nhanes 19992000 , 20012002 , 20032004 , and 20052006 are serial cross - sectional surveys including nationally representative samples of the noninstitutionalized civilian u.s .
nhanes 19992006 included 7,975 adults , aged 20 years , who attended the morning examination and had fasted for 924 h at the time of their blood collection .
participants missing fpg or a1c measurements ( n = 37 ) with a prior self - reported diagnosis of diabetes ( n = 537 ) and those meeting the criteria for diabetes ( fpg 126 mg / dl or a1c 6.5% ) were excluded ( n = 372 ) from the current analyses .
after these exclusions , the current analyses were based on data from 7,029 participants without diabetes .
of particular relevance to the current report , serum glucose was measured using a modified hexokinase enzymatic method , and a1c was measured using a high - performance liquid chromatography system by the diabetes diagnostic laboratory at the university of missouri 
columbia and by the fairview medical center laboratory at the university of minnesota for 20052006 .
a1c and glucose values were recalibrated for nhanes 20052006 to account for the differences in the assays used among laboratories ( 7,8 ) .
both assays have been validated and are diabetes complications and control trial  aligned ( 9 ) .
the coefficient of variation was < 3% in each 2-year period for glucose and < 2% for a1c . in 20052006 ,
a subset of 1,680 participants completed an ogtt after an overnight fast of 924 h. of these participants , the current analysis was conducted among 1,382 participants without diabetes ( i.e. , no self - report , a1c < 6.5% , fpg < 126 mg / dl , and ogtt < 200 mg / dl ) .
after the initial venipuncture , participants were asked to drink a calibrated dose , 75 g of glucose , and had a second venipuncture 2 h ( 15 min ) later .
participants were categorized into one of four mutually exclusive groups by the presence or absence of pre - diabetes according to ifg and a1c criteria .
characteristics of the study population were calculated for each of these four categories as mean  se , median ( 25th , 75th percentiles ) , or percentages , as appropriate .
the prevalence of pre - diabetes was then calculated for ifg and various cut points of a1c .
the sensitivity , specificity , and positive and negative predictive values for having pre - diabetes by ifg were then calculated for each a1c level .
adults with discordant pre - diabetes results based on ifg and a1c values was determined .
first , the test characteristics of pre - diabetes by a1c versus ifg defined as fpg levels of 110125 mg / dl , the previous fasting glucose range for defining pre - diabetes , were determined .
second , using the subset of participants with ogtt results , the sensitivity , specificity , and positive and negative predictive values were determined for pre - diabetes by ifg and a1c , separately , and for the presence of either or both of these test results using igt as the reference standard .
population and conducted using sudaan ( version 9 ; research triangle institute , research triangle park , nc ) to account for the complex survey design of nhanes .
adjustment of the sampling weights corrects for differences in missing data across age , sex , and race / ethnicity strata but assumes that data within strata are missing , randomly ( 10 ) .
participants were categorized into one of four mutually exclusive groups by the presence or absence of pre - diabetes according to ifg and a1c criteria .
characteristics of the study population were calculated for each of these four categories as mean  se , median ( 25th , 75th percentiles ) , or percentages , as appropriate .
the prevalence of pre - diabetes was then calculated for ifg and various cut points of a1c .
the sensitivity , specificity , and positive and negative predictive values for having pre - diabetes by ifg were then calculated for each a1c level .
adults with discordant pre - diabetes results based on ifg and a1c values was determined .
first , the test characteristics of pre - diabetes by a1c versus ifg defined as fpg levels of 110125 mg / dl , the previous fasting glucose range for defining pre - diabetes , were determined .
second , using the subset of participants with ogtt results , the sensitivity , specificity , and positive and negative predictive values were determined for pre - diabetes by ifg and a1c , separately , and for the presence of either or both of these test results using igt as the reference standard .
population and conducted using sudaan ( version 9 ; research triangle institute , research triangle park , nc ) to account for the complex survey design of nhanes .
adjustment of the sampling weights corrects for differences in missing data across age , sex , and race / ethnicity strata but assumes that data within strata are missing , randomly ( 10 ) .
participants with pre - diabetes by a1c but not by ifg were more likely to be women , non - hispanic blacks , and hypertensive and to have hypercholesterolemia , chronic kidney disease , microalbuminuria , elevated c - reactive protein , and lower triglycerides than those with pre - diabetes by ifg but normal a1c ( table 1 ) .
overall , participants with pre - diabetes by both criteria had higher levels of the cardiovascular risk factors investigated . characteristics of nhanes 19992006 study participants by a1c and fasting glucose data are  se , % , or median ( 25th75th percentiles ) .
adults categorized as having pre - diabetes by the a1c and/or ifg criteria . the recommended pre - diabetes a1c range between 5.7 and 6.4% provides the highest agreement with ifg . nonetheless , the overlap is low ; among u.s .
adults without diabetes , 7.7% have pre - diabetes according to both the ifg and a1c criteria , whereas 4.9% have pre - diabetes by the a1c but not the ifg criterion and 20.5% by the ifg but not the a1c criterion ( fig .
adults without diagnosed diabetes by the cross - classification of a1c and fasting glucose , using different a1c cut points data are prevalence estimates  se .
using ifg as the reference standard for pre - diabetes , a1c levels between 5.7% and 6.4% would reclassify 37.6 million americans with ifg as not having pre - diabetes and 8.9 million without ifg as having pre - diabetes for a total of 46.5 million reclassified ( table 3 ) . at
this modification decreases the sensitivity and negative predictive value of diagnosing pre - diabetes but at the same time increases the specificity and positive predictive value . the total number of u.s .
adults reclassified , using ifg as the reference standard for pre - diabetes , is lowest at an a1c level of 5.76.4% .
sensitivity , specificity , positive predictive value , negative predictive value , and number reclassified according to different a1c cut points for test characteristics , values higher than the a1c cut point are considered positive test results , and fasting plasma glucose of 100125 mg / dl is the reference standard for pre - diabetes . in calculating the number reclassified ,
specifically , sampling weights were calibrated based on the proportion of nhanes 19992004 participants missing data by age - group ( < 40 , 4059 , 6074 , and 75 years ) , sex , and race / ethnicity . adjusting the sampling weights correct for differences in missing data across age , sex , and race / ethnicity strata but assumes that data within strata are missing randomly ( 10 ) . when a more restrictive ifg definition ( i.e. , fpg of 110125 mg / dl ) is applied , the prevalence of pre - diabetes decreases from 28.27.7% . of the 20.5% of u.s . adults ( n = 37.6 million ) with pre - diabetes by ifg but not a1c
, 79.0% ( n = 29.8 million ) have fpg between 100 and 109 mg / dl .
adults have pre - diabetes by a1c but a fpg < 110 mg / dl , 4.9% have a1c in the normal range but fpg of 110125 mg / dl , and 3.4% have both pre - diabetes level a1c and fpg of 110125 mg / dl .
the test characteristics for pre - diabetes defined by a1c using fpg levels of 110125 mg / dl rather than 100125 mg / dl as the reference criterion , produces a lower sensitivity ( 45% ) and specificity ( 90% ) .
further , because the prevalence of pre - diabetes is lower , as expected , the positive predictive value ( 27% ) is lower and the negative predictive value ( 95% ) is higher .
the prevalence of pre - diabetes by igt was 16.5% , whereas 5.7 and 11.6% of u.s .
adults as not having pre - diabetes despite pre - diabetes by ifg and a1c , respectively . with igt as the reference standard
, the sensitivity , specificity , and positive and negative predictive values for pre - diabetes were 30 , 89 , 33 , and 87% by a1c ; 59 , 79 , 34 , and 91% by ifg ; 22 , 95 , 43 , and 87% by a1c and ifg ; and 66 , 73 , 31 , and 92% by a1c or ifg , respectively .
when a more restrictive ifg definition ( i.e. , fpg of 110125 mg / dl ) is applied , the prevalence of pre - diabetes decreases from 28.27.7% . of the 20.5% of u.s .
adults ( n = 37.6 million ) with pre - diabetes by ifg but not a1c , 79.0% ( n = 29.8 million ) have fpg between 100 and 109 mg / dl .
adults have pre - diabetes by a1c but a fpg < 110 mg / dl , 4.9% have a1c in the normal range but fpg of 110125 mg / dl , and 3.4% have both pre - diabetes level a1c and fpg of 110125 mg / dl .
the test characteristics for pre - diabetes defined by a1c using fpg levels of 110125 mg / dl rather than 100125 mg / dl as the reference criterion , produces a lower sensitivity ( 45% ) and specificity ( 90% ) .
further , because the prevalence of pre - diabetes is lower , as expected , the positive predictive value ( 27% ) is lower and the negative predictive value ( 95% ) is higher .
the prevalence of pre - diabetes by igt was 16.5% , whereas 5.7 and 11.6% of u.s .
adults as not having pre - diabetes despite pre - diabetes by ifg and a1c , respectively . with igt as the reference standard
, the sensitivity , specificity , and positive and negative predictive values for pre - diabetes were 30 , 89 , 33 , and 87% by a1c ; 59 , 79 , 34 , and 91% by ifg ; 22 , 95 , 43 , and 87% by a1c and ifg ; and 66 , 73 , 31 , and 92% by a1c or ifg , respectively .
data from the current study indicate that the 2010 ada recommendations for inclusion of a1c as an acceptable pre - diabetes diagnostic criterion will have a substantial impact on the number of u.s .
adults identified as having pre - diabetes with the classification being different for nearly 50 million americans .
if providers use a1c alone , they will classify 8.9 million people who would have been considered normal by fasting glucose as having pre - diabetes .
however , they will also reclassify 37.6 million people as not having pre - diabetes by a1c who would have been labeled as having pre - diabetes by the ifg criteria .
this discordance is in contrast to a relatively good agreement between a1c and fasting glucose when applied to the diagnosis of diabetes ( 11 ) .
the inclusion of a1c is designed to increase the feasibility and dissemination of diabetes screening because it eliminates the need for fasting before testing .
this practical advantage is likely to be well received by primary care providers working in environments with increasing constraints .
because a1c , fpg , and ogtt are all considered acceptable diagnostic tests for pre - diabetes by the ada , there may be a strong shift toward using a1c alone to identify patients with pre - diabetes and diabetes .
recent data demonstrating a1c as an independent predictor of incident cardiovascular disease and death in addition to diabetes will only reinforce this shift ( 12 ) .
the current data suggest that further discussion is needed because using a1c alone will lead to a reclassification as normal of many patients who previously ( i.e. , using ifg ) were considered to have pre - diabetes .
this reclassified group includes a large number of individuals ( n = 8 million ) with fasting glucose in the range of 110125 mg / dl .
fasting glucose in this range is associated with a substantially higher risk for diabetes incidence ( 57 times greater than that with fasting glucose of 100109 mg / dl ) ( 13 ) .
whereas combined use of either ifg or a1c as the criteria of pre - diabetes would be more sensitive , it would eliminate the practical advantages of using a1c alone .
it is important to recognize that either criterion ( fasting glucose or a1c ) is a diagnostic test , not a traditional screening test in that it is not compared with a true criterion standard .
astute clinicians may recognize the shortcomings of each test ; however , many providers will probably choose only one or the other for use in practice .
the clinical guidelines do not comment on the need for follow - up testing for pre - diabetes .
this situation increases the likelihood of higher degrees of variation in screening practices with a possibility of more confusion among providers and patients .
educational interventions may need to be developed to help primary care providers and patients understand the advantages and shortcomings of each test used alone or in combination .
pre - diabetes is a label developed to identify those at highest risk for incident diabetes in the near future .
data from observational studies suggest that 2540% of individuals with pre - diabetes will develop diabetes over the next 38 years ( 1416 ) .
currently , the most effective intervention for the prevention or delay of diabetes is intensive lifestyle behavior change with metformin therapy a less potent alternative ( 14 ) .
whereas intensive lifestyle interventions are recommended for individuals identified via ifg , a1c , or igt , current guidelines recommend that metformin be reserved for those with both combined ifg and igt plus other risk factors such as a1c > 6% , hypertension , low hdl cholesterol , elevated triglycerides , or a family history of diabetes in a first - degree relative who are obese and aged > 60 years ( 5 ) .
this recommendation has led some investigators to call for follow - up igt testing in all individuals identified as having pre - diabetes based on their fasting glucose ( 17 ) .
this is in part due to the observation that the odds for incident diabetes are fourfold higher among individuals with both ifg and igt than either alone ( odds ratio 39.5 vs. 10.0 and 10.9 , respectively ) ( 18 ) . with the use of a1c as a legitimate alternative diagnostic criterion for pre - diabetes ,
the need for a follow - up ogtt before prescribing metformin may become a point of contention .
if an ogtt is not performed , combined criteria of a1c with follow - up ifg testing could be used because this group would also be very high risk , and the data could be combined with other metabolic abnormalities using one of the established diabetes risk calculators to generate a more precise risk estimate ( 19,20 ) . which criterion is more accurate and clinically relevant for predicting diabetes and tailoring interventions will need to be examined in future prospective studies . the low concordance among a1c- , ifg- , and igt - based diagnosis of pre - diabetes highlights the multifactorial pathophysiology of glucose dysfunction .
ifg is predominately a dysfunction in hepatic insulin resistance , whereas igt is dominated by muscle insulin resistance ( 21 ) .
each is also associated with dysfunctional insulin secretion but with different patterns ( 21 ) .
in contrast to the daily glucose snapshot offered by ifg and igt , a1c represents chronic exposure ( over 23 months ) to basal and postprandial hyperglycemia and reflects a combination of these mechanisms ( 22 ) .
together , the different mechanisms underlying each test help explain the discordant diagnoses of pre - diabetes using ifg , a1c , and ogtt .
as diabetes itself develops , each underlying mechanism plays a role , which may help explain the reasonable concordance between a1c and ifg in diabetes ( 11 ) .
nevertheless , clinicians need to be aware that each test will classify as normal a substantial proportion of those found to be pre - diabetic by one of the other tests .
most notably , each test ( fpg , a1c , and ogtt ) was only performed once in nhanes 19992006 , and the test results may change over time . even though the coefficient of variation for a1c is quite small
, the clustering of pre - diabetes around 5.8% suggests that small differences could have a disproportionate impact on classification of pre - diabetes .
however , unpublished sensitivity analyses ( and table 2 ) that vary the pre - diabetes a1c criteria to 5.6% showed insignificant differences .
in addition , hemolytic anemias are known to artificially lower a1c levels although this concern is minimal , considering the relative rarity of these conditions compared with pre - diabetes . despite these limitations ,
most notably , nhanes 19992006 uses a complex stratified sampling design to recruit participants , which allows estimates to be made for the u.s . population .
in addition , nhanes 19992006 includes a broad range of demographic , medical , and biochemical data collected by trained staff , following a standardized protocol . in summary ,
the revised 2010 ada standards of medical care in diabetes includes three options for identifying patients at high risk for diabetes : fpg , a1c , and ogtt .
because a1c has significant practical advantages over ifg , it is likely to become the preferred test among primary care providers for diagnosing pre - diabetes .
the clinical impact of this change is not yet known , but the current analysis suggests that it will substantially alter the population identified as having pre - diabetes with tens of millions of americans who would have been considered to have pre - diabetes previously being classified as not having pre - diabetes .
this subgroup of individuals includes a substantial number with fasting glucose levels of 110125 mg / dl and a burden of cardiovascular risk factors similar to that of their counterparts with pre - diabetes by a1c and ifg .
policy makers and clinicians will need to consider the tradeoffs between performing both fpg and a1c testing alone or in combination .
 objectivenew clinical practice recommendations include a1c as an alternative to fasting glucose as a diagnostic test for identifying pre - diabetes . 
 the impact of these new recommendations on the diagnosis of pre - diabetes is unknown.research design and methodsdata from the national health and nutrition examination survey 19992006 ( n = 7,029 ) were analyzed to determine the percentage and number of u.s . 
 adults without diabetes classified as having pre - diabetes by the elevated a1c ( 5.76.4% ) and by the impaired fasting glucose ( ifg ) ( fasting glucose 100125 mg / dl ) criterion separately . 
 test characteristics ( sensitivity , specificity , and positive and negative predictive values ) using ifg as the reference standard were calculated.resultsthe prevalence of pre - diabetes among u.s . 
 adults was 12.6% by the a1c criterion and 28.2% by the fasting glucose criterion . 
 only 7.7% of u.s . 
 adults , reflecting 61 and 27% of those with pre - diabetes by a1c and fasting glucose , respectively , had pre - diabetes according to both definitions . 
 a1c used alone would reclassify 37.6 million americans with ifg to not having pre - diabetes and 8.9 million without ifg to having pre - diabetes ( 46.5 million reclassified ) . using ifg as the reference standard , 
 pre - diabetes by the a1c criterion has 27% sensitivity , 93% specificity , 61% positive predictive value , and 77% negative predictive value.conclusionsusing a1c as the pre - diabetes criterion would reclassify the pre - diabetes diagnosis of nearly 50 million americans . 
 it is imperative that clinicians and health systems understand the differences and similarities in using a1c or ifg in diagnosis of pre - diabetes . 