Tibolone and Atherosclerosis
Abstract & Commentary
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: Both tibolone and CEE/MPA showed increased progression of common CIMT. Translation of the increased common CIMT progression of the CEE/MPA group into cardiovascular disease risk could not fully explain the observed increased cardiovascular risk as observed in the WHI study.
Source: Bots ML, et al. The effect of tibolone and continuous combined conjugated equine oestrogens plus medroxyprogesterone acetate on progression of carotid intima-media thickness: the Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) study. Eur Heart J. [Epub ahead of print] January 16, 2006.
The Osteoporosis Prevention and Arterial Effects of tiboLone (OPAL) study was a 3-year, randomized, double-blind trial in 6 US centers and 5 European centers, treating 866 postmenopausal women with either 2.5 mg tiboLone daily, 0.625/2.5 mg daily of conjugated estrogens/medroxyprogesterone acetate, or placebo. The arterial end point of the study was carotid intima-media thickness measured by ultrasonography every 6 months. Overall, 603 women (70%) completed the trial, essentially 200 in each group. The average age of the subjects was 59 with an average of 10 years since menopause. About 47% had previously used hormone therapy. Both the tibolone-treated group and the estrogen/progestin-treated group demonstrated an increase in intima media thickness over the time period of the study, at a rate significantly greater than the placebo group. The authors concluded that both tibolone and estrogen/progestin treatment increased atherosclerosis compared with the placebo group.
It has been recognized for many years that tibolone lowers HDL cholesterol levels by 20-30%. This has raised concern that treatment with tibolone would have an adverse effect on arterial blood vessels. The OPAL study was designed to address this concern, but its results are disappointing for several reasons.
It is not a given that reducing HDL cholesterol will have an adverse impact, because what really counts is whether cholesterol continues to be removed from cells and metabolized (so-called cholesterol efflux). Studies of cholesterol efflux in monkeys and women indicate that efflux is not impaired despite a tibolone-induced reduction in HDL cholesterol.
Measurement of carotid intima-media thickness is an appropriate end point, because progression of thickness is correlated with risk of vascular disease. The problem therefore lies elsewhere. Why did treatment with estrogen/progestin increase intima-media thickness despite lowering HDL cholesterol, contrary to previous reports, most noteworthy being the EPAT study.1 Do the results reflect the fact that the study population was relatively older, an average of 10 years away from menopause? For example, the HERS secondary cardiovascular trial of older women found no beneficial effect of estrogen/progestin treatment.2
The European women differed from the American women in multiple ways: higher lipids, higher blood pressure levels, more smokers. Hysterectomized women were excluded in the United States, but not in Europe (28% of the study population). In an excellent editorial that accompanies this report, Tom Clarkson reviews the experimental results in his monkey model, indicating that tibolone has neither a beneficial nor an adverse effect on atherosclerosis, a finding that is in keeping with maintenance of cholesterol efflux despite lower HDL cholesterol levels. Clarkson further emphasizes the different results in the European women compared with the American women. The overall mean results, indeed, indicate a difference comparing both treatment groups to placebo. But in the European women, atherosclerosis, measured by intima-media thickness, improved in the placebo group, making it easy to calculate a significant difference compared to the treated groups! In American women, there were no differences comparing the 3 treatment groups, all demonstrated progression of thickness. Thus the overall conclusion is inordinately influenced by the results in the European women. The investigators could not explain these differences.
Changes in carotid intima-media thickness were compared to the values at baseline. And all three groups of women demonstrated an increase. But this increase was observed at the very first 6-month measurement. From that point on, there was little change. One could interpret the results in the following fashion: the 3 groups differed from each other in some unknown way before treatment, and treatment produced no major changes. The authors could find no explanation for this rapid change, and subsequent leveling off.
Tibolone treatment of postmenopausal women is as effective as estrogen therapy in relieving hot flushes, preventing bone loss, and increasing vaginal lubrication, but it stimulates libido to a greater degree than estrogen. The final target tissue response to tibolone depends on which of its active metabolites predominates in that tissue. Two of the metabolites are estrogenic and predominate in the circulation. The third metabolite is progestogenic and androgenic, and fortunately predominates in the endometrium. Thus tibolone, soon to be on the market in the United States, is an attractive choice for postmenopausal women and clinicians. The results from ongoing clinical trials will document the efficacy and safety of tibolone, especially for fractures and risk of breast cancer. Unfortunately, the OPAL trial did not achieve its goal of providing robust data on cardiovascular effects, due to the older age of the women and the notably different results in American and European women. There continues to be good reason to believe that tibolone will have a neutral effect on the cardiovascular system.
- Hodis HN, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001:135:939-953.
- Byington RP, et al. Effect of estrogen plus progestin on progression of carotid atherosclerosis in postmenopausal women with heart disease: HERS B-mode substudy. Arterioscler Thromb Vasc Biol. 2002;22:1692-697.