Early initiation of menopausal HT reduces all-cause mortality, CHD events in women
Women have a lower risk for all-cause mortality, coronary heart disease and other poor health outcomes when hormone therapy begins close to menopause and continues long term, according to a speaker.
“Menopausal HT is a cost-effective, sex-specific therapy that reduces all-cause mortality, cancer mortality, including breast cancer with conjugated estrogens alone, other mortality, including dementia and Alzheimer’s disease, CHD, bone fractures and new-onset diabetes, with rare risks when initiated around the time of menopause and continued long term,” Howard N. Hodis, MD, the Harry J. Bauer and Dorothy Bauer Rawlins professor of cardiology, professor of medicine and preventive medicine, and director of the atherosclerosis research unit at the University of Southern California, said during a presentation at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease virtual meeting. “The benefits of hormone replacement therapy outweigh the risks when initiated around the time of menopause.”
Reduced risk with earlier HT
Observational studies including the Nurses Health Study (NHS) and the Women’s Health Initiative showed that women who self-select HT have about a 50% lower risk for CHD than those who do not use HT. However, a pair of WHI randomized trials showed no difference between women who were randomized to HT and those who were not. Hodis said the difference is due to study design; observational studies included women aged 30 to 55 years who were on average less than 2 years from menopause when starting HT. Women enrolled into randomized trials were on average older than 63 years and more than 10 years removed from menopause when randomized to HT.
“These differences led to what’s called the HT timing hypothesis, which states that the effects of menopausal HT on atherosclerosis and clinical events are dependent upon when HT is initiated in relation to menopause and/or age,” Hodis said.
In a randomized trial confirming the HT timing hypothesis co-authored by Hodis in 2016, women who were within 6 years of menopause and randomized to estradiol had less progression of subclinical atherosclerosis than did those in the placebo group. Women 10 years or more removed from menopause, showed no difference in atherosclerosis between estradiol and placebo.
In a meta-analysis of 23 randomized controlled trials measuring CHD events, women who were less than 10 years since menopause and/or younger than 60 years and randomized to HT showed a 32% significant reduction in CHD (RR = 0.68; 95% CI, 0.48-0.96) whereas those who were 10 or more years since menopause and/or aged 60 years or older showed no effect (RR = 1.03; 95% CI, 0.91-1.16). Another meta-analysis of 30 randomized controlled trials showed that women younger than 60 years who received HT had a 39% significant reduction in all-cause mortality (RR = 0.61; 95% CI, 0.39-0.95) while those aged 60 years or older showed no effect (RR = 1.03; 95% CI, 0.9-1.18). A Cochrane meta-analysis confirmed these previous meta-analytical results.
Data from the WHI randomized trials showed that all-cause mortality, cancer mortality and other mortality were reduced in women randomized at ages 50 to 59 years to HT compared with placebo. In an 18-year follow-up, the risk for Alzheimer’s disease or dementia mortality was also reduced in women who received HT compared with placebo.
Statin vs. HT
According to meta-analyses of randomized controlled trials, lipid-lowering medication does not influence all-cause mortality and CHD rates in women when used as a primary prevention treatment, Hodis reported. Used in secondary prevention, lipid-lowering medication reduces CHD events but not all-cause mortality compared with placebo. Meta-analyses of primary CHD prevention studies show a clear difference between the sexes; statin therapy has no effect in reducing CHD or all-cause mortality in women whereas in men statin therapy reduces CHD events.
Studies show that statin therapy increases whereas HT reduces new onset diabetes compared with placebo.
At least four randomized trials showed that statin therapy increased the risk for breast cancer equal to or greater than the rare risk of breast cancer reported from WHI for estrogen and progestin combined. In both WHI trials, estrogen-only and estrogen and progestin combined, reduced risk for diabetes, bone fractures, cancer mortality and all-cause mortality in women randomized at ages 50 to 59 years.
“Similar to HT, the cumulated data indicate that, over all ages, lipid-lowering therapy has a null effect on the incidence of all-cause mortality and CHD in women in primary prevention,” Hodis said. “However, the data consistently support reduced all-cause mortality and CHD when HT is initiated close to the time of menopause, within 10 years, or when women are less than 60 years of age.”
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Hodis HN. Hormone replacement therapy, atherosclerosis and cardiovascular disease: An update. Presented at: World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease; Dec. 3-6, 2020 (virtual meeting).