in cross - sectional analyses , we evaluated the likelihood that americans with previously unrecognized pre - diabetes would meet ada consensus panel recommendations for consideration of metformin in addition to change in lifestyle .
criteria for consideration of metformin included the presence of both ifg and igt , with 1 additional diabetes risk factor : age < 60 years , bmi 35 kg / m , family history of diabetes , elevated triglycerides , reduced hdl cholesterol , hypertension , or a1c
, subjects were recruited to participate in the screening for impaired glucose tolerance ( sigt ) study ( 9 ) , a cross - sectional study that was approved by the emory institutional review board .
the invitation to participate was extended to employees of the grady health system , emory healthcare , and emory university and morehouse schools of medicine as well as to members of the community .
criteria for eligibility were age 18 years , non - hispanic white or black race , no prior diagnosis of diabetes , not pregnant or breast - feeding , not taking glucocorticoids , and being well enough to have worked during the previous week ( without requiring actual employment ) . during recruitment ,
4,024 individuals expressed initial interest in the study , among whom 2,111 were scheduled for first visits ( selected largely on the basis of need to balance participant sex and race ) , 1,658 completed first visits , and 1,581 completed the protocol .
all study visits were performed in the general clinical research centers at emory university hospital and grady memorial hospital .
we also evaluated subjects who took part in the third national health and nutrition examination survey ( nhanes iii ) ( 10 ) and the continuous national health and nutrition examination survey 20052006 ( nhanes 20052006 ) ( 11 ) .
nhanes is a program of studies conducted by the national center for health statistics of the centers for disease control and prevention that include both interviews and physical examinations in a nationally representative sample to assess the health and nutritional status of adults and children in the u.s .
nhanes iii was conducted between 1988 and 1994 . in 1999 , the survey became a continuous program examining 5,000 individuals each year , which includes nhanes 20052006 .
demographic information was collected by self - report and included family history of diabetes in a first - degree relative , race , history of hypertension , history of diabetes , and current medication use .
blood pressure was measured with digital manometers after subjects had been seated quietly for 5 min .
classification of glucose tolerance was determined by a 75-g ogtt in accordance with ada diagnostic criteria ( 12 ) : normal glucose tolerance ( ngt)fasting plasma glucose ( fpg ) < 100 mg / dl and 2-h postchallenge glucose < 140 mg / dl ; isolated ifg 
fpg 100125 mg / dl and 2-h postchallenge glucose < 140 mg / dl ; isolated igt 
fpg < 100 mg / dl and 2-h postchallenge glucose 140199 mg / dl ; any ifg 
fpg 100125 mg / dl and 2-h postchallenge glucose < 199 mg / dl ; any igt 
fpg < 126 mg / dl and 2-h postchallenge glucose 140199 mg / dl ; combined ifg and igt 
fpg 100125 mg / dl and 2-h postchallenge glucose 140199 mg / dl ; and diabetes 
isolated ifg was further subcategorized into fasting glucose between 100 and 109 mg / dl ( ifg 100109 ) and fasting glucose between 110 and 125 mg / dl ( ifg 110125 ) .
all ogtts were begun before 11:00 a.m. after an overnight fast , with blood samples drawn at baseline , 1 h , and 2 h. blood samples were also obtained for measurement of plasma lipids and a1c .
chemical analyses were performed in the central clinical laboratory of the grady health system using an lx-20 analyzer ( beckman coulter , brea , ca ) ; a1c measurement with this system is national glycohemoglobin standardization program - certified . in the nhanes iii database ,
we analyzed only those who had no known history of diabetes , had completed the ogtt in the morning before 11:00 a.m. after an overnight fast of at least 9 h , for whom the 2-h postchallenge glucose level was measured between 100 and 135 min after ingestion of the glucose load , and had a survey weight value > 0 . among this subset ( n = 2,833 ) , we included only those who were non - hispanic black or white ( to match our study population ) ( n = 2,057 ) . in the nhanes 20052006 population , all subjects
12 years who were seen in the morning session were asked to have an ogtt performed .
subjects were eligible for the ogtt if they had fasted overnight for at least 9 h , reported no use of oral medications or insulin for diabetes , were not pregnant , did not have hemophilia , and did not receive cancer chemotherapy in the previous 3 weeks .
all blood samples for the 2-h glucose measurement were drawn between 100 and 135 min after ingestion of the glucose load . for our analysis , we included only those who were 18 years , had no known history of diabetes , were non - hispanic black or white ( to match our study population ) , and had a survey weight value > 0 ( n = 1,154 ) . because some subjects had more than one blood pressure measurement , the average of the measurements was used for the analysis . for the sigt , nhanes iii , and nhanes 20052006 subjects , age , bmi , and a1c
were categorized using the cutoffs recommended by the ada : age < 60 years , bmi 35 kg / m , and a1c > 6.0% ( 8) .
other risk factors for diabetes that were not specifically defined by the ada were categorized according to the american heart association / national heart , lung , and blood institute ( aha / nhlbi ) diagnostic criteria for metabolic syndrome ( 12 ) : presence of hypertension by history , systolic blood pressure > 130 mmhg or diastolic blood pressure > 85 mmhg , triglyceride level 150 mg / dl , and hdl cholesterol < 40 mg / dl in men and < 50 mg / dl in women . given the high number of subjects in nhanes iii and nhanes 20052006 whose reporting of the diabetes status of one or more first - degree relatives was either not known or left blank ( nhanes iii , n = 1,163 ; nhanes 20052006 , n = 116 ) , relatives whose diabetes status was missing or not known were assumed to not have diabetes , a method that was also implemented for the analysis of the sigt study group .
in addition , subjects with missing values for the remaining risk factors were excluded from analysis ( nhanes iii : 1 missing blood pressure measurement or hypertension history , 7 missing a1c values , 27 missing triglyceride values , and 35 missing hdl cholesterol values ; nhanes 20052006 : 32 missing blood pressure measurements or hypertension history , 8 missing bmi measurements , 2 missing a1c values , 4 missing triglyceride values , and 4 missing hdl values ) , leaving 2,014 subjects in nhanes iii and 1,111 subjects in nhanes 20052006 to be analyzed for metformin consideration . means and frequencies were determined in aggregate and by subgroup analysis of the different glucose tolerance categories .
all sigt analyses were performed using spss 15.0 ( spss , chicago , il ) .
all nhanes iii and nhanes 20052006 analyses were conducted using sudaan statistical software ( version 10 ) to account for the complex survey design , and all estimates were weighted ( rti international , research triangle park , nc ) .
demographic information was collected by self - report and included family history of diabetes in a first - degree relative , race , history of hypertension , history of diabetes , and current medication use .
blood pressure was measured with digital manometers after subjects had been seated quietly for 5 min .
classification of glucose tolerance was determined by a 75-g ogtt in accordance with ada diagnostic criteria ( 12 ) : normal glucose tolerance ( ngt)fasting plasma glucose ( fpg ) < 100 mg / dl and 2-h postchallenge glucose < 140 mg / dl ; isolated ifg 
fpg 100125 mg / dl and 2-h postchallenge glucose < 140 mg / dl ; isolated igt 
fpg < 100 mg / dl and 2-h postchallenge glucose 140199 mg / dl ; any ifg 
fpg 100125 mg / dl and 2-h postchallenge glucose < 199 mg / dl ; any igt 
fpg < 126 mg / dl and 2-h postchallenge glucose 140199 mg / dl ; combined ifg and igt
 fpg 100125 mg / dl and 2-h postchallenge glucose 140199 mg / dl ; and diabetes 
isolated ifg was further subcategorized into fasting glucose between 100 and 109 mg / dl ( ifg 100109 ) and fasting glucose between 110 and 125 mg / dl ( ifg 110125 ) .
all ogtts were begun before 11:00 a.m. after an overnight fast , with blood samples drawn at baseline , 1 h , and 2 h. blood samples were also obtained for measurement of plasma lipids and a1c .
chemical analyses were performed in the central clinical laboratory of the grady health system using an lx-20 analyzer ( beckman coulter , brea , ca ) ; a1c measurement with this system is national glycohemoglobin standardization program - certified .
in the nhanes iii database , a subset of adults aged 40 years had an ogtt performed .
we analyzed only those who had no known history of diabetes , had completed the ogtt in the morning before 11:00 a.m. after an overnight fast of at least 9 h , for whom the 2-h postchallenge glucose level was measured between 100 and 135 min after ingestion of the glucose load , and had a survey weight value > 0 . among this subset ( n = 2,833 ) , we included only those who were non - hispanic black or white ( to match our study population ) ( n = 2,057 ) . in the nhanes 20052006 population , all subjects
12 years who were seen in the morning session were asked to have an ogtt performed .
subjects were eligible for the ogtt if they had fasted overnight for at least 9 h , reported no use of oral medications or insulin for diabetes , were not pregnant , did not have hemophilia , and did not receive cancer chemotherapy in the previous 3 weeks .
all blood samples for the 2-h glucose measurement were drawn between 100 and 135 min after ingestion of the glucose load . for our analysis
, we included only those who were 18 years , had no known history of diabetes , were non - hispanic black or white ( to match our study population ) , and had a survey weight value > 0 ( n = 1,154 ) .
because some subjects had more than one blood pressure measurement , the average of the measurements was used for the analysis . for the sigt , nhanes iii , and nhanes 20052006 subjects , age , bmi , and a1c
were categorized using the cutoffs recommended by the ada : age < 60 years , bmi 35 kg / m , and a1c > 6.0% ( 8) .
other risk factors for diabetes that were not specifically defined by the ada were categorized according to the american heart association / national heart , lung , and blood institute ( aha / nhlbi ) diagnostic criteria for metabolic syndrome ( 12 ) : presence of hypertension by history , systolic blood pressure > 130 mmhg or diastolic blood pressure > 85 mmhg , triglyceride level 150 mg / dl , and hdl cholesterol < 40 mg / dl in men and < 50 mg / dl in women .
given the high number of subjects in nhanes iii and nhanes 20052006 whose reporting of the diabetes status of one or more first - degree relatives was either not known or left blank ( nhanes iii , n = 1,163 ; nhanes 20052006 , n = 116 ) , relatives whose diabetes status was missing or not known were assumed to not have diabetes , a method that was also implemented for the analysis of the sigt study group .
in addition , subjects with missing values for the remaining risk factors were excluded from analysis ( nhanes iii : 1 missing blood pressure measurement or hypertension history , 7 missing a1c values , 27 missing triglyceride values , and 35 missing hdl cholesterol values ; nhanes 20052006 : 32 missing blood pressure measurements or hypertension history , 8 missing bmi measurements , 2 missing a1c values , 4 missing triglyceride values , and 4 missing hdl values ) , leaving 2,014 subjects in nhanes iii and 1,111 subjects in nhanes 20052006 to be analyzed for metformin consideration .
means and frequencies were determined in aggregate and by subgroup analysis of the different glucose tolerance categories .
all sigt analyses were performed using spss 15.0 ( spss , chicago , il ) .
all nhanes iii and nhanes 20052006 analyses were conducted using sudaan statistical software ( version 10 ) to account for the complex survey design , and all estimates were weighted ( rti international , research triangle park , nc ) .
among 1,581 volunteers who completed ogtts in the sigt study , average age was 48 years and bmi was 30.3 kg / m , 42% were male , and 58% were black ( table 1 ) .
in the selected nhanes iii population ( n = 2,014 ) , the average age was 55 years and bmi was 27.3 kg / m , 47% were male , and 10% were black , and in nhanes 20052006 ( n = 1,111 ) , the average age was 46 years and bmi was 28.5 kg / m , 49% were male , and 13% were black ( table 1 ) .
62.1% had normal fasting glucose and ngt , 18.0% had isolated ifg , 7.2% had isolated igt , 8.2% had both ifg and igt , and 4.6% had diabetes , similar to the proportions in nhanes iii ( 54.3% had ngt , 22.3% had isolated ifg , 6.4% had isolated igt , 9.4% had both ifg and igt , and 7.6% had diabetes ) and nhanes 20052006 ( 59.1% had ngt , 21.8% had isolated ifg , 5.0% had isolated igt , 9.0% had both ifg and igt , and 5.2% had diabetes ) .
all three populations had a comparable portion with either ifg or igt ( 33.4% in sigt , 38.1% nhanes iii , and 35.8% in nhanes 20052006 ) . when the associated risk factors for diabetes , as specified by the ada consensus statement ( 8) , were considered , among those with both ifg and igt , the presence of each risk factor was generally higher among sigt subjects , compared with subjects in nhanes iii and nhanes 20052006 , with the exception of elevated triglycerides and a1c levels ( table 2 ) .
even with the differences in the prevalence of risk factors , almost all subjects with both ifg and igt in all three populations had at least one risk factor ( 99% in sigt , 96% in nhanes iii , and 96% in nhanes 20052006 ) , which was similar among those with ifg ( isolated or with igt : 99% in sigt , 96% in nhanes iii , and 83% in nhanes 20052006 ) and those with igt ( isolated or with ifg : 99% in sigt , 96% in nhanes iii , and 94% in nhanes 20052006 ) . among all subjects with ifg ( isolated or with igt ) , one - quarter to one - third ( 31% in sigt , 29% in nhanes iii , and 28% in nhanes 20052006 ) met the recommended criteria for metformin treatment , and among all subjects with igt ( isolated or with ifg ) , one - half to two - thirds ( 53% in sigt , 57% in nhanes iii , and 62% in nhanes
overall , 1 in 12 individuals in these populations met the criteria for consideration of metformin ( 8.1% in sigt , 9.1% in nhanes iii , and 8.7% in nhanes 20052006 ) .
glucose tolerance categories : ifg ( igt ) , ifg with or without igt ; igt ( ifg ) , igt with or without ifg ; ifg + igt , both ifg and igt . * reduced hdl cholesterol defined as 40 mg / dl in men and 50 mg / dl in women .
hypertension defined by any of the following : history of hypertension , systolic blood pressure 130 mmhg , or diastolic blood pressure 85 mmhg .
metformin indicated per the ada consensus statement ( 8) criteria of the presence of both ifg and igt and one of the following diabetes risk factors : age < 60 years , bmi 35 kg / m , family history of diabetes , elevated triglycerides , reduced hdl cholesterol , and a1c > 6.0% .
risk factors for diabetes that were not specifically defined by the ada were categorized according to the aha / nhlbi diagnostic criteria for metabolic syndrome ( 12 ) : presence of hypertension by history , systolic blood pressure > 130 mmhg or diastolic blood pressure > 85 mmhg , triglyceride level 150 mg / dl , and hdl cholesterol < 40 mg / dl in men and < 50 mg / dl in women .
metformin is indicated per the ada consensus statement criteria of the presence of both ifg and igt and one of the following diabetes risk factors : age < 60 years , bmi 35 kg / m , family history of diabetes , elevated triglycerides , reduced hdl cholesterol , and a1c > 6.0% ( 8) .
risk factors for diabetes that were not specifically defined by the ada were categorized according to the aha / nhlbi diagnostic criteria for metabolic syndrome ( 12 ) : presence of hypertension by history , systolic blood pressure > 130 mmhg or diastolic blood pressure > 85 mmhg , triglyceride level 150 mg / dl , and hdl cholesterol < 40 mg / dl in men and < 50 mg / dl in women .
glucose tolerance categories are as follows : ifg 100109 , fpg levels 100109 mg / dl and 2-h postchallenge plasma glucose < 140 mg / dl ; ifg 110125 , fpg 110125 mg / dl and 2-h postchallenge plasma glucose < 140 mg / dl ; all ifg , isolated ifg ( fpg 100125 mg / dl and 2-h postchallenge plasma glucose < 140 mg / dl ) ; igt , isolated igt ; and ifg 100125 + igt , all ifg and igt .
in consideration of the enormous public health impact of diabetes and the evidence of benefit from pharmacological treatment for the prevention of diabetes , the ada issued a consensus statement recommending preventive treatment in individuals at high risk of developing diabetes , defined as those with more severe pre - diabetes ( both ifg and igt as well as an additional risk factor ) ( 8) .
to determine the proportion of individuals who would be targeted by such a recommendation , we examined a relatively healthy population without previously diagnosed diabetes ( sigt ) and representative samples of the u.s .
population ( nhanes iii and nhanes 20052006 ) and found that one - quarter to one - third had pre - diabetes . among those with ifg
, nearly one - third of subjects met the criteria for consideration of metformin treatment to prevent diabetes in accordance with the recent ada consensus statement , more than one - half of all of the subjects with igt qualified , and almost all of those with both ifg and igt qualified .
overall , 89% met the recommended criteria . assuming that our data are generalizable to the u.s .
population , 24 million americans might benefit from pharmacological treatment in addition to lifestyle modification .
the epidemic of diabetes and the insidious onset of its complications have prompted a call for early identification and preventive treatment of the disease .
diabetes is currently the leading cause of blindness , end - stage renal disease requiring dialysis , and nontraumatic amputations in the u.s . and increases the risk for cardiovascular disease and stroke by two- to fourfold , compared with those without diabetes ( 1 ) .
it is the seventh leading cause of death ( 1 ) and in 2007 cost $ 174 billion in both direct and indirect health care expenditures ( 2 ) .
in addition , the prevalence of diabetes has been on the rise in the adolescent population ( 13 ) , indicating that the epidemic is likely to continue into the next generation .
pre - diabetes , the stage preceding the development of diabetes , increases the risk for the development of diabetes , such that 2539% of patients with ifg or igt go on to develop diabetes over a period of 510 years ( 14,15 ) .
moreover , pre - diabetes alone has been associated with an increased risk for the development of cardiovascular disease ( 16,17 ) and microvascular complications typically seen with diabetes ( 18 ) . given these risks ,
in addition to lifestyle modification , pharmacological treatment with acarbose ( 5 ) , rosiglitazone ( 6 ) , orlistat ( 19 ) , or metformin ( 4 ) has shown efficacy in preventing or delaying the onset of diabetes in individuals with pre - diabetes .
the relative risk reduction for diabetes in the pre - diabetic population was 25% over 3.3 years in patients treated with acarbose ( 5 ) , 5262% over 24 years with orlistat ( 19 ) , 62% over 3 years with rosiglitazone ( 6 ) , and 2631% over 2.52.8 years with metformin ( 4 ) .
however , because many individuals with pre - diabetes are generally healthy , the benefit of preventive treatment must outweigh any associated side effects or additional risks , particularly because none of these medications have u.s .
gastrointestinal side effects are commonly associated with acarbose ( 5 ) and orlistat ( 19 ) , leading to poor patient compliance , whereas an increased risk of bone loss ( 20 ) , worsening or new - onset edema ( 21 ) , and heart failure ( 22 ) are associated with rosiglitazone .
therefore , metformin , which has been used for many years and is both generally well tolerated and relatively safe , has become the leading candidate for preventive treatment .
in addition to the recommendations of the ada , the american college of endocrinology ( ace ) has recently issued their consensus statement on the management of pre - diabetes ( 23 ) .
similar to the ada recommendations , the ace statement recognizes the need for preventive treatment , beginning with lifestyle modification , but also emphasizes the importance of treating relevant comorbid conditions , such as hypertension , hypercholesterolemia , and obesity , and provides a looser set of criteria regarding the initiation of pharmacological treatment .
acarbose and metformin are their recommended treatments for individuals who are at high risk of developing diabetes , which include , but are not limited to , those with ifg , igt , and/or the metabolic syndrome , worsening glycemia , cardiovascular disease , nonalcoholic fatty liver disease , a history of gestational diabetes , or polycystic ovary syndrome . taking into account the target populations
as defined by the ada and the ace , > 8% of americans could benefit from pharmacological treatment to prevent or delay development of diabetes .
use of pharmacological agents for the many americans who may benefit from preventive treatment would incur substantial costs : at current generic rates for metformin , possibly $ 4/month  12 months  24 million americans = $ 1.15 billion per year .
however , several studies suggest that diabetes prevention or delay with metformin is likely to be cost - effective and/or cost - saving ( 24 ) ; further evaluation using a variety of cost analysis methods may be required to reach a definitive conclusion regarding the cost of preventive treatment . to our knowledge ,
our findings are the first evaluation of the proportion of relatively healthy individuals who might benefit from metformin treatment for the prevention or delay of development of diabetes .
because all sigt subjects were recruited on a volunteer basis , there may have been a selection bias toward higher family history of diabetes and/or other risk factors for diabetes .
however , because many sigt subjects were recruited from university and health care settings , they may also follow healthier lifestyles , which could offset such a bias .
moreover , the proportion with diabetes or pre - diabetes in sigt was no higher than that in nhanes iii and was comparable to that in the more recent nhanes 20052006 , both of which represent randomized , stratified samples of the american population .
the morbidity , mortality , and cost of the epidemic of diabetes have prompted a call for primary prevention of diabetes in high - risk individuals by the use of metformin in addition to lifestyle changes .
population , close to 1 in 12 american adults may meet the recommended guidelines for consideration of metformin treatment for diabetes prevention or delay .
notably , eligibility for metformin use appeared to be almost completely determined by impaired glucose metabolism alone , because 99% of the sigt population and 96% of the nhanes populations with both ifg and igt had at least one risk factor .
therefore , once the presence of both ifg and igt has been established , the presence of additional risk factors could almost be assumed , and initiation of metformin should be considered . moreover , because nearly one - third of all subjects with ifg met the criteria for metformin treatment , providers should perform ogtts in all patients with ifg to test for the presence of igt ( or unrecognized diabetes ) and thereby determine whether they merit consideration of metformin treatment .
 objectiveto determine the proportion of the american population who would merit metformin treatment , according to recent american diabetes association ( ada ) consensus panel recommendations to prevent or delay the development of diabetes.research design and methodsrisk factors were evaluated in 1,581 screening for impaired glucose tolerance ( sigt ) , 2,014 third national health and nutrition examination survey ( nhanes iii ) , and 1,111 national health and nutrition examination survey 20052006 ( nhanes 20052006 ) subjects , who were non - hispanic white and black , without known diabetes . 
 criteria for consideration of metformin included the presence of both impaired fasting glucose ( ifg ) and impaired glucose tolerance ( igt ) , with 1 additional diabetes risk factor : age < 60 years , bmi 35 kg / m2 , family history of diabetes , elevated triglycerides , reduced hdl cholesterol , hypertension , or a1c 
 > 6.0%.resultsisolated ifg , isolated igt , and ifg and igt were found in 18.0 , 7.2 , and 8.2% of sigt ; 22.3 , 6.4 , and 9.4% of nhanes iii ; and 21.8 , 5.0 , and 9.0% of nhanes 20052006 subjects , respectively . in sigt , 
 nhanes iii , and nhanes 20052006 , criteria for metformin consideration were met in 99 , 96 , and 96% of those with ifg and igt ; 31 , 29 , and 28% of all those with ifg ; and 53 , 57 , and 62% of all those with igt ( 8.1 , 9.1 , and 8.7% of all subjects ) , respectively.conclusionsmore than 96% of individuals with both ifg and igt are likely to meet ada consensus criteria for consideration of metformin . because > 28% of all those with ifg met the criteria 
 , providers should perform oral glucose tolerance tests to find concomitant igt in all patients with ifg . to the extent that our findings are representative of the u.s . 
 population , 1 in 12 adults has a combination of pre - diabetes and risk factors that may justify consideration of metformin treatment for diabetes prevention . 
RESEARCH DESIGN AND METHODS
Measurements in the SIGT study population
Statistical analysis
RESULTS
CONCLUSIONS