participants ( n = 3,234 ) at high risk for developing type 2 diabetes were randomized to the dpp between 1996 and 1999 . characteristics of the study population are reported elsewhere ( 1 ) . in july 2001 , masked dpp treatment was discontinued after it was established that lifestyle intervention reduced incidence of diabetes by 58% and metformin by 31% compared with placebo ( 2 ) . all 3,150 surviving dpp participants who had not withdrawn consent were eligible for the dppos , and 2,665 enrolled . participants signed written consent forms after discussion of all aspects of the studies with study staff ( 3 ) . dpp / dppos participants brought all prescription medicines , including adms , to clinic visits . diabetes was diagnosed based on an annual oral glucose tolerance test or a semiannual fasting plasma glucose test . fasting insulin was measured at annual visits with the oral glucose tolerance test ( 2 ) . adm use was reported quarterly during the dpp and every 6 months during the dppos . cox proportional hazard models ( 1 ) were used to evaluate whether taking adms was associated with developing diabetes . adm use was defined as a time - dependent categorical variable up to each time point evaluated with three levels : never used , used intermittently ( at least once but not always ) , and used continuously ( at all visits ) . at each successive time point , the value of the variable was calculated based on all previous time points , including the current measurement . a significant interaction between adm use and treatment groups time - dependent covariate analyses ( 1 ) were used to model the above covariates and diabetes risk with adjustment for factors associated with an increased risk of developing diabetes ( race / ethnicity , age , sex , education , fasting plasma glucose at baseline , weight at baseline , and weight change during the study ) . we now present data over a median of 10 years since randomization , including the time period of the first phase of the dpp that was reported previously ( 1 ) . therefore , these analyses are not independent of the previous study and should be considered an extension , not a replication , of those findings . adm use was reported quarterly during the dpp and every 6 months during the dppos . cox proportional hazard models ( 1 ) were used to evaluate whether taking adms was associated with developing diabetes . adm use was defined as a time - dependent categorical variable up to each time point evaluated with three levels : never used , used intermittently ( at least once but not always ) , and used continuously ( at all visits ) . at each successive time point , the value of the variable was calculated based on all previous time points , including the current measurement . a significant interaction between adm use and treatment groups time - dependent covariate analyses ( 1 ) were used to model the above covariates and diabetes risk with adjustment for factors associated with an increased risk of developing diabetes ( race / ethnicity , age , sex , education , fasting plasma glucose at baseline , weight at baseline , and weight change during the study ) . we now present data over a median of 10 years since randomization , including the time period of the first phase of the dpp that was reported previously ( 1 ) . therefore , these analyses are not independent of the previous study and should be considered an extension , not a replication , of those findings . when other factors associated with an increased risk of developing diabetes were controlled , continuous adm use during the dpp / dppos ( compared with no use ) was strongly associated with diabetes risk ( fig . 1 ) for participants in the placebo ( hra 2.34 [ 95% ci 1.324.15 ] and lifestyle ( 2.48 [ 1.454.22 ] ) arms . in the placebo arm , the association between intermittent adm use and diabetes trended toward statistical significance ( 1.34 [ 0.991.81 ] ) . in the metformin arm , there was a significant difference between the lifestyle and metformin arms in the association between adm and diabetes risk . results did not change when we excluded participants taking adms that are more likely to cause weight gain ( tricyclic and tetracyclic agents ) . for each treatment group , from left to right , the three bars represent no exposure , intermittent exposure , and continuous exposure . the current findings extend those of our earlier report ( 1 ) , although over the longer follow - up in this study that includes the dppos , we did not find an association with intermittent adm use and diabetes risk in the lifestyle arm . these findings are similar to those in a previous report that long - term use of adm increased the risk of developing diabetes ( 4 ) . other studies ( 5,6 ) , have also reported increased adm - related diabetes risk . the association between adm use and diabetes risk remained significant when likely mediators of this association were controlled . this association could represent a medication effect , or it could reflect differences not assessed in the study between adm and non - adm users . although there is no obvious explanation for this latter finding , one study found that metformin induces the release of 5-hydroxytryptamine through neuronal and nonneuronal mechanisms and thus increases insulin secretion ( 7 ) . metformin also appears to ameliorate inflammation ( 8) , and inflammatory markers appear to be associated with depression ( 9 ) . strengths of the current study include the large , racially and ethnically diverse population , the definitive assessment of glucose tolerance and diabetes , repeated collection of data on both adm use and depression symptoms , and repeated assessment of metabolic diabetes risk factors . we were also able to more accurately determine the onset of diabetes  a considerable advance over studies that rely on clinical records that may not accurately capture when diabetes actually developed . potential dpp participants were excluded if they were taking bupropion or any adm in greater than the lowest therapeutic dose , so the study sample was not representative of the general population . the absolute number of diabetes cases in the continuous adm group was quite small ( placebo n = 18 , lifestyle n = 15 ) . during the dpp / dppos we did not collect data on adm dosage , so we could not examine the association between dosage and diabetes risk . strengths of the current study include the large , racially and ethnically diverse population , the definitive assessment of glucose tolerance and diabetes , repeated collection of data on both adm use and depression symptoms , and repeated assessment of metabolic diabetes risk factors . we were also able to more accurately determine the onset of diabetes  a considerable advance over studies that rely on clinical records that may not accurately capture when diabetes actually developed . potential dpp participants were excluded if they were taking bupropion or any adm in greater than the lowest therapeutic dose , so the study sample was not representative of the general population . the absolute number of diabetes cases in the continuous adm group was quite small ( placebo n = 18 , lifestyle n = 15 ) . during the dpp / dppos we did not collect data on adm dosage , so we could not examine the association between dosage and diabetes risk .