Raloxifene and Lipids

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Estrogen increases HDL cholesterol levels and decreases LDL cholesterol levels in humans39,171 as well in animal models of atherosclerosis, partly because of estrogen receptor-mediated upregulation of the hepatic LDL receptor.172 In ovariectomized rats, raloxifene treatment has been shown to reduce serum total cholesterol concentrations,97,173 and this reduction correlates with the extent of raloxifene binding to the estrogen receptor.97,173 These results are not surprising for a 'nonsteroidal antiestrogen,' as the original observations for clomiphene analogs and tamoxifen show (see 8.08 Tamoxifen). Raloxifene may also have cardioprotective effects because of its antioxidant properties. This is important since oxidative modifications of LDL have been implicated in atherogenesisis.174 Raloxifene also appears to have a favorable effect on lipid parameters in postmenopausal women. In the published European trial,78 treatment with raloxifene in a dosage of 30, 60, or 150 mg day_ 1 resulted in significant decreases in the serum concentrations of total and LDL cholesterol over a 24-month period (P < 0.05 versus placebo). These decreases were evident during the first 3 months of therapy and were maintained thereafter. Notably, none of the treatment groups showed any changes in serum concentrations of HDL cholesterol and triglycerides. The effect of raloxifene on serum lipid levels was also assessed in 390 healthy postmenopausal women.175 In this study, raloxifene (60 and 120 mg day_ 1) was compared with HRT (0.625 mg day-1 of conjugated estrogen and 2.5 mg day_ 1 of medroxyprogesterone given continuously) and placebo. Assessments were made at baseline, 3 months, and 6 months. Over the 6-month study period, both dosages of raloxifene lowered serum LDL cholesterol levels by about 12% compared with placebo (P < 0.001). This finding was similar to the 14% reduction that occurred with continuous HRT.78 The effect of raloxifene on cardiovascular events was also examined in osteoporotic postmenopausal women from the MORE trial. In the study design, patients were randomly assigned to receive raloxifene 60mgday_ 1 (n = 2557), or 120 mg day_ 1 (n = 2572), or placebo (n = 2576) for 4 years. Barrett-Connor and coworkers176 reported that raloxifene therapy for 4 years did not significantly affect the risk of cardiovascular events in the overall cohort but did significantly reduce the risk of cardiovascular events in the subset of women with increased cardiovascular risk. In addition, there was no evidence that raloxifene caused an early increase in risk of cardiovascular events.

To address the question of whether raloxifene reduces the risk of CHD, a total of 10 101 women (at increased risk of CHD) have been recruited to receive placebo or raloxifene in the RUTH trial, with cardiovascular disease as a primary endpoint.177 The RUTH trial (Figure 9) is designed to determine whether raloxifene (60mgday 1), compared with placebo, reduces the risk of coronary events and invasive breast cancer in postmenopausal women at risk for a major coronary event.

Figure 9 Study design of the Raloxifene for Use in The Heart (RUTH) trial. The RUTH trial is a double-blind, placebo-controlled, randomized clinical trial designed to evaluate whether 60 mg day-1 of oral raloxifene compared with placebo reduces the risk of coronary events. Between June 1998 and August 2000,11 767 women signed an informed consent agreement to participate in RUTH at 187 sites in 26 countries. After excluding 1411 women who did not meet inclusion criteria and 255 women who met more than one exclusion criteria, a total of 10101 women were randomized to raloxifene 60mgday-1 or placebo. Of these, 5070 were at increased risk for CHD events and 5031 had documented CHD. Women were eligible for randomization if they were aged 55 years or older, at least 1 year postmenopausal, and had documented CHD, peripheral artery disease, or multiple risk factors for CHD. Breast cancer incidence will be determined by mammograms performed 2, 4, and 6 years after the qualifying mammogram. The study is planned to end after the pre-specified number of participants experience their first acute coronary event. The total duration of treatment is projected to range from 5 to 7.25 years.

Figure 9 Study design of the Raloxifene for Use in The Heart (RUTH) trial. The RUTH trial is a double-blind, placebo-controlled, randomized clinical trial designed to evaluate whether 60 mg day-1 of oral raloxifene compared with placebo reduces the risk of coronary events. Between June 1998 and August 2000,11 767 women signed an informed consent agreement to participate in RUTH at 187 sites in 26 countries. After excluding 1411 women who did not meet inclusion criteria and 255 women who met more than one exclusion criteria, a total of 10101 women were randomized to raloxifene 60mgday-1 or placebo. Of these, 5070 were at increased risk for CHD events and 5031 had documented CHD. Women were eligible for randomization if they were aged 55 years or older, at least 1 year postmenopausal, and had documented CHD, peripheral artery disease, or multiple risk factors for CHD. Breast cancer incidence will be determined by mammograms performed 2, 4, and 6 years after the qualifying mammogram. The study is planned to end after the pre-specified number of participants experience their first acute coronary event. The total duration of treatment is projected to range from 5 to 7.25 years.

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