July 2007
|
Pathophysiologic Changes Occur in Women Years Before Clinical Diagnosis of Type 2 Diabetes
Clinicians need to be especially vigilant for the risk factors of type 2 diabetes and implement aggressive lifestyle modifications.
BY Karol Pohlman Pejman, PhD, FNP; Lisa Rafalson, PhD; Joan Dorn, PhD; Jacek Dmochowski, PhD; And Richard P. Donahue, PhD, MPH
Cardiovascular disease (CVD) remains the number one cause of death among men and women in the United States.1 Cardiovascular death rates in both male and female diabetic patients have remained relatively static.2 Although the reasons why the decline in coronary heart disease (CHD) death rates lag behind among those without diabetes, it has been theorized that the cause is most likely due to failures in both primary and secondary prevention.
Research has shown that symptom recognition of coronary artery disease (CAD) is poorer in female patients due at least in part, to a different clinical presentation compared with men.3-9 Other researchers have hypothesized that gender differences in coronary anatomy (ie, smaller vasculature, as well as more microvascular disease) contribute significantly to poorer outcomes in women. Although the reasons cannot be attributed entirely to gender differences in traditional CHD risk factors, diabetic women demonstrate a much higher risk for CHD than men with diabetes.3,10-13
The purpose of this analysis was to determine which traditional and emerging CVD risk factors predict the progression from normoglycemia to prediabetes and identify gender differences in those risk factor distributions.
RESEARCH DESIGN AND METHODS
The study design and methodology of this population-based investigation has been previously published.14,15 Briefly, participants in the this report were originally enrolled as healthy controls without known CVD in the Western New York Study, an epidemiologic case-control investigation of alcohol intake patterns and risk of CVD in Erie and Niagara Counties, New York, conducted from 1996 to 2001.
The initial cohort of control participants was randomly selected from driver's license lists for those aged <65 years and from the Health Care Finance Administration rolls for those aged 65 to 79 years. From 2001 to 2004 we conducted the first follow-up of the myocardial infarction (MI) control group. Eligible participants for the follow-up study were men and women aged 39 to 79 years selected from the baseline examination without known clinical CVD (self-reported MI, angina or revascularization surgery) or type 2 diabetes (measured fasting plasma glucose >125 mg/dL or self-report and taking medication) and who were capable of completing the current study protocol (n=2,652).
Exclusion criteria also included self-report of a medical condition that would prohibit participation, permanent change in out-of-state residence, deceased, or inability to contact and determine eligibility. This left 2,139 people eligible for this examination, 1,455 of whom completed the full clinic protocol. The mean follow-up time was 5.9 years (SD = 0.8 yrs). The protocol was approved by the University at Buffalo Health Science Institutional Review Board, and all participants provided written informed consent prior to participation.
STUDY PROTOCOL
At both the baseline and 6-year follow-up examinations, all participants received a clinical examination that included resting blood pressure, measures of height, weight, waist girth, and abdominal height (sagittal girth). Resting seated blood pressure was obtained according to a standardized protocol.16 Hypertension was defined as a systolic blood pressure greater ≥140 mm Hg or a diastolic blood pressure ≥90 mm Hg or use of antihypertensive medications regardless of blood pressure level. Body mass index (BMI) (kg/m²) was calculated and served as a measure of relative weight. Study participants also provided a fasting (≥10 hours overnight) blood sample and were asked to refrain for 24 hours from smoking or vigorous physical activity. Several standardized questionnaires were administered including cigarette use, physical activity (Stanford 7-Day Recall), alcohol use, general health and well-being, personal and family health history, medication use, and socioeconomic status. Participants were instructed to bring all medications to the clinic visits. The homeostasis model of insulin resistance (HOMA-IR) was calculated as fasting glucose X fasting insulin/22.4.17 A positive family history of type 2 diabetes was defined as a positive report in a first-degree relative.
LABORATORY METHODS
Methods have been previously described.18 For these analyses, we identified a case of prediabetes as an individual whose fasting serum glucose was <100 mg/dL at baseline but was between 100 mg/dL and 125 mg/dL (5.7-6.5 mmol/L) at follow-up. Each case was matched to three controls based on gender, ethnicity (white or nonwhite), and year of study enrollment. All control participants had a fasting blood glucose concentration <100 mg/dL at both the baseline and follow-up examinations.
The data were analyzed using statistical techniques that incorporated the matching variables as covariates. The distributions of fasting triglycerides and fasting insulin were log transformed (natural log) prior to analysis to achieve more normal distributions. General linear models19 or logistic regression techniques20 were used to compare the adjusted differences between cases and controls. Likelihood ratio tests were conducted to test for statistical interactions between gender and case-control status by comparing the log likelihood between the two nested models, one with only the main effects, and the other with both the main effects and the interaction terms in the model. All statistical tests were two-sided and a P-value of <.05 was considered statistically significant.
RESULTS
During a mean follow-up of 5.9 years (SD = 0.8 yrs) 52 women and 39 men progressed from normoglycemia to prediabetes (Table 1). Compared with controls, the prediabetic women were older and had a higher mean waist circumference after adjustment for age, ethnicity, and year of study enrollment. They also displayed higher age-adjusted mean levels of E-selectin, soluble intercellular adhesion molecule (sICAM), plasminogen activator inhibitor-1 (PAI-1), total triglycerides, fasting glucose, HOMA-IR, and a greater frequency of hypertension (P<.05). Mean concentrations of adiponectin were significantly lower among female cases compared to controls (P=.004). Among men, cases of prediabetes displayed significantly higher adjusted mean concentrations of high-sensitivity C reactive protein (hsCRP) (P=.047) and a marginally higher mean value in the HOMA-IR index (P=.08). No significant differences were noted for any of the endothelial biomarkers or PAI-1. Statistically significant gender by case-control interactions were observed for E-selectin, sICAM, and PAI-1 (all P<.05).
Table 2 presents the results adjusted further for BMI. Among women, differences in HOMA-IR and triglyceride concentrations diminished (P=.149 and .058, respectively). Differences in E-selectin, sICAM, and adiponectin, however, remained essentially unaltered. Among men, the results were also virtually unchanged, except for the HOMA-IR index, which was no longer significant (P=.829). The gender by case-control interactions noted in Table 1 remained significant. Additional adjustment for the HOMA-IR index (Table 3) resulted in nonsignificant differences in triglyceride concentrations among women. The overall pattern of higher mean values of biomarkers of endothelial dysfunction (E-selectin, sICAM), fibrinolysis (PAI-1), and lower mean values of adiponectin and a higher frequency of hypertension in the prediabetic case group remained.
Among men, only hsCRP was marginally elevated among the cases (P=.110), while PAI-1 was somewhat higher among the control group (P=.097 respectively). Formal tests for interaction between gender and case-control status were statistically significant for E-selectin (P=.042), PAI-1 (P=.001), sICAM (P=.011), and frequency of hypertension (P<.001), and were again suggestive for adiponectin (P=.150). It was not possible to adjust the gender differences in risk factors for waist circumference due to the limited overlap in the distributions between men and women (data not shown). To examine whether differences in endothelial function were moderated by inflammation, we further adjusted for hsCRP (data not shown). The results remained virtually unchanged. Further consideration of weight change between the two examinations did not alter these findings.
DISCUSSION
This community-based epidemiologic study demonstrated higher levels of markers of endothelial dysfunction and thrombosis as well as hypertension in women who progressed from normoglycemia to prediabetes. Although further studies will need to be performed, these results suggest that pathophysiologic changes begin long before the clinical diagnosis of diabetes is made. Clinically, these findings are significant in that clinicians will need to assess each individual's risk for developing diabetes and coronary artery disease and intervene as early as possible with lifestyle modification in order to prevent or delay type 2 diabetes, CVD, and their sequelae—especially in women. Primary care clinicians play a particularly key role. Clinicians must be vigilant for the risk factors for diabetes and regularly screen those with obesity (BMI >27 kg/m²), those aged >45 years, those with a family history of diabetes, and women who have delivered a baby weighing ≥9 lbs or who have had gestational diabetes.
The American Heart Association (AHA) has identified risk factors for CVD in women (Table 4)21; clinicians should pay particular attention to monitoring women for these risk factors as glycated hemoglobin is not strongly related to CHD risk.22 Primary prevention for both CVD and type 2 diabetes consists of recommendations that include 30 minutes of moderate to vigorous physical activity daily, weight control, alcohol in moderation, and a healthy diet (low in fat and complex carbohydrates and rich in fruits and vegetables). Certainly, clinicians need to identify and treat hypertension and hypercholesterolemia according to appropriate guidelines.16,23 Furthermore, aspirin-use guidelines recently released by the AHA should be adhered to, if appropriate for the individual patient.
Karol Pohlman Rejman, PhD, FNP, is in the School of Nursing and the Department of Social and Preventive Medicine, University at Buffalo, The State University of New York (SUNY). Lisa Rafalson, PhD, and Joan Dorn, PhD are in the Department of Social and Preventive Medicine, University at Buffalo, SUNY. Jacek Dmochowski, PhD, is in the Department of Mathematics and Statistics, UNC-Charlotte, Charlotte, NC. Richard P. Donahue, PhD, MPH is in the Department of Social & Preventive Medicine at the School of Public Health and Health Professions at the University at Buffalo, SUNY. He may be reached at rpd1@buffalo.edu; phone: 716-829-2975 ext. 614l; or fax: 716-829-2979.
|
