One in four women in the United States dies of heart disease while one in thirty dies of breast cancer. Even with aggressive invasive treatment for acute myocardial infarction women are twice as likely to die after heart attack vs. men. Improving preventative strategies is critical in regards to reducing the mortality rate in women.

But over 40 percent of patients with coronary disease have LDL cholesterol levels below this value, and most of these patients also have low levels of high-density lipoprotein (HDL) cholesterol, with or without increased levels of triglycerides. Overall, low levels of HDL cholesterol without high levels of LDL cholesterol characterize 20 to 30 percent of patients with coronary disease, representing several million people in the United States. It has been estimated that up to 40% of women have HDL cholesterol level less then 50mg per deciliter.  A recent analysis Treating to New Targets (TNT) study assessed the predictive value of  low HDL cholesterol levels in 9770 patients with LDL cholesterol levels below 70 mg per deciliter on Liptor. The HDL cholesterol level < 38mg per deciliter in patients receiving statins had 5yr CVD rate > 10% vs. patients with HDL > 55mg per deciliter had 5yr CVD rate < 6%.

Analysis of prospective cohort data from 15,632 healthy women (age, 45) in the Women's Health Study, researchers assessed the value of several markers.  After adjustment for age, smoking status, blood pressure, diabetes, and body-mass index, the hazard ratios for a first cardiovascular event were as follows: LDL cholesterol level, 1.62; apolipoprotein A-I level, 1.75; total cholesterol level, 2.08; HDL cholesterol level, 2.32; apolipoprotein B₁₀₀ level, 2.50; non-HDL cholesterol level, 2.51; C-reactive protein level, 2.98. Therefore low HDL is the strongest predictor of cardiovascular disease (CVD) in women, independent of LDL cholesterol. The advantage that women have over men in CVD risk prior to menopause seems to be at least partly due to their higher levels of HDL cholesterol: The average HDL level in women is 56 mg/dL, versus 46 mg/dL in men. This advantage begins to disappear after menopause, presumably because of changes in hormone levels and decreasing HDL-2 cholesterol, the most cardioprotective HDL fraction. In addition to the increased CVD risk associated with menopause, women of all ages in the United States have an increasing tendency—at almost epidemic rates—toward obesity and metabolic syndrome, which are known CVD risk factors. The dyslipidemia seen with those conditions is characterized by low HDL cholesterol and high triglycerides. Thus, maintaining healthy HDL levels is clearly an important goal for overall cardiovascular health, especially in women. In addition, HDL is the key lipoprotein associated with reverse cholesterol transport, the process of carrying excess cholesterol from peripheral tissues to the liver for catabolism.

Overall the current treatments focused on increasing HDL are limited to the following:

1.     Exercise level was inversely associated with cardiovascular risk in the Women’s Health Initiative, which followed a cohort of 73,743 women prospectively for an average of 3.2 years. Women at the highest quintile of exercise increase in HDL cholesterol as high as 15% and reduced their CVD risk by 53% over the lowest quintile. 

2.     Hormone replacement therapy (HRT) is no longer recommended to prevent CVD and should be given only for menopausal symptoms. Estrogen has been shown to raise HDL cholesterol by 8% in postmenopausal women but long term use in this population had increased CVD events thought to be related to the increased thrombic events induced by estrogen.

3.     Statins are a first choice for LDL reduction, but lead to only modest increases (4%–10%) in HDL levels.  

4.     Niacin in the Coronary Drug Project significantly reduced the risk of recurrent myocardial infarction in men. The Stockholm Ischemic Heart Study and HDL-Atherosclerosis Treatment Study, which studied combination therapy with niacin/simvastatin therapy, respectively, did include women. Women comprised 13% of the subjects in the HDL-Atherosclerosis Treatment Study. This study revealed a 60% to 90% reduction in the risk of coronary events and a decrease in angiographic progression with niacin/simvastatin. In a small study of lovastatin and niacin, LDL-C levels were reduced by 54.6% in women versus 38.2% in men. The long-term safety and effectiveness of this formulation has been studied in 814 patients with dyslipidemia, including 296 women. At escalating doses of ER niacin/lovastatin, from 500/10 mg to 2000/40 mg, dose-dependent effects were observed for all major lipid parameters. By week 16, LDL-C was lowered by 47%, triglycerides by 41%, and HDL-C was increased 30%. The combination of a statin with niacin is generally well tolerated. In the long-term study described above, 10% of patients withdrew because of flushing, and there were no cases of drug-induced myopathy.

5.     Fibrate therapies have been documented mainly in men. In the Helsinki Heart Study, gemfibrozil reduced the incidence of CHD events by 34%. In the Veterans Affairs High-density lipoprotein Intervention Trial, gemfibrozil reduced the risk of coronary death or nonfatal myocardial infarction by 22% in men with CHD, low HDL, and normal LDL. Fibrates are used in combination with statins, particularly in patients with renal impairment. In 871 reports of statin-associated rhabdomyolysis, concomitant use of fibrates was listed in 80 cases (9.2%) Fenofibrate may carry a lower safety risk than gemfibrozil in combination therapy with a statin.

Currently data would suggest given nearly two-thirds of patients with CVD that were prescribed a statin had an HDL cholesterol below goal level of 50 women and 40 for men. But current only 15% of these patients were prescribed a non-statin HDL cholesterol– raising medications. Based on published studies, normalizing low HDL cholesterol in this cohort would correspond to an estimated CVD mortality reduction of 42% in women and 23% in men.

 Overall, HDL is the strongest predictor of cardiovascular disease (CVD) in women, independent of LDL cholesterol. And with increased recognition and treatment of low HDL levels in women with intermediate cardiac risk and with low CVD we could have dramatically improved cardiac outcomes in our mothers and daughters.