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Rising Prediabetes, Undiagnosed Diabetes, and Risk Factors in Young Women

  • Yilin Yoshida
    Correspondence
    Address correspondence to: Yilin Yoshida, PhD, Section of Endocrinology & Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans LA 70112.
    Affiliations
    Section of Endocrinology & Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana

    Tulane Center of Excellence: Sex-Based Biology & Medicine, Tulane University, New Orleans, Louisiana

    VA Southeast Louisiana Health Care, New Orleans, Louisiana
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  • Jia Wang
    Affiliations
    Section of Endocrinology & Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
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  • Yuanhao Zu
    Affiliations
    Department of Biostatistics and Data Science, Tulane University School of Public Health & Tropical Medicine, New Orleans, Louisiana
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  • Vivian A. Fonseca
    Affiliations
    Section of Endocrinology & Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana

    VA Southeast Louisiana Health Care, New Orleans, Louisiana
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  • Franck Mauvais-Jarvis
    Affiliations
    Section of Endocrinology & Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana

    Tulane Center of Excellence: Sex-Based Biology & Medicine, Tulane University, New Orleans, Louisiana

    VA Southeast Louisiana Health Care, New Orleans, Louisiana
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Open AccessPublished:November 25, 2022DOI:https://doi.org/10.1016/j.amepre.2022.10.001

      Introduction

      Women of reproductive age are less prone to cardiovascular disease than men. However, diabetes mellitus negates this female advantage. The prevalence change of prediabetes (prediabetes mellitus) and diabetes mellitus and diabetes mellitus‒associated cardiovascular risk factors have not been clearly described in women before menopause.

      Methods

      Using National Health and Nutrition Examination Survey data (1999–2018), this study estimated the age-adjusted prevalence of prediabetes mellitus (2005–2018), diagnosed diabetes mellitus, and undiagnosed diabetes mellitus in premenopausal women. Logistic regression was used to examine cardiovascular risk factors, including obesity, central obesity, hypercholesterolemia, hypertension, and hypertriglyceridemia, associated with prediabetes mellitus, diagnosed diabetes mellitus, or undiagnosed diabetes mellitus in premenopausal women. The magnitude of the association among age-matched men and postmenopausal women was compared. The analysis was conducted in 2022.

      Results

      Premenopausal women experienced an increased prevalence of prediabetes mellitus and undiagnosed diabetes mellitus, contrasting with steady trends in all U.S. adults over the last 2 decades. Premenopausal women with prediabetes mellitus or diabetes mellitus (versus those with normoglycemia) have significant obesity risk, and the risk is equivalent to that among age-matched men and higher than that among postmenopausal women. The association between prediabetes mellitus and hypercholesterolemia or hypertriglyceridemia was significant in premenopausal women only. Hypercholesterolemia and hypertension associated with undiagnosed diabetes mellitus were significant in premenopausal women and men of the same age, respectively. Diagnosed and undiagnosed diabetes mellitus was associated with hypertriglyceridemia in men and postmenopausal women, respectively.

      Conclusions

      Premenopausal women had increased prediabetes mellitus and undiagnosed diabetes mellitus in the past 2 decades. They face a considerable cardiovascular risk burden associated with prediabetes mellitus and diabetes mellitus. Cardiometabolic risk screening and patient education should be improved in young and early middle-aged adults, particularly in women.

      INTRODUCTION

      Women of reproductive age are less prone to cardiovascular disease (CVD) than men, partly because of the cardioprotection of estrogens. However, diabetes mellitus (DM) negates this female advantage.
      • Mauvais-Jarvis F.
      Gender differences in glucose homeostasis and diabetes.
      Of note, women can develop CVD with a lower glucose level than men and may be at a higher risk of CVD associated with prediabetes (pre-DM).
      • Koro CE
      • Bowlin SJ
      • Rabatin V
      • Fedder DO.
      Cardiovascular disease risk among subjects with impaired fasting glucose in the United States: results from NHANES 1999–2004.
      ,
      • Levitzky YS
      • Pencina MJ
      • D'Agostino RB
      • et al.
      Impact of impaired fasting glucose on cardiovascular disease: the Framingham Heart Study.
      Women are more likely to have undiagnosed DM than men because of inequitable healthcare access and screening and lower disease risk awareness.
      • Danaei G
      • Friedman AB
      • Oza S
      • Murray CJL
      • Ezzati M.
      Diabetes prevalence and diagnosis in U.S. states: analysis of health surveys.
      Untreated DM is associated with a higher mortality risk and CVD hospitalization than diagnosed/controlled DM.
      • Navarro-Pérez J
      • Orozco-Beltran D
      • Gil-Guillen V
      • et al.
      Mortality and cardiovascular disease burden of uncontrolled diabetes in a registry-based cohort: the ESCARVAL-risk study.
      Among individuals with pre-DM or undiagnosed DM, the raised cardiometabolic risk factors are likely to go undetected and untreated, contributing to future risk of CVD, particularly in women. Understanding of cardiovascular complications in DM and the sex difference in diabetic CVD are primarily based on late middle-aged and elderly cohorts.
      • Hubbard D
      • Colantonio LD
      • Tanner RM
      • et al.
      Prediabetes and risk for cardiovascular disease by hypertension status in black adults: the Jackson Heart study.
      • Abdelbagi O
      • Musa IR
      • Musa SM
      • Altigani SA
      • Adam I.
      Prevalence and associated factors of hypertension among adults with diabetes mellitus in northern Sudan: a cross-sectional study.
      • Ballantyne CM
      • Hoogeveen RC
      • McNeill AM
      • et al.
      Metabolic syndrome risk for cardiovascular disease and diabetes in the ARIC study.
      • Wong ND
      • Zhao Y
      • Patel R
      • et al.
      Cardiovascular risk factor targets and cardiovascular disease event risk in diabetes: a pooling project of the atherosclerosis risk in communities study, multi-ethnic study of atherosclerosis, and Jackson Heart study.
      Premenopausal women with pre-DM or DM may already have accumulated more pronounced cardiometabolic risks than men of the same age, which is yet to be verified. Furthermore, the prevalence change of pre-DM and DM among premenopausal women has not been clearly described. This study examined the 20-year trends of pre-DM, diagnosed DM, and undiagnosed DM and associated cardiometabolic risk factors in premenopausal women compared with those in age-matched men and postmenopausal women.

      METHODS

      Data were drawn from the National Health and Nutrition Examination Survey (NHANES) (1999–2000 to 2017–2018).

      About National Health and Nutrition Examination Survey. Centers for Disease Control and Prevention. https://www.cdc.gov/nchs/nhanes/about_nhanes.htm. Accessed October 2019.

      The study included men and nonpregnant women aged 20–84 years with information on DM measurements, menopause status (women), and other key covariates. For regression analysis, we excluded those with a previous history of CVD (Appendix Figure 1, available online).
      Premenopausal status was defined as having regular periods over the last 12 months, not having regular periods owing to menopause (i.e., pregnancy; breastfeeding; medical conditions/treatments, including contraceptive use), or being aged <41 years.
      • Shirazi TN
      • Hastings WJ
      • Rosinger AY
      • Ryan CP
      Parity predicts biological age acceleration in post-menopausal, but not pre-menopausal, women.
      A lower limit of 41 years was chosen for premenopause because the average age of menopause in the U.S. is 51 years and because perimenopause may last up to 10 years.
      • Lobo RA.
      Chapter 15. Menopause and aging.
      ,
      • El Khoudary SR
      • Aggarwal B
      • Beckie TM
      • et al.
      Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association.
      Postmenopausal women in this study were those without regular periods over the last 12 months owing to menopause.
      Diagnosed DM was self-reported. For those without a diagnosis, fasting glucose (FG)≥126 mg/dL, HbA1c≥6.5% (FG and HbA1c were available for all cycles), or oral glucose tolerance test≥200 mg/dL (available from cycle 2005–2006 to 2017–2018) was classified as undiagnosed DM. Pre-DM was defined by FG of 100–126 mg/dL, HbA1c of 5.7%–6.5%, or oral glucose tolerance test of 140–200 mg/dL.
      American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in Diabetes-2021.
      Outcomes included obesity (BMI≥30 kg/m2), central obesity (waist circumference≥102 cm in men and ≥88 cm in women), hypercholesterolemia (total cholesterol≥240 mg/dL), hypertension (systolic blood pressure≥140 mmHg or diastolic blood pressure≥90 mmHg), and hypertriglyceridemia (triglycerides≥200 mg/dL).
      The study calculated the age-adjusted prevalence of pre-DM, diagnosed DM, and undiagnosed DM by the direct methods of the 2000 U.S. Census standard population. Multivariable logistic regressions were performed for the association between cardiometabolic risk factors and pre-DM, diagnosed DM, and undiagnosed DM in premenopausal women; age-matched men (1:1 match; Appendix Text 1, available online); and postmenopausal women adjusted for age, race/ethnicity, education, income, insurance, smoking, BMI, total calorie intake, physical activity, and use of any antihypertensive or lipid-lowering medications. The study employed survey-related commands to adjust for the complex survey design effect. The primary sampling unit and stratum for each observation were considered in the analyses. SAS, Version 9.4 (SAS Institute Inc, Cary, NC), was used for analysis.

      RESULTS

      In women of reproductive age, nearly 1 in 4 had pre-DM, 5.2% had diagnosed DM, and 2.5% had undiagnosed DM (Appendix Tables 1 and 2, available online). The result showed an increased prevalence of pre-DM in premenopausal women, rising from 20% in years 2005–2008 to 28% in the years 2015–2018, contrasting with the high but steady trend of pre-DM in all adults (∼34.5%). The prevalence of undiagnosed DM in premenopausal women doubled from the years 1999–2002 (1.7%) to the years 2015–2018 (3.5%) as opposed to a slight decline in all adults (3.1%‒2.9%). Diagnosed DM steadily increased in premenopausal women (Figure 1).
      Figure 1
      Figure 1Age-adjusted prevalence of (A) prediabetes, (B) diagnosed diabetes, (C) undiagnosed diabetes in premenopausal W and all adults, NHANES 1999–2000 to 2017–2018.
      NHANES, National Health and Nutrition Examination Survey; W, women.
      In adjusted analysis, premenopausal women with pre-DM were associated with an almost threefold risk of obesity (OR=2.8; 95% CI=2.1, 3.7) and central obesity (OR=2.8; 95% CI=2, 3.9) compared with those with normoglycemia; the magnitude of the association was less pronounced in age-matched men or postmenopausal women. Undiagnosed DM was associated with more than fourfold obesity risk in premenopausal women (obesity OR=5.4, 95% CI=2.6, 11.4; central obesity OR=4, 95% CI=1.2, 12.9) and men (obesity OR=4.8, 95% CI=1.8, 12.6; central obesity OR=4.6, 95% CI=2, 10.2) and with twofold obesity risk in postmenopausal women (obesity OR=2, 95% CI=1.3, 3.2; central obesity OR=2.6, 95% CI=1.3, 4.7). The magnitude of the association between diagnosed DM and obesity/central obesity was greater in premenopausal women than in age-matched men or postmenopausal women (Figure 2).
      Figure 2
      Figure 2AORa of prediabetes, diagnosed diabetes, and undiagnosed diabetes and cardiometabolic risk factors in premenopausal women, age-matched men, and postmenopausal women, NHANES 1999–2000 to 2017–2018.
      aAdjusted for age, race/ethnicity, education, income, insurance, smoking, BMI, total calorie intake, physical activity, and use of any antihypertensive or lipid-lowering medications. The reference group in each logistic regression was individuals with normoglycemia (i.e., premenopausal women with normoglycemia, age-matched men with normoglycemia, and postmenopausal women with normoglycemia).
      NHANES, National Health and Nutrition Examination Survey.
      The association between undiagnosed DM and hypertension was significant in premenopausal women only (OR=2.1; 95% CI=1.1, 4.2), whereas the association between pre-DM and hypertension was significant in age-matched men only. Pre-DM was associated with hypertriglyceridemia risk in premenopausal women (OR=2.5; 95% CI=1.4, 4.4), age-matched men (OR=3.8; 95% CI=2.4, 6), and postmenopausal women (OR=4.1; 95% CI=1.7, 9.7). Undiagnosed DM was associated with hypertriglyceridemia risk in age-matched men (OR=3.1; 95% CI=1.3, 7.6) and postmenopausal women (OR=2.8; 95% CI=1.3, 6.6) but not in premenopausal women (Figure 2).

      DISCUSSION

      The study found upward trends of undiagnosed DM and pre-DM among premenopausal women. In all adults, a declining trend of undiagnosed DM is related to changes in diabetes diagnostic and screening practices.
      • Selvin E
      • Ali MK.
      Declines in the incidence of diabetes in the U.S.-real progress or artifact?.
      The increasing prevalence of undiagnosed DM and pre-DM in premenopausal women signals a lack of screening and low awareness of DM risk in this group relative to that in men of the same age and older women. In addition, the upward trends of pre-DM and DM in premenopausal women run parallel to the rising obesity in young and middle-aged adults,
      • Stierman B
      • Afful J
      • Carroll MD
      • et al.
      National Health and Nutrition Examination Survey 2017-March 2020 prepandemic data files development of files and prevalence estimates for selected health outcomes.
      suggesting the need for a more robust effort to improve nutrition and physical activity in women of reproductive age.
      Premenopausal women with pre-DM or DM face more cardiometabolic risk factors than those with normoglycemia. Notably, their risk profiles were equivalent to or even worse than those of men of the same age and postmenopausal women. Previous research suggests that obesity, hypertension, and dyslipidemia are concomitant risk factors in DM, and aggregation of these risk factors synergistically increases the risk of CVD.
      • Hubbard D
      • Colantonio LD
      • Tanner RM
      • et al.
      Prediabetes and risk for cardiovascular disease by hypertension status in black adults: the Jackson Heart study.
      • Wong ND
      • Zhao Y
      • Patel R
      • et al.
      Cardiovascular risk factor targets and cardiovascular disease event risk in diabetes: a pooling project of the atherosclerosis risk in communities study, multi-ethnic study of atherosclerosis, and Jackson Heart study.
      However, these findings were mainly derived from middle-aged or elderly cohorts.
      • Hubbard D
      • Colantonio LD
      • Tanner RM
      • et al.
      Prediabetes and risk for cardiovascular disease by hypertension status in black adults: the Jackson Heart study.
      • Wong ND
      • Zhao Y
      • Patel R
      • et al.
      Cardiovascular risk factor targets and cardiovascular disease event risk in diabetes: a pooling project of the atherosclerosis risk in communities study, multi-ethnic study of atherosclerosis, and Jackson Heart study.
      This study quantifies the extent to which pre-DM, diagnosed DM, and undiagnosed DM correlate with cardiometabolic risk factors in women of reproductive age and highlights the concerning cardiovascular consequences if risk factors are left uncontrolled. These findings, in part, explain women's disadvantage in diabetic CVD in middle and late adulthood and suggest that the decline of cardiometabolic health in women starts as early as young adulthood.

      Limitations

      Limitations of this study included self-reported menopausal status. In addition, the cross-sectional design of NHANES precludes quantifying future CVD risk in premenopausal women.

      CONCLUSIONS

      Although premenopausal women have a lower prevalence of pre-DM, DM, and undiagnosed DM, all the 3 conditions have been increasing at a greater rate among women of reproductive age than among the overall adult population. Premenopausal women face a significant cardiovascular risk burden associated with pre-DM and DM. This study indicates the need to increase cardiometabolic risk screening and improve patient education about the risks and consequences of pre-DM and DM in women of reproductive age.

      ACKNOWLEDGMENTS

      No financial disclosures were reported by the authors of this paper.

      CRediT AUTHOR STATEMENT

      Yilin Yoshida: Conceptualization, Data curation, Formal analysis, Supervision, Writing–original draft. Jia Wang: Formal analysis. Yuanhao Zu: Formal analysis Vivian A. Fonseca: Writing–review and editing. Franck Mauvais-Jarvis: Writing–review and editing.

      Appendix. SUPPLEMENTAL MATERIAL

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