Statin Use in Women

Feature |
August 17, 2015

Statin Use in Women

  1. Chrisandra L. Shufelt, MD, MS and
  2. JoAnn E. Manson, MD, DrPH

Benefits and risks of statin therapy for primary prevention remain less well defined in women than in men.

  1. Chrisandra L. Shufelt, MD, MS and
  2. JoAnn E. Manson, MD, DrPH

Cardiovascular disease (CVD) remains the leading cause of death in U.S. women; moreover, since 1983, more women than men have died of CVD annually.1 In secondary prevention settings, statins reduce risk for recurrent CVD events and CVD mortality, with benefits of comparable magnitude in men and women.2 Although primary prevention studies have shown that statin therapy lowers the incidence of cardiovascular events by about 20%, the study populations predominantly included men; hence, questions remain about the efficacy and safety of statins for preventing CVD in women.

Primary Prevention

CVD primary prevention trials have been grossly underpowered with respect to enrollment of women, limiting the ability to stratify results by sex. This lack of adequate data has often been interpreted as a lack of statin efficacy for primary prevention in women. Recently, however, a large meta-analysis of 22 statin therapy trials with >174,000 participants (27% women) demonstrated that statin therapy has similar effectiveness for preventing both primary and secondary major CVD events and CVD-related mortality in women and men.3 The results showed that, for every reduction of low-density lipoprotein cholesterol (LDL-C) by 1 mmol/L (18 mg/dL), CVD events in women were reduced by 15% in primary prevention.3 Furthermore, among women with 5-year risk <10%, statin therapy lowered risk by 26% (i.e., 9 major CVD events were prevented per 1 mmol/L reduction of cholesterol per 1000 treated throughout 5 years).3

The Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER), a primary prevention trial, enrolled 17,802 study participants, 38% of whom were women. This study tested the effect of statin therapy in individuals with low levels of LDL cholesterol (<130 mg/dL) but elevated (≥2 mg/dL) high-sensitivity C-reactive protein (hsCRP). Statin therapy prevented some CVD events in women (hazard ratio, 0.54); the 5-year number needed to treat to prevent a major CVD event was 31 for women versus 17 for men, reflecting lower baseline risk.4

Secondary Prevention

Women clearly benefit from statin therapy for secondary prevention. After acute coronary syndrome, women randomized to high-dose statin therapy (80 mg atorvastatin daily) versus standard therapy (20 mg pravastatin daily) experienced a 25% reduction in CVD events and mortality.5 Two separate meta-analyses have also reported similar findings. The first included 11,000 women from 11 secondary prevention trials and found that statin therapy reduces CVD risk by 19%; the other included >40,000 women from 18 trials and found clear benefit for both CVD (odds ratio, 0.78) and stroke (OR, 0.74).2,6

Safety

The safety concerns regarding statins are particularly important in women. The most common side effect is myalgia, which has been reported in up to 20% of women and is a major cause of intolerance and discontinuation.7 Statins may be teratogenic and should be avoided in women who are pregnant, breast-feeding, or planning to become pregnant. The FDA recognizes that, while liver injury is a rare side effect of statin therapy, routine monitoring of liver enzymes is not effective for detecting or preventing such injury. Liver enzymes should be checked before statin therapy is initiated or if symptoms of liver damage emerge (e.g., right upper abdominal discomfort, dark urine, yellowing of skin). Statins have been associated with a 12% increased risk for developing elevated blood sugar or diabetes, yet the cardiac benefits outweigh potential risks in populations with high baseline CVD risk.8 Finally, no clear association between statins and cognitive decline has been established, although the FDA has reported rare cases of nonsevere cognitive impairment.

Guidelines and CVD Risk Assessment

Prior American College of Cardiology/American Heart Association (ACC/AHA) guidelines focused on treating to a targeted LDL-C; however, randomized, controlled trials (RCTs) had not indicated what the LDL-C target should be, so this approach was not evidence-based. In 2013, the ACC/AHA released updated guidelines based on RCTs of statin therapy for management of blood cholesterol. These guidelines, the first to encompass identification of candidates using a CVD risk calculator that takes sex into account, recommend statin therapy for four specific patient populations9:

  1. Those with established CVD

  2. Those with LDL-C ≥190 mg/dL

  3. Those aged 40 to 75 with type 1 or type 2 diabetes mellitus and LDL-C 70 mg/dL to 189 mg/dL

  4. Those aged 40 to 75 with LDL-C 70 mg/dL to 189 mg/dL and 10-year risk for CVD ≥7.5% (based on the new risk calculator)

The fourth patient group reflects a specific recommendation for using the global risk calculator to guide discussions about statin therapy in the primary prevention setting. This risk calculator uses a formula that estimates 10-year and lifetime atherosclerotic cardiovascular disease (ASCVD) risk, defined as risk for first nonfatal myocardial infarction, coronary heart disease death, and nonfatal or fatal stroke.10 The calculation takes into account age, sex, race, smoking, blood pressure, treatment for hypertension, diabetes, and total and HDL cholesterol.

While the guidelines continue to stress that the cornerstone of CVD primary prevention is to first recommend lifestyle changes such as diet, exercise, and weight loss, the purpose of the risk assessment is to more accurately identify higher-risk individuals for primary prevention with statin therapy. For 10-year risk between 5% and 7.5%, additional parameters, such as family history of premature CVD, hsCRP level, coronary artery calcium score, and ankle-brachial index, can be considered.

Conclusion

Although the mortality gap between the sexes in CVD is beginning to close, the narrowing has taken 3 decades and can be attributed partly to sex-specific CVD guidelines.1 The 2013 ACC/AHA guidelines focus on identifying both women and men who are candidates for statin therapy because of elevated risk for CVD, using sex-specific tools for risk assessment. However, until future trials of statins enroll women in substantial numbers, the benefits and risks of statin therapy for primary prevention will remain less well defined in women than in men.

Dr. Shufelt is the Associate Director of the Barbra Streisand Women's Heart Center & Preventive and Rehabilitative Cardiac Center; the Director of the Women's Hormone and Menopause Program at Cedars–Sinai Heart Institute; and an Assistant Professor at Cedars–Sinai Medical Center in Los Angeles, California.

Dr. Manson is a Professor of Medicine, the Michael and Lee Bell Professor of Women's Health, and Chief of the Division of Preventive Medicine at Harvard Medical School and Brigham and Women's Hospital in Boston, Massachusetts.

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