the study was approved by the emory university institutional review board and used data from 1,573 adults in the sigt study , described previously ( 5 ) . briefly , this study recruited participants without known diabetes between january 2005 and march 2008 . the participants first visits were at different times of the day , without an overnight fast . rcg and rpg were measured , a 50-g glucose drink was given , and gctcap and gctpl glucose levels were measured 1 h later . at a second visit , a1c was measured and a 75-g oral glucose tolerance test ( ogtt ) was begun before 11:00 a.m. , after an overnight fast . diabetes included fasting glucose 126 mg / dl ( 7 mmol / l ) or 2-h ogtt glucose 200 mg / dl ( 11.1 mmol / l ) ; a1c 6.5% ( 48 mmol / mol ) was included in sensitivity analyses . our definition of prediabetes110 included the following : ifg110 , which is fasting glucose 110125 mg / dl ( 6.16.9 mmol / l ) and 2-h ogtt glucose < 140 mg / dl ( 7.8 mmol / l ) ; igt , which is fasting glucose < 110 mg / dl and 2-h ogtt glucose 140199 mg / dl ( 7.811.1 mmol / l ) ; and ifg110 with igt ( ifg plus igt ) , which is fasting glucose 110125 mg / dl ( 6.16.9 mmol / l ) and 2-h ogtt glucose 140199 mg / dl ( 7.811.1 mmol / l ) . cost components and base - case cost assessment also are shown in supplementary table 1 . health system costs were costs that would be incurred in a united states health care system with the government - funded medicare program as the primary health insurer . included were direct medical costs associated with testing , direct medical costs of false - negative results , and direct medical costs for treatment of true - positive results ( including cases of prediabetes110 and diabetes ) with generic metformin . two cost scenarios were considered , health system costs of screening and treatment for dysglycemia110 and health system costs for screening and treatment of diabetes only . all cost scenarios were calculated for a 3-year period of time . the direct medical costs of testing included 2007 medicare costs for the laboratory tests , the cost of the glucose challenge test glucose drink , as well as staff costs based on 2007 united states bureau of labor services wages . we assumed that blood draws for gctpl , rpg , and ogtt assessments would be obtained on - site , and that medical staff would measure rcg and gctcap . because we assumed that initial screening would be opportunistic during a visit , the visit time was not included . we used 70% specificity cut - offs to define positive screen results for each test to detect diabetes or dysglycemia110 , using the ogtt data , to determine these cut - offs . for our cost analyses , we assumed that those participants with a positive screen result would have a subsequent confirmatory ogtt with fasting and postchallenge glucose cut - offs for prediabetes110 and diabetes as defined . the cost of a false - positive result for each screen included the cost of the follow - up ogtt test as per protocol . for the base - case analyses undetected prediabetes110 or diabetes  as 10% of the projected incremental 3-year medical costs for that condition , assuming that these incremental costs could be decreased by appropriate management , as they were in the diabetes prevention program ( dpp ) ( 8,9 ) . we assumed that the cost of a false - negative result would include the 3-year direct medical cost of diabetes , prediabetes110 , or prediabetes110 that progressed to diabetes . we based the direct medical costs for diabetes on medical expenditure panel survey costs from 2000 to 2004 , which was $ 4,174 per year in 2005 united states dollars for a 50-year - old with new - onset diabetes ( 10 ) . we calculated the costs for prediabetes based on the cost of patients with ifg110 in kaiser permanente northwest who had incremental direct medical costs of $ 1,316 per year ( 11 ) , although igt might incur higher costs ( 12 ) . we based the direct medical costs for a true positive result ( prediabetes110 or diabetes ) on 3-year costs for the dpp metformin group . this group s incremental costs for laboratory tests , physician visits , and follow - up were $ 703 ( 9 ) . we assumed that all true - positive results would be treated with metformin , and we substituted recent pharmacy - based generic costs for metformin 850 mg twice per day . the direct medical cost incurred outside of the study for the dpp metformin versus placebo arms was used as the other component for the health system cost of true - positive results ( 9 ) ; the direct medical cost outside the study was $329 for the metformin versus placebo arms . we analyzed costs for subgroups of our study population based on the presence of the following risk characteristics : age < 40 , age 4055 , and age > 55 years ; bmi < 25 , 2535 , > 35 kg / m ; waist circumference with cut - offs of < 88 cm in men and < 102 cm in women ( low - risk ) or 88 cm in men and 102 cm in women ( high - risk ) ; triglycerides < 150 mg / dl ( 1.695 mmol / l ; low - risk ) or 150 mg / dl ( 1.695 mmol / l ; high - risk ) ; hdl 40 mg / dl ( 1.036 mmol / l ) in men and 50 mg / dl ( 1.295 mmol / l ) in women ( low - risk ) or < 40 mg / dl ( 1.036 mmol / l ) in men and < 50 mg / dl ( 1.295 mmol / l ) in women ( high - risk ) ; presence or absence of a family history of diabetes in first - degree relatives ; and presence or absence of elevated blood pressure , defined as systolic blood pressure < 130 ( low - risk ) or 130 mmhg ( high - risk ) . for each characteristic , we examined the costs when we included a1c results of 6.5% ( 48 mmol / mol ) in the definition of diabetes . we examined the following alternatives for the cost components to determine whether our findings were robust : substituting veterans affairs system costs for testing and treatment with metformin to provide a single - payer perspective ; using lower costs for false - negative results , assuming 5% of projected incremental 3-year medical costs , similar to the outside medical care costs of participants in the dpp ( 8) ; and using costs for treatment with lifestyle modification rather than metformin , assuming group intervention costs and costs for other lifestyle changes as described in the dpp protocol ( 13 ) . societal costs included the additional nonmedical costs of testing , indirect ( lost labor productivity ) costs of false - negative results , and direct nonmedical and indirect costs of true - positive results . indirect costs for false - negative results ( absenteeism , reduced productivity at work and for those who did not work ) were derived from the american diabetes association 2007 economic assessment and were attributed only to those with diabetes or whose prediabetes progressed to diabetes during the 3 years ( 14 ) . costs of screening and treatment were expressed as mean  sem for the five types of screens for each risk group . we compared overall high - risk versus low - risk group costs as average costs for the seven higher - risk or highest - risk versus lower - risk or lowest - risk groups . we used nonparametric mann - whitney tests for statistical comparisons of cost variables using sas 9.1.3 ( sas institute , cary nc ) ( 15 ) . diabetes included fasting glucose 126 mg / dl ( 7 mmol / l ) or 2-h ogtt glucose 200 mg / dl ( 11.1 mmol / l ) ; a1c 6.5% ( 48 mmol / mol ) was included in sensitivity analyses . our definition of prediabetes110 included the following : ifg110 , which is fasting glucose 110125 mg / dl ( 6.16.9 mmol / l ) and 2-h ogtt glucose < 140 mg / dl ( 7.8 mmol / l ) ; igt , which is fasting glucose < 110 mg / dl and 2-h ogtt glucose 140199 mg / dl ( 7.811.1 mmol / l ) ; and ifg110 with igt ( ifg plus igt ) , which is fasting glucose 110125 mg / dl ( 6.16.9 mmol / l ) and 2-h ogtt glucose 140199 mg / dl ( 7.811.1 mmol / l ) . cost components and base - case cost assessment also are shown in supplementary table 1 . health system costs were costs that would be incurred in a united states health care system with the government - funded medicare program as the primary health insurer . included were direct medical costs associated with testing , direct medical costs of false - negative results , and direct medical costs for treatment of true - positive results ( including cases of prediabetes110 and diabetes ) with generic metformin . two cost scenarios were considered , health system costs of screening and treatment for dysglycemia110 and health system costs for screening and treatment of diabetes only . the direct medical costs of testing included 2007 medicare costs for the laboratory tests , the cost of the glucose challenge test glucose drink , as well as staff costs based on 2007 united states bureau of labor services wages . we assumed that blood draws for gctpl , rpg , and ogtt assessments would be obtained on - site , and that medical staff would measure rcg and gctcap . because we assumed that initial screening would be opportunistic during a visit , the visit time was not included . we used 70% specificity cut - offs to define positive screen results for each test to detect diabetes or dysglycemia110 , using the ogtt data , to determine these cut - offs . for our cost analyses , we assumed that those participants with a positive screen result would have a subsequent confirmatory ogtt with fasting and postchallenge glucose cut - offs for prediabetes110 and diabetes as defined . the cost of a false - positive result for each screen included the cost of the follow - up ogtt test as per protocol . for the base - case analyses , we evaluated the cost of a false negative result undetected prediabetes110 or diabetes  as 10% of the projected incremental 3-year medical costs for that condition , assuming that these incremental costs could be decreased by appropriate management , as they were in the diabetes prevention program ( dpp ) ( 8,9 ) . we assumed that the cost of a false - negative result would include the 3-year direct medical cost of diabetes , prediabetes110 , or prediabetes110 that progressed to diabetes . we based the direct medical costs for diabetes on medical expenditure panel survey costs from 2000 to 2004 , which was $ 4,174 per year in 2005 united states dollars for a 50-year - old with new - onset diabetes ( 10 ) . we calculated the costs for prediabetes based on the cost of patients with ifg110 in kaiser permanente northwest who had incremental direct medical costs of $ 1,316 per year ( 11 ) , although igt might incur higher costs ( 12 ) . we based the direct medical costs for a true positive result ( prediabetes110 or diabetes ) on 3-year costs for the dpp metformin group . this group s incremental costs for laboratory tests , physician visits , and follow - up were $ 703 ( 9 ) . we assumed that all true - positive results would be treated with metformin , and we substituted recent pharmacy - based generic costs for metformin 850 mg twice per day . the direct medical cost incurred outside of the study for the dpp metformin versus placebo arms was used as the other component for the health system cost of true - positive results ( 9 ) ; the direct medical cost outside the study was $329 for the metformin versus placebo arms . we analyzed costs for subgroups of our study population based on the presence of the following risk characteristics : age < 40 , age 4055 , and age > 55 years ; bmi < 25 , 2535 , > 35 kg / m ; waist circumference with cut - offs of < 88 cm in men and < 102 cm in women ( low - risk ) or 88 cm in men and 102 cm in women ( high - risk ) ; triglycerides < 150 mg / dl ( 1.695 mmol / l ; low - risk ) or 150 mg / dl ( 1.695 mmol / l ; high - risk ) ; hdl 40 mg / dl ( 1.036 mmol / l ) in men and 50 mg / dl ( 1.295 mmol / l ) in women ( low - risk ) or < 40 mg / dl ( 1.036 mmol / l ) in men and < 50 mg / dl ( 1.295 mmol / l ) in women ( high - risk ) ; presence or absence of a family history of diabetes in first - degree relatives ; and presence or absence of elevated blood pressure , defined as systolic blood pressure < 130 ( low - risk ) or 130 mmhg ( high - risk ) . for each characteristic , we examined the costs when we included a1c results of 6.5% ( 48 mmol / mol ) in the definition of diabetes . we examined the following alternatives for the cost components to determine whether our findings were robust : substituting veterans affairs system costs for testing and treatment with metformin to provide a single - payer perspective ; using lower costs for false - negative results , assuming 5% of projected incremental 3-year medical costs , similar to the outside medical care costs of participants in the dpp ( 8) ; and using costs for treatment with lifestyle modification rather than metformin , assuming group intervention costs and costs for other lifestyle changes as described in the dpp protocol ( 13 ) . societal costs included the additional nonmedical costs of testing , indirect ( lost labor productivity ) costs of false - negative results , and direct nonmedical and indirect costs of true - positive results . indirect costs for false - negative results ( absenteeism , reduced productivity at work and for those who did not work ) were derived from the american diabetes association 2007 economic assessment and were attributed only to those with diabetes or whose prediabetes progressed to diabetes during the 3 years ( 14 ) . costs of screening and treatment were expressed as mean  sem for the five types of screens for each risk group . we compared overall high - risk versus low - risk group costs as average costs for the seven higher - risk or highest - risk versus lower - risk or lowest - risk groups . we used nonparametric mann - whitney tests for statistical comparisons of cost variables using sas 9.1.3 ( sas institute , cary nc ) ( 15 ) . baseline characteristics of participants have been reported previously and are shown in table 1 ; 366 ( 23% ) had dysglycemia110 and 72 ( 5% ) had diabetes . more than 75% of participants were 45 years of age or older or had bmi 25 kg / m . however , only 12% had a triglyceride level 150 mg / dl ( 1.695 mmol / l ) , 26% had systolic blood pressure 130 mmhg , and 46% had a family history of diabetes . the higher - risk groups were more likely to have diabetes or dysglycemia110 ; the latter was present in 35% of participants with age > 55 years , bmi > 35 kg / m , or systolic blood pressure 130 mmhg compared with 1019% in the corresponding lower - risk groups . baseline characteristics of 1,573 participants from the sigt study the health system cost components and overall assessment for screening ( and 3 years of treatment ) for dysglycemia110 are shown in supplementary table 1 . these health system costs and the differences in health system costs for screening versus no screening are shown by risk group for each screening test in table 2 and fig . 1 ; in these analyses ,  negative cost differences  for screening versus no screening indicate projected net cost - savings .  the relative cost - savings of screening versus no screening would be greater ( more  negative  ) for the higher - risk groups for every risk group assessed ( p < 0.01 for each higher - risk or highest - risk versus lower - risk or lowest - risk group ) , with average cost - savings of 19% for the highest bmi and 18% for the elevated blood pressure groups ( both p < 0.01 compared with lowest - risk and lower - risk groups ) . among the different tests , screening of the higher - risk groups was generally least expensive when gctpl was used for screening , with cost - savings of 21% for the highest bmi and elevated blood pressure groups . screening lower - risk groups would result in less cost - savings , or a net increase in costs , and in those groups rpg or rcg tended to be the least expensive tests . health system costs for screening and treatment of dysglycemia110 of 1,573 participants by risk group and percent cost difference for screening and treatment compared with no screening * the average percent cost differences between health system costs for screening and treatment of dysglycemia110 by risk group compared with no screening . shown are the average percent differences in cost for screening with the five different screens and management of dysglycemia110 compared with no screening for different risk groups . the 95% cis are depicted by the upper or lower lines or both . for each risk group , the prevalence of dysglycemia110 is shown along the top of the chart , and the costs of no screening per person are shown along the bottom of the chart . the prevalence of dysglycemia110 and the cost of no screening per person increased with higher - risk characteristics among the risk groups . sbp , systolic blood pressure ; tg , triglycerides ; fam hx , family history . the health system costs for screening ( and treatment ) for diabetes are shown in table 3 , with the differences in costs for screening versus no screening in table 3 and supplementary fig . 1 . for all of these groups , screening would produce cost - savings compared with no screening , and cost - savings with targeting of diabetes would be greater than with dysglycemia110 ( for all subjects , cost - savings of 26 vs. 9% ; p < 0.01 ) . as with dysglycemia110 , cost - savings resulting from screening for diabetes would be greater with higher - risk and highest - risk groups compared with lower - risk and lowest - risk groups ( 34 vs. 12% , over all groups ; p < 0.01 ) ; screening those with elevated blood pressure , the highest bmi , and the oldest age groups would provide the greatest cost - savings ( 39 , 38 , and 36% , respectively ; all p < 0.01 versus the relevant lowest - risk group ) . gctpl testing would provide the lowest costs for the higher - risk groups , with cost - savings of up to 46% for those with elevated blood pressure , and rcg or rpg would provide the lowest costs with the lowest - risk groups . health system costs for screening and treatment of diabetes of 1,573 participants by risk group and percent cost difference for screening and treatment compared with no screening * the impact of screening on overall costs depends on the prevalence of the disease in the population , the cost of undetected disease ( false - negative results ) , the cost of screening , and characteristics of different screening tests . with our study population and base - case assumptions , cost - savings for screening with gctpl versus rcg would be achieved in screening for diabetes when the prevalence in the population is 4% and for dysglycemia110 when the prevalence is 20% ( supplementary fig . is shown in supplementary table 2 and is illustrated for screening with gctpl versus rcg in supplementary fig . greater cost - savings are achieved with gctpl , a more accurate but more expensive test , either when cost of undetected disease is high or when prevalence of disease is high , and especially when both are high . testing costs per true - positive result also decrease as prevalence of the disease in the population increases . in screening for dysglycemia110 , average testing costs for the five screens for those with bmi < 25 kg / m would be $ 203  40 per true - positive result compared with $ 64  7 for those with bmi > 35 kg / m ( p < 0.01 ) . in screening for diabetes , average testing costs per true - positive result would be $ 836  156 for those with bmi < 25 kg / m compared with $ 185  17 for those with bmi > 35 kg / m ( p < 0.01 ) . when we included a1c 6.5% ( 48 mmol / mol ) in our definition of diabetes , we identified 10 additional participants with diabetes in this cohort ; however , the total number of participants with dysglycemia110 did not change . screening the higher - risk groups for diabetes continued to be significantly more cost - saving compared with no screening and compared with screening the equivalent low - risk group . for example , screening with gctpl for those with an elevated blood pressure versus those without an elevated blood pressure resulted in cost - savings of 37.5 versus 2.5% , respectively ( p < 0.01 ) , both compared with no screening . for both higher - risk and lower - risk groups , screening for dysglycemia110 or diabetes from a veterans affairs perspective would result in greater cost - savings compared with medicare - based costs ( supplementary tables 4 and 5 ) if false - negative result costs were only 5% of projected incremental medical costs over 3 years , then health system costs would be cost - neutral for screening for diabetes compared with no screening for some but not all of the higher - risk groups ( supplementary table 6 ) , but screening and treatment of dysglycemia110 would not produce cost - savings for any group ( not shown ) . the health system costs with a lifestyle change intervention would be similar to costs with generic metformin , with cost - savings particularly for higher - risk groups ( supplementary tables 7 , 8) . from a societal perspective , screening ( and treatment with metformin ) for dysglycemia110 ( supplementary table 9 ) would result in cost - savings compared with no screening only in the highest - risk groups with substantial prevalence of disease , particularly for those with bmi > 35 kg / m or elevated blood pressure , with 11% savings compared with no screening . in contrast , societal costs for screening and treatment of diabetes ( supplementary table 10 ) would produce broader cost - savings in both high - risk and lower - risk groups . when we included a1c 6.5% ( 48 mmol / mol ) in our definition of diabetes , we identified 10 additional participants with diabetes in this cohort ; however , the total number of participants with dysglycemia110 did not change . screening the higher - risk groups for diabetes continued to be significantly more cost - saving compared with no screening and compared with screening the equivalent low - risk group . for example , screening with gctpl for those with an elevated blood pressure versus those without an elevated blood pressure resulted in cost - savings of 37.5 versus 2.5% , respectively ( p < 0.01 ) , both compared with no screening . for both higher - risk and lower - risk groups , screening for dysglycemia110 or diabetes from a veterans affairs perspective would result in greater cost - savings compared with medicare - based costs ( supplementary tables 4 and 5 ) if false - negative result costs were only 5% of projected incremental medical costs over 3 years , then health system costs would be cost - neutral for screening for diabetes compared with no screening for some but not all of the higher - risk groups ( supplementary table 6 ) , but screening and treatment of dysglycemia110 would not produce cost - savings for any group ( not shown ) . the health system costs with a lifestyle change intervention would be similar to costs with generic metformin , with cost - savings particularly for higher - risk groups ( supplementary tables 7 , 8) . from a societal perspective , screening ( and treatment with metformin ) for dysglycemia110 ( supplementary table 9 ) would result in cost - savings compared with no screening only in the highest - risk groups with substantial prevalence of disease , particularly for those with bmi > 35 kg / m or elevated blood pressure , with 11% savings compared with no screening . in contrast , societal costs for screening and treatment of diabetes ( supplementary table 10 ) would produce broader cost - savings in both high - risk and lower - risk groups . our previous analyses demonstrated that screening the sigt study population for either diabetes or dysglycemia110 would be cost - saving from a health system perspective over a 3-year horizon ( 4 ) . we now show that the majority of cost - savings would come from screening individuals with higher risk , based on any one of the characteristics of age , bmi , triglycerides , hdl cholesterol , waist circumference , systolic blood pressure , or family history of diabetes . in most of the higher - risk groups , however , the greatest cost - savings would be attained with screening of individuals with bmi > 35 kg / m or systolic blood pressure 130 mmhg . of the five screening tests considered , the gctpl appears to be the least expensive screening test in most higher - risk groups . higher - risk groups would have higher costs associated with no screening . because these groups have a higher prevalence of diabetes and dysglycemia110 , failure to screen would result in more patients with missed diagnoses , with associated increases in downstream treatment costs . and as the costs of no screening increase , greater cost - savings can be obtained with a more accurate test , i.e. , gctpl compared with rcg ( supplementary fig . one review concluded that it would be very cost - effective to screen for diabetes using current american diabetes association guidelines among african americans 4554 years of age ( 16 ) . another study examined screening with fasting plasma glucose on the basis of age or blood pressure or both and found that it would be more cost - effective to screen at 3045 years of age than at older age , and even more cost - effective to screen beginning at 30 years of age in people with hypertension ( 2 ) . two other studies found that targeted screening for diabetes with fasting or rcg based on hypertension , and for prediabetes based on obesity , would be more cost - effective compared with universal screening ( 17,18 ) , but those studies also did not consider other risk factors or other screening tests . whether screening should target prediabetes as well as diabetes also has been debated . most analyses have found that it should be cost - effective to screen for and treat prediabetes to reduce both the risk of cardiovascular disease and progression to diabetes ( 1820 ) . our study confirms that even over a 3-year time period , it should be cost - saving to screen for and treat dysglycemia110 ( prediabetes110 as well as diabetes ) , particularly among higher - risk groups . the study participants were volunteers , which might have resulted in selection bias from disproportionate participation of those at high risk . however , the prevalence of prediabetes and diabetes in the study population was similar to or lower than that in recent national surveys , such as nhanes 20052006 ( 21 ) . although we did gather information regarding risk of diabetes , information on history of gestational diabetes was not collected or used as a risk factor in our analyses . we also did not calculate costs associated with screening for either dysglycemia110 or diabetes with a fasting glucose alone . whereas a fasting glucose may be considered an acceptable test for patients who do not mind fasting before a visit , many cases of postchallenge dysglycemia would be missed , leading to a higher number of false - negative results and higher overall costs . our analyses rely on estimates of testing , treatment , and false - negative result costs , which may not be applicable to every health system . our estimates for the cost of false - negative results ( that 10% of projected incremental 3-year medical costs of diabetes or dysglycemia110 could be reduced with detection and management ) might be excessive . however , we project that cost - savings still could be achieved in higher - risk groups with a false - negative result cost of at least 5% , which was achieved in the tightly controlled environment of the dpp study ( 8) . some groups have found the cost of undiagnosed diabetes and prediabetes to be lower than the costs we used in our analyses , but it is still to be determined how much of these costs could be reduced with detection and management ( 22,23 ) . we are not aware of other sources for the costs of false - negative results . in sensitivity analyses addressing costs associated with lifestyle changes as treatment for dysglycemia110 or diabetes , we based our costs on group - based interventions designed by the dpp study . more recent studies have found that community - based interventions based on the dpp protocol could be performed with reduced costs . these studies generally have found that treatment with lifestyle interventions are cost - effective in the long - term ( 2426 ) and possibly even are cost - saving in the short - term ( 26 ) . finally , our cost estimates projected a 3-year time period . such a period might be relevant to employer - based health systems in which insurers are changed every few years , but lifetime cost analyses would be needed to determine if the cost - savings found in higher - risk groups are likely to be sustained . our findings show that screening and treatment for diabetes and dysglycemia110 should be cost - saving from a health system perspective in people with any single risk factor for these conditions . this likely is a large proportion of the united states adult population , because at least one such risk factor was present in 98% of our study subjects and in 96% of adult african american and white participants in nhanes 20052006 . we also found that the greatest cost - savings likely would be attained with screening of individuals with bmi > 35 kg / m , systolic blood pressure 130 mmhg , or age > 55 years . the gctpl , previously shown to have the greatest accuracy for detection of diabetes or dysglycemia110 , appears to be the least expensive screening test in most higher - risk groups and should be considered for use in clinical practice .