Therapy of dyslipidemia in women starts with the estimation of risk of ASCVD in Indian patients using the LAI criteria, as there is no specific equation for Indian patients [Table 1]. Additionally, it is important to consider, gender specific “risk enhancers” which when present elevates the risk to next level (like mild risk to moderate risk). These gender-specific risk enhancers include PCOS, premature menopause (<40 years), history of adverse pregnancy outcome (e.g., PIH and GDM), and female predominant inflammatory factors (such as SLE and rheumatoid arthritis, etc).

PCOS

Women with PCOS are at an elevated risk for ASCVD in the future by two-fold.^[22] The common lipid phenotype is low HDL-C, elevated TG, and small dense LDL particles, along with hyperandrogenism and insulin resistance.

Menopause and hormonal replacement therapy (HRT)

The protection against ASCVD during reproductive years is attributed to cardioprotective effects of endogenous estrogens.

Estrogen levels are inversely correlated with TC and LDL-C and directly correlated with HDL-C. During menopause with the cessation of endogenous estradiol, women have a decline in HDL and an increase in TC, LDL, and TG, with a high atherogenic index (TC/HDL ratio) as compared to the pre-menopausal state. In addition, unfavorable non-lipid parameters like an increase in visceral adiposity, increased BP, and sympathetic activity and endothelial dysfunction contribute to increased risk for ASCVD. Menopause hormonal therapy (MHT) has a positive effect on the reduction of LDL-C and an increase in HDL. At the same time, it improves vasodilation by increasing nitric oxide availability. In addition, estrogens also increase TG and high-sensitivity CRP with an increase in prothrombin and a decrease in antithrombin III which results in a prothrombotic state, particularly in women with established ASCVD. Even in older women who took HRT within 10 years of the postmenopausal period, randomized clinical trials of MHT have not shown any reduction of CV events.^[25] The current guidelines do not recommend HRT for lipid management or ASCVD prevention in women.

Therapy of dyslipidemia is focused on LDL-C with statins and non-statin pharmacotherapy. Equally common dyslipidemia among the Indian population is mixed dyslipidemia which consists of elevated LDL-C, TG, and decrease in HDL-C. The basis of combined dyslipidemia includes genetic disorders (familial combined hyperlipidemia and familial dysbetalipoproteinemia), DM, metabolic syndrome, and with use of certain drugs (immunosuppressive drugs, protease inhibitors, and highly active antiretroviral therapy). NonHDL-C is the lipid parameter to assess the degree of mixed dyslipidemia and the effect of pharmacotherapy. Therapy for mixed dyslipidemia starts with identifying secondary causes, with appropriate therapy to control such as DM, metabolic syndrome, and ethanol abuse.^[26] Appropriate therapy includes lifestyle modification, diet, exercise, weight reduction, and pharmacotherapy, aimed at reducing LDL, non-HDL-C by statins, ezetimibe, and (PCSK-9) inhibition which have shown ASCVD event reduction. Persistent elevation of TG in spite of the above therapy should favor eicosapentaenoic acid (EPA) as add-on therapy to reduce CV events. The mechanism of benefit with EPA is beyond lipid-lowering effect and includes anti-inflammation, anti-, and plaque stabilization. Dosage of EPA is 4G/day in two divided doses.

The following is the algorithm for management of dyslipidemia in women [Figure 3].

Close

Figure 3:

Algorithm for dyslipidemia management.

Export to PPT

DYSLIPIDEMIA MANAGEMENT – IN PREGNANCY

CONCLUSION

Women have different biological changes related to hormonal changes. These changes are present throughout the reproductive years and later on as well. Women have additional – “gender-specific risk factors” which increase the risk of ASCVD, and consequently, more aggressive therapy for dyslipidemia is warranted. Further, drug therapy for dyslipidemia in females must take into consideration the safety to the fetus during pregnancy and lactation which limits the options and efficacy, exposing them to a higher risk of ASCVD during their lifetime, which in the majority is longer than men.

Pharmacotherapy of dyslipidemia in women results in a similar reduction of ASCVD and vascular events as compared to men for the same degree of risk.

Finally, do women require separate guidelines in the management of dyslipidemia?

Yes they do, as gender-specific risk factors for vascular disease in addition to common risk factors, enhance their risk for ASCVD. Further, they go through specific life situations resulting in hormonal changes that impact the progression of disease and modifications of pharmacotherapy. In general, the response to pharmacotherapy in reducing CV events is on par with men.