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Pharmacotherapy Series

Overview of Lipid Therapy in Women

Kristi W. Kelley, PharmD, BCPS; Amy R. Donaldson, PharmD, BCPS

Cardiovascular disease (CVD) is the leading cause of death and disability in US women.¹ More than 500,000 women died from CVD—primarily coronary heart disease (CHD)—in the year 2000.¹ Although the average age at onset of CHD in women tends to lag behind that in men by approximately 10 years (20 years for more serious events such as myocardial infarction), CHD has claimed the lives of approximately 50,000 more women than men in every year since 1984.^1,2 However, the perception that heart disease primarily affects men and carries a more benign prognosis in women persists. Indeed, a recent survey revealed that more women consider cancer (particularly breast cancer) as the greatest health problem for women.³ Heart disease was identified as the leading cause of death in women by only 31% of respondents.³ In reality, one in 29 women will die from breast cancer, while one in 2.4 women will die from CVD.¹

SCREENING

Women should be screened for hyperlipidemia starting at age 20 years, and then at least once every 5 years thereafter if the patient remains at low risk.⁴ A fasting lipid profile should be obtained, including total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride (TG) levels. Pretest fasting should last for 9 to 12 hours. Patients with multiple risk factors should undergo more frequent screening; for example, women with diabetes should be screened yearly for hyperlipidemia.

RISK FACTORS

The major risk factors associated with CHD in men are also present in women, including smoking, hypertension, diabetes, hyperlipidemia, obesity, and sedentary life-style. In fact, diabetes and dyslipidemia have been identified as more powerful risk factors in women.^5,6

The leading preventable cause of CHD is cigarette smoking, with more than 50% of myocardial infarctions (MIs) in middle-aged women attributed to tobacco use.⁵ Heavy smoking (ie, more than 20 cigarettes per day) increases the risk of CHD by 2-fold to 4-fold over that of nonsmokers, and even light smokers still have double the normal risk of CHD.² Smoking cessation decreases the risk of CHD within months of cessation, with the risk level falling to that of nonsmokers in 3 to 5 years.⁵

Elevated systolic and diastolic blood pressure is associated with an increased risk of CHD in both women and men. Hypertension raises the risk by 4-fold in women and 3-fold in men.⁵ Isolated systolic hypertension, which is more common in elderly women (30%), is also of concern.⁵

Diabetes is a greater risk predictor for women than men.⁶ It is associated with a 3-fold to 7-fold increase in CHD mortality, compared with a 2-fold to 3-fold increase in men.⁵ The excess risk associated with diabetes is partly due to lower HDL and higher TG levels, and an increase in blood pressures.⁷

Obesity and physical inactivity have reached epidemic proportions in the past few decades. Both obesity and physical inactivity can be related to an increased risk of CHD. Obesity is now more common in women than normal body weight,⁸ and abdominal obesity is a particular risk factor for CHD in women.⁹ The risk of developing CHD is increased by 3-fold when the body mass index (BMI) is 29 kg/m², compared with a BMI of 21 kg/m².⁸

Menopause quadruples the risk of a coronary event compared with age-matched premenopausal women.⁷ The increase in coronary disease is due in part to the decline in endogenous estrogen that confers coronary protection. This loss of estrogen affects lipoprotein levels adversely, and may result in increased total and LDL cholesterol levels, decreased HDL cholesterol levels, and increased TG levels. Levels of LDL cholesterol increase by an average of 2 mg/dL per year in women between the ages of 40 and 60 years.¹⁰ Depressed HDL cholesterol has been shown to be a stronger predictor of CHD mortality in women of all ages, more so than in men.² Elevated TG levels also appear to be a more significant risk factor in women than men, especially if the HDL level falls below 40 mg/dL.³ Thus, there are gender differences in LDL cholesterol and HDL cholesterol profiles, and women with diabetes tend to have a worse outcome than men. Women with multiple risk factors have a compounded risk for CHD.

TREATMENT

Although there is relatively little information about therapy to lower cholesterol levels of women in the literature, the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (NCEP-ATP III) does provide specific data on lowering lipids in women.⁴ In hyperlipidemic women aged 20 to 45 years, treatment should emphasize therapeutic life-style changes (TLC) and risk factor control. Drug therapy is recommended when young women cannot achieve LDL goals on TLC alone.⁴ Women aged 45 to 75 years have the same basic treatment recommendations as men, but NCEP-ATP III provides additional recommendations for women regarding risk factor management as well.⁴ The basic recommendations still apply to women older than age 75 years, but in NCEP-ATP III, lipid-lowering therapy assumes greater importance than previously thought in this age group.⁴

Therapeutic Life-style Changes

Healthy life-style modifications should be encouraged in every patient (Table 1). Patients whose LDL levels are elevated but below the target for beginning lipid-lowering therapy should be tried on TLC for at least 6 weeks, and then reevaluated.⁴ If LDL levels are still above the goal, the TLC plan should be intensified for another 6 weeks.⁴ If the LDL levels remain high, initiation of drug therapy should be considered. Even in patients for whom drug therapy is required, TLC is essential. All patients adhering to a TLC plan should be monitored every 4 to 6 months to assess efficacy.⁴

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Table 1. Therapeutic Life-style Changes4

Statins

The mainstay of LDL-lowering treatment has become 3-hydroxy-3-methyl-glutaryl (HMG-CoA) reductase inhibitors, more commonly known as statins. Statins competitively inhibit HMG-CoA reductase, an enzyme implicated in early cholesterol biosynthesis.^4,11,12 Statins affect all components of the lipid profile, reducing total cholesterol, LDL cholesterol, and TGs, and increasing HDL cholesterol. The extent to which each statin affects each of these parameters varies based on the compound and the dose used.^11,12 Although a response may be seen in 1 to 2 weeks with pravastatin and atorvastatin, the maximum lipid-lowering effect for a specific dose of a statin is generally evident within 4 weeks after initiation, and will persist throughout the course of therapy. Because it requires 4 weeks to achieve maximum effect, testing and dosage adjustments should be done no more frequently than every 4 weeks. Each doubling of the statin dosage will lower the LDL level by an additional 6%.⁴ For example, raising a patient’s dosage from simvastatin, 40 mg at bedtime to 80 mg at bedtime should raise the LDL reduction from 41% to 47%.¹³ The lowering of LDL at other dosages and with other statins may differ.

Statins have a good overall safety record.⁴ However, they may cause systemic side effects such as rash, gastrointestinal disturbances, or nervous system symptoms (headaches, sleep disturbances, loss of concentration).¹⁴ The incidence of these systemic effects is less than 10%. However, with the manufacturer’s voluntary recall of cerivastatin in August 2001, there has been extensive negative publicity about the rare serious adverse effects of statins, including myopathy and rhabdomylosis.⁴ Three thousand thirty-nine cases of statin-associated rhabdomyolysis were noted in the US Food and Drug Association database between 1990 and 2002, but the rate of myalgia is not significantly different from placebo and ranges from 1% to 5%.¹⁵ Although the withdrawal of cerivastatin was unfortunate, it did prompt a refocus on safety concerns with statins.¹⁶ To identify patients who may be at higher risk for myopathy, myalgia, or rhabdomyolysis, all statins carry recommendations for monitoring the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The drug should be discontinued if the values of ALT and AST are greater than 3 times the upper limit of normal (Table 2). The American College of Cardiology/American Heart Association/National Heart, Lung, and Blood Institute issued a clinical advisory in 2002 on the use and safety of statins that recommends monitoring patients for symptoms (headaches, dyspepsia, muscle soreness, muscle tenderness, pain) and ALT, AST, and creatine kinase values.¹⁶ Strategies to decrease the risk of statin-associated myopathy, such as caution in older patients and those with small body or taking multiple medications, are also included.¹⁶

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Table 2. Monitoring of Liver Enzymes (ALT, AST) With Statins

Four of the six statins currently available in the United States are significantly metabolized through cytochrome P450 (CYP) in the liver. However, pravastatin only undergoes phase II reactions in the liver, and rosuvastatin is less than 10% metabolized.^17,18 Many of the more significant drug interactions have been attributed to statins that are metabolized by CYP3A4 pathway.¹⁷ Administering drugs that inhibit CYP3A4 in conjunction with statins metabolized by CYP3A4 may raise statin levels and increase the risk of myopathy and/or rhabdomyolysis,¹⁷ and the potential for such interactions should be considered in drug selection (Table 3).

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Table 3. Drug Interactions with Statins

All statins are listed as pregnancy category X, and it is recommended that women not breast-feed while using them.^13,18-23 Women should discontinue statins prior to conception if pregnancy is planned, or as soon as pregnancy is confirmed. Nonetheless, the limited human data available do not indicate that statins are significant human teratogens.²⁴ This information can be used to reassure women who inadvertently become pregnant while taking statins.²⁴

Although the cholesterol-lowering properties of statins are well known, other beneficial effects have also been reported. Statins may help to prevent osteoporosis; small studies of bone mineral density have shown higher values in the hip and spine in patients taking statins.²⁵ To date, the evidence has been conflicting about whether such effects vary among specific statins.²⁵ The risk of fracture in patients taking statins has also been investigated, but these results are likewise conflicting. Much of this information has come from secondary analysis of the major lipid-lowering trials (ie, the Long-Term Intervention with Pravastatin in Ischaemic Disease, Scandinavian Simvastatin Survival Study) or tertiary outcomes from the Heart Protection Study.²⁵ Simvastatin and pravastatin have not been shown to reduce the fracture rate.²⁵

Another area of investigation is the use of statins to prevent and treat dementia. Because of the known beneficial effects of statins on reducing the incidence of stroke, it was postulated that they could decrease dementia due to macrovascular causes such as stroke.²⁵ However, the evidence to date does not support using statins in patients with Alzheimer disease, either early or advanced, solely for the purpose of treating the dementia.²⁵

Although statins share many similar characteristics as a class, they are not therapeutically equivalent. Therefore, it is important to consider all characteristics of a specific statin, as well as the NCEP-ATP III goals, when choosing a drug for a given patient (Table 4).¹²

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Table 4. Comparison of Statin Therapy

Niacin

Niacin, or nicotinic acid, is used to treat dyslipidemia. Nicotinic acid should not be confused with nicotinamide, which has the vitamin properties of niacin but cannot affect lipid levels.^4,11 Nicotinic acid has an impact on the entire lipid profile. At a dosage of 2 g/d, nicotinic acid will increase HDL levels by 30% to 40%.^11,26 At higher doses (2 to 3 g/d), patients will experience a decrease in their total cholesterol, LDL, and TG levels.^4,11 Nicotinic acid reduces lipid levels by inhibiting the mobilization of free fatty acids from tissues in the periphery, which in turn decreases synthesis of lipoproteins and very-low–density lipoproteins in the liver.^4,14

The most troublesome side effect associated with niacin formulations is flushing of the skin, which becomes intolerable in up to 10% of patients and often leads to discontinuation. Flushing may be diminished or eliminated by taking niacin with food, taking one aspirin tablet 30 minutes beforehand, and/or avoiding niacin use in conjunction with hot liquids or alcohol. ^14,26,27 Niaspan, a once-daily, extended-release niacin formulation, has been demonstrated to cause four times less flushing compared with equivalent doses of immediate-release niacin, and was only half as likely to cause flushing initially.²⁶

Other adverse effects that may be associated with niacin include gastrointestinal distress, plus potentially major adverse effects such as hepatotoxicity, hyperuricemia, and hyperglycemia, all of which are more likely to occur at doses greater than 2 g/d.^4,14,26 The incidence of hepatotoxicity is greatest with sustained-release preparations, except for Nisapan.²⁶ Because of this risk, niacin formulations should be used with caution in patients with a history of alcohol abuse or liver disease; those with active liver disease should not use niacin.^14,26 The recommendations for monitoring AST and ALT are at baseline, and then every 6 to 12 weeks for the first year of therapy with Niaspan.²⁸ Recommendations for monitoring with other niacin formulations are less specific, but periodic AST/ALT testing should still be considered. Although rare, rhabdomyolysis has been reported with concomitant administration of nicotinic acid and statins. Clinicians should monitor these patients closely for signs and symptoms of myalgias, especially when the dose of either agent is increased.²⁷ The incidence of hyperglycemia has not been shown to differ dramatically between immediate-release niacin and Niaspan, with an increase in blood glucose readings of approximately 5 mg/dL.²⁶ Uric acid levels may rise by as much as threefold in patients using immediate-release niacin.²⁶ Because of the potential for nicotinic acid to slightly increase serum glucose and uric acid levels, patients under treatment for diabetes or hyperuricemia should be monitored closely.²⁶ Nicotinic acid is listed as pregnancy category C.²⁸

Niaspan has been shown to be as effective as immediate-release niacin in lowering lipid levels, but immediate-release niacin can be obtained over the counter.²⁶ Niaspan has been shown to have fewer adverse effects than other formulations, and may be administered once daily at bedtime.^26,28

Bile-acid Sequestrants

Bile-acid sequestrants (BASs), also known as resins, are one of the oldest classes of agents used to reduce lipids. Two of the agents—cholestyramine and colestipol—have been available for several years, while the newly added colesevelam has been available in the United States since 2000.^11,29 These drugs work by binding to bile acids in the intestine, which are then excreted in the stool. This interruption in the enterohepatic circulation of bile acids increases bile acid production by utilizing hepatic stores of LDL cholesterol receptors, leading to increased LDL clearance and an overall reduction in total cholesterol levels.^11,29

As BASs are not absorbed systemically, they are among the safer LDL-lowering agents. However, patients often cannot tolerate the gastrointestinal side effects that can occur at maximum doses.¹¹ The BASs lower LDL cholesterol by a maximum of 20%, with the full therapeutic effect reached at 1 month.³⁰ Levels of HDL cholesterol may increase by approximately 5%.²⁹ However, BAS therapy may increase TG values by 10% to 14%, and are therefore not suitable for monotherapy in patients with elevated TG levels.²⁹ One major difference between colesevelam and the older BAS agents is the dose-response effect on LDL lowering, with a 15% decrease in LDL at colesevelam 3.8 g and an 18% decrease at colesevelam 4.5 g.³⁰ By contrast, the drop in LDL does not rise with an increase in dose for cholestyramine and colestipol, but there is an increase in gastrointestinal side effects that can affect compliance.²⁹ The incidence of gastrointestinal side effects is equal to or only slightly greater than placebo for colesevelam.^29,30

Drug interactions are numerous because BASs bind to other drugs. They also interfere with the intestinal absorption of vitamins and minerals (eg, vitamins A, D, E, and K, folic acid, magnesium, iron). Therefore, other medications should be administered 1 hour before or 4 hours after a BAS.^29-32 All BASs have been approved for use in combination with statins, but the statins must be administered according to the recommendations above for full effect.^29-32 Cholestyramine and colesevelam are both listed as pregnancy category B, while colestipol is listed as pregnancy category C.^30-32

The NCEP-ATP-III recommends BASs as the safest agents to use in young women and those who may become pregnant.⁴ Use of the traditional BASs has been limited because of their relatively complex dosing regimens and unpalatability.²⁹ However, the introduction of colesevelam, which may be administered once daily, provides another nonsystemic option to lower LDL.^29-32

Fibrates

Fibric acid derivates, also known as fibrates, are an option for drastically lowering TGs (20% to 45%), modestly decreasing LDL (10% or less), and dramatically raising HDL (7% to 15%). Their mechanism of action is complex, and remains unclear.^4,11 The fibrates on the US market include fenofibrate and gemfibrozil; clofibrate is no longer available in this country due to its potential to cause cholelithiasis, pancreatitis, and malignancy.³³ All fibrates are absorbed more efficiently when taken with food.³⁴ The dosage of fenofibrate must be adjusted in patients with severe renal impairment and gemfibrozil is contraindicated in these patients; neither agent should be used in patients with hepatic dysfunction.^35,36 Both fibrates are listed as pregnancy category C.^35,36 The most common adverse effects involve gastrointestinal disturbance, and the most severe adverse effect is myopathy, the risk of which is increased when fibrates are used in combination with statins.^4,34 Because fibrates are highly protein-bound, they may displace other drugs that are also highly protein-bound. Therefore, patients taking warfarin and oral hypoglycemic agents should be monitored carefully.³⁴ Furthermore, as the fibrates are metabolized by CYP3A4, administration of fibrates with agents that inhibit CYP3A4 (eg, erythromycin, ketoconazole, itraconazole) could cause significant interactions.³⁴

Cholesterol Absorption Inhibitors

The newest addition to the lipid-lowering armamentarium is ezetimibe. This drug reduces cholesterol through potent, selective inhibition of cholesterol absorption in the small intestine, increasing synthesis of LDL receptors and decreasing LDL levels.^37,38 Ezetimibe is approved for both monotherapy and combination therapy with statins. It can be administered with or without food at 10 mg/d, and can be taken at the same time as a statin. However, ezetimibe should be taken either 2 hours before or 4 hours after administration of a BAS.³⁷ Ezetimibe appears to be safe in patients regardless of age, sex, or organ function. The manufacturer makes no recommendations to adjust for renal or hepatic impairment, but it seems prudent to exercise caution in using ezetimibe in a patient with moderate or severe liver impairment because of unknown long-term safety.^37,38 To date, no drug interactions have been documented.³⁷ Side effects are limited to gastrointestinal and musculoskeletal disorders at an incidence only slightly greater than that seen with placebo.³⁷ Ezetimibe has demonstrated the ability to lower LDL by 18% with monotherapy, as well as slightly decreasing TGs (8%) and minimally increasing HDL (1%).³⁷ It is listed as pregnancy category C, and should only be used in nursing mothers if the benefit justifies the risk to the infant.³⁷

Combination Therapy

Because of the aggressive goals outlined in the NCEP-ATP III and the prevalence of patients with mixed dyslipidemias, many patients will not achieve their lipid goals with one lipid-lowering agent. For these patients, combination therapy is an appropriate option. Advicor is a formulation that combines extended-release niacin and lovastatin in dosages of 500 mg/20 mg, 750 mg/20 mg, and 1,000 mg/20 mg respectively; dosages of more than 2,000 mg/40 mg per day are not recommended.³⁹ The decrease in LDL varies from 30% with 1,000 mg/20 mg to 42% with 2,000 mg/40 mg, while decreases in TGs range from 32% to 44% and the increase in HDL varies from 20% to 30%.³⁹ Advicor demonstrates the principle that the lipid-lowering effects or increases in HDL from using two agents in combination may exceed the additive effects of the two agents alone.

Other combinations of lipid-lowering drugs may also be appropriate. Important principles to remember when using agents in combination are to choose agents with different lipid-lowering mechanisms; to consider drug interactions and separation of dosing, especially with BASs; to monitor appropriate laboratory values; and to assess patients for adverse effects that may be more likely to occur with combination therapy (Table 5).^4,40

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Table 5. Dosing Guidelines for Lipid-lowering Therapy

Hormone Therapy

Although estrogen therapy may favorably affect lipid levels by decreasing LDL and increasing HDL, the Heart and Estrogen/progestin Replacement Study (HERS) demonstrated that hormone therapy (HT) is not effective for secondary prevention of CHD in women.⁴ In HERS, progestin, which may attenuate the HDL-increasing effects of estrogen, was administered together with estrogen. It also demonstrated that patients on estrogen/progestin HT had an increased incidence of both nonfatal MI and CHD death, especially during the first year of therapy. However, women on estrogen/progestin HT may experience cardiovascular benefits later in therapy.⁴ At present, HT should not be prescribed solely to lower LDL in postmenopausal women. Women may use HT for other benefits, including relief of menopausal symptoms and osteoporosis prevention, while at the same time implementing other measures to reduce CHD risk.⁴

RECOMMENDATIONS

All patients should be encouraged to follow TLC as outlined in Table 1, whether alone or in conjunction with drug therapy. While the goals of therapy depend on risk factors, reduction of LDL cholesterol is still the primary goal. Statins are the first-line therapy for lowering LDL by 18% to 55%. The choice of statin depends on the patient’s baseline LDL level and on the other medications she is taking (Table 3). Other options for decreasing LDL cholesterol are listed in Table 6. In some patients, it may be necessary to use combination therapy to achieve the desired LDL level.

Once the patient’s LDL target is achieved, it is important to focus on the other parameters of the lipid panel (Table 6). In patients who need dramatic TG reductions (20% to 50%), nicotinic acid or a fibric acid is recommended. In patients who need an increase in HDL, the drug of choice is nicotinic acid, which can raise HDL by 15% to 35%. Patients should be followed for efficacy with periodic lipid panels, as well as monitored for safety.

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Table 6. Choices for Lipid Therapy4

CONCLUSION

Despite the documented benefits of cholesterol management in women, many women do not achieve their treatment goals. In the Lipid Treatment Assessment Project, only 39% of women achieved their target LDL cholesterol level.⁴¹ The HERS study of postmenopausal women with established heart disease demonstrated that only 47% of participants were taking a lipid-lowering medication, and that LDL cholesterol levels were over 100 mg/dL in 91%.⁴²

Clear guidelines have been provided for lipid goals in all patients by ATP III, including female patients. Adopting the NCEP III guidelines will increase the number of patients who qualify for drug therapy. Based on a subsample of participants from the Third Annual National Health and Nutrition Survey, Fedder et al⁴³ have estimated that approximately 16 million women are eligible for primary preventive drug therapy—a 122% increase from the NCEP II recommendations. Of those women who are eligible for treatment, 24% can be targeted for aggressive LDL lowering (to less than 100 mg/dL).⁴³

Although most of the large primary and secondary prevention studies have included relatively small numbers of women, there is substantial evidence to support the beneficial effects of LDL cholesterol reduction on their CHD morbidity and mortality. These trials have demonstrated that statins can reduce cardiovascular risk by 11% to 46%.^44-48 A meta-analysis of four major statin trials showed that the relative risk reduction for major coronary events was similar in women and men (29% and 31%, respectively).⁴⁹ The absolute risk reduction (33 per 1,000 for women, 37 per 1,000 for men) and the number of patients necessary to treat a major coronary event (number needed to treat [NNT] = 31 for women, NNT = 27 for men) were also similar in men and women.⁴⁹

The increased inclusion and analysis of women in clinical trials for the effects of various lipid-lowering therapies will continue to generate specific, evidence-based recommendations for women with lipid abnormalities. In the meantime, it is important to consider the patient as a whole and choose an appropriate medication based on the individual lipid profile, reproductive status, medical status, and medication profile.

Kristi W. Kelley, PharmD, BCPS, is assistant clinical professor at Auburn University, Harrison School of Pharmacy, and clinical pharmacist at Carraway Medical Foundation, Birmingham, Ala; Amy R. Donaldson, PharmD, BCPS, is assistant clinical professor at Auburn University Harrison School of Pharmacy, and clinical assistant professor at the University of Alabama Birmingham Department of Family Medicine, Huntsville Regional Campus, Huntsville, Ala.

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Disclosures

Drs Kelley and Donaldson have not received financial support from the manufacturers of any of the products listed in the context of this article.

Acknowledgements

The authors wish to acknowledge Katherine C. Herndon, PharmD, BCPS, for her assistance.

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