Lipid Luminations: Primary Prevention of Cardiovascular Disease in Women with Statins and Gender-Specific Management of Dyslipidemia

There has been long-standing debate over the efficacy of statins in women for the primary prevention of cardiovascular disease (CVD), largely stemming from the under-enrollment of women in clinical trials.1 Here we summarize the data on use of statins in primary prevention of CVD in women and gender-specific management.

Prevention Trials
A 2004 meta-analysis of all primary prevention trials that included women was unable to demonstrate any beneficial effect of lipid-lowering therapy to reduce all-cause or CVD mortality.2 A meta-analysis by Ray, et al., in those (of both genders, but relatively more women than in prior analyses) without known CVD showed a non-significant reduction in all-cause mortality in women (risk ratio RR=0.91; 95 percent CI 0.83-1.01).3  In a 2010 meta-analysis of primary prevention trials in women, Bukkapatnam, et al., showed a significant reduction in coronary heart disease events (RR 0.78; 95 percent CI 0.64-0.96) and a non-significant reduction in all-cause mortality (RR 0.90; 95 percent CI 0.60-1.35).4

The Justification for the Use of Statins in Prevention:  An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial enrolled the largest number of women in any primary prevention trial. Rosuvastatin reduced CVD events in women (HR 0.54; 95 percent CI 0.37-0.80) and in men (HR 0.58; 95 percent CI 0.45-0.73), but with no significant reduction in mortality (HR 0.77; 95 percent CI 0.55-1.06) in women.5 A meta-analysis of CVD prevention trials of women by the JUPITER investigators found a significant reduction in primary CVD events with statins (RR 0.63; 95 percent CI 0.49-0.82) and a non-significant reduction in total mortality (RR 0.78; 95 percent CI 0.53-1.15).5

In 2012, the Cholesterol Treatment Trialists (CTT) published a meta-analysis of primary and secondary prevention trials in men and women. Even in those who fell into low-risk categories for major vascular events (<5 percent and >5 to 10 percent five-year risk), there was a significant reduction in major vascular events with the use of statins (RR per 1.0 mmol/L reduction of 0.62 [99 percent CI 0.47-0.81], 0.69 [99 percent CI 0.60-0.79]).6 In 2013, the Cochrane Research Group performed a meta-analysis of primary prevention trials of both genders, finding that all-cause mortality was reduced by statins (OR 0.86; 95 percent CI 0.79-0.94), as was combined fatal and non-fatal CVD (OR 0.75; 95 percent CI 0.70-0.81).7

In April 2015, an important meta-analysis was published by the CTT, specifically to address whether statins benefit women. Statin therapy resulted in all-cause mortality reductions for both women (RR 0.91; 99 percent CI 0.84-0.99) and men (RR 0.90; 99 percent CI 0.86-0.95). In those at < 10 percent predicted five-year absolute CVD risk, there was a significant proportional reduction per 1.0 mmol/L reduction in low-density lipoprotein (LDL) cholesterol in major vascular events; this was similar in women (RR 0.84; 99 percent CI 0.78-0.91) and men (RR 0.78; 99 percent CI 0.75-0.81).8

Management of Dyslipidemia in Women
Management of dyslipidemia is detailed in the 2013 American College of Cardiology/American Heart Association (ACC/ AHA) blood cholesterol guidelines and the 2014 National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia, with generally similar management between men and women. However, when considering treating women with dyslipidemia, several factors arise unique to women. Thyroid disorders occur more frequently in women. In addition, women may be on hormone therapy or oral contraception. These factors may impact the lipid panel. In women of child-bearing age, most lipid-lowering medications should be avoided if effective contraception is not in place. However, in women with familial hypercholesterolemia (FH), medications are recommended during child-bearing ages to lower these women’s lifelong risk of CVD. Statins are contra-indicated in pregnancy and in breast-feeding. Only one lipid-lowering medication — a bile acid sequestrant — may be considered in pregnancy and breast-feeding.  As an alternative, lipid- lowering therapy may be held during pregnancy and lactation and resumed afterward, although the cholesterol level will rise off of medications and because of the pregnancy itself.

Conclusions
A reduction in vascular events when statins are the primary prevention in women has been demonstrated in recent meta- analyses. Guidelines recommend similar management of dyslipidemia in men and women. Several sex-specific considerations — related to hypothyroidism, contraception, pregnancy, and lactation — do apply to women.

Disclosure statement: Dr. Sharma has no disclosures to report. Dr. Gulati’s spouse has received salary for employment at Bayer.

References are listed on page 37 of the PDF.