Published online before print September 4, 2003, doi: 10.1161/01.ATV.0000093471.58663.ED
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© 2003 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Elevated Carotid Artery Intima-Media Thickness Levels in Individuals Who Subsequently Develop Type 2 Diabetes
From the Division of Clinical Epidemiology (K.J.H., K.W., S.M.H., M.P.S.), Department of Medicine, University of Texas Health Science Center at San Antonio; Centro de Estudios en Diabetes (D.R., C.G.V.), The American-British Cowdray Medical Center, Mexico City, Mexico; the Department of Radiology (D.H.O’L.), Tufts–New England Medical Center, Boston, Mass; and Unidades de Investigación Médica en Enfermedades Metabólicas y Epidemiología Clínica (C.G.V.), Hospital Gabriel Mancera, Instituto Mexicano del Seguro Social, Mexico City, Mexico.
Correspondence to Kelly J. Hunt, PhD, Division of Clinical Epidemiology, UTHSCSA, 7703 Floyd Curl Dr, San Antonio, TX 78229[hyphen]3900. E-mail huntk{at}uthscsa.edu
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Abstract |
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Objective— We examined whether B-mode ultrasound–detected carotid artery intima-media thickness (IMT) was elevated before the onset of clinical diabetes.
Methods and Results— The study population for these analyses included 1127 nondiabetic participants, 66 prediabetic participants, and 303 diabetic participants with a mean age of 49.8 years who participated in the Mexico City Diabetes Study, a prospective cohort study. Common carotid artery (CCA) and internal carotid artery (ICA) IMTs were measured bilaterally by B-mode ultrasound. Age- and sex-adjusted mean ICA and CCA IMTs were both significantly higher among prediabetic individuals {0.81 mm [95% confidence interval (CI), 0.75–0.88] and 0.72 mm [95% CI, 0.69–0.75], respectively} than in individuals who remained free of diabetes [0.71 mm (95% CI, 0.69–0.72) and 0.69 mm (95% CI, 0.68–0.69), respectively]. However, after adjustment for established cardiovascular risk factors, ICA IMT, but not CCA IMT, remained significantly higher among prediabetic individuals [0.81 mm (95% CI, 0.75–0.88) and 0.71 mm (95% CI, 0.68–0.74)] than in individuals who remained free of diabetes [0.71 mm (95% CI, 0.69–0.72) and 0.69 mm (95% CI, 0.68–0.70)].
Conclusions— The present study provides direct evidence at the vascular level that atherosclerosis levels are elevated before the clinical onset of diabetes.
Key Words: atherosclerosis • carotid arteries • imaging • diabetes mellitus
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Introduction |
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Although previous studies have established that coronary heart disease (CHD) risk factors are elevated before the clinical onset of diabetes1–5 and a recent study has reported increased cardiovascular disease risk before the clinical onset of diabetes,6 direct evidence of increased atherosclerosis before a clinical diagnosis of diabetes has not been documented. Documenting not only increased cardiovascular risk factors but increased atherosclerosis as well provides direct evidence that the atherosclerotic process is accelerated before the onset of clinical diabetes. Moreover, although type 2 diabetes is commonly considered a risk factor for CHD, treatment and control of hyperglycemia in type 2 diabetes have, at best, only a modest effect on reducing the risk of CHD associated with diabetes.7 If the atherosclerotic process is accelerated before the onset of clinical diabetes, then preventing diabetes itself, either by altering lifestyle or pharmacologically, might be the optimum way to reduce the CHD risk associated with diabetes.
See page 1715
Recently, the Diabetes Prevention Program was one of several clinical trials to indicate that either through diet and exercise or with the aid of a pharmacologic agent it is possible to lower the incidence of diabetes among individuals at high risk for the disease.8–10 In short, there are lifestyle and pharmacologic interventions available that prevent diabetes. Hence, evidence suggesting that prediabetic individuals have not only elevated CHD risk factors but also elevated levels of subclinical atherosclerosis would indicate the importance of a lifestyle or pharmacologic intervention before the onset of clinical diabetes.
Therefore, we examined (1) whether B-mode ultrasound–detected carotid artery intima-media thickness (IMT) was elevated in prediabetic individuals when compared with individuals who remained free of diabetes and (2) whether increased carotid artery IMT predicted incident diabetes.
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Methods |
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The Mexico City Diabetes Study
The Mexico City Diabetes Study is a population-based cohort of 2282 men and women first examined between 1990 and 1992 who were invited to return for 2 follow-up exams, the first conducted between 1993 and 1995 and the second from 1997 to 1999.11 Participants were randomly selected from 6 low-income "colonias" (equivalent to US census tracts) in Mexico City and were 35 to 64 years of age at entry into the study.12 The Institutional Review Boards of the University of Texas Health Science Center at San Antonio and the Centro De Estudios en Diabetes approved the study. All participants gave informed consent.
Examinations were standardized across the 3 contacts and included interviews, blood pressure measurements, anthropometry, a fasting venipuncture, and a 75-g oral glucose tolerance test. Trained interviewers obtained information on basic demographic variables, medical history, medication use, and smoking status. Examinations occurred in the morning after participants had fasted for at least 12 hours. The methods for measuring blood pressure, body mass index (BMI), serum total and HDL cholesterol, triglycerides, insulin, and glucose have been previously described in detail.12
Diabetes was defined as a fasting plasma glucose 
126 mg/dL and/or a 2-hour postload glucose value 200 mg/dL.13 Participants not meeting these criteria but who reported current therapy with diabetes medication (either oral or insulin) for diabetes were also considered to have diabetes. Hypertension was defined as systolic blood pressure 140 mm Hg, diastolic blood pressure 90 mm Hg, or current treatment with antihypertensive medication.
Based on information available from a participant’s baseline, first follow-up, and second follow-up examinations, participants were classified as nondiabetic, prediabetic, and currently diabetic at their first follow-up examination: nondiabetic participants were those without evidence of diabetes at any of the 3 examinations; prediabetic participants were without evidence of diabetes at their baseline examination and were confirmed to be nondiabetic participants at their first follow-up examination but became diabetic by their second follow-up examination; and diabetic participants were those with diabetes at their first follow-up examination.
B-Mode Ultrasound Examination
B-mode ultrasound evaluations of atherosclerosis were completed bilaterally on segments of the extracranial carotid arteries at the first follow-up examination (1993–1995). The scanning and reading protocols were identical to those used in the Cardiovascular Health Study.14 Ultrasound images were recorded on videotape (super-VHS) and read by a single reader who had been trained as both a sonographer and a reader at the central carotid ultrasound reading center used for the Cardiovascular Health Study.14 The IMT readings were not done blinded to a participant’s diabetes status at their first follow-up examination; however, because during the first follow-up examination it was impossible to know who was prediabetic, IMT readings of prediabetics were blinded with respect to prediabetic status.
The ultrasound reader measured near- and far-wall IMTs bilaterally for a single CCA view and for 3 different views of the ICA centered on the site of maximum wall thickness. Mean CCA and ICA IMTs were calculated as the overall mean of the available IMT measurements (up to 4 for CCA IMT and up to 12 for ICA IMT). Of the 1773 people who returned for their first follow-up examination, mean CCA IMT was calculated for the 1749 (98.6%) who had at least 1 measurement of CCA IMT available, and mean ICA IMT was calculated for the 1519 (85.7%) who had at least 1 measurement of ICA IMT available. In a repeatability analysis with 58 randomly chosen ultrasound scans, the average percent differences between the first and second readings relative to the first reading for mean CCA IMT and mean ICA IMT measurements were 2.3% [95% confidence interval (CI), -24 to 24%] and -3.7% (95% CI, -48 to 48%), respectively.
Statistical Analysis
Cross-sectional analyses were carried out to examine whether B-mode ultrasound–detected carotid artery IMT was higher in prediabetic individuals, as well as diabetic individuals, than in individuals who remained free of diabetes. Covariates as well as carotid artery IMT were measured at the first follow-up examination, and age and sex-adjusted means and proportions were determined for these variables.
For each category of diabetes status (non, pre, and current), age- and sex-adjusted CCA and ICA IMT levels were determined by ANCOVA. The association between diabetes status and either CCA IMT or ICA IMT was also assessed after controlling for established cardiovascular risk factors, including age, sex, BMI, total and HDL cholesterol, systolic blood pressure, and smoking status (current and former). Age, BMI, total and HDL cholesterol, and systolic blood pressure levels were modeled as linear continuous variables.
Finally, prospective analyses were carried out after excluding participants who were considered currently diabetic at their first follow-up examination. Quartiles of CCA and ICA IMT were determined, and for each measure, participants in the upper quartile were compared with those in the lower 3 quartiles. Logistic-regression models were used to calculate age- and sex-adjusted odds ratios (ORs) for incident diabetes in relation to CCA and ICA IMT. The association between CCA and ICA IMT quartile and incident diabetes was also assessed after controlling for established diabetes risk factors, including age, sex, waist circumference, total and HDL cholesterol, triglycerides (high vs low; 200 mg/dL), systolic blood pressure, 2-hour glucose, and a family history of diabetes (first-degree relative; yes vs no). Age, waist circumference, total and HDL cholesterol, systolic blood pressure levels, and 2-hour glucose were modeled as continuous variables that were linear in the log (odds) scale.
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Results |
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These analyses excluded individuals who did not participate in the first follow-up examination (n=509), individuals without CCA B-mode ultrasound information available at their first follow-up examination (n=25), and individuals whose diabetes status with respect to their first and second follow-up examinations could not be established because of missing (n=237) or inconsistent (n=15) data. Hence, the study population for these analyses included 1127 nondiabetic participants, 66 prediabetic participants, and 303 diabetic participants.
For each diabetes category, age- and sex-adjusted means and proportions were calculated for the variables of interest (Table 1). Relative to nondiabetic individuals, prediabetics were of similar age but had a higher BMI, a larger waist circumference, higher insulin levels (fasting and 2 hour), higher 2-hour glucose levels, and worse lipid profiles (higher triglycerides and lower HDL cholesterol levels) and were more likely to be hypertensive. Participants with diabetes were slightly older, had a larger waist circumference, higher glucose levels (fasting and 2 hour), and worse lipid profiles (higher triglycerides and total cholesterol levels), and were more likely to be hypertensive than nondiabetic individuals. In many instances, however, these covariates were worse in the prediabetic than in the diabetic participants, with the former having, on average, a higher BMI, a larger waist circumference, and a worse blood pressure profile and being less likely to have quit smoking than the latter.
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For each diabetes category, CCA and ICA IMT measurements are presented in the Figure. CCA and ICA IMTs were modeled separately, with the initial models adjusted solely for age and sex, and subsequent models were further adjusted for the established cardiovascular risk factors. After adjustment for age and sex, CCA and ICA IMTs were significantly higher among prediabetic individuals than in individuals who remained free of diabetes (Table 1 and the Figure). After adjusting for additional covariates, CCA IMT remained higher among prediabetic individuals [0.71 mm (95% CI, 0.68–0.74)] than in individuals who remained free of diabetes [0.69 mm (95% CI, 0.68–0.70)], although it was no longer statistically significant. Conversely, ICA IMT remained significantly higher in prediabetic individuals [0.81 mm (95% CI, 0.75–0.88)] than in individuals who remained free of diabetes [0.71 (95% CI, 0.69–0.72)]. Both CCA IMT and ICA IMT were significantly higher in each model in individuals with diabetes than in those who remained free of diabetes.
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); second models were additionally adjusted for BMI, total and HDL cholesterol, systolic blood pressure, and smoking status (
. *Significant difference (P<0.05) in comparison with nondiabetic individuals. CCA IMT and ICA IMT were modeled separately; reported n’s correspond to the number included in the initial model.In addition, the age- and sex-adjusted OR for incident diabetes, when we compared those in the upper quartile of CCA IMT to those in the lower 3 quartiles, was 1.99 (95% CI, 1.11–3.58). Furthermore, the corresponding OR for ICA IMT was 1.61 (95% CI, 0.93–2.81). After further controlling for the established diabetes risk factors, the OR for CCA IMT was attenuated, whereas the OR for ICA IMT, though not statistically significant, remained unchanged (Table 2).
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Discussion |
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After controlling for age and sex, we report not only that CHD risk factors but also that CCA and ICA IMTs are elevated in individuals before the onset of clinical diabetes. Moreover, increased CCA IMT predicted diabetes. Hence, in our study population, we have established that early atherogenesis, not merely elevated cardiovascular risk factors, is present before the development of clinical diabetes, and thus, enhanced atherogenesis is not solely dependent on the clinical manifestation of diabetes.
Jarrett,15 Jarrett and Shiply,16 and later Stern17,18 hypothesized not only that diabetes and cardiovascular disease are related as cause and effect but also that both conditions originate from a "common soil." This hypothesis suggests an atherogenic state before the onset of clinical diabetes, which is consistent with the regularly reported finding that CHD risk factors are elevated in prediabetic individuals1–5 and the recently reported finding in the Nurses’ Health Study (NHS) of elevated cardiovascular disease risk before a clinical diagnosis of diabetes.6 Possible candidates for the common etiology underlying diabetes and CHD are chronic, subclinical inflammation and the metabolic syndrome. Prospective studies have indicated that subclinical inflammation and the metabolic syndrome are associated with both incident CHD and incident diabetes.19–26
Currently, B-mode ultrasound of the carotid arteries is a noninvasive procedure used to identify and measure subclinical atherosclerosis for research purposes. As measured by this method, carotid artery IMT is an early quantitative marker of generalized atherosclerosis that is associated with incident CHD and its risk factors.14,27–30 Elevated CHD risk factors have routinely been reported in prediabetic individuals1–5 and in the past have been the evidence used to support the "common soil" hypothesis. Because we hypothesized that they either are the common antecedents underlying diabetes and CHD or the result of the common antecedents underlying diabetes and CHD, we were not surprised that adjusting for these risk factors in our study population attenuated the differences in CCA IMT and ICA IMT between prediabetic and nondiabetic participants. Likewise, adjusting for the established diabetes risk factors attenuated the OR for incident diabetes when we compared those in the upper quartile of CCA IMT with those in the lower 3 quartiles. If the relation between diabetes and cardiovascular disease is explained or partially explained by common antecedents that share a single pathway, then adjustment for risk factors on the common pathway to both diseases should attenuate the association between the diseases.
Several studies have examined the relation between glucose levels and carotid artery IMT in nondiabetic individuals. The Atherosclerosis Risk in Communities (ARIC) Study reported a positive, nonsignificant association between fasting glucose and carotid artery IMT, whereas a case-control study nested within this cohort reported a positive association between increasing quartile of glycosylated hemoglobin and elevated carotid artery IMT that was somewhat attenuated with adjustment for covariates.31 The Insulin Resistance Atherosclerosis Study (IRAS) reported no elevation in either CCA IMT or ICA IMT in individuals with impaired glucose tolerance when compared with individuals with normal glucose tolerance.32 A primary prevention study carried out in a Japanese community reported a positive association between glycosylated hemoglobin and IMT in women (n=715) but not in men (n=620).33 Finally, in a cohort of individuals at risk of developing diabetes (n=502) or in the early stages of diabetes (n=80), although carotid artery IMT was associated with fasting plasma glucose and glycosylated hemoglobin, it was more strongly associated with postchallenge plasma glucose and postchallenge plasma glucose spikes.34 In summary, glucose levels might be moderately predictive of atherosclerosis in nondiabetic individuals; it is apparent, however, that they are not strong predictors.
Similar to the NHS,6 the current study identified individuals who subsequently developed diabetes and compared them with those who remained free of diabetes. Hence, the current study examined the actual prediabetic state in relation to atherosclerosis and not merely markers of the prediabetic state, such as impaired glucose tolerance.
One would expect carotid artery IMT and the established diabetes risk factors to be at least as elevated in diabetic individuals as in prediabetic individuals. Hence, the lower ICA IMT among prevalent diabetic participants when compared with prediabetic participants, though not statistically significant, along with the more favorable risk factor profile among prevalent diabetic participants when compared with prediabetic participants, was somewhat unexpected. Both CCA IMT and ICA IMT are viewed as quantitative markers of generalized atherosclerosis; unfortunately, the latter, where plaques are more likely to occur, is more difficult to measure than the former. The ability to measure ICA IMT is associated with obesity, neck height, arterial depth, and bifurcation height. In our study population, CCA IMT measurements were missing for only 1.4% of participants; however, whereas 13.1% of the nondiabetic and 14.9% of the diabetic participants with CCA IMT measurements were missing ICA IMT measurements, only 4.6% of the prediabetic participants were missing these measurements. This suggests that ICA IMT measurements were not missing randomly and consequently could explain the unexpected results with respect to ICA IMT. Furthermore, the BMI and waist circumference differences between diabetic and prediabetic participants could have been due to weight loss after the onset of clinical diabetes; smoking differences could have been due to health education and a greater health consciousness after diabetes had been diagnosed. Hence, limited statistical power, a higher percentage of missing ICA IMT measurements, and a higher prevalence of former smokers (ie, healthier behaviors) among diabetic participants are possible explanations for the lower ICA IMT among prevalent diabetic participants when compared with prediabetic participants.35 An alternative explanation is that survival favored diabetic individuals with lower levels of atherosclerosis in the ICA.
Moreover, in the current study, the expected difference between CCA IMT and ICA IMT was present in the prediabetic (0.09 mm) participants but not in the nondiabetic (0.02 mm) or diabetic (0.03 mm) participants. In the ARIC study, ICA IMT was 
0.11 mm thicker than the CCA IMT overall,36 whereas in the IRAS, ICA IMT was 0.11, 0.10, 0.02, and 0.14 mm thicker than the CCA IMT in nondiabetic individuals, individuals with impaired glucose tolerance, individuals with undiagnosed diabetes, and individuals with diagnosed diabetes, respectively.37 Again, a potential explanation for this in our study is the higher frequency of missing ICA IMT measurements in nondiabetic and diabetic participants than in prediabetic participants.
Potential limitations of the study include the modest sample size, the completeness of the follow-up, and the high rate of missing ICA IMT measurements, as well as the uncertain generalizability of the study results. Of the 1496 study participants, there were only 66 individuals identified as prediabetic (or incident-diabetic at the second follow-up examination), limiting the power to detect significant associations. As a result, even well-established risk factors for the development of diabetes, such as a family history of diabetes, were not statistically significantly associated with the development of diabetes in our multivariate logistic-regression models. Furthermore, of the original cohort (N=2282), only 65.6% had complete information on diabetes status and CCA IMT, and only 57.0% had complete information on diabetes status and ICA IMT. Hence, the response rate does not rule out the potential for selection bias that might influence external validity and generalizability of the study.
Documenting subclinical carotid atherosclerosis before the onset of clinical diabetes provides direct evidence, at the vascular level, that atherosclerosis levels are elevated before the clinical onset of diabetes. Before the recent report from the NHS6 and this study, support for the hypothesis that diabetes and cardiovascular disease shared common antecedents was merely an inference based on elevated levels of cardiovascular risk factors in prediabetic individuals. Although results from the NHS indicate that cardiovascular disease events were elevated before the onset of clinical diabetes, results from the present study indicate that atherosclerosis itself was also elevated before the onset of clinical diabetes. Hence, results from the current study suggest again that increased atherosclerosis is responsible for elevated cardiovascular disease before the onset of clinical diabetes. If, as we and the recent publication from the NHS suggest,6 the association between diabetes and CHD stems mainly from common antecedents, one way to prevent the development of atherosclerosis would be to identify and intervene in those at high risk of developing diabetes.
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Acknowledgments |
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We acknowledge support from the National Heart, Lung, and Blood Institute (R01-HL24799, T32-HL07446); the American Diabetes Association (mentor-based award); the American Heart Association, Texas Affiliate (postdoctoral fellowship); and Consejo Nacional de Ciencia y Tecnología CONACYT (2092/M9303, F677-M9407, and 3502-M9607). The Fundación Mexicana para la Salud provided administrative support.
Received July 30, 2003; accepted August 20, 2003.
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F. B. Hu and M. J. Stampfer Is Type 2 Diabetes Mellitus a Vascular Condition? Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1715 - 1716. [Full Text] [PDF]
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