Postmenopausal Hormone Replacement, Simvastatin, and Hyperlipidemia


Synopsis: Simvastatin lowers serum LDL more than does postmenopausal hormone replacement therapy, but both treatments appear effective in raising HDL levels.

Source: Darling GM, et al. N Engl J Med 1997;337: 595-601.

In this crossover trial, darling and colleagues randomized 58 postmenopausal women with fasting total serum cholesterols greater than 250 to two treatment phases: 1) an eight-week course of 10 mg daily simvastatin and 2) another eight-week course of up to 1.25 mg daily conjugated equine estrogens with 5 mg daily medroxyprogesterone acetate. All participants had an eight-week washout period between these two treatments.

The simvastatin and the hormone replacement therapy were equally effective in raising serum HDL cholesterol, which increased an average of 7% in each treatment group. Simvastatin lowered LDL cholesterol an average of 36%, while the hormonal therapy lowered it 24%—a significant difference. Simvastatin also lowered total serum cholesterol significantly more (26% vs 14% with hormone replacement therapy). The only potentially unfavorable lipid change was with triglycerides, which hormone replacement increased by 29%. Simvastatin decreased triglycerides by 14%. In a subgroup analysis, the lipid profiles of those participants at particular risk for coronary artery disease, after treatment, were similar to those of the general study population.


More women in the United States die from coronary artery disease than from any other condition. Despite epidemiologic data suggesting that postmenopausal estrogen replacement therapy cuts this mortality risk approximately in half, hormone replacement remains a controversial topic about which many American women are still uneducated.

Postmenopausal estrogen/progestin replacement has already been shown to raise HDL levels while lowering LDL levels. Darling et al are the first, however, to stack hormone replacement therapy against an HMG-CoA reductase inhibitor in a direct comparison of lipid-lowering effects. As Darling et al suggest, the benefits of hormone replacement therapy were clearly reinforced, especially because raising HDL may prove to be more important than lowering LDL in the prevention of coronary artery disease.

Does it really matter that hormone replacement therapy raises triglycerides? Elevated trigylcerides have been implicated as an independent risk factor for coronary artery disease in women, but the investigators correctly assert that estrogen-induced hypertriglyceridemia may be different. This issue will need to be clarified in future research.

The real answers to all of these questions await the results of the first randomized controlled trials on hormone replacement therapy and coronary artery disease, such as the ongoing Women’s Health Initiative, which will determine whether hormone replacement decreases coronary artery disease mortality. Serum lipid levels are at best a limited surrogate for these data. In the meantime, this study furthers our understanding of the complex relationships between hormone replacement and hyperlipidemia. This article provides more support for discussing hormone replacement with our postmenopausal patients. It joins an increasing body of evidence that this therapy prevents heart disease, osteoporosis, urogenital atrophy, and perhaps even dementia and tooth loss. An important question for future research will be whether hormone replacement in combination with a conventional lipid-lowering agent more effectively improves hyperlipidemia than does either therapy alone.