By Seema Gupta, MD, MSPH

Clinical Assistant Professor, Department of Family and Community Health, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV

Dr. Gupta reports no financial relationships relevant to this field of study.

SYNOPSIS: Research using data from the long-term follow-up of the Women’s Health Initiative Memory Study found that higher levels of estrogen can increase the risk of cognitive decline and dementia in older women with type 2 diabetes.

SOURCE: Espeland MA, et al. Impact of type 2 diabetes and postmenopausal hormone therapy on incidence of cognitive impairment in older women. Diabetes Care 2015;38:2316-2324.

Type 2 diabetes is associated with an increased risk of cognitive impairment and dementia. This increased risk of dementia may include both Alzheimer’s disease and vascular dementia. Based on epidemiologic studies, physicians believed estrogen to be a protective factor for dementia. However, recent evidence has revealed that estrogens provide no benefit, and instead may be associated with an increased risk of dementia and cognitive decline in certain groups. The Women’s Health Initiative Memory Study (WHIMS) found that for women ≥ 65 years of age who are at increased risk for brain atrophy due to type 2 diabetes, prescription of postmenopausal hormone therapy was associated with lower gray matter volumes compared to placebo.1 Similarly, a French study found that in postmenopausal women ≥ 65 years of age, higher endogenous estradiol level is an independent predictor of incident dementia, and the risk is dramatically higher in women with diabetes compared with nondiabetic women.2 In a multicenter, randomized, double-blind, placebo-controlled clinical trial of a subgroup of women who participated in the WHIMS, conjugated equine estrogens with or without medroxyprogesterone acetate, administered to women ≥ 65 years of age, not only failed to protect against dementia or cognitive decline but substantially increased the risk of dementia of any cause as well as cognitive decline.3

In their study, Espeland et al examined data from the long-term follow-up of the WHIMS to determine whether the effect of postmenopausal hormone therapy on cognitive impairment incidence varies depending on type 2 diabetes status of women. A total of 7233 women between 65 and 80 years of age were assigned to hormone therapy or matching placebo for an average of 4.7 to 5.9 years. Women were classified according to type 2 diabetes status and followed for probable dementia and cognitive impairment. Through a maximum 18 years of follow-up, researchers found that women with type 2 diabetes had an increased risk of probable dementia (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.16-2.06) and cognitive impairment (HR, 1.83; 95% CI, 1.50-2.23). They also found that the combination of diabetes and random assignment to hormone therapy increased the risk of dementia (HR, 2.12; 95% CI, 1.47-3.06) and cognitive impairment (HR, 2.20; 95% CI, 1.70-2.87) compared to women without these conditions. The interactions seemed to be limited to women assigned to unopposed conjugated equine estrogens. The authors concluded that higher levels of estrogen may exacerbate risks that type 2 diabetes pose for cognitive function decline in older women.

COMMENTARY

The study by Espeland et al finds that women with type 2 diabetes who were assigned to receive hormone therapy were more likely to develop dementia and cognitive impairment than those receiving placebo, while women without type 2 diabetes who were assigned to receive placebo were the least likely to develop dementia and cognitive impairment. This study suggests that women with type 2 diabetes may be more likely to develop dementia and cognitive impairment than women without diabetes. The effect of hormone therapy seemed to last through 18 years of follow-up. The study included only postmenopausal women, and it is still unknown if the results apply to younger women. However, it seems clear that the adverse effects of diabetes on the cognitive function of older women appear to be augmented by higher levels of estrogen, such as in older women on hormone replacement therapy. Therefore, based on this evidence, estrogens cannot be recommended in non-demented older women with type 2 diabetes as preventive therapy for maintaining cognitive function.

REFERENCES

  1. Espeland MA, et al. Postmenopausal hormone therapy, type 2 diabetes mellitus, and brain volumes. Neurology 2015;85:1131-1138.
  2. Carcaillon L, et al. High plasma estradiol interacts with diabetes on risk of dementia in older postmenopausal women. Neurology 2014;82:504-511.
  3. Craig MC, et al. The Women’s Health Initiative Memory Study: Findings and implications for treatment. Lancet Neurol 2005;4:190-194.