ARIC Manuscript Proposal #1233. PC Reviewed: 4_/_10/07 Status: _A Priority: 2_ SC Reviewed: Status: Priority:

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1 ARIC Manuscript Proposal #1233 PC Reviewed: 4_/_10/07 Status: _A Priority: 2_ SC Reviewed: Status: Priority: 1.a. Full Title: Subclinical atherosclerosis precedes type 2 diabetes in the ARIC study cohort b. Abbreviated Title (Length 26 characters): CIMT and diabetes 2. Writing Group: Writing group members: Anna Kucharska-Newton, Gerardo Heiss, David Couper, A. Richey Sharrett, Linda Kao I, the first author, confirm that all the coauthors have given their approval for this manuscript proposal. AMK-N [please confirm with your initials electronically or in writing] First author: Address: Anna Kucharska-Newton Department of Epidemiology, CVD Program Bank of America Center 137 E. Franklin St. Chapel Hill, NC CB# 8050 Phone: (919) Fax: (919) Anna_Newton@unc.edu Corresponding/senior author (if different from first author correspondence will be sent to both the first author & the corresponding author): Address: Anna Kucharska-Newton (as above) 3. Timeline: Data analysis to be started immediately following approval of the proposal and completed by April Manuscript preparation to be completed by June 2007.

2 4. Rationale: Micro- and macrovascular morbidity and their associated mortality are the most common complications of type 2 diabetes (1), the incidence and prevalence of which continues to increase (2). Research, however, suggests that a cardiovascular risk profile precedes diagnosis of diabetes (3) and clustering of traditional cardiovascular disease risk factors is associated with increased risk of diabetes (4-6). We wish to address the degree to which macrovascular damage occurs prior to manifest type 2 diabetes (T2DM), or even prediabetes. In a study based on the Nurses Health Study cohort, Hu et al. (7) reported a significantly elevated risk of myocardial infarction (MI) among women free of diabetes at baseline, who subsequently to the diagnosis of MI, developed type 2 diabetes. This study is to our knowledge the only one which has documented an association of cardiovascular events with risk of subsequent diabetes. It is however a retrospective analysis in which the outcome and exposure are diagnosed disease states. We propose that a prospective analysis of baseline subclinical atherosclerosis, determined on the basis of carotid intimamedia thickness, and its hypothesized association with incident prediabetes and diabetes would be more informative. Use of carotid intima-media thickness (CIMT) as a measure of subclinical atherosclerosis has been validated in many studies and although discussions persist, increased thickness at the carotid artery sites is understood to reflect systemic burden of atherosclerosis of the coronary vessels (8-10). High fasting insulin levels, high fasting glucose levels and diagnosed diabetes have all been found to be associated with elevated CIMT (11-14). Furthermore, autopsy studies indicate that levels of coronary atherosclerosis in individuals with diabetes, free of clinical cardiovascular disease, approach those of nondiabetic individuals with overt cardiovascular disease (15). These data provide the basis for the study proposed here, aimed at a detailed examination of a possible association of subclinical atherosclerosis / cardiovascular risk with subsequent development of hyperglycemic states. References: 1. Standl E, Schnell O. A new look at the heart in diabetes mellitus: from ailing to failing. Diabetologia 2000;43: King H, Aubert R, Herman W. Global burden of diabetes, : prevalence, numerical estimates, and projections. Diabetes Care 1998;21: Haffner SM, Stern MP, Hazuda HP, et al. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA 1990;263: Grundy SM, Hansen B, Smith SC, Jr, et al. Clinical Management of Metabolic Syndrome: Report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association Conference on Scientific Issues Related to Management. Circulation 2004;109: Hanson RL, Imperatore G, Bennett PH, et al. Components of the "metabolic syndrome" and incidence of type 2 diabetes. Diabetes 2002;51:

3 6. Laaksonen DE, Lakka H-M, Niskanen LK, et al. Metabolic Syndrome and Development of Diabetes Mellitus: Application and Validation of Recently Suggested Definitions of the Metabolic Syndrome in a Prospective Cohort Study. Am. J. Epidemiol. 2002;156: Hu FB, Stampfer MJ, Haffner SM, et al. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care 2002;25: Pignoli P, Tremoli E, Poli A, et al. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation 1986;74: Salonen JT, Salonen R. Ultrasonographically Assessed Carotid Morphology and the Risk of Coronary Heart Disease. [Article]. Arteriosclerosis, Thrombosis & Vascular Biology September/October 1991;11: Wofford JL, Kahl FR, Howard GR, et al. Relation of Extent of Extracranial Carotid Artery Atherosclerosis as Measured by B-Mode Ultrasound to the Extent of Coronary Atherosclerosis. [Article]. Arteriosclerosis, Thrombosis & Vascular Biology November/December 1991;11: Chambless LE, Folsom AR, Davis V, et al. Risk factors for progression of common carotid atherosclerosis: The Atherosclerosis Risk in Communities Study, American Journal of Epidemiology 2002;155: Yamasaki Y, Kawamori R, Matsushima H, et al. Asymptomatic hyperglycaemia is associated with increased intimal plus medial thickness of the carotid artery. Diabetologia 2003;38: Folsom AR, Eckfeldt JHM, Weitzman S, et al. Relation of Carotid Artery Wall Thickness to Diabetes Mellitus, Fasting Glucose and Insulin, Body Size, and Physical Activity. [Article]. Stroke January 1994;25: Crouse J, Toole J, McKinney W, et al. Risk factors for extracranial carotid artery atherosclerosis. Stroke 1987;18: Goraya TY, Leibson CL, Palumbo PJ, et al. Coronary atherosclerosis in diabetes mellitus: A population-based autopsy study. J Am Coll Cardiol 2002;40: Carroll RJD,, D R, et al. Measurement Error in Nonlinear Models. 1995;London: Chapman & Hall/CRC. 17. Howard G, Wagenknecht LE, Burke GL, et al. Cigarette Smoking and Progression of Atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Study. JAMA 1998;279: Haffner SM, Stern MP, Hazuda HP, et al. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA 1990;263: Main Hypothesis/Study Questions: We posit that incident diabetes and pre-diabetes are positively associated with prior levels of subclinical atherosclerosis. Further, intima media thickness is inversely related to time to prediabetes and manifest / diagnosed diabetes. Study objectives: The main objective of this study is to assess the extent of subclinical atherosclerosis as measured by levels of carotid intima-media thickness, as a function of time to the development of pre-diabetes and diabetes. In order to fulfill this objective we will: 1. Characterize the average baseline age-adjusted far-wall carotid intima-media thickness (CIMT) in members of the ARIC cohort who are at baseline free of

4 CHD diagnosis and have normal glucose levels, according to incident prediabetes and diabetes status during follow-up. 2. Quantify the risk of incident pre-diabetes in normoglycemic individuals according to baseline CIMT 3. Quantify the risk of incident type 2 diabetes (in individuals free of diabetes at baseline) according to baseline CIMT 6. Design and analysis (study design, inclusion/exclusion, outcome and other variables of interest with specific reference to the time of their collection, summary of data analysis, and any anticipated methodologic limitations or challenges if present). 1. Study population: ARIC cohort members free of prevalent coronary heart disease, diabetes and prediabetes at baseline, as determined by absence of diagnosis of diabetes and/ or fasting blood glucose levels <=100 mg/dl. Additional exclusions: ARIC cohort members with race other than black or white and black cohort participants from Washington County, MD and Minneapolis, MN as well as ARIC cohort participants missing exposure data. 2. Preliminary power analyses based on definition of elevated carotid intima media thickness as thickness greater than 90% of the sample distribution indicate a minimal detectable hazard ratio of 1.75 with 90% power and 95% confidence. 3. Diabetes will be defined as either a physician s diagnosis of diabetes, use of hypoglycemic medications, or fasting blood glucose level greater than 126 mg/dl. Prediabetes will be defined as fasting blood glucose levels mg/dl. 4. Carotid intima media thickness will be determined as the average of imputed intima-media thickness values of the far wall measured across three segments (common carotid artery, carotid bifurcation and internal carotid artery) in the left and right carotid arteries. This analysis will be based primarily on carotid intima media thickness (CIMT) measurements obtained during the initial baseline visit (gender and race specific, imputed, reader and trend-adjusted far wall thickness, or mna45_1). Statistical techniques of regression calibration (16) will be used to account for CIMT measurement error (11) 5. Data analysis: since information concerning incidence of diabetes is available only at follow-up visits we will use interval-censored Cox proportional hazard regression models in our analysis of the risk of prediabetes and diabetes. We will compare data obtained from those models with Cox proportional hazard regression analyses performed using interpolated diabetes incidence data. 6. Variables to be included in analysis: age, race, gender, body mass index (BMI), waist hip ratio (WHR), cigarette smoking, HDL-cholesterol, hypertension, family history of diabetes, fasting insulin levels, ARIC center, use of anti-inflammatory medications. Our multivariable analysis will include the following models: demographic model: variables: age, gender, race, and ARIC center

5 diabetes risk model 1: demographic model plus hypertension, cigarette smoking (ever versus never), use of anti-inflammatory medications diabetes risk model 2: diabetes risk model 1 plus HDL-cholesterol, triglycerides, body mass index, waist hip ratio diabetes risk model 3: diabetes risk model 2 plus glucose, family history of diabetes, fasting insulin levels, fasting glucose levels Potentially confounding effects of age, HDL-cholesterol and BMI on the association of CIMT and incidence of prediabetes and type 2 diabetes will be addressed by adjusting for those variables in the multivariable analysis (diabetes risk models 2 and 3). Possible effect modification of the association of CIMT and incidence of prediabetes and type 2 diabetes by gender, race, cigarette smoking, family history of diabetes, and hypertension will be examined in the context of diabetes risk model 3 by incorporation into the model of those variables plus their two-way interaction terms with a dichotomously coded CIMT variable. Additional assessment of potential effect measure modification of smoking on the association of carotid intima media thickness (17) with diabetes will be done by repeating the analyses using models stratified by smoking status (current, former and never smokers). Fasting insulin levels predict cardiovascular risk factor pattern in prediabetic subjects (18); we will therefore examine the association of CIMT and incident prediabetes and type2 diabetes as a function of baseline fasting insulin levels. 7.a. Will the data be used for non-cvd analysis in this manuscript? X_ No Yes b. If Yes, is the author aware that the file ICTDER02 must be used to exclude persons with a value RES_OTH = CVD Research for non-dna analysis, and for DNA analysis RES_DNA = CVD Research would be used? Yes No (This file ICTDER02 has been distributed to ARIC PIs, and contains the responses to consent updates related to stored sample use for research.) 8.a. Will the DNA data be used in this manuscript? X No Yes 8.b. If yes, is the author aware that either DNA data distributed by the Coordinating Center must be used, or the file ICTDER02 must be used to exclude those with value RES_DNA = No use/storage DNA? Yes No 9.The lead author of this manuscript proposal has reviewed the list of existing ARIC Study manuscript proposals and has found no overlap between this proposal and

6 previously approved manuscript proposals either published or still in active status. ARIC Investigators have access to the publications lists under the Study Members Area of the web site at: X Yes No 10. What are the most related manuscript proposals in ARIC (authors are encouraged to contact lead authors of these proposals for comments on the new proposal or collaboration)? MS# 473 Kao et al. Carotid artery atherosclerosis and the risk of non-insulin dependent diabetes mellitus. This study is similar in concept to our proposed study. However, it addresses only the question of the risk of diabetes at the time six years past baseline and proposed a case-cohort design. Our study differs in that its aim is to assess carotid IMT preceding incident prediabetes and diabetes, from baseline through up to 3 follow-up visits conducted in the ARIC study, and to do this in the entire eligible cohort. MS# 546: Duncan B et al. Subclinical markers and incident CHD in diabetes mellitus. Proposal was withdrawn 11. a. Is this manuscript proposal associated with any ARIC ancillary studies or use any ancillary study data? Yes X No 11.b. If yes, is the proposal A. primarily the result of an ancillary study (list number* ) B. primiarly based on ARIC data with ancillary data playing a minor role (usually control variables; list number(s)* ) *ancillary studies are listed by number at Manuscript preparation is expected to be completed in one to three years. If a manuscript is not submitted for ARIC review at the end of the 3-years from the date of the approval, the manuscript proposal will expire.