HRT and Risk of Cardiovascular Disease in Women With Diabetes

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CVD is the most common cause of death in type 2 diabetes. This increased risk is particularly apparent in women with diabetes in which the relative protection afforded by the female sex is lost (107). For women without diabetes, prospective cohort surveys such as the Nurse's Health Cohort Study, suggest that estrogen therapy decreases the risk of CHD in postmenopausal women who were initially healthy at the time of enrollment (5). However, data from the HERS and WHI clinical trials have questioned the validity of epidemiological evidence by reporting an increased risk of CHD among women assigned to HRT (6,7).

Little is known about the effect of HRT on CHD in women with diabetes. Secondary analyses among small subgroups of women with diabetes from case-control studies have been equivocal, some reporting a non significant reduced risk (168,169) and others nonsignificant increased risk of CHD with exposure to HRT (170). In a 3-year follow-up observational study of a cohort of25,000 diabetic women aged 50 years and older from the Northern California Kaiser Permanente Registry, the risk of acute MI associated with current use of different hormone regimens was examined (171). The data revealed that current HRT use was associated with a significant 16% lower rate of fatal and nonfatal MIs. Lower risk of acute MI was observed among women using low or medium doses of estrogen (<0.625 mg CEE) but not among those using a high dose. However, among women with a recent MI, current HRT use was associated with an 80% higher rate of recurrent acute MI, and the rate of recurrent events was fourfold higher during the first year of HRT (171). The observed decreased risk of acute MI associated with current HRT in diabetic women without a recent MI is reminiscent of the results from observational studies in nondiabetic women without CHD (74). On the other hand, the results among diabetic women who have had a recent MI, are consistent with those of the HERS trial (6) and a prospective , observational study of women with pre-existing CHD (172).

A recent large prospective observational study in Denmark, examined the association between HRT, based on a different regimen (17^-estradiol and norethisterone acetate)

and ischemic heart disease (IHD), MI, and total number of deaths among a cohort of almost 20,000 Danish nurses aged 41 years and older (173). The data showed that current users of HRT smoked more, consumed more alcohol, had lower self-rated health, but were slimmer and had a lower prevalence of diabetes than never users. In current users without diabetes, HRT had no protective effect on IHD or MI compared with never users. However current users with diabetes had an increased risk of death, IHD and MI compared with never users with diabetes. These findings suggest that HRT does not protect women against IHD. Rather the effect of treatment is modified by diabetes, with an increased risk among women with diabetes using HRT.

With respect to the effect of HRT on the progression of atherosclerosis, Dubuison and associates (174) conducted a cross-sectional analysis and found that the beneficial effect of ERT/HRT on carotid intima-media wall thickness—a common measure of subclinical atherosclerosis—was similar in diabetic and nondiabetic postmenopausal women. In the HERS trial, nearly 23% of the participants had diabetes. A post hoc subgroup analysis revealed that HRT imparted no treatment effect for patients with diabetes (175). Similarly, the investigators of the WHI trial (4.4% of patients had diabetes) in a subgroup analysis demonstrated no increased risk among patients with diabetes taking HRT (7).The findings of the above studies of a neutral or harmful effect of HRT among women with diabetes are in line with the previous observations that the cardioprotection associated with being female was lost in women with diabetes.

Although the biological mechanism for this lack of effect remains speculative it is consistent with the fact that estrogen does not improve the endothelium-dependent va-sodilation in women with type 2 diabetes, previously reported (109,162). One possible explanation is that HRT does not benefit the damaged endothelium and the proinflammatory and/or procoagulant effects of treatment may dominate when the endothelium is already damaged. However, data from controlled clinical trials in diabetic women are needed to understand the possible risks and benefits of HRT. The Raloxifene use for the Heart Study, an ongoing RCT that includes a large sample of women with diabetes, will add to our knowledge of the magnitude of the effect of the risks and benefits of HRT in women with diabetes (176).

At present, the situation regarding the use of HRT for the prophylaxis or treatment of CVD in women with diabetes is unclear in the absence of data from randomized clinical studies. Women should be informed of the current uncertainty regarding HRT and CVD before initiating treatment for other reasons. However, this should not prevent women with diabetes from receiving HRT for menopausal symptoms or for treatment or prophylaxis of osteoporosis.

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