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Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Nondiabetic Adults Elizabeth Selvin, Ph.D., M.P.H., Michael W. Steffes, M.D., Ph.D., Hong Zhu, B.S., Kunihiro Matsushita, M.D., Ph.D., Lynne Wagenknecht, Dr.P.H., James Pankow, Ph.D., M.P.H., Josef Coresh, M.D., Ph.D., and Frederick L. Brancati, M.D., M.H.S.
From the Department of Epidemiology Fasting glucose is the standard measure used to diagnose diabetes in the United States. and the Welch Center for Prevention, Epi- Recently, glycated hemoglobin was also recommended for this purpose.
demiology, and Clinical Research (E.S.,
K.M., J.C., F.L.B.), and the Department of
Biostatistics (H.Z., J.C.), Johns Hopkins Methods
Bloomberg School of Public Health; and We compared the prognostic value of glycated hemoglobin and fasting glucose for
the Division of General Internal Medicine, Department of Medicine, Johns Hopkins identifying adults at risk for diabetes or cardiovascular disease. We measured glycated University (E.S., J.C., F.L.B.) — all in Bal- hemoglobin in whole-blood samples from 11,092 black or white adults who did not timore; the Department of Laboratory have a history of diabetes or cardiovascular disease and who attended the second Medicine and Pathology, Medical School (M.W.S.), and the Division of Epidemiol- visit (occurring in the 1990–1992 period) of the Atherosclerosis Risk in Communi- ogy and Community Health (J.P.), Uni- ties (ARIC) study.
versity of Minnesota, Minneapolis; and
the Division of Public Health Sciences, Results
Wake Forest University School of Medi-cine, Winston-Salem, NC (L.W.). Address The glycated hemoglobin value at baseline was associated with newly diagnosed reprint requests to Dr. Selvin at Johns diabetes and cardiovascular outcomes. For glycated hemoglobin values of less than Hopkins Bloomberg School of Public Health, 2024 E. Monument St., Suite 2-600, 5.0%, 5.0 to less than 5.5%, 5.5 to less than 6.0%, 6.0 to less than 6.5%, and 6.5% Baltimore, MD 21287, or at lselvin@ or greater, the multivariable-adjusted hazard ratios (with 95% confidence intervals) for diagnosed diabetes were 0.52 (0.40 to 0.69), 1.00 (reference), 1.86 (1.67 to 2.08), N Engl J Med 2010;362:800-11.
4.48 (3.92 to 5.13), and 16.47 (14.22 to 19.08), respectively. For coronary heart dis- Copyright 2010 Massachusetts Medical Society. ease, the hazard ratios were 0.96 (0.74 to 1.24), 1.00 (reference), 1.23 (1.07 to 1.41), 1.78 (1.48 to 2.15), and 1.95 (1.53 to 2.48), respectively. The hazard ratios for stroke were similar. In contrast, glycated hemoglobin and death from any cause were found to have a J-shaped association curve. All these associations remained significant after adjustment for the baseline fasting glucose level. The association between the fast- ing glucose levels and the risk of cardiovascular disease or death from any cause was not significant in models with adjustment for all covariates as well as glycated hemoglobin. For coronary heart disease, measures of risk discrimination showed sig- nificant improvement when glycated hemoglobin was added to models including fasting glucose.
Conclusions
In this community-based population of nondiabetic adults, glycated hemoglobin was
similarly associated with a risk of diabetes and more strongly associated with risks of cardiovascular disease and death from any cause as compared with fasting glu- cose. These data add to the evidence supporting the use of glycated hemoglobin as a diagnostic test for diabetes.
n engl j med 362;9 nejm.org march 4, 2010 Downloaded from www.nejm.org at UNIVERSITAET BERN on March 22, 2010 . Copyright 2010 Massachusetts Medical Society. All rights reserved. Glycated Hemoglobin, Diabetes, and Cardiovascular Risk Fasting glucose is the standard mea- with three follow-up visits taking place, each ap- sure used for the diagnosis of diabetes in the proximately every 3 years.11,12 Visit 2 (during United States.1,2 Historically, glycated hemo- 1990–1992), attended by 14,348 participants, was globin has been recommended only for the deter- the only visit for which stored whole-blood sam- mination of glucose control among persons who ples were available for measurement of glycated have already received the diagnosis of diabetes. hemoglobin; this was the baseline visit in the pres- New clinical practice recommendations from the ent study. We excluded participants who identified American Diabetes Association advocate the use themselves as other than white or black, as well of glycated hemoglobin in the diagnosis of diabe- as those who had self-reported diabetes or use of tes, largely on the basis of the established associa- diabetes medication (as recorded during visit 1 or tion between glycated hemoglobin and microvas- visit 2), or a history of cardiovascular disease (as cular disease.3 Compared with fasting glucose, recorded during visit 1 or visit 2) or a validated glycated hemoglobin has several advantages as a cardiovascular event between visit 1 and visit 2 or diagnostic test: it has higher repeatability,4-6 can who were in a nonfasting state or had missing data. be assessed in the nonfasting state, and is the pre- Our final sample size was 11,092 persons. Insti- ferred test for monitoring glucose control.1 Long- tutional review boards at each clinical site approved term prognostic data are also useful for informing the study protocol, and written informed consent diagnostic cutoff points for asymptomatic condi- was obtained from all participants.
tions, and there is evidence that elevated glycated hemoglobin values may be a risk factor for mac- Measurement of Glycated Hemoglobin
rovascular disease.
We thawed and assayed frozen whole-blood sam- This study was designed to characterize and ples collected at ARIC visit 2 for the measurement compare the relationships between values of gly- of glycated hemoglobin using high-performance cated hemoglobin and fasting glucose and the risk liquid chromatography (with the use of the Tosoh of diabetes, coronary heart disease, ischemic A1c 2.2 Plus Glycohemoglobin Analyzer method stroke, and death from any cause in a large com- in 2003–2004 and the Tosoh G7 method in 2007– munity-based cohort of middle-aged adults who 2008, Tosoh Corp). (Both instruments were stan- did not have a history of diabetes. We also inves- dardized to the Diabetes Control and Complica- tigated whether the association of glycated he- tions Trial assay.) moglobin with newly diagnosed cardiovascular disease could be explained by the intervening Assessment of Diabetes
development of diabetes. We hypothesized that The serum glucose level was measured by means glycated hemoglobin would be superior to fast- of the hexokinase method. We used two defini- ing glucose as an indicator of risk for the devel- tions of newly identified diabetes: a visit-based opment of diabetes and cardiovascular disease and definition and an interview-based definition. Visit- for death, with possible differences on the basis of based diabetes was defined according to a race or ethnic group. Blacks who have diabetes are standard time-to-diabetes definition based on glu- well known to have higher glycated hemoglobin cose measurements, a self-reported diagnosis of values than their white counterparts; the same diabetes, or medication use for a maximum of disparity holds among nondiabetic adults.7-10 How- 6 years of follow-up.13 Interview-based diabetes ever, the clinical implications of these disparities was defined on the basis of a self-reported diabe- are unknown, and few data exist on glycated he- tes diagnosis or diabetes medication use during moglobin and outcomes among blacks.
the ARIC visits and subsequent annual telephone calls for a maximum of 15 years of follow-up.
Other Variables of Interest
Plasma lipid level,14-17 body-mass index (BMI), The Atherosclerosis Risk in Communities (ARIC) waist-to-hip ratio,18 and blood pressure19 were mea- study is a community-based prospective cohort sured according to the published methods. Hyper- study of 15,792 middle-aged adults from four U.S. tension was defined as the average of two blood- communities. The first examination of participants pressure readings at the visit (with systolic blood (visit 1) took place during the 1987–1989 period, pressure having a cutoff point of 140 mm Hg or n engl j med 362;9 nejm.org march 4, 2010 Downloaded from www.nejm.org at UNIVERSITAET BERN on March 22, 2010 . Copyright 2010 Massachusetts Medical Society. All rights reserved. higher and diastolic blood pressure having a cut- (4950) and was used as the reference category. To off point of 90 mm Hg or higher) or the use of hy- assess the continuous associations between the pertension medication. Participants reported their glycated hemoglobin value and clinical outcomes education level, alcohol use, and smoking status. in the models, we generated piecewise linear The level of physical activity was assessed with the splines with knots corresponding to the glycated use of Baecke's questionnaire at ARIC visit 1.20 hemoglobin cutoff points used in this study; we also implemented restricted cubic splines to ob- Surveillance for Newly Diagnosed Coronary
tain a smoother fit to the data. Model discrim- Heart Disease, Stroke, and Death from Any Cause ination was assessed with the use of Harrell's
The ascertainment of deaths and classification of C statistic.23 cardiovascular events are detailed elsewhere.21,22 We tested for interactions with race and sex. Briefly, potential cardiovascular hospitalizations To investigate whether a diagnosis of diabetes were reported annually by participants and also made before a cardiovascular event or death could identified through community-wide hospital sur- explain potential associations with glycated hemo- veillance. Trained personnel abstracted hospital globin, we conducted analyses in which cases of records related to possible cardiovascular events.22 diagnosed diabetes occurring before the event of Silent myocardial infarctions, as detected by means interest were censored. We also conducted analy- of electrocardiography during the visits, were iden- ses examining the association of each outcome tified and recorded. We defined newly diagnosed with the baseline glycated hemoglobin value after coronary heart disease as a definite or probable excluding persons with a fasting glucose level of myocardial infarction, a death from coronary heart 126 mg per deciliter or higher at either ARIC visit disease, a cardiac procedure, or electrocardio- 1 or 2. To assess whether glycated hemoglobin was graphic evidence of a silent myocardial infarction. associated with a risk of the outcomes across cat- We also examined definite or probable ischemic egories of fasting glucose at baseline, we con- stroke. Adjudicated follow-up data for cardiovas- ducted analyses of combined categories of glycated cular events were available up to January 1, 2006. hemoglobin and fasting glucose. To evaluate the overall improvement in risk classification for the addition of glycated hemoglobin to fully adjusted Baseline characteristics of the study population models including fasting glucose, we calculated (from ARIC visit 2) were calculated both overall the net-reclassification-improvement statistic and and according to categories of glycated hemoglo- the integrated-discrimination-improvement sta- bin values (<5.0%, 5.0 to <5.5%, 5.5 to <6.0%, 6.0 tistic.24 to <6.5%, and ≥6.5%). Adjusted hazard ratios and All reported P values are two-sided. They are corresponding 95% confidence intervals were es- not adjusted for multiple comparisons.
timated with the use of Cox proportional-hazards models. The three core models were as follows: Model 1 was adjusted for age, sex, and race. Model 2 was adjusted for age, sex, race, low-density and Baseline characteristics of the study population, high-density cholesterol levels, triglyceride level, both overall and according to the glycated hemo- BMI, waist-to-hip ratio, hypertension, family his- globin category, are shown in Table 1. Glycated tory of diabetes, education level, alcohol use, physi- hemoglobin and fasting glucose levels at baseline cal activity, and smoking status. We evaluated mod- were highly correlated (r = 0.73). Participants with els 1 and 2 with regard to either the glycated elevated glycated hemoglobin levels were more hemoglobin categories (called models 1a and 2a) likely to be black than white, and to have fewer or standard fasting glucose categories (<100, 100 years of education, and to have an adverse lipid pro- to <126, and ≥126 mg per deciliter [5.6, 5.6 to <7.0, file and a higher BMI and were less likely to be and ≥7.0 mmol per liter, respectively]) (called mod- current drinkers than to have formerly or never els 1b and 2b). Finally, model 3 was adjusted for all used alcohol. As documented in previous studies, the variables in model 2 plus either the baseline in our nondiabetic population, blacks had sig- fasting glucose level (model 3a) or the baseline gly- nificantly higher mean glycated hemoglobin val- cated hemoglobin value (model 3b).
ues (5.8%) than whites (5.4%) (P<0.001).
The glycated hemoglobin category of 5.0 to less The median follow-up time was approximately than 5.5% had the largest number of participants 14 years. More than 80% of the participants at- n engl j med 362;9 nejm.org march 4, 2010 Downloaded from www.nejm.org at UNIVERSITAET BERN on March 22, 2010 . Copyright 2010 Massachusetts Medical Society. All rights reserved. Glycated Hemoglobin, Diabetes, and Cardiovascular Risk Table 1. Selected Characteristics of the Study Participants, According to the Glycated Hemoglobin Value at Baseline.*
Glycated Hemoglobin Category
Glycated hemoglobin (%) Fasting glucose (mg/dl) Fasting glucose category (%) 100 to <126 mg/dl Fasting cholesterol (mg/dl) Fasting triglycerides (mg/dl) Interquartile range Body-mass index§ Waist-to-hip ratio Family history of diabetes (%) Less than high school High school or equivalent Baecke's physical-activity index score¶ Smoking status (%) * Plus–minus values are means ±SD. To convert the values for fasting glucose to millimoles per liter, multiply by 0.05551. To convert the val- ues for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. HDL denotes high-density lipoprotein, and LDL low-density lipoprotein.
† The 699 persons (6.3%) with a fasting glucose level of 126 mg per deciliter (7 mmol per liter) or higher at baseline (8, 56, 112, 185, and 338 persons with a glycated hemoglobin category of <5.0%, 5.0 to <5.5%, 5.5 to <6.0%, 6.0 to <6.5%, and ≥6.5%, respectively) were excluded from the visit-based analysis examining the risk of diabetes with the use of fasting glucose levels during the first 6 years of follow-up but were included in the interview-based analysis of diagnosed diabetes during the 15 years of follow-up.
‡ Race was self-reported.
§ The body-mass index is the weight in kilograms divided by the square of the height in meters.
¶ Baecke's physical-activity index is measured with the use of a questionnaire about leisure-time sports activities developed by Baecke et al.20 The scale ranges from 1 to 4, with a score of 4 indicating the greatest activity.
n engl j med 362;9 nejm.org march 4, 2010 Downloaded from www.nejm.org at UNIVERSITAET BERN on March 22, 2010 . Copyright 2010 Massachusetts Medical Society. All rights reserved. tended each clinic visit, and retention of ARIC threshold for the risk of coronary heart disease. participants during the follow-up period was high There was no significant association between the (>90%). During the first 6 years of follow-up, 620 glycated hemoglobin value and the risk of coro- participants were identified as having diabetes, nary heart disease at glycated hemoglobin values of according to the visit-based diabetes definition. less than 5.0%, but as compared with that cate- During the full 15 years of follow-up, 2251 par- gory, glycated hemoglobin values of 5.5% or higher ticipants reported a diagnosis of diabetes or use of were associated with a hazard ratio for coronary diabetes medication (the interview-based defi- heart disease of 1.38 (95% confidence interval [CI], nition of diabetes), there were 1198 validated cases 1.22 to 1.56). For death from any cause, we ob- of coronary heart disease and 358 valida ted cases served a J-shaped association. Participants with of ischemic stroke, and 1447 participants died.
glycated hemoglobin values in the lowest catego- The crude cumulative 15-year incidence (calcu- ry (<5.0%) had a significantly higher risk of death lated as the incidence proportion) of self-reported from any cause as compared with those with gly- diabetes was 20%. (See the Supplementary Appen- cated hemoglobin levels of 5.0 to less than 5.5% dix, available with the full text of this article at (Table 2 and Fig. 2). In post hoc analyses, the NEJM.org, for a discussion of self-reported diabe- J-shaped association persisted after the exclusion tes vs. verified diabetes.) The cumulative incidence of participants with anemia, adjustment for he- of diagnosed diabetes was 6%, 12%, 21%, 44%, matocrit level and mean corpuscular volume, and and 79% among participants with a glycated he- the exclusion of deaths that occurred during the moglobin value of less than 5.0%, 5.0 to less than first 3 years of follow-up (data not shown). In 5.5%, 5.5 to less than 6.0%, 6.0 to less than 6.5%, analyses censoring data for persons who received and 6.5% or higher, respectively. The incidence a diagnosis of diabetes during the follow-up pe- rates (per 1000 person-years) are shown according riod, the associations remained significant be- to the category of glycated hemoglobin in Figure 1. tween glycated hemoglobin and coronary heart The adjusted hazard ratios (and 95% confidence disease, stroke, and death from any cause.
intervals) of the 6-year risk of visit-based diabetes The fasting glucose categories were associat- and 15-year risk of the other outcomes are shown ed with the risks of outcomes in the minimally in Table 2 according to the category of glycated adjusted models, but these associations were at- hemoglobin. A baseline glycated hemoglobin value tenuated after adjustment for other risk factors of less than 5.0%, as compared with a value of 5.0 (Table 3). As compared with a baseline fasting to less than 5.5%, was associated with approxi- glucose level of less than 100 mg per deciliter, mately half the risk of visit-based or diagnosed a level of 100 to less than 126 mg per deciliter was diabetes (hazard ratios for each outcome in mod- associated with diagnosed diabetes (hazard ratio, els 1 and 2, approximately 0.50). Additional adjust- 2.31; 95% CI, 2.06 to 2.59) but not with coronary ment for the fasting glucose level (in model 3a) heart disease (hazard ratio, 1.03; 95% CI, 0.91 to attenuated this association, but the glycated he- 1.18), ischemic stroke (hazard ratio, 0.97; 95% CI, moglobin category remained strongly associated 0.76 to 1.23), and death from any cause (hazard with diagnosed diabetes. We also observed sig- ratio, 1.07; 95% CI, 0.96 to 1.21) after adjustment nificant trends of an increasing risk of coronary for covariates (model 2b) (Table 3), whereas un- heart disease, ischemic stroke, and death from diagnosed diabetes (defined as a fasting glucose any cause with higher levels of baseline glycated level of 126 mg per deciliter or higher at base- hemoglobin. These associations persisted even af- line) was significantly, independently associated ter adjustment for fasting glucose (model 3a).
with the development of coronary heart disease Figure 2 depicts the adjusted hazard ratios for (hazard ratio, 1.29; 95% CI, 1.04 to 1.61), ischemic diagnosed diabetes, coronary heart disease, stroke, stroke (hazard ratio, 1.89; 95% CI, 1.33 to 2.69), and death from any cause and the baseline gly- and death from any cause (hazard ratio, 1.31; 95% cated hemoglobin category — per each absolute CI, 1.07 to 1.61). After additional adjustment for increase of 1 percentage point in the glycated he- glycated hemoglobin in model 3b, there was no moglobin value. There was no evidence of a thresh- significant association between fasting glucose old value of glycated hemoglobin for diagnosed category and the risk of coronary heart disease, diabetes, but there was evidence for a possible ischemic stroke, or death from any cause. Among n engl j med 362;9 nejm.org march 4, 2010 Downloaded from www.nejm.org at UNIVERSITAET BERN on March 22, 2010 . Copyright 2010 Massachusetts Medical Society. All rights reserved. Glycated Hemoglobin, Diabetes, and Cardiovascular Risk the 10,069 participants with a fasting glucose level of less than 126 mg per deciliter at visit 1 and visit 2, the glycated hemoglobin category was similarly associated, in model 3b as compared with models 1b and 2b, with diagnosed diabetes, coronary heart disease, stroke, and death from any cause (Table 2 in the Supplementary Appendix).
We also assessed the associations of three cat- egories of glycated hemoglobin (<6.0%, 6.0 to <6.5%, and ≥6.5%) with the risks of outcomes among participants stratified according to the (per 1000 person-yr)
fasting glucose category (<100, 100 to <126, and ≥126 mg per deciliter) (Table 3 in the Supplemen- tary Appendix). The glycated hemoglobin catego- Incidence Rate of Diagnosed Diabetes
ries of 6.0 to less than 6.5% and 6.5% or higher were significantly associated with all outcomes within each fasting glucose category, with the as- sociation increasing with higher glycated hemo- Baseline Glycated Hemoglobin (%)
globin categories. In contrast, if the glycated he- Figure 1. The Incidence Rate of Self-Reported Diagnosed Diabetes in the
moglobin value was less than 6.0%, fasting glucose Study Population, According to the Baseline Glycated Hemoglobin Category.
was not significantly associated with coronary The incide FIGURE: s are shown, per 1000 person-years, for th 3rd heart disease, ischemic stroke, or death from any each glycated hemoglobin category. The I bars denote the 95% confidence There was no significant interaction between sex and glycated hemoglobin category for any of AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
the clinical outcomes (P>0.20 for all interactions). Please check carefully.
There was also no significant interaction between race and glycated hemoglobin value regarding the Among the people in the United States who do risk of coronary heart disease, ischemic stroke, or not have a diagnosis of diabetes, over 2.4 million death from any cause (P>0.80 for all interactions). have a glycated hemoglobin value higher than 6.5% However, race did appear to modify the asso- and 7 million have a value higher than 6.0%.7 Our ciation between the glycated hemoglobin value findings show that people with a glycated hemo- and the risk of diagnosed diabetes during 15 years globin value of 6.0% or higher are at high risk for of follow-up (P = 0.007 for interaction), but there the development of diabetes, even after adjustment was no interaction between race and the asso- for other risk factors and independently of base- ciation between glycated hemoglobin value and line fasting glucose levels. We also observed that the 6-year risk of visit-based diabetes (P = 0.81 glycated hemoglobin is a marker of cardiovascu- for interaction). As compared with whites, blacks lar risk. In this nondiabetic population, glycated had lower adjusted hazard ratios for reporting a hemoglobin remained associated with cardiovas- diagnosis of diabetes during the 15 years of fol- cular disease and death even after we accounted low-up, within each category of glycated hemo- for baseline fasting glucose levels; in contrast, fast- globin. A similar interaction was also observed ing glucose was not significantly associated after between race and fasting glucose level regarding adjustment for the glycated hemoglobin value. the risk of self-reported diabetes (P = 0.01 for in- We also demonstrated improved risk reclassifica- tion for coronary heart disease with the inclusion The net-reclassification-improvement and in- of glycated hemoglobin in fully adjusted models, tegrated-discrimination-improvement statistics for suggesting that glycated hemoglobin may be su- diagnosed diabetes and coronary heart disease perior to fasting glucose for characterizing long- were significantly improved with the addition of term risk.
glycated hemoglobin (modeled continuously) to Glycated hemoglobin values reflect the 2-to-3- the model of fasting glucose (as a continuous vari- month average endogenous exposure to glucose, able) and other covariates (see the Supplementary including postprandial spikes in the blood glucose level, and have low intraindividual variability, par- n engl j med 362;9 nejm.org march 4, 2010 Downloaded from www.nejm.org at UNIVERSITAET BERN on March 22, 2010 . Copyright 2010 Massachusetts Medical Society. All rights reserved. Table 2. Adjusted Hazard Ratios for Selected Clinical Outcomes in the Study Population during the 15-Year Study Period, According to
the Glycated Hemoglobin Category at Baseline and the Model.*

Glycated hemoglobin category — hazard ratio (95% CI) 0.49 (0.27–0.89) 0.50 (0.28–0.90) 0.57 (0.31–1.03) 5.0 to <5.5% (reference) 2.91 (2.33–3.63) 2.44 (1.95–3.05) 1.77 (1.41–2.22) 13.38 (10.51–17.03) 9.20 (7.18–11.78) 5.08 (3.93–6.56) 50.73 (37.44–68.74) 32.77 (23.96–44.82) 14.53 (10.53–20.04) P value for trend Glycated hemoglobin value — hazard ratio (95% CI) 2.73 (2.56–2.91) 2.75 (2.55–2.96) 2.57 (2.35–2.81) Glycated hemoglobin category — hazard ratio (95% CI) 0.51 (0.39–0.67) 0.52 (0.40–0.69) 0.53 (0.40–0.69) 5.0 to <5.5% (reference) 2.12 (1.90–2.37) 1.86 (1.67–2.08) 1.80 (1.61–2.01) 6.29 (5.52–7.17) 4.48 (3.92–5.13) 4.03 (3.52–4.61) 27.19 (23.61–31.31) 16.47 (14.22–19.08) 10.40 (8.80–12.28) P value for trend Glycated hemoglobin value — hazard ratio (95% CI) 1.97 (1.92–2.03) 1.80 (1.75–1.86) 1.44 (1.35–1.55) Coronary heart disease
Glycated hemoglobin category — hazard ratio (95% CI) 0.89 (0.69–1.15) 0.96 (0.74–1.24) 0.95 (0.73–1.22) 5.0 to <5.5% (reference) 1.45 (1.27–1.66) 1.23 (1.07–1.41) 1.25 (1.09–1.44) 2.37 (1.98–2.84) 1.78 (1.48–2.15) 1.88 (1.55–2.28) 2.91 (2.31–3.67) 1.95 (1.53–2.48) 2.46 (1.84–3.28) P value for trend Glycated hemoglobin value — hazard ratio (95% CI) 1.34 (1.27–1.42) 1.19 (1.11–1.27) 1.50 (1.33–1.68) Glycated hemoglobin category — hazard ratio (95% CI) 1.06 (0.65–1.71) 1.09 (0.67–1.76) 1.09 (0.68–1.77) 5.0 to <5.5% (reference) 1.27 (0.97–1.67) 1.17 (0.89–1.53) 1.16 (0.89–1.53) 2.63 (1.92–3.61) 2.22 (1.60–3.08) 2.19 (1.58–3.05) 3.68 (2.56–5.30) 3.16 (2.15–4.64) 2.96 (1.87–4.67) P value for trend Glycated hemoglobin value — hazard ratio (95% CI) 1.41 (1.30–1.54) 1.34 (1.22–1.48) 1.55 (1.28–1.88) n engl j med 362;9 nejm.org march 4, 2010 Downloaded from www.nejm.org at UNIVERSITAET BERN on March 22, 2010 . Copyright 2010 Massachusetts Medical Society. All rights reserved. Glycated Hemoglobin, Diabetes, and Cardiovascular Risk Table 2. (Continued.)
Death from any cause
Glycated hemoglobin category — hazard ratio (95% CI) 1.43 (1.17–1.74) 1.48 (1.21–1.82) 1.48 (1.21–1.81) 5.0 to <5.5% (reference) 1.34 (1.18–1.52) 1.18 (1.04–1.35) 1.19 (1.05–1.35) 1.92 (1.63–2.27) 1.59 (1.34–1.89) 1.61 (1.35–1.91) 1.92 (1.54–2.40) 1.65 (1.31–2.08) 1.71 (1.30–2.25) P value for trend§ Glycated hemoglobin value — hazard ratio (95% CI) 1.21 (1.13–1.28) 1.12 (1.05–1.21) 1.18 (1.05–1.32) * Hazard ratios for glycated hemoglobin values are for each absolute increase of 1 percentage point. Model 1a was adjusted for age, sex, and race (black or white). Model 2a was adjusted for the variables in model 1a plus low-density and high-density lipoprotein cholesterol levels, log-transformed triglyceride level, body-mass index, waist-to-hip ratio, hypertension (yes or no), family history of diabetes (yes or no), educa- tion (less than high school, high school or equivalent, or college or above), alcohol use (currently, formerly, or never), physical-activity index score, and smoking status (current smoker, former smoker, or never smoked). Model 3a was adjusted for all variables in model 2a plus the baseline fasting glucose level. CI denotes confidence interval.
† Visit-based diabetes was defined on the basis of elevated fasting glucose levels (≥126 mg per deciliter [7 mmol per liter]), report of physi- cian diagnosis, or use of diabetes medication during the first 6 years of follow-up. This analysis included only the 9432 persons who had a baseline fasting glucose level of less than 126 mg per deciliter and were not missing glucose measurements during the follow-up visits.
‡ Diagnosed diabetes was defined on the basis of a self-reported diabetes diagnosis or use of diabetes medication during 15 years of follow-up.
§ Owing to significant nonlinearity of the data for death from any cause, the P values from the test for linear trend are not reported.
ticularly in persons without diabetes.4,25 These (using a case–cohort design) associations of gly- characteristics may contribute to the superiority cated hemoglobin with coronary heart disease of glycated hemoglobin over fasting glucose for and stroke in a subgroup of the ARIC popula- long-term macrovascular risk stratification.
tion with low fasting glucose levels (at two time Recommendations for the diagnosis of diabe- points) and low glycated hemoglobin values37 and, tes are based on the relations of fasting glucose separately, among persons with diabetes.38 None- and glycated hemoglobin with microvascular dis- theless, recent clinical trials have shown little ease, typically retinopathy.1,3 Nonetheless, cardio- benefit, and possibly some harm, of lowering the vascular disease is the leading cause of illness, glycated hemoglobin value in patients with dia- death, and hospitalization in persons with dia- betes to prevent cardiovascular outcomes.39-43 In betes.26,27 Our data suggest that glycated hemo- contrast, the microvascular benefits of glucose globin values in the normal range can identify control are well established.44,45 Although the persons at increased risk for coronary heart dis- causal role of glucose itself in the development of ease, stroke, and death before the diagnosis of cardiovascular disease is unclear, our data dem- diabetes, indicating that glycated hemoglobin is onstrate that glycated hemoglobin within the nor- a useful marker of cardiovascular risk and death mal range can be a useful marker of cardiovas- from any cause. The J-shaped relation between the cular risk. Therefore, glycated hemoglobin values glycated hemoglobin value and the risk of death exceeding 6.0% may be a clinically useful mark- from any cause suggests that further exploration er to identify persons at risk for the development of the health risks associated with the low-nor- of not only diabetes but also cardiovascular dis- mal glycemic state and possible nonglycemic de- ease and death.
terminants of glycated hemoglobin is warranted.
Despite significant differences between blacks As in the present study, the literature has docu- and whites in glycated hemoglobin values at base- mented an increase in cardiovascular risk with line, race did not modify the associations between increases in glycated hemoglobin values within the glycated hemoglobin value and cardiovascular out- nondiabetic range.28-36 We have previously shown comes and death in this population. We did, how- n engl j med 362;9 nejm.org march 4, 2010 Downloaded from www.nejm.org at UNIVERSITAET BERN on March 22, 2010 . Copyright 2010 Massachusetts Medical Society. All rights reserved. Restricted-cubic-spline model with 4 knots 3-Knot linear spline model (knots at 5.0%, 5.5%, and 6.0%) Adjusted Hazard Ratio for
Adjusted Hazard Ratio for
Coronary Heart Disease
Glycated Hemoglobin (%)
Glycated Hemoglobin (%)
Death from Any Cause
Adjusted Hazard Ratio for
Adjusted Hazard Ratio for Stroke
Glycated Hemoglobin (%)
Glycated Hemoglobin (%)
Figure 2. Adjusted Hazard Ratios for Sel AUTHOR:
d Diagnosed Diabetes and Coronary Heart Disease, Ischemic Stroke, and Death
from Any Cause, According to the Baseline Glycated Hemoglobin Value.
The hazard ratios are per each absolute increase of 1 percentage point in the glycated hemoglobin value at baseline. The shaded area is the 95% confidence interval from the rest ARTIST: ubic-spline model. Both models are centered at the median (5.4%) and the plot was truncated at the 2.5th and 97.5th percentiles of glycated hemoglobin (4.7% and 6.8%, 7 col respectively). The hazard ratios were adjusted for age, sex, and race (black or white), low-density and high-density cholesterol levels, log36p6 -transformed triglyceride level, body-mass index, waist-to-hip ratio, hypertension (yes or no), family histor AUTHOR, PLEASE NOTE:
y of diabetes (yes or n o), education (less than high school, high school or equiv- alent, or college or above), alcohol use (curren Figure has been redrawn and type has been reset.
tly, formerly, or never), physical-activity index score, and smoking status (current smoker, Please check carefully.
former smoker, or never smoked). The data are shown on a natural-log scale.
ever, observe a significant interaction between race the use of race-specific glycated hemoglobin cut- and diagnosed diabetes during the 15 years of off points for the identification of persons at risk follow-up (but not for the 6-year visit-based defi- for diabetes, cardiovascular disease, or death.
nition), revealing that blacks were significantly less Important limitations of this study include the likely than whites to report a diabetes diagnosis, reliance on single glycated hemoglobin and glu- across all categories of glycated hemoglobin. We cose measurements at baseline, a limited number observed a similar race interaction for baseline of fasting glucose measurements during the fol- fasting glucose level and subsequent diagnosis of low-up period, and the lack of validation of self- diabetes. Thus, higher values of glycated hemoglo- reported diabetes for the 15-year analyses. None- bin in nondiabetic blacks as compared with non- theless, among sensitivity analyses comparing diabetic whites might be partially explained by diabetes definitions based on fasting glucose level, delays in diagnosis. Our findings do not support medication use, and self-reported information — n engl j med 362;9 nejm.org march 4, 2010 Downloaded from www.nejm.org at UNIVERSITAET BERN on March 22, 2010 . Copyright 2010 Massachusetts Medical Society. All rights reserved. Glycated Hemoglobin, Diabetes, and Cardiovascular Risk Table 3. Adjusted Hazard Ratios for Selected Clinical Outcomes in the Study Population during the 15-Year Study
Period, According to the Fasting Glucose Category at Baseline and the Model.*

Fasting glucose category — hazard ratio (95% CI) <100 mg/dl (reference) 100 to <126 mg/dl 3.01 (2.69–3.37) 2.31 (2.06–2.59) 2.19 (1.95–2.45) 21.5 (18.7–24.6) 12.3 (10.7–14.2) 8.07 (6.92–9.42) P value for trend Fasting glucose — hazard ratio (95% CI) per 1.244 (1.233–1.254) 1.202 (1.191–1.214) 1.088 (1.063–1.112) 10 mg/dl increase Coronary heart disease
Fasting glucose category — hazard ratio (95% CI) <100 mg/dl (reference) 100 to <126 mg/dl 1.19 (1.05–1.35) 1.03 (0.91–1.18) 1.01 (0.88–1.14) 1.80 (1.46–2.22) 1.29 (1.04–1.61) 1.00 (0.77–1.30) P value for trend Fasting glucose — hazard ratio (95% CI) per 1.058 (1.034–1.082) 1.013 (0.986–1.041) 0.913 (0.877–0.950) 10 mg/dl increase Fasting glucose category — hazard ratio (95% CI) <100 mg/dl (reference) 100 to <126 mg/dl 1.06 (0.84–1.34) 0.97 (0.76–1.23) 0.93 (0.73–1.18) 2.33 (1.68–3.24) 1.89 (1.33–2.69) 1.30 (0.85–1.98) P value for trend Fasting glucose — hazard ratio (95% CI) per 1.089 (1.057–1.121) 1.068 (1.034–1.104) 0.950 (0.893–1.012) 10 mg/dl increase Death from any cause
Fasting glucose category — hazard ratio (95% CI) <100 mg/dl (reference) 100 to <126 mg/dl 1.11 (0.99–1.24) 1.07 (0.96–1.21) 1.06 (0.94–1.19) 1.42 (1.17–1.73) 1.31 (1.07–1.61) 1.16 (0.91–1.47) P value for trend Fasting glucose — hazard ratio (95% CI) per 1.035 (1.012–1.058) 1.021 (0.997–1.045) 0.980 (0.945–1.018) 10 mg/dl increase * Model 1b was adjusted for age, sex, and race (black or white). Model 2b was adjusted for the variables in model 1b plus low-density and high-density lipoprotein cholesterol levels, log-transformed triglyceride level, body-mass index, waist-to-hip ratio, hypertension (yes or no), family history of diabetes (yes or no), education (less than high school, high school or equivalent, or college or above), alcohol use (currently, formerly, or never), physical-activity index score, and smoking status (current smoker, former smoker, or never smoked). Model 3b was adjusted for all variables in model 2b plus the glycated hemoglobin value. To convert the values for fasting glucose to millimoles per liter, multiply † Diagnosed diabetes was defined on the basis of a self-reported diabetes diagnosis or diabetes medication use during 15 years of follow-up.
n engl j med 362;9 nejm.org march 4, 2010 Downloaded from www.nejm.org at UNIVERSITAET BERN on March 22, 2010 . Copyright 2010 Massachusetts Medical Society. All rights reserved. all available for the first 6 years of the follow-up In this community-based study population of period — our results were similar (see the Supple- black or white nondiabetic adults, glycated hemo- mentary Appendix). Owing to the observational globin was superior to fasting glucose for assess- nature of our investigation, the possibility of re- ment of the long-term risk of subsequent cardio- sidual confounding cannot be completely elim- vascular disease, especially at values above 6.0%. inated. Nonetheless, this effort is one of the Such prognostic data may add to the evidence largest, community-based studies of glycated he- supporting the use of glycated hemoglobin as a moglobin involving information about the devel- diagnostic test for diabetes.
opment of diabetes and validated cardiovascular Supported by grants from the National Institutes of Health, events during follow-up. Major strengths of this National Institute of Diabetes and Digestive and Kidney Diseas- es (NIDDK) (R21 DK080294 and K01 DK076595, to Dr. Selvin; ARIC ancillary study were the use of comprehen- and K24 DK62222, to Dr. Brancati); contracts with the National sive surveillance and adjudication of cardiovas- Heart, Lung, and Blood Institute (N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, cular events and rigorous measurement of risk and N01-HC-55022); and an NIDDK grant (P60 DK079637, to Dr. factors. The large population of blacks was an Brancati through the Johns Hopkins Diabetes Research and additional strength, permitting us to conduct ro- Training Center).
Financial and other disclosures provided by the authors are bust analyses of possible racial differences in risk. available with the full text of this article at NEJM.org.
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