Cardiovascular Effects of Selective Estrogen Receptor Modulators

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Cardiovascular Effects of Selective Estrogen Receptor Modulators
(SERMs)
L. Mosca
Columbia University College of Physicians and Surgeons, New York, New York, U.S.A.
Summary
Selective estrogen receptor modulators (SERMs) share many biological effects on the
cardiovascular system in common with hormone replacement therapy (HRT) that may be
cardioprotective. However, unlike HRT, SERMs do not increase high-density lipoprotein (HDL)
cholesterol or triglycerides, and do not appear to increase C reactive protein (CRP), a
proinflammatory marker. Tibolone lowers HDL levels, but in animal studies has no adverse
cardiovascular consequences. It is not known if differential effects on surrogate endpoints will
translate into different clinical cardiovascular disease (CVD) outcomes in women. In
retrospective analyses, the effect of tamoxifen on cardiovascular outcomes has been mixed, and
raloxifene has been associated with lower cardiovascular events among high-risk women.
Randomized trials in progress will provide more definitive information about the role of HRT in
the primary prevention of CVD and the impact of raloxifene in diverse populations of women
with and without CVD.
Introduction
          Women experience initial manifestations of coronary heart disease 10 years later than
men, suggesting that estrogen may play a cardioprotective role. Clinical outcome studies of
traditional HRT have not supported a beneficial role in women with CVD, and have shown early
adverse effects of HRT. This paradox may be due to differences between endogenous estrogen
and currently available HRT in the net impact on the cardiovascular system. Moreover, progestin
therapy combined with estrogen to prevent endometrial hyperplasia may mitigate some
beneficial effects of estrogen on the cardiovascular system. Estrogen loss associated with natural
menopause is correlated with an increase in inflammatory markers, yet HRT has been shown to
significantly increase levels of CRP, a proinflammatory marker that is related to increased
cardiovascular events in women. These data suggest that although estrogen may have anti-
atherogenic properties, its clinical impact may be dependent on the extent to which the estrogen
receptor is stimulated, and the presence of other hormone and non-hormone factors.
          The role of HRT in the primary prevention of CVD is not resolved because major trials
have been limited to populations of women that are well beyond the menopause or who have
established CVD. HRT may be more effective in preventing early atherosclerosis than it is in
treating later stages of the disease. This theory is supported by the finding that as women age,
they have increased methylation of the promoter region of the estrogen receptor gene, thereby
inhibiting transcription, rendering the older woman potentially less receptive to estrogen’s
stimulatory effects. Moreover, atherosclerotic tissue has been associated with reduced expression
of estrogen receptors compared to healthy tissue, consistent with an overall neutral impact of
HRT in secondary prevention studies. Even if traditional HRT proved to beneficial for the
primary prevention of CVD, the side effects and the fear of breast cancer are limiting factors for
its utility as a chronic prophylactic therapy for many postmenopausal women. Because of this,
more tissue selective agents, such as SERMs may provide an important option for
postmenopausal women who do not have climacteric symptoms.
          SERMs are nonhormonal agents that bind to the estrogen receptor with high affinity and
exhibit estrogen agonist or estrogen antagonistic effects, depending on the target tissue. SERMs
that are in broad clinical use to be discussed include tamoxifen and raloxifene. Tibolone is also
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considered, even though it is not a SERM, because it is used in the treatment of climacteric
symptoms and osteoporosis prevention, and has established effects on cardiovascular markers.
Tibolone is a synthetic steroid that has estrogenic, progestational and androgenic metabolites.
Many SERMs are currently in development and, although they are considered a single class of
drugs, different degrees of tissue selectivity associated with each compound may contribute to a
variable impact on cardiovascular markers. Results of studies of different SERMs may not be
generalizable to each other. The premise of a role of SERMs in the prevention of CVD is linked
to the estrogen-anti-atherosclerosis hypothesis. The purpose of this paper is to describe the
similarities and differences in the effect of SERMs and HRT on markers of cardiovascular risk.
The underlying hypothesis is that results of current studies of HRT and CVD may not necessarily
predict the outcome of studies of SERMs and CVD.
Cardiovascular Effects of SERMs
         SERMs share many biological effects with HRT on the cardiovascular system and have a
few notable differential effects. The beneficial effect of HRT on lipids that has been observed in
epidemiological studies has accounted for less than half of its cardioprotective effect but is still
believed to be an important mechanism of action for CVD prevention. Both raloxifene and
tamoxifen have been shown to have hypocholesterolemic effects that are rapid, sustained and
similar in magnitude to traditional HRT. Other lipids that are favorably altered by SERMs and
HRT include apolipoprotein B, lipoprotein (a), and apoliporotein A1. HRT has a beneficial effect
on raising high-density lipoprotein (HDL) cholesterol, whereas SERMs typically have no effect.
Tibolone, lowers HDL cholesterol, most likely due to its androgenic metabolite, yet animal
studies showed no adverse cardiovascular consequences. HRT is associated with elevations in
triglycerides of 20-30% and SERMs appear to have no effect. Both HRT and SERMs may
improve LDL oxidation.
         Endothelial dysfunction may be an early indicator of atherosclerosis and both estrogen
and raloxifene have been shown to improve endothelial-dependent vasodilitation by stimulating
the release of nitric oxide (NO) by increasing endothelial NO synthase activity. Homocysteine
may have damaging effects on the endothelium and SERMs have been shown to lower levels by
7-20%. HRT has also been shown to significantly reduce homocysteine. Inflammatory mediators
contribute to endothelial dysfunction by increasing the expression of vascular adhesion
molecules, such as E selectin and intracellular adhesion molecule 1 (ICAM-1), which are
reduced by both HRT and SERMs. Another marker of vascular activation, vascular cell adhesion
molecule (VCAM)-1 is reduced by HRT but not by SERMs. In contrast, the expression of matrix
metalloproteinases (MMP), a feature of vascular inflammation, is increased with HRT but is not
significantly affected by SERMs. CRP is one of the most widely studied inflammatory markers,
and elevations in CRP levels are correlated with increased risk of cardiovascular events in
women. Tamoxifen has been shown to decrease CRP whereas raloxifene has no effect and HRT
significantly increases levels by up to 80%.
         Several hemostatic factors are also indicators of CVD risk and the effect of HRT and
SERMs on these markers are inconsistent. However, both have been shown to decrease
fibrinogen levels, yet both have been shown to increase risk of venous thromboembolic events. It
is not known if factors that increase the risk of venous events are also correlated with an increase
in risk of arterial events. The net effect of HRT and SERMs on fibrinolysis and procoagulation
cascades is not clear and awaits further study.
         Raloxifene has been shown to attenuate intimal thickening in animal models in response
to arterial injury and prevent migration of vascular smooth muscle cells in culture. Tamoxifen
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inhibits fatty streak lesions in mice. Tamoxifen and estrogen have been shown to slow the
progression of atherosclerosis in cynomologus monkeys whereas raloxifene did not have a
significant effect. In studies of postmenopausal women, HRT has been associated with reduced
progression of atherosclerosis among women with no evidence for subclinical atherosclerosis,
however among women with documented coronary disease or an increased carotid wall
thickness, HRT has had no effect. Similar data are not available for SERMs.
Preliminary Cardiovascular Endpoint Studies
        It is not known if differential effects of HRT and SERMs on surrogate endpoints will
translate into different clinical outcomes. Although this question can only be definitively
answered through prospectively designed randomized clinical endpoint studies, retrospective
analyses from studies of osteoporosis and breast cancer prevention have provided an opportunity
to begin to examine this issue. Data on tamoxifen and cardiovascular endpoints has been mixed.
An initial meta-analysis showed that women randomly assigned to tamoxifen for breast cancer
treatment had less coronary events compared to placebo, however a more recent meta-analysis of
55 studies showed no significant effect of tamoxifen on reducing cardiovascular events.
        In the largest raloxifene osteoporosis prevention trial completed to date which enrolled
over 7700 women, raloxifene was associated with a 62% reduction in the risk of stroke and a
40% reduction in the risk of cardiovascular events (coronary and stroke combined) among
women who were considered to be at high risk for cardiovascular events. There was no increase
in early adverse cardiovascular events in the overall cohort or among those at high risk of CVD
events.
The Raloxifene Use for the Heart Trial
        This Raloxifene Use for the Heart (RUTH) trial, is a double blind, placebo controlled
international study of 10,101 women at high risk for cardiovascular events. The cardiovascular
outcome is a composite of hospitalized acute coronary syndromes other than myocardial
infarction, non-fatal myocardial infarction and coronary death. Invasive breast cancer is a co-
primary endpoint. In addition, several secondary endpoints will be evaluated including stroke,
venous thromboembolism, fractures, all causes of death or hospitalization, and individual
cardiovascular endpoints. The trial enrolled women between 1998 and 2000 and will be
completed after the pre-specified number of cardiovascular events occurs (expected in 2005),
unless it is stopped early. The study includes women from 26 countries with nearly equal
numbers of women with established cardiovascular disease and those with multiple risk factors,
and will generate important data about the effect of raloxifene in diverse primary and secondary
prevention populations.
Current Recommendations for HRT and SERMs and CVD
Several authorities have generated recommendations for the use of HRT in the primary and
secondary prevention of CVD. Although there has been less consensus with respect to the role of
HRT in the primary prevention of CVD, most guidelines have stated that there is not currently a
role for HRT in the secondary prevention of CVD, and definitive recommendations regarding
primary prevention should await the results of ongoing trials. The American Heart Association
recently addressed the issue of SERMs and CVD prevention in a Scientific Advisory on HRT
and CVD. Although it was noted that SERMs have shown beneficial effects on some surrogate
markers of CVD, due to the lack of clinical endpoint data, no recommendation was made
regarding use for prevention of CVD. Likewise for HRT and primary prevention, more definitive
answers regarding SERMs and CVD will be forthcoming from ongoing trials.
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