Effects of Raloxifene on Serum Lipids and Coagulation Factors in Healthy Postmenopausal Women

Abstract

Context.-Raloxifene is a selective estrogen receptor modulator that has estrogen-agonistic effects on bone and estrogen-antagonistic effects on breast and uterus. Objective.-To identify the effects of raloxifene on markers of cardiovascular risk in postmenopausal women, and to compare them with those induced by hormone replacement therapy (HRT). Design.-Double-blind, randomized, parallel trial. Setting.-Eight sites in the United States. Participants.-390 healthy postmenopausal women recruited by advertisement. Intervention.-Participants were randomized to receive 1 of 4 treatments: raloxifene, 60 mg/d; raloxifene, 120 mg/d; HRT (conjugated equine estrogen, 0.625 mg/d, and medroxyprogesterone acetate, 2.5 mg/d); or placebo. Main Outcome Measures.-Change and percent change from baseline of lipid levels and coagulation parameters after 3 months and 6 months of treatment. Results.-At the last visit completed, compared with placebo, both dosages of raloxifene significantly lowered low-density lipoprotein cholesterol (LDL-C) by 12% (P Ͻ .001), similar to the 14% reduction with HRT (P Ͻ .001). Both dosages of raloxifene significantly lowered lipoprotein(a) by 7% to 8% (P Ͻ .001), less than the 19% decrease with HRT (P Ͻ .001). Raloxifene increased high-density lipoprotein-2 cholesterol (HDL 2-C) by 15% to 17% (P Ͻ .05), less than the 33% increase with HRT (P Ͻ .001). Raloxifene did not significantly change high-density lipoprotein cholesterol (HDL-C), triglycerides, or plasminogen activator inhibitor-1 (PAI-1); whereas HRT increased HDL-C by 11% and triglycerides by 20%, and decreased PAI-1 by 29% (for all, P Ͻ .001). Raloxifene significantly lowered fibrinogen by 12% to 14% (P Ͻ .001), unlike HRT, which had no effect. Neither treatment changed fibrinopeptide A or prothrombin fragment 1 and 2. Conclusions.-Raloxifene favorably alters biochemical markers of cardiovascular risk by decreasing LDL-C, fibrinogen, and lipoprotein(a), and by increasing HDL 2-C without raising triglycerides. In contrast to HRT, raloxifene had no effect on HDL-C and PAI-1, and a lesser effect on HDL 2-C and lipoprotein(a). Further clinical trials are necessary to determine whether these favorable biochemical effects are associated with protection against cardiovascular disease.

Relation Between Soluble Intercellular Adhesion Molecule-1, Homocysteine, and Fibrinogen Levels and Race/Ethnicity in Women Without Cardiovascular Disease

“…HRT resulted in statistically significant decreases in homocysteine and fibrinogen levels among participants, a finding that is consistent with most published reports related to oral HRT use (19)(20)(21). Of note, transdermal HRT does not appear to significantly affect fibrinogen levels (19,22), whereas raloxifene seems to lower fibrinogen levels (20,23). Finally, a majority of reports regarding the effect of HRT on homocysteine concentrations indicate that both oral HRT and raloxifene decrease homocysteine levels (24)(25).…”

Two Decades of Cardiovascular Trials With Primary Surrogate Endpoints: 1990–2011

“…Among these 59 surrogate endpoint trials that had a subsequent clinical endpoint trial, in 24 cases the clinical endpoint trial results validated the positive surrogate trials, while in 20 the subsequent clinical endpoint trial was negative (Table 3). 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 A negative surrogate endpoint trial was less likely to be followed by a positive outcome trial and we identified only 3 such examples ( P =0.02, Figure 2). …”

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

“…Raloxifene also causes decreases in circulating low density lipoprotein cholesterol [134] and for this reason was evaluated as a preventive for coronary heart disease in the study named raloxifene use for the heart (RUTH) ( * see footnote). Although raloxifene prevents an increase in breast cancer incidence in the RUTH trial, there is no benefit in protecting against coronary heart disease and myocardial infarction [135].…”

“…The results from the study of tamoxifen and raloxifene (STAR) ( * see footnote) in high risk postmenopausal women show that tamoxifen and raloxifene are equivalent in reducing the incidence of breast cancer but there is a decrease in the incidence of endometrial cancer, pulmonary emboli, deep vein thrombosis and endometrial hyperplasia noted with raloxifene. Raloxifene and tamoxifen, as would be expected for two SERMs, both have equivalent activity in preventing fractures [133].Raloxifene also causes decreases in circulating low density lipoprotein cholesterol [134] and for this reason was evaluated as a preventive for coronary heart disease in the study named raloxifene use for the heart (RUTH) ( * see footnote). Although raloxifene prevents an increase in breast cancer incidence in the RUTH trial, there is no benefit in protecting against coronary heart disease and myocardial infarction [135].…”