we conducted a cross - sectional study of participants from the atherosclerosis risk in communities ( aric ) study who participated in the aric carotid mri ( carmri ) substudy . the aric study is an ongoing prospective cohort study of 15,792 black and white adults originally enrolled between 1987 and 1989 ( 6 ) . just over 2,000 participants from the original cohort , now aged 6084 years , were recruited into the carmri substudy in 2004 and 2005 using a stratified sampling plan ( 7 ) . in addition to the mri examination , trained technicians performed a comprehensive clinical examination , obtained blood specimens , and conducted an interview to obtain information on health status and risk factors . our study sample was limited to 1,600 participants ( 227 with a history of diabetes and 1,323 without ) after excluding those who fasted less than 8 h ( n = 20 ) or who were missing variables of interest ( n = 402 ) . an additional 51 participants had missing or ungradable retinal photographs and were further excluded from our analyses of retinopathy . institutional review boards at each clinical site approved the study protocol , and written informed consent was obtained from all participants . hba1c was measured from whole - blood samples as part of the original carmri protocol using the tina - quant ii method ( roche diagnostics , basel , switzerland ) implemented on a roche hitachi 911 analyzer . , we measured glycated albumin ( asahi kasei lucica ga - l ; asahi kasei pharma corporation , tokyo , japan)expressed as a percentage of total serum albumin , fructosamine ( roche diagnostics ) , and 1,5-ag ( glycomark , winston - salem , nc ) from stored serum specimens using a roche modular p800 system . the interassay coefficients of variation ( cvs ) were 2.7% for glycated albumin , 3.7% for fructosamine , and 4.8% for 1,5-ag . we focused on three microvascular conditions : chronic kidney disease , albuminuria , and retinopathy . serum creatinine was measured using a roche enzymatic assay , calibrated by the manufacturer to be traceable to reference method procedures ( standard creatinine ) . the glomerular filtration rate ( gfr ) was estimated using the four - variable modification of diet in renal disease ( mdrd ) study formula re - expressed to use standard creatinine and reported in milliliters per minute per 1.73 m ( 810 ) . people with estimated gfr ( egfr ) below 60 ml / min/1.73 m were considered to have chronic kidney disease ( 11 ) . urine albumin and creatinine were measured from random spot urine collected at the carmri visit using a clean - catch technique and sterile containers . we defined albuminuria as a urine albumin - to - creatinine ratio of 30 mg / g or higher and conducted sensitivity analyses excluding those people with macroalbuminuria ( albumin - to - creatinine ratio 300 mg / g ) . retinal photographs were taken following a standardized protocol that has been previously documented ( 12 ) . briefly , after 5 min of dark adaptation , a nonmydriatic 45-degree retinal photograph centered on the optic disc and macula was taken of one randomly selected eye . we defined retinopathy ( moderate to severe ) as a severity score greater than or equal to 35 according to a modification of the airlie house classification system , as used in the early treatment diabetic retinopathy study ( etdrs ) ( 12,13 ) . other measurement protocols in aric carmri were identical to those implemented in the original aric study ( 7 ) . blood samples were assayed for total and high - density lipoprotein cholesterol , glucose , and high - sensitivity c - reactive protein using conventional techniques . information on cigarette smoking and alcohol consumption was elicited during the interview . resting systolic blood pressure ( average of two readings ) was measured using a random - zero sphygmomanometer . participants were asked to bring current medications to the visit , and information on cholesterol- and blood pressure - lowering medications was also obtained during the interview . diabetes history was determined by use of glucose - lowering medications or a self - reported physician diagnosis of diabetes . previous history of coronary heart disease included a reported history of coronary heart disease and/or an adjudicated coronary heart disease event during active surveillance up to the carmri visit ( 14 ) . we also compared mean values of each glycemic marker by categories of important risk factors separately in people with and without a history of diagnosed diabetes . we used multivariable logistic regression models to assess the independent association of each glycemic marker with microvascular conditions : chronic kidney disease , albuminuria , and retinopathy . for comparability , we divided the population into diabetes - specific tertiles of each glycemic marker . because 1,5-ag is lowered while the other glycemic markers are increased in the setting of hyperglycemia , we transformed 1,5-ag to 1/1,5-ag for consistency in interpretation of the diabetes - specific tertiles ( the ranking of individuals is unchanged by inverse transformation ) . model 1 was adjusted for age ( in years ) , sex , education level ( less than high school ; high school or equivalent ; some college or higher ) , family history of diabetes , previous history of coronary heart disease , average systolic blood pressure ( in mmhg ) , use of blood pressure medication , use of cholesterol - lowering medication , total cholesterol concentration ( in mg / dl ) , hdl cholesterol concentration ( in mg / dl ) , smoking status ( current ; former ; never ) , bmi ( in kg / m ) , and high - sensitivity c - reactive protein concentration ( in mg / l ) . because there is ongoing debate regarding the need for correction of fructosamine assays for serum albumin ( 15 ) , models of fructosamine were additionally adjusted for serum albumin concentration ( in g / dl ) . model 2 was adjusted for all variables in model 1 plus hba1c ( in percentages ) . all analyses were weighted by the inverse of the sample fractions in the study sampling strata using methods for the analysis of complex sample survey design data ( 7 ) . all reported p values are two - sided , and p values < we conducted a cross - sectional study of participants from the atherosclerosis risk in communities ( aric ) study who participated in the aric carotid mri ( carmri ) substudy . the aric study is an ongoing prospective cohort study of 15,792 black and white adults originally enrolled between 1987 and 1989 ( 6 ) . just over 2,000 participants from the original cohort , now aged 6084 years , were recruited into the carmri substudy in 2004 and 2005 using a stratified sampling plan ( 7 ) . in addition to the mri examination , trained technicians performed a comprehensive clinical examination , obtained blood specimens , and conducted an interview to obtain information on health status and risk factors . our study sample was limited to 1,600 participants ( 227 with a history of diabetes and 1,323 without ) after excluding those who fasted less than 8 h ( n = 20 ) or who were missing variables of interest ( n = 402 ) . an additional 51 participants had missing or ungradable retinal photographs and were further excluded from our analyses of retinopathy . institutional review boards at each clinical site approved the study protocol , and written informed consent was obtained from all participants . hba1c was measured from whole - blood samples as part of the original carmri protocol using the tina - quant ii method ( roche diagnostics , basel , switzerland ) implemented on a roche hitachi 911 analyzer . this method is aligned to the diabetes control and complications trial assay . in 2009 , we measured glycated albumin ( asahi kasei lucica ga - l ; asahi kasei pharma corporation , tokyo , japan)expressed as a percentage of total serum albumin , fructosamine ( roche diagnostics ) , and 1,5-ag ( glycomark , winston - salem , nc ) from stored serum specimens using a roche modular p800 system . the interassay coefficients of variation ( cvs ) were 2.7% for glycated albumin , 3.7% for fructosamine , and 4.8% for 1,5-ag . we focused on three microvascular conditions : chronic kidney disease , albuminuria , and retinopathy . serum creatinine was measured using a roche enzymatic assay , calibrated by the manufacturer to be traceable to reference method procedures ( standard creatinine ) . the glomerular filtration rate ( gfr ) was estimated using the four - variable modification of diet in renal disease ( mdrd ) study formula re - expressed to use standard creatinine and reported in milliliters per minute per 1.73 m ( 810 ) . people with estimated gfr ( egfr ) below 60 ml / min/1.73 m were considered to have chronic kidney disease ( 11 ) . urine albumin and creatinine were measured from random spot urine collected at the carmri visit using a clean - catch technique and sterile containers . we defined albuminuria as a urine albumin - to - creatinine ratio of 30 mg / g or higher and conducted sensitivity analyses excluding those people with macroalbuminuria ( albumin - to - creatinine ratio 300 mg / g ) . retinal photographs were taken following a standardized protocol that has been previously documented ( 12 ) . briefly , after 5 min of dark adaptation , a nonmydriatic 45-degree retinal photograph centered on the optic disc and macula was taken of one randomly selected eye . trained readers masked to participant information evaluated each of the photographs . we defined retinopathy ( moderate to severe ) as a severity score greater than or equal to 35 according to a modification of the airlie house classification system , as used in the early treatment diabetic retinopathy study ( etdrs ) ( 12,13 ) . other measurement protocols in aric carmri were identical to those implemented in the original aric study ( 7 ) . blood samples were assayed for total and high - density lipoprotein cholesterol , glucose , and high - sensitivity c - reactive protein using conventional techniques . information on cigarette smoking and alcohol consumption was elicited during the interview . resting systolic blood pressure ( average of two readings ) was measured using a random - zero sphygmomanometer . participants were asked to bring current medications to the visit , and information on cholesterol- and blood pressure - lowering medications was also obtained during the interview . diabetes history was determined by use of glucose - lowering medications or a self - reported physician diagnosis of diabetes . previous history of coronary heart disease included a reported history of coronary heart disease and/or an adjudicated coronary heart disease event during active surveillance up to the carmri visit ( 14 ) . we also compared mean values of each glycemic marker by categories of important risk factors separately in people with and without a history of diagnosed diabetes . we used multivariable logistic regression models to assess the independent association of each glycemic marker with microvascular conditions : chronic kidney disease , albuminuria , and retinopathy . for comparability , we divided the population into diabetes - specific tertiles of each glycemic marker . because 1,5-ag is lowered while the other glycemic markers are increased in the setting of hyperglycemia , we transformed 1,5-ag to 1/1,5-ag for consistency in interpretation of the diabetes - specific tertiles ( the ranking of individuals is unchanged by inverse transformation ) . model 1 was adjusted for age ( in years ) , sex , education level ( less than high school ; high school or equivalent ; some college or higher ) , family history of diabetes , previous history of coronary heart disease , average systolic blood pressure ( in mmhg ) , use of blood pressure medication , use of cholesterol - lowering medication , total cholesterol concentration ( in mg / dl ) , hdl cholesterol concentration ( in mg / dl ) , smoking status ( current ; former ; never ) , bmi ( in kg / m ) , and high - sensitivity c - reactive protein concentration ( in mg / l ) . because there is ongoing debate regarding the need for correction of fructosamine assays for serum albumin ( 15 ) , models of fructosamine were additionally adjusted for serum albumin concentration ( in g / dl ) . model 2 was adjusted for all variables in model 1 plus hba1c ( in percentages ) . all analyses were weighted by the inverse of the sample fractions in the study sampling strata using methods for the analysis of complex sample survey design data ( 7 ) . all reported p values are two - sided , and p values < 0.05 were considered statistically significant . the prevalence estimates for each the microvascular conditions in people with a history of diabetes were as follows : 27.7% had chronic kidney disease , 23.0% had albuminuria ( 4.1% macroalbuminuria ) , and 11.4% had retinopathy . in people without a history of diabetes , the corresponding prevalence estimates were 18.1% for chronic kidney disease , 10.4% for albuminuria ( 0.9% macroalbuminuria ) , and 2.8% for retinopathy . people with a history of diagnosed diabetes were more likely to be men and african american and have a high - school education or less and a family history of diabetes compared with people in the study sample with no history of diabetes . people with diagnosed diabetes also had poorer cardiovascular risk profiles and were less likely to be current smokers . participant characteristics overall and by diabetes history data are weighted means ( se ) , weighted median [ iqr ] , or weighted proportions ( se ) . mean levels of the different glycemic markers differed substantially by diabetic status ( tables 2 and 3 ) . the mean glycated albumin , fructosamine , 1,5-ag , hba1c , and fasting glucose values in people without a history of diagnosed diabetes were 13.6% , 230.1 mol / l , 17.9 g / ml , 5.6% , and 102.7 mg / dl , respectively . in people with diabetes , the corresponding means were 17.8% , 274.3 mol / l , 12.6 g / ml , 6.7% , and 140.1 mg / dl , respectively . table 2 reveals substantial differences in the associations of each marker with basic demographic and clinical characteristics . in people without diabetes , glycated albumin was significantly higher and 1,5-ag was lower in people aged 65 years and older compared with people < 65 years of age ; fructosamine , hba1c , and fasting glucose did not differ by age group . whereas fructosamine and glycated albumin appeared similar by sex , men had significantly higher 1,5-ag , higher hba1c , and higher fasting glucose . bmi was significantly associated with all markers but not in the expected direction for glycated albumin or fructosamine , which were both lower , and for 1,5-ag , which was higher , at higher bmi levels . by contrast , hba1c and fasting glucose were both significantly higher at higher bmi levels . levels of glycated albumin and fructosamine were also significantly higher in people who have never smoked compared with former or current smokers . substantial racial differences were seen across all markers in both people with and without diabetes , with african americans having higher levels of glycemia as indicated by each marker , although the results were not statistically significant for 1,5-ag in people with or without diabetes . fasting glucose was higher , but not statistically significantly so , in diabetic african americans compared with whites ( p value = 0.13 ) . in these unadjusted analyses , we observed associations between some of the glycemic markers and prevalent chronic kidney disease , albuminuria , and retinopathy , but these results were variable across the different measures of hyperglycemia ( tables 2 and 3 ) . mean levels of glycemic markers by demographic and clinical characteristics in participants without a history of diabetes ( n = 1,323 ) data are weighted means ( se ) . mean levels of glycemic markers by demographic and clinical characteristics in participants with diagnosed diabetes ( n = 277 ) data are weighted means ( se ) . in our adjusted logistic regression models of microvascular outcomes in the total population comparing diabetes - specific tertiles of each glycemic marker , we observed significant positive trends in the associations of each marker with albuminuria and retinopathy ( fig . 1 and supplementary table 1 ) , even after accounting for demographic , clinical , and lifestyle factors the associations with chronic kidney disease were similar in magnitude and direction but not significant for all markers : glycated albumin ( p trend = 0.005 ) , fructosamine ( p trend = 0.003 ) , and hba1c ( p trend = 0.005 ) were significantly and positively associated with the presence of chronic kidney disease , but 1/1,5-ag ( p trend = 0.72 ) and fasting glucose ( p trend = 0.66 ) were not . after further adjustment for hba1c in these models ( supplementary fig . 1 and supplementary table 2 ) , we observed significant trends in the associations of glycated albumin with retinopathy ( p trend = 0.01 ) and borderline significant trends for chronic kidney disease ( p trend = 0.05 ) and albuminuria ( p trend = 0.07 ) . after adjustment for hba1c , positive trends for fructosamine also remained significant for chronic kidney disease ( p trend = 0.03 ) and retinopathy ( p trend = 0.02 ) and borderline significant for albuminuria ( p trend = 0.05 ) . 1/1,5-ag remained significantly positively associated with albuminuria ( p trend = 0.04 ) but not with chronic kidney disease ( p trend = 0.63 ) or retinopathy ( p trend = 0.42 ) . overall trends for fasting glucose were not significant for any outcome after adjustment for hba1c ( all p trends > 0.3 ) ; however , the lowest tertile of fasting glucose in people with diagnosed diabetes was significantly associated with chronic kidney disease and albuminuria . hba1c , by contrast , was no longer statistically significantly associated with any of these outcomes in these fully adjusted models ( all p values > 0.05 ) . adjusted odds ratios ( 95% ci ) for microvascular conditions by diabetes - specific tertiles of each glycemic marker ; odds ratios are adjusted for age , sex , education level , family history of diabetes , previous coronary heart disease , use of blood pressure medication , use of cholesterol - lowering medication , smoking status , bmi , systolic blood pressure , total cholesterol , hdl cholesterol , and c - reactive protein . chronic kidney disease was defined as an estimated glomerular filtration rate < 60 ml / min/1.73 m. we compared nontraditional serum markers of glycemia ( glycated albumin , fructosamine , and 1,5-ag ) to the standard measures used in clinical practice ( fasting glucose and hba1c ) in their associations with microvascular conditions . we observed intriguing differences in the associations of each glycemic marker with basic demographic and clinical characteristics . to the extent that cross - sectional risk factor associations differ , this may indicate that the different glycemic markers contribute independent clinical information and may enhance the prognostic value of standard glycemic markers . indeed , we observed qualitative differences in the associations of the various glycemic markers with smoking status and bmi . there is evidence that both smoking and higher levels of adiposity can lead to a state of increase oxidative stress because of increased reactive oxygen species ( 16 ) . our data may indicate that circulating concentrations of glycated albumin and fructosamine are differentially affected by these states of oxidant stress compared with traditional glycemic markers . it is also possible that glycated albumin , fructosamine , and 1,5-ag are more strongly affected by postprandial glycemic excursions compared with hba1c , contributing to the observed differences ( 17,18 ) . after adjustment for confounding factors , we found that glycated albumin , fructosamine , and hba1c were similarly positively associated with prevalent chronic kidney disease , albuminuria , and retinopathy . fasting glucose and 1,5-ag were associated with albuminuria and retinopathy but not chronic kidney disease . the associations of glycated albumin and fructosamine with microvascular outcomes were evident even after adjustment for hba1c , suggesting that these serum markers of glycemic control may contribute independent risk information . the less robust results for fasting glucose , particularly among people with a diagnosis of diabetes in the upper two tertiles of the glycemic markers , may partially reflect that nearly all people with diagnosed diabetes reported current use of glucose - lowering medication(s ) . fructosamine is often used in clinical practice to monitor glycemic control in people with conditions that interfere with the interpretation or measurements of hba1c , such as the presence of some hemoglobin variants , certain anemias , dialysis treatment , or other conditions that cause hemolysis or otherwise alter erythrocyte turnover . the colorometric process of the fructosamine assay is challenging to perform , and there is ongoing debate regarding the need for correction of fructosamine assays for serum albumin concentrations ( 15,19 ) . an additional general concern regarding fructosamine is the fluctuating concentrations of other serum proteins that may affect the assay result . our study demonstrates excellent reliability of this fructosamine assay with an interassay cv = 3.7% and significant associations of fructosamine with microvascular outcomes . the glycated albumin assay examined here is a newer automated assay not yet approved for clinical use in the u.s . but which also showed excellent laboratory performance , interassay cv = 2.7% . in this assay , glycated albumin is expressed as a percentage of total serum albumin ( 20 ) , simplifying the interpretation of the result . indeed , additional adjustment for serum albumin in our analyses of glycated albumin and microvascular outcomes did not appreciably alter our results ( data not shown ) . it has also been suggested that glycated albumin itself , beyond its role as marker of hyperglycemia , may contribute directly to the development of complications ( 21 ) , including diabetic nephropathy ( 22,23 ) . 1,5-ag is a novel marker of glycemia , reflecting a nonglycation - dependent biological process : it is thought to reflect hyperglycemic excursions over the past 1 to 2 weeks ( 4 ) . urinary excretion of 1,5-ag is accelerated in the setting of hyperglycemia and high circulating concentrations of glucose ( exceeding the renal threshold ) will cause serum 1,5-ag concentrations to fall ( 24 ) . the attractiveness of 1,5-ag is that it may capture additional information on glycemic excursions not reflected in fasting glucose , hba1c , fructosamine , or glycated albumin values ( 17 ) . however , it is unclear whether concentrations of 1,5-ag may be altered in the presence of moderately impaired kidney function or albuminuria , raising questions regarding reverse causality . limitations that should be considered in the interpretation of these data include the cross - sectional design ; we could not determine the temporality of the observed associations , and we had only a limited number of people with known diabetes ( n = 277 ) . the direct comparison between results for glycated albumin versus those for fructosamine remains challenging . to our knowledge , there is no reference method procedure for glycated albumin or for those measurements related to glycation of proteins circulating in blood . thus , the fructosamine assay ( a colorimetric assay based on ketoamines reducing nitrotetrazolium - blue ) does not directly relate to the measure of glycated albumin ( an enzymatic method using ketoamine oxidase and an albumin - specific protease ) , and differences in results across these measurements are difficult to interpret in the context of an epidemiologic study . important strengths of this study include the comparison of a panel of novel serum markers with those that are used in standard practice , the community - based biracial sample of people with and without diabetes , which allowed us to assess these epidemiologic associations across the full range of glycemia . additional advantages to conducting this study nested within the aric cohort included the rigorous measurement of known risk factors for diabetes using standardized protocols and assessment of multiple microvascular conditions . physicians typically use multiple biomarkers to assess the metabolic status of their patients , but the additional clinical utility of serum glycemic markers beyond standard measures of glycemia is unclear . in our cross - sectional analyses , two serum markers of glycemia glycated albumin and fructosamine  were as strongly , or more strongly , associated with microvascular conditions as hba1c . our results suggest that serum glycemic markers , particularly glycated albumin and/or fructosamine , may add important clinical information for the identification of people at risk for microvascular conditions and possibly the management of diabetes . measurement of hba1c requires a whole - blood sample ; sometimes relatively labor - intensive assay methodologies and concerns have been raised about the performance of hba1c in certain subpopulations ( 25 ) . the markers examined here can be measured reliably in serum using standard , automated methods and may be useful in settings where whole blood is not available . whether serum glycemic markers might complement or outperform hba1c in terms of long - term predictive value requires further investigation .
objectiveto compare the associations of nontraditional ( fructosamine , glycated albumin , 1,5-anhydroglucitol [ 1,5-ag ] ) and standard ( fasting glucose , hba1c ) glycemic markers with common microvascular conditions associated with diabetes mellitus.research design and methodswe conducted a cross - sectional study of 1,600 participants ( 227 with a history of diabetes and 1,323 without ) from the atherosclerosis risk in communities ( aric ) study , a community - based population . 
 we conducted logistic regression analyses of the associations of diabetes - specific tertiles of fructosamine , glycated albumin , 1/(1,5-ag ) , fasting glucose , and hba1c with prevalence of chronic kidney disease , albuminuria , and retinopathy after adjustment for demographic , clinical , and lifestyle variables.resultswe observed significant positive trends in the associations of each marker with albuminuria and retinopathy , even after accounting for demographic , clinical , and lifestyle factors ( all p trends < 0.05 ) . 
 the associations with chronic kidney disease were similar in direction but were only significant for higher glycated albumin ( p trend = 0.005 ) , fructosamine ( p trend = 0.003 ) , and hba1c ( p trend = 0.005 ) values . 
 after further adjustment for hba1c , glycated albumin and fructosamine remained significantly or borderline significantly associated with the microvascular outcomes.conclusionsin cross - sectional analyses , two serum markers of glycemia  glycated albumin and fructosamine  are as , or more strongly , associated with microvascular conditions as hba1c . 
 these markers may be useful in settings where whole blood is not available . 
 whether they might complement or outperform hba1c in terms of long - term predictive value requires further investigation .