Effect of hormone replacement therapy on cardiac risk for diabetic women may depend on premenopausal cardiovascular health

Data from a large observational study of hormone replacement therapy in women with diabetes suggest that the effect of therapy may depend on whether an individual woman had a previous myocardial infarction, according to an article in the December 3rd rapid access issue of Circulation.

One notable finding was in diabetic women who had not had a myocardial infarction within a year of enrollment: For this group, replacement therapy was associated with a 16 percent lower risk of future myocardial infarction compared with no replacement therapy.

“Our results are inconsistent with the results from the Women’s Health Initiative, a randomized trial in women without heart disease, which reported a 30 percent increased risk of heart disease in women taking hormone replacement therapy compared with women on placebo,” said lead author Assiamira Ferrara, M.D., Ph.D.

“Dr. Ferrara’s research adds to the pool of literature regarding the cardiovascular effects of hormone replacement therapy in postmenopausal women, but observational studies such as this, as opposed to prospective clinical trials like the Women’s Health Initiative, are not definitive and often raise more questions than they answer,” said American Heart Association President Robert Bonow, M.D. “And this study does raise an important question about hormone replacement therapy in diabetic women - a question that can only be answered by a randomized clinical trial.”

As was noted widely in the professional and lay press, the Women’s Health Initiative trial was stopped in July 2002 when the study demonstrated no benefit, and possibly an increased risk, for myocardial infarction and stroke in women taking combined replacement therapy with estrogen and progestin.

In the current study, an American team followed 24,420 women (average age 65 years) with no history of myocardial infarction within the past year and 580 women (average age 69 years) with a recent infarction.

Among women without a recent myocardial infarction, 2,526 were using estrogen alone and 2,088 were using estrogen plus progestin as replacement therapy. After an average of three years of follow-up, there were 256 fatal myocardial infarctions and 854 nonfatal infarctions. Current use of estrogen plus progestin was associated with a 22 percent lower rate of myocardial infarction compared with the rate among women who did not take hormone replacement therapy. The infarction rate among women on estrogen alone was 11 percent lower, but this difference was not statistically significant. Risk estimates did not change significantly after researchers adjusted for heart disease risk factors, ethnicity, education, and body mass index.

“Another key finding was that women taking low or medium doses of estrogen had a lower risk of heart attack, but women taking high doses did not,” Ferrara noted.

Women on low doses had a 51 percent lower risk and women on medium doses had a 19 percent lower risk of myocardial infarction than women who did not take estrogen. High dose estrogen was associated with a 7 percent increased risk of myocardial infarction.

In addition to differences based on dosage of estrogen, researchers found that duration of replacement therapy was significant among women without previous myocardial infarction. Risk of infarction for women using replacement therapy for less than one year was about the same as the risk for women who did not use replacement therapy. For women on replacement therapy for longer than one year, risk of myocardial infarction was 19 percent lower than among women who did not use it.

In the group of 580 women with a recent myocardial infarction, 15 percent were using hormone replacement therapy at baseline. After an average follow-up of 2.5 years, women on replacement therapy had a 78 percent higher risk of recurrent myocardial infarction than women who did not use hormones. In addition, women who used replacement therapy for less than one year had nearly a four-fold increased risk for recurrent infarction than women who did not use replacement therapy. There was no association between hormone replacement therapy and risk of recurrent infarction in women who took hormones for one year or longer.

In an editorial that will appear in the printed issue of Circulation, David M. Herrington, M.D., notes that this study illustrates yet another “awkward reality” of clinical research on hormone replacement therapy.

“Observational studies like this one are likely to provide an overly optimistic view of the effect of hormone replacement therapy because they are not well suited to detect early adverse effects,” he writes. “That is a likely explanation for the difference between the Ferrara study and Women’s Health Initiative results.”

In the absence of data from randomized clinical trials involving women with diabetes, the American Heart Association advises that women should not start or continue combined hormone replacement therapy to prevent coronary heart disease.


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