Early Menopause and Cardiovascular Disease Risk in Women With or Without Type 2 Diabetes: A Pooled Analysis of 9,374 Postmenopausal Women

OBJECTIVE Early menopause may be associated with higher cardiovascular disease (CVD) risk. Type 2 diabetes (T2DM), coupled with early menopause, may result in even greater CVD risk in women. We examined CVD risk in women with early compared to normal-age menopause, with and without T2DM overall and by race/ethnicity. RESEARCH DESIGN AND METHODS We pooled data from the Atherosclerosis Risk in Communities Study, the Multi-Ethnic Study of Atherosclerosis, and the Jackson Heart Study. We included women with data on menopausal status, menopausal age, and T2DM, excluding pre- or peri-menopausal women, and those with prevalent CVD. Outcomes included incident coronary heart disease (CHD), stroke, heart failure (HF), and atherosclerotic cardiovascular disease (ASCVD; CHD or stroke). We estimated the risk associated with early (<45 years) compared to normal-age menopause using Cox proportional hazards models. Covariates included age, race/ethnicity, education, body mass index, blood pressure, cholesterol, smoking, alcohol consumption, antihypertensive medication, lipid-lowering medication, hormone therapy use, and pregnancy history. RESULTS We included 9,374 postmenopausal women for a median follow-up of 15 years. We observed 1,068 CHD, 659 stroke, 1,412 HF and 1,567 ASCVD events. T2DM significantly modified the effect of early menopause on CVD risk. Adjusted HRs for early menopause and the outcomes were greater in women with T2DM versus without (CHD 1.15, 1.00-1.33 vs 1.09, 1.03-1.15; stroke 1.21, 1.04-1.40 vs 1.10, 1.04-1.16; ASCVD 1.29, 1.09-1.51 vs 1.10, 1.04-1.17; HF 1.18, 1.00-1.39 vs 1.09, 1.03-1.16)). The modifying effect of T2DM on the association between early menopause and ASCVD was only statistically significant in black compared to white women. CONCLUSION Early menopause was associated with increased risk for CVD in postmenopausal women. T2DM may further augment the risk, particularly in black women. </p

Lifetime risk of any CKD, by baseline BMI category and age.

The difference in lifetime risk of any CKD between persons age 50–64 with obesity and normal weight was statistically significant at the 1% level. No other differences were statistically significant. Abbreviations: CKD = Chronic Kidney Disease, BMI = Body Mass Index.</p

Lifetime risk of CKD, by baseline BMI category and highest CKD stage attained.

The difference in lifetime risk or any CKD between persons with obesity and normal weight was statistically significant at the 1% level. No other differences were statistically significant. Abbreviations: CKD = Chronic Kidney Disease, BMI = Body Mass Index.</p

Model parameters for relative risks related to obesity and annual change in BMI.

Model parameters for relative risks related to obesity and annual change in BMI.</p

One-way sensitivity analysis of +/- 25% changes in key parameters on the difference in lifetime risk of any stage CKD between persons with obesity and persons with normal weight.

In the main analysis, the difference in lifetime risk between persons with normal weight and obesity was 8.5%. Bars to the left of this value in the figure show the change in results if parameters are decreased by 25% and bars to the right of this value show the change in results if the parameters are increased by 25%. Abbreviations: eGFR = estimated glomerular filtration rate.</p

Baseline characteristics of the Chronic Renal Insufficiency Cohort study Analytic sample.

Baseline characteristics of the Chronic Renal Insufficiency Cohort study Analytic sample.</p

Model parameters for annual change in eGFR based on person characteristics and conditions and baseline eGFR.

Model parameters for annual change in eGFR based on person characteristics and conditions and baseline eGFR.</p

CKD Progression and Mortality among Hispanics and Non-Hispanics

Although recommended approaches to CKD management are achieved less often in Hispanics than in non-Hispanics, whether long-term outcomes differ between these groups is unclear. In a prospective longitudinal analysis of participants enrolled into the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC Studies, we used Cox proportional hazards models to determine the association between race/ethnicity, CKD progression (50% eGFR loss or incident ESRD), incident ESRD, and all-cause mortality, and linear mixed-effects models to assess differences in eGFR slope. Among 3785 participants, 13% were Hispanic, 43% were non-Hispanic white (NHW), and 44% were non-Hispanic black (NHB). Over a median follow-up of 5.1 years for Hispanics and 6.8 years for non-Hispanics, 27.6% of all participants had CKD progression, 21.3% reached incident ESRD, and 18.3% died. Hispanics had significantly higher rates of CKD progression, incident ESRD, and mean annual decline in eGFR than did NHW (P<0.05) but not NHB. Hispanics had a mortality rate similar to that of NHW but lower than that of NHB (P<0.05). In adjusted analyses, the risk of CKD progression did not differ between Hispanics and NHW or NHB. However, among nondiabetic participants, compared with NHB, Hispanics had a lower risk of CKD progression (hazard ratio, 0.61; 95% confidence interval, 0.39 to 0.95) and incident ESRD (hazard ratio, 0.50; 95% confidence interval, 0.30 to 0.84). At higher levels of urine protein, Hispanics had a significantly lower risk of mortality than did non-Hispanics (P<0.05). Thus, important differences in CKD progression and mortality exist between Hispanics and non-Hispanics and may be affected by proteinuria and diabetes

APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease

Background Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients. Methods In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline. Results In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons). Conclusions Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.