the accord trial design , inclusion criteria , subject characteristics , and main results have been previously published ( 2 ) . the accord trial was designed to determine whether cardiovascular event rates in t2 dm could be reduced through intensive glycemic control , intensive blood pressure control , and lipid management targeting triglycerides and hdl cholesterol in addition to ldl cholesterol . each participant was randomized to either intensive ( a1c goal < 6.0% ) or standard ( a1c goal 7.07.9% ) glycemic control and was assigned to either the blood pressure trial ( intensive vs. standard arm ) or the lipid trial ( statin alone vs. statin plus fenofibrate ) . this article represents a post hoc analysis of data available for accord participants in both glycemia arms who completed at least 2 years of follow - up in the trial and had weight and a1c data available at the end of 2 years . since most of weight gain occurred in the first 2 years , we focused our evaluation on this period . furthermore , we have presented results from > 90% of participants in the trial . at the time of discontinuation of the glycemic arm of the trial ( and stopping intensive treatment ) , a large proportion of participants had not completed 3 years in the trial . weight measurements were obtained at every scheduled clinic visit ( every 2 months in the intensive arm and every 4 months in the standard arm ) . weight measurement of participants in the accord trial was standardized by the use of high - quality scales in the clinics with a firm , flat surface and a zeroing system , weighing participants with minimal clothing and without shoes , and with weight distributed over both feet as evenly as possible . information on baseline demographics , clinical characteristics , treatment , and treatment changes was obtained from the accord trial database . we used general linear models to examine the association between each baseline characteristic and weight change at the 2-year visit . for continuous variables , we then added the glycemia randomization arm and included an interaction term between the baseline characteristic and glycemia arm . to examine the relationship between the 1- and 2-year change in weight and change in a1c , we first fit a linear regression of these changes from baseline to year 1 by each arm . we chose to do this analysis at the end of the first year because most of the changes in a1c occurred in the first year . we examined this relationship by tertiles of baseline a1c . to examine the effect of medications on weight change , we considered both baseline and postrandomization medication use . for all analyses , each medication except insulin was represented as an indicator regardless of dosing . we used general linear models to examine the association between each medication at baseline and weight change at the 1- and 2-year visits . due to significant interactions between the effects of medication by arm , we limited our analyses of medications to those that had a significant effect ( p < 0.05 ) on weight change both at baseline and postrandomization . ( 3 ) , which allows the direct comparison of the predictive effects of time - varying variables on an outcome measured at repeated time points . we used separate models for intensive and standard glycemia with the following predictors : baseline medications , baseline a1c , on - study medication , change in a1c and time interactions at 4-month intervals modeling the change in weight , at 4-month intervals . to determine whether the effects of the medication were different during the first and second years , we further stratified the analysis by first and second year . we considered all data available regardless of length of participation within the study . to estimate the on - trial effects of medication , we fit separate repeated - measures linear models for standard and intensive arms with time - dependent covariates in which the dependent variable is change in weight measured at 4-month intervals through year 2 . since there were significant levels of interaction between the effects of on - study medication and use prior to study entry , we created combinations of patterns of each medication the baseline and on - study medications for each arm . this approach facilitated analysis of the effect of medications that were not used at baseline but started during the trial . for this analysis , insulin was categorized as on or off , regardless of dose or type . the accord trial design , inclusion criteria , subject characteristics , and main results have been previously published ( 2 ) . the accord trial was designed to determine whether cardiovascular event rates in t2 dm could be reduced through intensive glycemic control , intensive blood pressure control , and lipid management targeting triglycerides and hdl cholesterol in addition to ldl cholesterol . each participant was randomized to either intensive ( a1c goal < 6.0% ) or standard ( a1c goal 7.07.9% ) glycemic control and was assigned to either the blood pressure trial ( intensive vs. standard arm ) or the lipid trial ( statin alone vs. statin plus fenofibrate ) . this article represents a post hoc analysis of data available for accord participants in both glycemia arms who completed at least 2 years of follow - up in the trial and had weight and a1c data available at the end of 2 years . since most of weight gain occurred in the first 2 years , we focused our evaluation on this period . furthermore , we have presented results from > 90% of participants in the trial . at the time of discontinuation of the glycemic arm of the trial ( and stopping intensive treatment ) , a large proportion of participants had not completed 3 years in the trial . weight measurements were obtained at every scheduled clinic visit ( every 2 months in the intensive arm and every 4 months in the standard arm ) . weight measurement of participants in the accord trial was standardized by the use of high - quality scales in the clinics with a firm , flat surface and a zeroing system , weighing participants with minimal clothing and without shoes , and with weight distributed over both feet as evenly as possible . information on baseline demographics , clinical characteristics , treatment , and treatment changes was obtained from the accord trial database . we used general linear models to examine the association between each baseline characteristic and weight change at the 2-year visit . for continuous variables , we then added the glycemia randomization arm and included an interaction term between the baseline characteristic and glycemia arm . to examine the relationship between the 1- and 2-year change in weight and change in a1c , we first fit a linear regression of these changes from baseline to year 1 by each arm . we chose to do this analysis at the end of the first year because most of the changes in a1c occurred in the first year . we examined this relationship by tertiles of baseline a1c . to examine the effect of medications on weight change , we considered both baseline and postrandomization medication use . for all analyses , each medication except insulin was represented as an indicator regardless of dosing . we used general linear models to examine the association between each medication at baseline and weight change at the 1- and 2-year visits . due to significant interactions between the effects of medication by arm , all further analyses were performed separately by glycemia arm . we limited our analyses of medications to those that had a significant effect ( p < 0.05 ) on weight change both at baseline and postrandomization . ( 3 ) , which allows the direct comparison of the predictive effects of time - varying variables on an outcome measured at repeated time points . we used separate models for intensive and standard glycemia with the following predictors : baseline medications , baseline a1c , on - study medication , change in a1c and time interactions at 4-month intervals modeling the change in weight , at 4-month intervals . to determine whether the effects of the medication were different during the first and second years , we further stratified the analysis by first and second year . we considered all data available regardless of length of participation within the study . to estimate the on - trial effects of medication , we fit separate repeated - measures linear models for standard and intensive arms with time - dependent covariates in which the dependent variable is change in weight measured at 4-month intervals through year 2 . since there were significant levels of interaction between the effects of on - study medication and use prior to study entry , we created combinations of patterns of each medication the baseline and on - study medications for each arm . this approach facilitated analysis of the effect of medications that were not used at baseline but started during the trial . for this analysis , insulin was categorized as on or off , regardless of dose or type . we used general linear models to examine the association between each baseline characteristic and weight change at the 2-year visit . for continuous variables , we then added the glycemia randomization arm and included an interaction term between the baseline characteristic and glycemia arm . to examine the relationship between the 1- and 2-year change in weight and change in a1c , we first fit a linear regression of these changes from baseline to year 1 by each arm . we chose to do this analysis at the end of the first year because most of the changes in a1c occurred in the first year . to examine the effect of medications on weight change , we considered both baseline and postrandomization medication use . for all analyses , we used general linear models to examine the association between each medication at baseline and weight change at the 1- and 2-year visits . due to significant interactions between the effects of medication by arm , we limited our analyses of medications to those that had a significant effect ( p < 0.05 ) on weight change both at baseline and postrandomization . ( 3 ) , which allows the direct comparison of the predictive effects of time - varying variables on an outcome measured at repeated time points . we used separate models for intensive and standard glycemia with the following predictors : baseline medications , baseline a1c , on - study medication , change in a1c and time interactions at 4-month intervals modeling the change in weight , at 4-month intervals . to determine whether the effects of the medication were different during the first and second years , we further stratified the analysis by first and second year . we considered all data available regardless of length of participation within the study . to estimate the on - trial effects of medication , we fit separate repeated - measures linear models for standard and intensive arms with time - dependent covariates in which the dependent variable is change in weight measured at 4-month intervals through year 2 . since there were significant levels of interaction between the effects of on - study medication and use prior to study entry , we created combinations of patterns of each medication the baseline and on - study medications for each arm . this approach facilitated analysis of the effect of medications that were not used at baseline but started during the trial . for this analysis , insulin was categorized as on or off , regardless of dose or type . as previously described ( 2 ) , there was significantly more weight gain in the intensive glycemia arm of the trial compared with the standard arm . the first 2 years accounted for approximately two - thirds of average weight gain . at the end of the second year , the average (  sd ) weight gain was 3.0 (  7.0 ) kg in the intensive arm . weight gain in the standard arm was not only more modest but also did not continue beyond 24 months . figure 1 illustrates the time course of the weight gain over the duration of the trial in both the intensive and standard groups . time course of weight gain in the accord trial by treatment allocation . by univariate analysis ( table 1 ) , the baseline characteristics of participants associated with increase in weight at 2 years in both glycemia arms were decreasing age , male sex , living with another person , smoking history , baseline a1c > 8.5 , high baseline bmi , race , high blood pressure , impaired renal function , low hdl cholesterol in males , high triglycerides , baseline insulin use , baseline metformin use , and not using diuretics . on multivariate analysis , younger age , male sex , asian race , no smoking history , high a1c , bmi of 2535 , high waist circumference , insulin use , and metformin use were independently associated with weight gain over 2 years . baseline characteristics associated with weight gain at 2 years in both glycemia arms while most of the weight change occurred during the first 2 years , univariate analysis ( supplementary table 1 ) demonstrates that the baseline characteristics of participants associated with increase in weight from years 26 were younger age , diastolic blood pressure , hdl in females , metformin , and sulfonylurea use . the relationship between the baseline and postrandomization a1c and change in weight differed by glycemia arm ( supplementary table 2 ) . overall , the relationship between change in a1c and change in weight for those allocated to intensive glucose control was statistically significant ( p < 0.001 ) with a fall in a1c associated with weight gain . in the intensive treatment arm , decreased a1c ( when defined as a decrease of 0.5% in a1c from baseline ) and weight gain occurred in 59.9% of participants , whereas weight loss and decreased a1c occurred in 28.8% of participants . few intensive participants experienced weight gain and increased a1c . in only 6% of intensive participants did weight gain occur without any change in a1c . figure 2 plots the relationship of change in weight with change in a1c over the first year by glycemia arm stratified by the baseline a1c categorized into thirds . in both treatment arms , participants with in contrast , when a1c was < 7.8% at baseline , a drop in a1c during treatment was associated with a decrease in weight in both arms . lines represent the estimated equation from the 5th to 95th percentile for each combination of baseline a1c and glycemia arm . supplementary table 3 summarizes the relationships between various medication - related factors and weight gain . the overall change in weight due to medication use accounted for < 15% of the variability in any of the models . the glucose - lowering medications that had the most effect on weight gain were insulin , tzds ( mainly rosiglitazone ) , and metformin ( tables 2 and 3 ) . the medications taken at baseline and follow - up and change in a1c explain 6 and 14% of the variability in the weight change from baseline during the first year 1 , in the standard and intensive arms , respectively , and 10 and 12% of the variability in weight change during the second year , respectively . weight gain by metformin use weight gain by insulin and tzd use the effects of insulin and tzd were not the same when considered in a linear mixed model . therefore , we redefined tzd and insulin use in the following classification for both models in the standard and intensive arms . table 3 summarizes the weight changes during use of various tzd / insulin combinations and metformin in the intensive group in the trial . there was a significant increase in weight ( 1.4 to 6.3 kg ) . these changes in weight with this combination were more marked in participants in the intensive arm of the trial . intensive participants who never took insulin or a tzd ( n = 95 ) had an average weight loss of 2.9 kg during the first 2 years of the trial . in contrast , intensive participants who had never previously used insulin or tzd but began this combination at some time after enrolling in the accord trial had a weight gain of 4.6 to 5.3 kg at 2 years . for participants who entered the accord trial on metformin , were enrolled in the intensive arm , and began taking both a tzd and insulin over the first 2 years of the trial , the mean weight gain at 2 years was 4.9 kg . metformin use was significantly associated with weight change in participants in the intensive arm of the trial only . participants in the intensive arm of the trial who never used metformin ( n = 244 ) had a mean weight gain of 2.7 kg . participants who entered the trial on metformin and continued ( n = 2,784 ) gained an average of 1.9 kg , and those who had metformin added during the trial ( n = 1,588 ) gained an average of 0.7 kg ( p < 0.001 for effect ) . there was no interaction effect between the tzd / insulin combinations and metformin use . by univariate analysis ( table 1 ) , the baseline characteristics of participants associated with increase in weight at 2 years in both glycemia arms were decreasing age , male sex , living with another person , smoking history , baseline a1c > 8.5 , high baseline bmi , race , high blood pressure , impaired renal function , low hdl cholesterol in males , high triglycerides , baseline insulin use , baseline metformin use , and not using diuretics . on multivariate analysis , younger age , male sex , asian race , no smoking history , high a1c , bmi of 2535 , high waist circumference , insulin use , and metformin use were independently associated with weight gain over 2 years . baseline characteristics associated with weight gain at 2 years in both glycemia arms while most of the weight change occurred during the first 2 years , univariate analysis ( supplementary table 1 ) demonstrates that the baseline characteristics of participants associated with increase in weight from years 26 were younger age , diastolic blood pressure , hdl in females , metformin , and sulfonylurea use . the relationship between the baseline and postrandomization a1c and change in weight differed by glycemia arm ( supplementary table 2 ) . overall , the relationship between change in a1c and change in weight for those allocated to intensive glucose control was statistically significant ( p < 0.001 ) with a fall in a1c associated with weight gain . in the intensive treatment arm , decreased a1c ( when defined as a decrease of 0.5% in a1c from baseline ) and weight gain occurred in 59.9% of participants , whereas weight loss and decreased a1c occurred in 28.8% of participants . few intensive participants experienced weight gain and increased a1c . in only 6% of intensive participants did weight gain occur without any change in a1c . figure 2 plots the relationship of change in weight with change in a1c over the first year by glycemia arm stratified by the baseline a1c categorized into thirds . in both treatment arms , participants with in contrast , when a1c was < 7.8% at baseline , a drop in a1c during treatment was associated with a decrease in weight in both arms . lines represent the estimated equation from the 5th to 95th percentile for each combination of baseline a1c and glycemia arm . supplementary table 3 summarizes the relationships between various medication - related factors and weight gain . the overall change in weight due to medication use accounted for < 15% of the variability in any of the models . the glucose - lowering medications that had the most effect on weight gain were insulin , tzds ( mainly rosiglitazone ) , and metformin ( tables 2 and 3 ) . the medications taken at baseline and follow - up and change in a1c explain 6 and 14% of the variability in the weight change from baseline during the first year 1 , in the standard and intensive arms , respectively , and 10 and 12% of the variability in weight change during the second year , respectively . weight gain by metformin use weight gain by insulin and tzd use the effects of insulin and tzd were not the same when considered in a linear mixed model . therefore , we redefined tzd and insulin use in the following classification for both models in the standard and intensive arms . table 3 summarizes the weight changes during use of various tzd / insulin combinations and metformin in the intensive group in the trial . there was a significant increase in weight ( 1.4 to 6.3 kg ) . these changes in weight with this combination were more marked in participants in the intensive arm of the trial . intensive participants who never took insulin or a tzd ( n = 95 ) had an average weight loss of 2.9 kg during the first 2 years of the trial . in contrast , intensive participants who had never previously used insulin or tzd but began this combination at some time after enrolling in the accord trial had a weight gain of 4.6 to 5.3 kg at 2 years . for participants who entered the accord trial on metformin , were enrolled in the intensive arm , and began taking both a tzd and insulin over the first 2 years of the trial , the mean weight gain at 2 years was 4.9 kg . metformin use was significantly associated with weight change in participants in the intensive arm of the trial only . participants in the intensive arm of the trial who never used metformin ( n = 244 ) had a mean weight gain of 2.7 kg . participants who entered the trial on metformin and continued ( n = 2,784 ) gained an average of 1.9 kg , and those who had metformin added during the trial ( n = 1,588 ) gained an average of 0.7 kg ( p < 0.001 for effect ) . the relationship between the baseline and postrandomization a1c and change in weight differed by glycemia arm ( supplementary table 2 ) . overall , the relationship between change in a1c and change in weight for those allocated to intensive glucose control was statistically significant ( p < 0.001 ) with a fall in a1c associated with weight gain . in the intensive treatment arm , decreased a1c ( when defined as a decrease of 0.5% in a1c from baseline ) and weight gain occurred in 59.9% of participants , whereas weight loss and decreased a1c occurred in 28.8% of participants . few intensive participants experienced weight gain and increased a1c . in only 6% of intensive participants did weight gain occur without any change in a1c . figure 2 plots the relationship of change in weight with change in a1c over the first year by glycemia arm stratified by the baseline a1c categorized into thirds . in both treatment arms , participants with in contrast , when a1c was < 7.8% at baseline , a drop in a1c during treatment was associated with a decrease in weight in both arms . lines represent the estimated equation from the 5th to 95th percentile for each combination of baseline a1c and glycemia arm . supplementary table 3 summarizes the relationships between various medication - related factors and weight gain . the overall change in weight due to medication use accounted for < 15% of the variability in any of the models . the glucose - lowering medications that had the most effect on weight gain were insulin , tzds ( mainly rosiglitazone ) , and metformin ( tables 2 and 3 ) . the medications taken at baseline and follow - up and change in a1c explain 6 and 14% of the variability in the weight change from baseline during the first year 1 , in the standard and intensive arms , respectively , and 10 and 12% of the variability in weight change during the second year , respectively . weight gain by metformin use weight gain by insulin and tzd use the effects of insulin and tzd were not the same when considered in a linear mixed model . therefore , we redefined tzd and insulin use in the following classification for both models in the standard and intensive arms . table 3 summarizes the weight changes during use of various tzd / insulin combinations and metformin in the intensive group in the trial . there was a significant increase in weight ( 1.4 to 6.3 kg ) . these changes in weight with this combination were more marked in participants in the intensive arm of the trial . n = 95 ) had an average weight loss of 2.9 kg during the first 2 years of the trial . in contrast , intensive participants who had never previously used insulin or tzd but began this combination at some time after enrolling in the accord trial had a weight gain of 4.6 to 5.3 kg at 2 years . for participants who entered the accord trial on metformin , were enrolled in the intensive arm , and began taking both a tzd and insulin over the first 2 years of the trial , the mean weight gain at 2 years was 4.9 kg . metformin use was significantly associated with weight change in participants in the intensive arm of the trial only . participants in the intensive arm of the trial who never used metformin ( n = 244 ) had a mean weight gain of 2.7 kg . participants who entered the trial on metformin and continued ( n = 2,784 ) gained an average of 1.9 kg , and those who had metformin added during the trial ( n = 1,588 ) gained an average of 0.7 kg ( p < 0.001 for effect ) . there was no interaction effect between the tzd / insulin combinations and metformin use . weight gain with intensive glycemia treatment was reported in the main accord trial results paper ( 2 ) . we report in this paper a description of the time course of weight changes in the accord trial , along with baseline characteristics and medications and changes in a1c that were associated with changes in body weight following institution of intensive glycemic therapy in participants with type 2 diabetes . no single factor was strongly associated with , and potentially responsible for , the change in weight in each group . the models we tested explain only about 15% of the variability in body weight gain over the first 2 years of the trial . in both treatment arms , participants with in contrast , when a1c was lower than 7.8% at baseline , a drop in a1c during treatment was associated with a decrease in weight in both arms . however , the degree of both a1c decline and weight loss in these participants was relatively small . thus , in clinical practice , an attempt to intensify treatment in patients with a very high a1c is likely to lead to a significant weight gain . it is unclear whether the weight gain in such patients relates just to improvement in glycemia itself or greater use of insulin and tzd in patients who have higher baseline a1cs . we have presented results from > 90% of participants in the trial . at the time of discontinuation of the glycemic arm of the trial ( and stopping intensive treatment ) , a large proportion of participants had not completed 3 years in the trial . thus , although the data suggest some continued weight gain beyond 2 years , the number of participants decreases rapidly over the years . due to the lack of power , none of the statistical tests used are appropriate for use beyond the 2-year time point . some of the results are not surprising , particularly the associations of weight gain with high baseline a1c and insulin use subsequent to randomization . similarly , the greatest gain in weight occurred in participants using combination of insulin and tzd during the trial . this combination was used more extensively in the intensive treatment arm of the trial . those participants who used insulin at entry into the trial tended to gain more weight , perhaps due to substantial increases in their insulin dose and/or the addition of a tzd . change in a1c during the trial did not predict weight gain uniformly , suggesting that it is possible to improve glycemic control without weight gain in some individuals , perhaps using appropriate strategies to change lifestyle ( 4,5 ) . without adjustment for baseline a1c , a weight gain of 0.65 kg was associated with each 1% ( absolute ) reduction of a1c . however , assessment within treatment groups and by stratification according to the a1c at baseline showed in some circumstances either little change or a decrease in weight accompanying reductions of a1c . this may reflect the success of strategies to change lifestyle in some participants in the intensive arm , some of whom successfully lost weight while improving glycemic control . the medications taken at baseline and follow - up explain 6 and 14% of the variability in the weight change from baseline during the first year in the standard and intensive arms , respectively , and 10 and 12% of the variability in weight change during the second year , respectively . of interest , during the first year of treatment , variability in the subjects ' baseline medications and baseline a1c account for almost all ( 88% ) of the change in weight in the intensive arm but less than half of the weight change in the standard arm . overall , tzd use accounted for a much higher percent of variability in weight in the intensive than the standard arm . this difference may relate to a greater use of tzds in the intensive compared with the standard arm . it should also be noted that the overall amount of variability explained by medication use after randomization was relatively modest , never accounting for > 15% of the variability in any of the models . however , in clinical practice , what matters most is the net effect on weight . our data suggest that intensive therapy will probably cause weight gain ( unless appropriate lifestyle interventions are instituted ) , and weight gain is likely to be maximal when the intensive therapy consists of a tzd - plus - insulin combination . metformin use at baseline was associated with weight gain during the trial compared with those who did not enter the trial on metformin . this may relate to the known effect of metformin to decrease body weight , which may have already occurred with maximal effect prior to entry into the study . in contrast , we were unable to observe an effect of metformin on attenuation of weight gain when used in conjunction with insulin , as has been seen in other studies ( 6,7 ) . lack of attenuation of insulin - induced weight gain by metformin has been observed in other studies ( 8) , although these analyses may have been confounded by differences in doses of insulin used between those using or not using metformin . furthermore , the a1c goals in these other trials may have been higher than in accord , leading to less uptitration of insulin . it is important to recognize that while we examined the relationship between the insulin dose ( units per kilogram ) and body - weight change , we did not do such an analysis for other medications . this is due to the wide range of doses used in insulin titration , whereas dose titration with oral medications were usually two to three steps only and included both increases and decreases in dose . the physiologic mechanisms underlying weight gain in this study are not clarified by our analyses . other studies have suggested that several factors are involved , including a reduction in glycosuria and thus retention of calories otherwise lost , changes in food intake , or changes in energy expenditure ( 913 ) . in addition , insulin is known to be an anabolic hormone that also has some effects on weight regulation via the central nervous system , and tzds have effects on adipogenesis . drugs that have a lower propensity to cause weight gain or even weight loss , such as those affecting the incretin system or insulin detemir , were used only in a small proportion of participants in the accord trial and for a relatively short duration , as they were not available at the start of the trial . second , we could only include data on participants who had weight data available at 2 years and excluded those whose weight was not recorded or who had died or withdrawn from the study . all patients were advised regarding lifestyle changes according to american diabetes association guidelines , with varying degrees of compliance . we also did not assess factors associated with weight gain beyond the first 2 years in the trial , due to the fact that a large proportion of patients had not completed 3 years in the trial at the time of discontinuation of intensive treatment . we have included the baseline factors associated with weight gain during years 26 ( supplementary table 1 ) , although because of the diminishing number of patients , these data should be interpreted cautiously . in summary , we have identified and characterized many features associated with weight gain with intensification of glycemic control . on multivariate analysis , younger age , male sex , asian race , no smoking history , high a1c , bmi of 2535 , high waist circumference , insulin use , and metformin use at baseline were independently associated with weight gain over 2 years . following randomization , the intensive group participants with the greatest reduction in a1c gained the most weight . however , all of these factors explain only a small proportion of the weight gain . nevertheless , appreciation of these characteristics may help develop strategies to prevent weight gain when initiating intensive glycemic control in the future .