today ( treatment options for type 2 diabetes in adolescents and youth ) was the first and largest randomized clinical trial to examine approaches to management of youth - onset type 2 diabetes . among the primary findings of today was that metformin monotherapy was inadequate for maintenance of glycemic control in almost half of participants after median time to failure of 11 months ( 1 ) . furthermore , there were distinct sex and racial / ethnic differences in the pattern of failure overall and across treatment arms . this degree of failure on monotherapy was higher than expected from studies of adults with type 2 diabetes ( 2,3 ) and only partially prevented by the addition of rosiglitazone . taken together , the findings suggest that type 2 diabetes among adolescents can be more rapidly progressive than in adults ( 47 ) . on the other hand , 50% of today participants maintained durable glycemic control regardless of treatment group . this suggests that type 2 diabetes among adolescents is a heterogeneous disorder grossly divided between those who are and are not able to maintain glycemic control on oral therapy . if so , it would be of substantial clinical importance to properly classify patients early in the course of the disease so that appropriate treatment can be planned . in this analysis , we address the hypothesis that readily available demographic and metabolic characteristics determined early in the course of type 2 diabetes can distinguish adolescents who will display durable glycemic control from those at risk for loss of glycemic control on oral therapy . today clinical trial rationale , design , and methods have been reported in detail ( 8) and are described briefly . between july 2004 and february 2009 , 699 youth aged 1017 years , diagnosed with type 2 diabetes according to american diabetes association ( ada ) criteria ( 9 ) for < 2 years , with bmi 85th percentile , and negative for diabetes autoantibodies , were enrolled ( 10 ) . after screening to determine eligibility , subjects completed a 2- to 6-month prerandomization run - in period in which they demonstrated mastery of standard diabetes education , were weaned from nonstudy diabetes medications , demonstrated tolerance of metformin 5001,000 mg twice daily , maintained hba1c < 8% ( < 64 mmol / mol ) monthly for at least 2 months on metformin alone , and demonstrated adherence to study medication and visit attendance ( 11 ) . participants were randomized to one of three treatment arms : metformin alone , metformin plus rosiglitazone , and metformin plus lifestyle program . study baseline data were collected after run - in and before start of randomized treatment assignment . participants attended clinic visits for medical management every 2 months in the first year and quarterly thereafter . the goal of diabetes medical management was to maintain hba1c levels as close to the normal range as possible in order to reduce long - term diabetes complications . during the trial , the investigators and the participants were blinded to specific hba1c values but were informed if hba1c was 1 ) 8% ( 64 mmol / mol ) , 2 ) 68% ( 4264 mmol / mol ) and increased from previous value by 0.8% ( 8.7 mmol / mol ) , or 3 ) 6% ( 42 mmol / mol ) ( target ) . the primary objective was to compare the three treatment arms on time to treatment failure , defined as either hba1c 8% ( 64 mmol / mol ) over a 6-month period or inability to wean from temporary insulin therapy within 3 months after acute metabolic decompensation . the protocol was approved by an external evaluation committee convened by the national institute of diabetes and digestive and kidney diseases ( niddk ) of the national institutes of health and by the institutional review boards of each participating institution . all participants provided written informed consent , and minor children confirmed assent according to local guidelines . materials developed and used for the today standard diabetes education program and the intensive lifestyle intervention program are available to the public at https://today.bsc.gwu.edu/. two outcome groups were defined for analysis . group 1 participants remained in glycemic control ( i.e. , did not reach the primary outcome , as defined above ) for at least 48 months of follow - up , and group 2 reached the primary outcome before 48 months ; beyond 48 months , sample size was inadequate for analysis and data are not included . demographic and baseline characteristics in the analysis were age , sex , race / ethnicity ( classified as non - hispanic black [ nhb ] , hispanic [ h ] , non - hispanic white [ nhw ] , or other ) , household annual income , highest education level of parents or guardians , first - degree family history of diabetes , tanner stage ( by physician examination ) , months since diagnosis of type 2 diabetes , and presence of depressive symptoms based on the children s depression inventory ( 12 ) for participants age 15 years or the beck depression inventory ( 13 ) for participants age 16 years . baseline measures were bmi , hba1c at screening and randomization , c - peptide , and adiposity . were derived from the 2-h oral glucose tolerance test as follows : insulin inverse = 1/insulinmin 0 , and insulinogenic index = ( insulinmin 30  insulinmin 0)/(glucosemin 30  glucosemin 0 ) . measures of adiposity were waist circumference and dxa measures of fat ( kg ) and lean ( kg ) body mass ; in approximately one - quarter of the subjects , dxa scans were excluded owing to weight limitations ( weight > 140 kg ) . logistic regression was used to model outcome group as a function of demographic variables , baseline characteristics , and baseline measures in univariate and multivariate analyses . receiver operating characteristic ( roc ) curve analyses were performed to identify optimal baseline hba1c cut points predictive of failure ( as indicated by outcome group ) . the standard logistic regression model and the trapezoidal rule method were used to compute the total area under the curve ( auc ) and its associated 95% ci in the overall analysis sample by sex , by race / ethnicity ( nhb , h , nhw ) , and for the six sex - by - race / ethnicity combinations . sensitivity and specificity were computed and the youden index method was used to select the optimal threshold point from the roc curve ( 14 ) . the youden index [ maximum ( sensitivity + specificity  1 ) ] maximizes the vertical distance from the line of equality to identify the point on the curve farthest from chance ( 15,16 ) and maximizes the classification rate . the positive likelihood ratio ( plr ) ( sensitivity/1  specificity ) was used to determine whether a baseline hba1c cutoff usefully changed the probability of failing oral therapy ; plr > 1 indicates the test result is associated with increased probability ( 17 ) . p values were considered exploratory and were not adjusted for multiple testing ; the study was powered only for the time - to - failure primary outcome . today clinical trial rationale , design , and methods have been reported in detail ( 8) and are described briefly . between july 2004 and february 2009 , 699 youth aged 1017 years , diagnosed with type 2 diabetes according to american diabetes association ( ada ) criteria ( 9 ) for < 2 years , with bmi 85th percentile , and negative for diabetes autoantibodies , were enrolled ( 10 ) . after screening to determine eligibility , subjects completed a 2- to 6-month prerandomization run - in period in which they demonstrated mastery of standard diabetes education , were weaned from nonstudy diabetes medications , demonstrated tolerance of metformin 5001,000 mg twice daily , maintained hba1c < 8% ( < 64 mmol / mol ) monthly for at least 2 months on metformin alone , and demonstrated adherence to study medication and visit attendance ( 11 ) . participants were randomized to one of three treatment arms : metformin alone , metformin plus rosiglitazone , and metformin plus lifestyle program . study baseline data were collected after run - in and before start of randomized treatment assignment . participants attended clinic visits for medical management every 2 months in the first year and quarterly thereafter . the goal of diabetes medical management was to maintain hba1c levels as close to the normal range as possible in order to reduce long - term diabetes complications . during the trial , the investigators and the participants were blinded to specific hba1c values but were informed if hba1c was 1 ) 8% ( 64 mmol / mol ) , 2 ) 68% ( 4264 mmol / mol ) and increased from previous value by 0.8% ( 8.7 mmol / mol ) , or 3 ) 6% ( 42 mmol / mol ) ( target ) . the primary objective was to compare the three treatment arms on time to treatment failure , defined as either hba1c 8% ( 64 mmol / mol ) over a 6-month period or inability to wean from temporary insulin therapy within 3 months after acute metabolic decompensation . the protocol was approved by an external evaluation committee convened by the national institute of diabetes and digestive and kidney diseases ( niddk ) of the national institutes of health and by the institutional review boards of each participating institution . all participants provided written informed consent , and minor children confirmed assent according to local guidelines . materials developed and used for the today standard diabetes education program and the intensive lifestyle intervention program are available to the public at https://today.bsc.gwu.edu/. group 1 participants remained in glycemic control ( i.e. , did not reach the primary outcome , as defined above ) for at least 48 months of follow - up , and group 2 reached the primary outcome before 48 months ; beyond 48 months , sample size was inadequate for analysis and data are not included . demographic and baseline characteristics in the analysis were age , sex , race / ethnicity ( classified as non - hispanic black [ nhb ] , hispanic [ h ] , non - hispanic white [ nhw ] , or other ) , household annual income , highest education level of parents or guardians , first - degree family history of diabetes , tanner stage ( by physician examination ) , months since diagnosis of type 2 diabetes , and presence of depressive symptoms based on the children s depression inventory ( 12 ) for participants age 15 years or the beck depression inventory ( 13 ) for participants age 16 years . baseline measures were bmi , hba1c at screening and randomization , c - peptide , and adiposity . were derived from the 2-h oral glucose tolerance test as follows : insulin inverse = 1/insulinmin 0 , and insulinogenic index = ( insulinmin 30  insulinmin 0)/(glucosemin 30  glucosemin 0 ) . measures of adiposity were waist circumference and dxa measures of fat ( kg ) and lean ( kg ) body mass ; in approximately one - quarter of the subjects , dxa scans were excluded owing to weight limitations ( weight > 140 kg ) . logistic regression was used to model outcome group as a function of demographic variables , baseline characteristics , and baseline measures in univariate and multivariate analyses . receiver operating characteristic ( roc ) curve analyses were performed to identify optimal baseline hba1c cut points predictive of failure ( as indicated by outcome group ) . the standard logistic regression model and the trapezoidal rule method were used to compute the total area under the curve ( auc ) and its associated 95% ci in the overall analysis sample by sex , by race / ethnicity ( nhb , h , nhw ) , and for the six sex - by - race / ethnicity combinations . sensitivity and specificity were computed and the youden index method was used to select the optimal threshold point from the roc curve ( 14 ) . the youden index [ maximum ( sensitivity + specificity  1 ) ] maximizes the vertical distance from the line of equality to identify the point on the curve farthest from chance ( 15,16 ) and maximizes the classification rate . the positive likelihood ratio ( plr ) ( sensitivity/1  specificity ) was used to determine whether a baseline hba1c cutoff usefully changed the probability of failing oral therapy ; plr > 1 indicates the test result is associated with increased probability ( 17 ) . p values were considered exploratory and were not adjusted for multiple testing ; the study was powered only for the time - to - failure primary outcome . 1 . flow of participants into the two groups analyzed based on time to study primary outcome ( failure to maintain glycemic control on randomized treatment assignment ) . demographic and baseline characteristics in group 1 ( n = 172 ) versus group 2 ( n = 305 ) are shown in table 1 . group 1 had a significantly higher percentage of nhw and lower of nhb , a lower prevalence of depressive symptoms at the time of entry into the study , and a lower percentage of first - degree relatives with diabetes ; total annual household income ( $50,000 ) barely missed statistical significance ( p = 0.0512 ) . there were no differences by sex , treatment group , age , duration of diabetes , tanner stage , or highest household education at study entry . there was also no difference in tanner stage by sex in the analysis sample ( 90.5% of females and 87.3% of males were tanner stage 4 or 5 ) . there was no difference at any time between groups 1 and 2 in percentage of participants with study medication adherence 80% ( data not shown ) . demographic and baseline characteristics by analysis group data are mean ( sd ) unless otherwise indicated . ged , general equivalency diploma ; m , metformin alone ; m+l , metformin plus lifestyle program ; m+r , metformin plus rosiglitazone ; mo , months ; po , primary outcome , i.e. , failure to maintain glycemic control on randomized treatment assignment . test performed on log transform to normalize distribution . in univariate analysis , screening and baseline hba1c and baseline insulinogenic index were identified as the only significant metabolic factors distinguishing those with durable glycemic control irrespective of treatment group ; participants with durable control had significantly lower hba1c and higher insulinogenic index . baseline measures of insulin sensitivity ( fasting c - peptide and insulin inverse ) , measures of body fatness ( bmi , waist circumference , and dxa fat mass ) , and dxa lean mass were not different between groups . calculation of oral disposition index did not contribute beyond insulinogenic index alone ( data not shown ) . in multivariate models including all baseline demographic and metabolic factors significant in univariate analysis , only hba1c and insulinogenic index remained significant ( p < 0.0001 and p = 0.0002 , respectively ) . this was also true when treatment assignment was included in the model . with all other variable values held as fixed , there was a 16% increase in the odds of failing within 48 months of treatment for each 0.1% ( 1.1 mmol / mol ) increase in hba1c from study baseline ( after stabilization of hba1c < 8% [ < 64 mmol / mol ] during run - in but before start of study randomized treatment ) . similarly , there was a 16% increase in the odds of failing within 48 months of treatment for each 0.1-unit decrease in insulinogenic index from study baseline . figure 2 shows a shift in the distributions of baseline hba1c for groups 1 and 2 . because hba1c is easily obtained in the clinical setting , this shift suggested a clinically practical basis for distinguishing between the groups . overall , the youden index identified an hba1c cutoff of 6.3% ( 45 mmol / mol ) that maximized correct classification of participants ( fig . figure 3b shows a sex difference in hba1c operator characteristics . although both sexes had the same auc ( 0.77 ) , the roc curves crossed , indicating that hba1c had higher specificity in females and higher sensitivity in males . the youden index identified hba1c of 6.3% ( 45 mmol / mol ) for females ( sensitivity 59% , specificity 87% , and plr 4.4 ) and 5.6% ( 38 mmol / mol ) for males ( sensitivity 88% , specificity 59% , and plr 2.1 ) as the optimal cutoffs for classifying the risk of loss of durable control . this sex difference in optimal cutoff was true across race / ethnicity ; the youden index identified optimal hba1c cutoffs of 6.3 , 6.4 , and 6.6% ( 45 , 46 , and 49 mmol / mol ) for nhb , h , and nhw females , respectively , but 5.8% ( 40 mmol / mol ) for nhb and 5.6% ( 38 mmol / mol ) for h and nhw males . figure 4 summarizes hba1c cutoffs , auc , and plr overall and by sex and race / ethnicity in the sample of groups 1 and 2 combined . ( supplementary table 1 gives sensitivity , specificity , and plr overall by sex , by race / ethnicity , and by the interaction of sex with race / ethnicity . ) distribution of baseline hba1c in each of the analysis groups . baseline hba1c was measured after a run - in period in which participants had to maintain hba1c < 8% ( < 64 mmol / mol ) monthly for at least 2 months on metformin alone in order to remain eligible for randomization in the clinical trial . the graphic suggests that hba1c on metformin monotherapy is a clinically practical indicator of ability to maintain glycemic control on oral agents . mo , months ; po , primary outcome , i.e. , failure to maintain glycemic control on randomized treatment assignment . roc curves and hba1c cutoffs , sensitivity , specificity , and plr based on the youden index over all participants ( a ) and by sex ( b ) . plr > 1 indicates that the test result is associated with increased probability of failing oral therapy . the youden index hba1c cutoffs , auc and its 95% ci , and plr overall and by sex and racial / ethnic subgroups (  other  race / ethnicity not presented ) . auc is a measure of diagnostic accuracy ranging from 0.0 to 1.0 , where 0.5 is equivalent to a coin toss ( the  curve  looks like a diagonal line ) ; auc values 0.60.7 represent poor ability to predict failure , values 0.70.8 represent fair ability , and 0.80.9 represent good ability . the auc 95% ci includes 0.50 only for nhw males ( n = 35 ) indicating that the cutoff is equivalent to simply guessing . a plr ( sensitivity/1  specificity ) > 1 indicates that the test result ( hba1c ) is associated with presence of the disease , and the larger the plr , the greater the likelihood of disease . since the ada recommends a treatment target of 6.5% ( 48 mmol / mol ) , this value is often used by diabetes health care providers as a cutoff for determining whether to alter therapy . we compared the cutoff of 6.3 vs .6.5% ( 45 vs. 48 mmol / mol ) in our analysis sample . sensitivity for identification of participants who will lose glycemic control was 54 vs. 43% , while specificity rose from 86 to 91% . the plr for an hba1c of 6.3% ( 45 mmol / mol ) was 3.7 vs. 5.0 for 6.5% ( 48 mmol / mol ) . at an hba1c of 5.9% ( 41 mmol / mol ) , the plr for loss of glycemic control was still > 2 . as expected from the sex - specific differences in youden index , a cutoff of 6.5% ( 48 mmol / mol ) had even lower sensitivity for identifying those likely to fail among males ( 35% , plr 3.0 ) than females ( 48% , plr 6.7 ) . at an hba1c of 6.0% ( 42 mmol / mol ) , the plr for both males and females was > 2 . the today primary outcome analysis demonstrated that type 2 diabetes presenting during adolescence was characterized by high rates of loss of glycemic control over a relatively brief period of time compared with adults ( 1 ) . although addition of rosiglitazone to metformin reduced the rate of loss of glycemic control by 23% over the course of the study , the median time to glycemic failure was the same regardless of treatment assignment . furthermore , the incidence of loss of glycemic control plateaued over time regardless of treatment assignment . taken together , these observations suggest that there may be subsets of adolescents with type 2 diabetes characterized as those at risk of losing glycemic control rapidly , those who will maintain glycemic control for a prolonged period of time , and those who may respond to addition of a second oral agent with improved maintenance of glycemic control . in particular , the early ability to distinguish patients who maintain glycemic control from those who are going to rapidly lose glycemic control would allow clinicians to identify high - risk patients who would benefit from closer monitoring and earlier intensification of therapy while supporting a less aggressive approach for those who are likely to maintain good glycemic control on metformin alone . to examine this question , we analyzed the effect of demographic , anthropometric , and biochemical characteristics of the participants at the time of their randomization into today on the likelihood of loss of glycemic control during follow - up . in univariate analysis , nhb race / ethnicity , depressive symptoms , first - degree family history of diabetes , and lower family income were all associated with rapid loss of glycemic control , as might be expected from previous literature in adults ( 1821 ) . surprisingly , age , duration of diabetes , bmi , waist circumference , fat mass , and lean body mass at randomization had no effect on outcome , though this may be due , in part , to the relatively narrow range of each of these measures in the today cohort ( 22 ) . among metabolic measures , only screening and baseline hba1c and insulinogenic index were associated with maintenance of glycemic control ; insulin sensitivity did not differ between the groups . we did not explore screening hba1c further because the heterogeneous nature of the screened cohort in terms of treatment modalities made generalization of findings to a clinical population difficult . in multivariate analysis , studies in adults ( 2,3 ) and previous studies in the today cohort ( 23,24 ) have shown that -cell function is a strong determinant of hba1c . although both measures were significant predictors of durable control , hba1c is clinically more accessible than determination of insulinogenic index . similarly , although demographic factors were shown to contribute to diabetes outcome in univariate analysis , it may be that the hba1c value already reflects these contributions , and these factors , therefore , disappeared as significant contributors to prediction of glycemic control in multivariate analysis in this cohort . given the limitations of our data , we can only speculate on how these factors affect hba1c , perhaps through genetic , hormonal , nutritional , or behavioral influences on -cell function . this analysis suggests that hba1c obtained after a short course of metformin monotherapy in adolescents with type 2 diabetes can function as a simple clinical measure to predict outcome and allow more effective targeting of therapy to those at highest risk for loss of glycemic control . the next question is whether there is a specific hba1c cutoff value that is useful as a predictor of likely outcome . roc analysis identified an hba1c of 6.3% ( 45 mmol / mol ) as the optimal youden cutoff for correctly categorizing an individual s risk for loss of glycemic control on oral therapy , with an auc of 0.77 . the optimal cutoff was similar for females , reflecting the > 60% representation of females in the cohort , but was substantially lower for males . this cutoff is lower than the ada - recommended treatment target of 6.5% ( 48 mmol / mol ) and probably lower than the level at which most clinicians would consider addition of a second agent . at a minimum , the analysis suggests that an hba1c cutoff of 6.5% ( 48 mmol / mol ) has low sensitivity for identifying those adolescents ; a youth with hba1c > 6.5% ( > 48 mmol / mol ) after a few months on metformin had a > 70% chance of experiencing loss of glycemic control in a relatively short time on oral therapy alone . indeed , both boys and girls with an hba1c > 6.0% ( > 42 mmol / mol ) had approximately double the risk for failure as individuals with an hba1c < 6.0% ( < 42 mmol / mol ) . together these data indicate that adolescents with type 2 diabetes who do not attain a non  diabetes range hba1c after a few months on metformin are at increased risk for losing glycemic control , and the clinicians caring for these youth should not be reassured that hba1c is  in target . these individuals may benefit from closer monitoring or earlier initiation of supplemental therapy , despite an hba1c that meets current targets . for example , females with baseline hba1c higher than their optimal cutoff of 6.3% ( 45 mmol / mol ) treated with rosiglitazone and metformin had a failure rate of 52% compared with 83% for metformin alone ( supplementary data ) . although the future role of rosiglitazone in the treatment of youth with type 2 diabetes remains unclear , these results point out the potential benefits of initiating combination therapy in selected patients who do not reach the optimal cutoff after a short course of metformin . conversely , a youth with hba1c < 6.0% ( < 42 mmol / mol ) after a few months on metformin had a better than 70% chance of remaining in control on monotherapy for at least 4 years . these findings do not suggest that there is benefit to treating patients to a lower hba1c than the ada target ; we did not perform an intervention trial with different targets to address this question . rather , the analysis suggests that hba1c at the end of a relatively short course of metformin in these adolescents may reflect the severity of the underlying disorder and may be a marker of risk . given the association of durable control with insulinogenic index and our previous demonstration that hba1c is strongly determined by insulin secretion in these youth ( 23,24 ) , those who are not able to get their hba1c into the non  diabetes range within a few months are likely to have substantial deterioration in -cell function already . first , although the analysis sample is composed of participants in a randomized clinical trial with rigorous eligibility criteria who remained in follow - up for at least 4 years , the demographics of the analyzed sample are comparable with demographics of the general population of youth - onset type 2 diabetes in the u.s . second , the participants in today have been extensively characterized , allowing analysis of a broad set of demographic , anthropometric , and biochemical measures . third , the cohort was followed longitudinally and all diabetes care was provided to the participants , allowing for analysis of causal relationships not possible in small and/or cross - sectional studies . on the other hand , despite the relatively large size of the today cohort , the sample size is too small for more than exploratory analysis of sex - by - racial / ethnic subgroups . in addition , the roc analysis yields auc values in the range indicating fair predictive ability for hba1c , suggesting that there are other factors involved in determining likelihood of failure that are not fully reflected in hba1c . however , despite this limitation , hba1c remains the strongest predictor of likelihood of success or failure on metformin monotherapy in youth with type 2 diabetes and is an easily obtained clinical measure that may provide important clinical insight . in summary , the population of youth with type 2 diabetes is heterogeneous and consists of subsets of individuals who are more or less likely to have durable glycemic control on oral therapy . furthermore , the analysis demonstrates that hba1c after a few months of metformin monotherapy was the strongest predictor of response , likely reflecting underlying insulin secretion . finally , these analyses indicate that adolescents with type 2 diabetes who do not attain a non  diabetes range hba1c after a few months on metformin are at increased risk of losing glycemic control , and the clinician caring for these youth should not be reassured with an hba1c  in target . these findings suggest that hba1c obtained after a short course of metformin monotherapy in adolescents with type 2 diabetes may be a simple clinical measure to predict short- and medium - term outcome and allow better targeting of therapy to those adolescents at highest risk for loss of glycemic control . in the future , long - term follow - up of the today cohort will be used to confirm and readjust our analysis and understanding of early markers for both diabetes control and diabetes - related complications and comorbidities .
objectiveto determine whether clinically accessible parameters early in the course of youth - onset type 2 diabetes predict likelihood of durable control on oral therapy.research design and methodstoday was a randomized clinical trial of adolescents with type 2 diabetes . 
 two groups , including participants from all three treatments , were defined for analysis : 1 ) those who remained in glycemic control for at least 48 months of follow - up and 2 ) those who lost glycemic control before 48 months . 
 outcome group was analyzed in univariate and multivariate models as a function of baseline characteristics ( age , sex , race / ethnicity , socioeconomic status , bmi , waist circumference , tanner stage , disease duration , depressive symptoms ) and biochemical measures ( hba1c , c - peptide , lean and fat body mass , insulin inverse , insulinogenic index ) . 
 receiver operating characteristic curves were used to analyze hba1c cut points.resultsin multivariate models including factors significant in univariate analysis , only hba1c and insulinogenic index at randomization remained significant ( p < 0.0001 and p = 0.0002 , respectively ) . 
 an hba1c cutoff of 6.3% ( 45 mmol / mol ) ( positive likelihood ratio [ plr ] 3.7 ) was identified that optimally distinguished the groups ; sex - specific cutoffs were 6.3% ( 45 mmol / mol ) for females ( plr 4.4 ) and 5.6% ( 38 mmol / mol ) for males ( plr 2.1).conclusionsidentifying youth with type 2 diabetes at risk for rapid loss of glycemic control would allow more targeted therapy . 
 hba1c is a clinically accessible measure to identify high risk for loss of glycemic control on oral therapy . 
 adolescents with type 2 diabetes unable to attain a non  diabetes range hba1c on metformin are at increased risk for rapid loss of glycemic control .