type 2 diabetes mellitus ( t2 dm ) is a progressive disease , meaning that most patients will require the introduction of insulin into their treatment regimen at some point during the continuum of care 1 . to facilitate the transition to insulin
, numerous clinical and real - world studies have investigated the efficacy and safety of initiating long - acting analogue insulins . in clinical studies , both insulin glargine ( gla ; lantus , sanofi us , inc . ,
bridgewater , nj , usa ) and insulin detemir ( det ; levemir , novo nordisk a / s , bagsvaerd , denmark ) have been shown to result in equivalent improvements in glycaemic control with a low incidence of hypoglycaemia when used as part of a basal - bolus regimen 24 .
although glycaemic outcomes in such trials have been similar for these two basal analogue insulins , it has been noted that higher doses and twice - daily dosing are often required with det compared with gla 3,4 . a recent trial has suggested that when both det and gla are used once daily as an adjunct to metformin , a greater proportion of patients treated with gla reached glycated haemoglobin ( hba1c ) levels  < 7.0% than did patients treated with det 5 .
attempts to examine the relative advantages of these insulin analogues in a real - world setting have proved difficult to interpret .
some studies have reported enhanced glycaemic control with gla compared with det , along with improved adherence and persistence , with no difference with regard to hypoglycaemia , healthcare costs or weight gain 68 ; however , other studies found no difference in glycaemic control between the two insulin types 9,11 , with one suggesting that patients initiating det were 30% less likely to gain 0.9  kg or more in body weight than gla users 10 .
studies investigating the efficacy and safety of switching from gla to det are similarly conflicting in their findings .
although once - daily dosing of gla and det has been shown to result in equivalent 24-h glycaemic control , switching from gla to det was associated with improved hba1c levels and fewer hypoglycaemic events , compared with remaining on gla in an observational study of patients with type 1 diabetes mellitus ( t1 dm ) and t2 dm 7,11,12 . a retrospective analysis , however , reported that switching from gla to det did not improve glycaemic control among a cohort of patients with t2 dm 13 . a recent longitudinal study sought to expand on these data by assessing real - world outcomes using a retrospective analysis of two large , independent , national , us databases comprising commercially insured and medicare populations : the impact and humana cohorts 14
the study found that , at 1-year follow - up , patients who had remained on gla showed significantly higher persistence with and adherence to treatment compared with those who switched to det ( p  <  0.001 ) .
in addition , 37% of patients who switched to det restarted gla ( p  <  0.05 ) , compared with only 20% of gla users returning to det after having switched to gla .
overall hypoglycaemia rates were significantly higher for patients continuing on gla than for patients switching to det in the humana cohort ( 16 vs. 11% ; p  <  0.05 ) , but overall hypoglycaemia rates were similar in the impact cohort ( 11 vs. 12% ; p  =  0.490 ) . in the present study , to further evaluate the consequences of insulin switching , we used data from patients ' medical records to investigate retrospectively the real - world clinical outcomes for patients with t2 dm who switched between these two basal insulin analogues .
the present analysis was a retrospective cohort study using the ge centricity electronic medical records ( emr ) database from 1 july 2005 to 31 december 2012 . in 2007 ,
the ge centricity emr database contained the medical records of 30  million patients in 49 us states .
as the analysis was performed on de - indentified data , approval from an ethics committee was not necessary .
we analysed two cohorts in the present study : cohort 1 included patients who were previously treated with gla and switched to det ( det - s ) or who remained on gla ( gla - c ) ; and cohort 2 included patients previously treated with det and subsequently switched to gla ( gla - s ) or who remained on det ( det - c ) . in cohort 1
, the patients in the det - s subgroup were required to have  1 physician prescription for gla  < 6  months before first det physician prescription order date ( after 1 january 2006 ) .
patients in the gla - c subgroup were required to have  2 gla physician prescriptions starting from the third - quarter of 2005 , without a subsequent physician prescription order of det , with  1 of the orders being 
the index date was a randomly selected date between the second to the last gla physician prescription . in cohort 2
, patients in the gla - s subgroup were required to have  1 physician prescription for det  < 6  months before the first gla prescription order date ( after 1 july 2006 ) .
patients in the det - c subgroup were required to have  2 det physician prescriptions starting from the first - quarter of 2006 , without a subsequent physician prescription order for gla .
the index date was a randomly selected date between the second and last det physician prescriptions dates .
patients aged 18  years on the index date were included in the analysis if they had a diagnosis of t2 dm [ international classification of diseases , ninth revision , clinical modification ( icd-9-cm ) codes : 250.x0 or 250.x2 ] with emr activity data for  6  months pre - index ( baseline ) and 12  months post - index ( follow - up ) .
patients were further required to have : 1 baseline hba1c measure taken during the period 90  days before up to 15  days after the index date ; 1 baseline body mass index ( bmi ) measure taken in the period 30  days before up to 15  days after the index date ; and  1 follow - up hba1c measure from the second - quarter until 3  months after the 1-year follow - up . in cohort 1 , patients with baseline prescriptions for premixed insulin or basal insulins other than gla [ i.e. neutral protamine hagedorn ( nph ) insulin , lente , or ultralente ] were excluded .
similarly , in cohort 2 , patients with baseline prescriptions for premixed insulin or basal insulins other than det ( i.e. nph insulin , lente or ultralente ) were excluded .
baseline demographic and clinical characteristics included age , gender , region , race , geographic region , insurance type , bmi , weight , individual comorbidities and prescribed diabetes medications .
in addition , the charlson comorbidity index ( cci ) score was calculated , which is the weighted sum of 19 categories of comorbidity defined using icd-9-cm diagnoses codes , with a higher score indicating a more severe burden of comorbidity and a higher mortality risk 15,16 .
clinical outcome variables were measured 1  year after the index date ( follow - up ) and included follow - up hba1c , change in hba1c from baseline , follow - up hypoglycaemic events , follow - up bmi , change in bmi from baseline follow - up body weight , change in body weight from baseline and follow - up oral antidiabetes drug ( oad ) use ( including gla , det and rapid - acting insulin ) .
baseline hba1c measures were defined as those occurring between 90  days before and up to 15  days after the index date ; baseline body weight and bmi measures were defined as  1 baseline measurement between 30  days before and up to 15  days after the index date .
follow - up hba1c values were defined as those occurring during the period from the second - quarter until 3  months after 1-year follow - up , and follow - up body weight and bmi values were defined as those occurring during the 30  days before or after the end of the 1-year follow - up period ( index date  +  360  days ) .
if patients had multiple hba1c , body weight or bmi results during this period , the value dated closest to the index date was used as the baseline value , and the value dated closest to the end of the follow - up period was used as the follow - up value .
hypoglycaemia was defined as a healthcare encounter ( outpatient , inpatient or emergency department visit ) with a primary or secondary icd-9-cm diagnosis code for hypoglycaemia , based on the algorithm published by ginde et al .
17 . both the proportion of patients with  1 hypoglycaemic event ( prevalence rate ) and the average number of hypoglycaemic events per patient ( event rate ) during the baseline and 1-year follow - up period were identified .
treatment persistence was defined as the patient remaining on the index long - acting insulin ( gla for gla - c and det for det - s for cohort 1 ; det for det - c and gla for gla - s for cohort 2 ) during the 1-year follow - up period without discontinuation after study drug initiation .
based on the published methodology 18 , study medication was considered discontinued if the prescription was not re - ordered by the physician within the expected time of medication coverage ( the pre - defined 90th percentile of the time between first and second physician prescriptions among patients with  1 prescription ) .
patients who restarted their initial medication after a period of not having used this medication during follow - up were considered non - persistent .
persistence days were measured as the number of days between the index date and the discontinuation date .
sensitivity analyses were also conducted using 75th and 95th percentiles of the expected time of medication coverage .
descriptive and multivariate statistical methodologies were used to assess the baseline characteristics and to compare the outcomes over the 1-year follow - up period . to address potential selection bias in the real - world setting , in each cohort ,
patients from the two subgroups were matched by propensity - score matching , with a 1 up to 5 ratio in cohort 1 and a 1 up to 3 ratio in cohort 2 , to balance baseline age , gender , race , geographic region , insurance type , physician specialty , index year , baseline comorbidity , baseline oad use , concomitant medication , hba1c and bmi .
these ratios and matchings were chosen because our preliminary analysis revealed a prescription imbalance , with significantly more eligible patients in the gla group when compared with the det group , and a much lower number of patients in the 
additionally , one - to - many matching has previously been validated as a method to increase precision in cohort studies , compared with one - to - one matching , and has also been supported in a recent review assessing the quality of statistical methodologies in matched case 
matching was implemented without replacement and any patient without  1 match was excluded from the analysis . between - group
covariate balance was evaluated using descriptive t - tests and chi - squared tests ( with corresponding p - values ) and standardized differences , where a standardized difference < 10 indicated adequate balance 21 . because not every patient in the matched cohorts had follow - up bmi or body weight data , we conducted , as sensitivity analysis , ordinary least squares regressions for bmi and body weight changes , adjusting for potential baseline imbalances .
the model used a larger set of covariates , which included patient demographics ( age , gender , geographic locations and bmi categories ) , baseline comorbidities and some basic clinical characteristics ( baseline oad use , statins for baseline concomitant medication use , baseline hba1c level and baseline hypoglycaemic events ) .
we analysed two cohorts in the present study : cohort 1 included patients who were previously treated with gla and switched to det ( det - s ) or who remained on gla ( gla - c ) ; and cohort 2 included patients previously treated with det and subsequently switched to gla ( gla - s ) or who remained on det ( det - c ) . in cohort 1
, the patients in the det - s subgroup were required to have  1 physician prescription for gla  < 6  months before first det physician prescription order date ( after 1 january 2006 ) .
patients in the gla - c subgroup were required to have  2 gla physician prescriptions starting from the third - quarter of 2005 , without a subsequent physician prescription order of det , with  1 of the orders being 
the index date was a randomly selected date between the second to the last gla physician prescription . in cohort 2
, patients in the gla - s subgroup were required to have  1 physician prescription for det  < 6  months before the first gla prescription order date ( after 1 july 2006 ) .
patients in the det - c subgroup were required to have  2 det physician prescriptions starting from the first - quarter of 2006 , without a subsequent physician prescription order for gla .
the index date was a randomly selected date between the second and last det physician prescriptions dates .
patients aged 18  years on the index date were included in the analysis if they had a diagnosis of t2 dm [ international classification of diseases , ninth revision , clinical modification ( icd-9-cm ) codes : 250.x0 or 250.x2 ] with emr activity data for  6  months pre - index ( baseline ) and 12  months post - index ( follow - up ) .
patients were further required to have : 1 baseline hba1c measure taken during the period 90  days before up to 15  days after the index date ; 1 baseline body mass index ( bmi ) measure taken in the period 30  days before up to 15  days after the index date ; and  1 follow - up hba1c measure from the second - quarter until 3  months after the 1-year follow - up . in cohort 1 , patients with baseline prescriptions for premixed insulin or basal insulins other than gla [ i.e. neutral protamine hagedorn ( nph ) insulin , lente , or ultralente ] were excluded .
similarly , in cohort 2 , patients with baseline prescriptions for premixed insulin or basal insulins other than det ( i.e. nph insulin , lente or ultralente ) were excluded .
baseline demographic and clinical characteristics included age , gender , region , race , geographic region , insurance type , bmi , weight , individual comorbidities and prescribed diabetes medications .
in addition , the charlson comorbidity index ( cci ) score was calculated , which is the weighted sum of 19 categories of comorbidity defined using icd-9-cm diagnoses codes , with a higher score indicating a more severe burden of comorbidity and a higher mortality risk 15,16 .
clinical outcome variables were measured 1  year after the index date ( follow - up ) and included follow - up hba1c , change in hba1c from baseline , follow - up hypoglycaemic events , follow - up bmi , change in bmi from baseline follow - up body weight , change in body weight from baseline and follow - up oral antidiabetes drug ( oad ) use ( including gla , det and rapid - acting insulin ) .
baseline hba1c measures were defined as those occurring between 90  days before and up to 15  days after the index date ; baseline body weight and bmi measures were defined as  1 baseline measurement between 30  days before and up to 15  days after the index date .
follow - up hba1c values were defined as those occurring during the period from the second - quarter until 3  months after 1-year follow - up , and follow - up body weight and bmi values were defined as those occurring during the 30  days before or after the end of the 1-year follow - up period ( index date  +  360  days ) .
if patients had multiple hba1c , body weight or bmi results during this period , the value dated closest to the index date was used as the baseline value , and the value dated closest to the end of the follow - up period was used as the follow - up value .
hypoglycaemia was defined as a healthcare encounter ( outpatient , inpatient or emergency department visit ) with a primary or secondary icd-9-cm diagnosis code for hypoglycaemia , based on the algorithm published by ginde et al .
17 . both the proportion of patients with  1 hypoglycaemic event ( prevalence rate ) and the average number of hypoglycaemic events per patient ( event rate ) during the baseline and 1-year follow - up period were identified .
treatment persistence was defined as the patient remaining on the index long - acting insulin ( gla for gla - c and det for det - s for cohort 1 ; det for det - c and gla for gla - s for cohort 2 ) during the 1-year follow - up period without discontinuation after study drug initiation . based on the published methodology 18 ,
study medication was considered discontinued if the prescription was not re - ordered by the physician within the expected time of medication coverage ( the pre - defined 90th percentile of the time between first and second physician prescriptions among patients with  1 prescription ) .
patients who restarted their initial medication after a period of not having used this medication during follow - up were considered non - persistent .
persistence days were measured as the number of days between the index date and the discontinuation date .
sensitivity analyses were also conducted using 75th and 95th percentiles of the expected time of medication coverage .
descriptive and multivariate statistical methodologies were used to assess the baseline characteristics and to compare the outcomes over the 1-year follow - up period . to address potential selection bias in the real - world setting , in each cohort ,
patients from the two subgroups were matched by propensity - score matching , with a 1 up to 5 ratio in cohort 1 and a 1 up to 3 ratio in cohort 2 , to balance baseline age , gender , race , geographic region , insurance type , physician specialty , index year , baseline comorbidity , baseline oad use , concomitant medication , hba1c and bmi .
these ratios and matchings were chosen because our preliminary analysis revealed a prescription imbalance , with significantly more eligible patients in the gla group when compared with the det group , and a much lower number of patients in the 
additionally , one - to - many matching has previously been validated as a method to increase precision in cohort studies , compared with one - to - one matching , and has also been supported in a recent review assessing the quality of statistical methodologies in matched case 
matching was implemented without replacement and any patient without  1 match was excluded from the analysis . between - group covariate balance was evaluated using descriptive t - tests and chi - squared tests ( with corresponding p - values ) and standardized differences , where a standardized difference < 10 indicated adequate balance 21 . because not every patient in the matched cohorts had follow - up bmi or body weight data , we conducted , as sensitivity analysis , ordinary least squares regressions for bmi and body weight changes , adjusting for potential baseline imbalances .
the model used a larger set of covariates , which included patient demographics ( age , gender , geographic locations and bmi categories ) , baseline comorbidities and some basic clinical characteristics ( baseline oad use , statins for baseline concomitant medication use , baseline hba1c level and baseline hypoglycaemic events ) .
a total of 25  290 eligible patients were identified with 19  811 patients from cohort 1 ( gla - c , n  =  17  783 and det - s , n  =  2028 ) and 5479 from cohort 2 ( det - c , n  =  4431 and gla - s , n  =  1048 ) .
significant baseline differences existed between the subgroups in each cohort ( table s1 ) . in cohort 1 ,
when compared with patients in the det - s subgroup , patients in the gla - c subgroup were older , were more likely to be black , were more likely to reside in the midwest or west , were more likely to be enrolled in medicare , had higher cci scores and had lower hba1c values .
no significant differences were found for bmi or body weight between the gla - c and det - s subgroups at baseline . in cohort 2 , when compared with the det - c subgroup , patients in the gla - s subgroup were younger , were more likely to be black , were more likely to reside in the midwest or west , had higher hba1c values , and had higher body weight and bmi values .
patients in the gla - s and det - c subgroups had similar cci scores at baseline .
for both cohorts , no significant differences were found for baseline hypoglycaemic events between groups .
bmi , body mass index ; emr , electronic medical records ; hba1c , glycated haemoglobin ; t2 dm , type 2 diabetes mellitus .
after propensity - score matching , the final matched study population included 13  942 patients overall , with 10  657 from cohort 1 ( gla - c , n  =  8860 and det - s , n  =  1797 ; female patients 54.7% , age 58.4  years , hba1c level 8.7% , bmi 35.1  kg / cm , weight 99.3  kg ) and 3285 patients from cohort 2 ( det - c , n  =  2427 and gla - s , n  =  858 ; female 53.5% , age 58.3  years , hba1c level 8.8% , bmi 35.4  kg / cm , weight 100.7  kg ) .
the baseline demographic and clinical characteristics were balanced between treatment groups in each cohort ( table1 ) .
baseline characteristics among matched patients in cohorts 1 and 2 det , insulin detemir ; gla , insulin glargine ; det - s , patients previously treated with gla who switched to det ; gla - c , patients who remained on gla ; gla - s , patients previously treated with det who switched to gla ; det - c , patients who remained on det ; bmi , body mass index ; cci , charlson comorbidity index ; hba1c , glycated haemoglobin ; oad , oral antidiabetes drug ; s.d . , standard deviation . during 1-year follow - up ,
overall , switching from gla to det resulted in lower persistence with treatment , whereas switching from det to gla resulted in higher persistence . among patients in cohort 1 ,
those in the det - s subgroup versus those in the gla - c subgroup had significantly lower persistence with treatment ( 52.4 vs. 61.3% , respectively ; p  <  0.0001 ) and significantly fewer treatment persistent days ( 311.6 vs. 331.0  days ; p  <  0.0001 ) . in cohort 2 , however , the gla - s and the det - c subgroups had similar levels of treatment persistence ( 56.5 vs. 58.5% , respectively ; p  =  0.292 ) yet fewer treatment persistent days ( 320.7 vs. 325.3  days ; p  =  0.015 ) . sensitivity analysis using 75th and 95th percentile of the time duration yielded similar results : 75th percentile : cohort 1 gla - c versus det - s subgroup , 21.2 versus 35.7% ( p  < 
0.0001 ) ; cohort 2 det - c versus gla - s subgroup , 24.7 versus 31.6% ( p  =  0.0001 ) ; 95th percentile : cohort 1 gla - c versus det - s subgroup , 63.1 versus 68.2% ( p  < 
0.0001 ) ; cohort 2 det - c versus gla - s subgroup , 67.0 versus 66.0% ( p  =  0.622 ) . in cohort 1 ,
the use of rapid - acting insulin was significantly higher among the patients in the det - s subgroup than among those in the gla - c subgroup ( 57.6 vs. 52.5% ; p  <  0.0001 ; figure 2 ) , and 26.9% of patients in the det - s subgroup restarted gla . in cohort 2
, however , similar proportions of patients used rapid - acting insulin in the det - c and gla - s subgroups ( 50.4 vs. 51.1% ; p  =  0.712 ) , and 18.6% of patients in the gla - s subgroup restarted det . patients requiring rapid - acting insulin ( rai ) .
det , insulin detemir ; gla , insulin glargine ; det - s , patients previously treated with gla who switched to det ; gla - c , patients who remained on gla ; gla - s , patients previously treated with det who switched to gla ; det - c , patients who remained on det .
the baseline mean hba1c level was similar between the treatment groups in each of the cohorts . in cohort 1 ,
patients in the det - s subgroup had a significantly higher follow - up hba1c level ( figure 3a ) , a significantly lower hba1c reduction ( figure 3b ) , and significantly lower proportions of patients achieved hba1c < 7.0% ( figure 3c ) and hba1c  < 8.0% ( figure 3d ) at the end of 1-year follow - up compared with patients in the gla - c subgroup . in cohort 2 , however , compared with patients in the det - c subgroup , patients in the gla - s subgroup had a significantly lower follow - up hba1c ( figure 3a ) and a numerically higher ( although not statistically significant ) hba1c reduction ( figure 3b ) , but there were no differences in the proportions of patients achieving an hba1c level  < 7.0% ( figure 3c ) or  < 8.0% ( figure 3d ) .
( a ) one - year follow - up glycated haemoglobin ( hba1c ) values , ( b ) change in hba1c from baseline , ( c ) proportion of patients achieving target hba1c  < 7.0% , and ( d ) proportion of patients achieving target hba1c  < 8.0% .
det , insulin detemir ; gla , insulin glargine ; det - s , patients previously treated with gla who switched to det ; gla - c , patients who remained on gla ; gla - s , patients previously treated with det who switched to gla ; det - c , patients who remained on det . for both prevalence and event rates of any hypoglycaemic events ,
no significant differences were found after follow - up between the det - s and gla - c subgroups in cohort 1 or between the gla - s and det - c subgroups in cohort 2 [ prevalence rate : 2.0 vs. 2.1% , p  =  0.889 ; event rate ( number of events / patient year ) : 0.023 vs. 0.026 , p  =  0.4424 ] or between the gla - c and det - s subgroups in cohort 2 ( 2.3 vs. 1.6% , p  =  0.2314 ; event rate : 0.028 vs. 0.021 , p  =  0.3727 ) . in both cohorts ,
baseline bmi and body weight were similar between the groups ( table1 ) . in cohort 1 ,
bmi at 1-year follow - up was 35.0  kg / m for both the det - s and gla - c subgroups ( p  =  0.843 ) .
there were also no significant differences in bmi change for patients in the det - s and gla - c subgroups after follow - up ( figure 4a ) .
the 1-year follow - up weight was similar for the det - s and gla - c subgroups ( 99.3 vs. 99.4  kg ; p  =  0.881 ) , with similar weight changes between patients in the det - s subgroup and those in the gla - c subgroup ( figure 4b ) .
changes in ( a ) body mass index ( bmi ) and ( b ) body weight at 1-year follow - up .
det , insulin detemir ; gla , insulin glargine ; det - s , patients previously treated with gla who switched to det ; gla - c , patients who remained on gla ; gla - s , patients previously treated with det who switched to gla ; det - c , patients who remained on det . in cohort 2 , at the end of 1-year follow - up , patients in the gla - s subgroup had a higher bmi ( 36.3 vs. 35.5  kg / m ; p  =  0.052 ) , but this was not statistically significant .
there were no significant differences at 1-year follow - up for body weight between patients in the gla - s and det - c subgroups ( 102.2 vs. 100.9  kg ; p  =  0.299 ) ; however , patients in the gla - s subgroup had a greater change from baseline in body weight compared with those in the det - c subgroup ( figure 4b ) .
sensitivity analyses using ordinary least squares regressions yielded similar results : adjusted weight change : cohort 1 det - s versus gla - c subgroup , 0.18 versus + 0.10  kg ( p  =  0.329 ) ; cohort 2 gla - s versus det - c subgroup , + 1.48 versus + 0.02  kg ( p  < 
0.001 ) ; adjusted bmi change : cohort 1 gla - c versus det - s subgroup , 0.18 versus 0.04  kg ( p  =  0.122 ) ; cohort 2 gla - s versus det - c subgroup , + 0.48 versus    0.05  kg ( p  <  0.001 ) .
during 1-year follow - up , overall , switching from gla to det resulted in lower persistence with treatment , whereas switching from det to gla resulted in higher persistence . among patients in cohort 1 ,
those in the det - s subgroup versus those in the gla - c subgroup had significantly lower persistence with treatment ( 52.4 vs. 61.3% , respectively ; p  <  0.0001 ) and significantly fewer treatment persistent days ( 311.6 vs. 331.0  days ; p  <  0.0001 ) . in cohort 2 , however , the gla - s and the det - c subgroups had similar levels of treatment persistence ( 56.5 vs. 58.5% , respectively ; p  =  0.292 ) yet fewer treatment persistent days ( 320.7 vs. 325.3  days ; p  =  0.015 ) . sensitivity analysis using 75th and 95th percentile of the time duration yielded similar results : 75th percentile : cohort 1 gla - c versus det - s subgroup , 21.2 versus 35.7% ( p  < 
0.0001 ) ; cohort 2 det - c versus gla - s subgroup , 24.7 versus 31.6% ( p  =  0.0001 ) ; 95th percentile : cohort 1 gla - c versus det - s subgroup , 63.1 versus 68.2% ( p  < 
0.0001 ) ; cohort 2 det - c versus gla - s subgroup , 67.0 versus 66.0% ( p  =  0.622 ) . in cohort 1 ,
the use of rapid - acting insulin was significantly higher among the patients in the det - s subgroup than among those in the gla - c subgroup ( 57.6 vs. 52.5% ; p  <  0.0001 ; figure 2 ) , and 26.9% of patients in the det - s subgroup restarted gla . in cohort 2
, however , similar proportions of patients used rapid - acting insulin in the det - c and gla - s subgroups ( 50.4 vs. 51.1% ; p  =  0.712 ) , and 18.6% of patients in the gla - s subgroup restarted det .
det , insulin detemir ; gla , insulin glargine ; det - s , patients previously treated with gla who switched to det ; gla - c , patients who remained on gla ; gla - s , patients previously treated with det who switched to gla ; det - c , patients who remained on det .
the baseline mean hba1c level was similar between the treatment groups in each of the cohorts . in cohort 1 ,
patients in the det - s subgroup had a significantly higher follow - up hba1c level ( figure 3a ) , a significantly lower hba1c reduction ( figure 3b ) , and significantly lower proportions of patients achieved hba1c < 7.0% ( figure 3c ) and hba1c  < 8.0% ( figure 3d ) at the end of 1-year follow - up compared with patients in the gla - c subgroup . in cohort 2 , however , compared with patients in the det - c subgroup , patients in the gla - s subgroup had a significantly lower follow - up hba1c ( figure 3a ) and a numerically higher ( although not statistically significant ) hba1c reduction ( figure 3b ) , but there were no differences in the proportions of patients achieving an hba1c level  < 7.0% ( figure 3c ) or  < 8.0% ( figure 3d ) .
( a ) one - year follow - up glycated haemoglobin ( hba1c ) values , ( b ) change in hba1c from baseline , ( c ) proportion of patients achieving target hba1c  < 7.0% , and ( d ) proportion of patients achieving target hba1c  < 8.0% .
det , insulin detemir ; gla , insulin glargine ; det - s , patients previously treated with gla who switched to det ; gla - c , patients who remained on gla ; gla - s , patients previously treated with det who switched to gla ; det - c , patients who remained on det . for both prevalence and event rates of any hypoglycaemic events ,
no significant differences were found after follow - up between the det - s and gla - c subgroups in cohort 1 or between the gla - s and det - c subgroups in cohort 2 [ prevalence rate : 2.0 vs. 2.1% , p  =  0.889 ; event rate ( number of events / patient year ) : 0.023 vs. 0.026 , p  =  0.4424 ] or between the gla - c and det - s subgroups in cohort 2 ( 2.3 vs. 1.6% ,
p  =  0.2314 ; event rate : 0.028 vs. 0.021 , p  =  0.3727 ) . in both cohorts ,
baseline bmi and body weight were similar between the groups ( table1 ) . in cohort 1 ,
bmi at 1-year follow - up was 35.0  kg / m for both the det - s and gla - c subgroups ( p  =  0.843 ) .
there were also no significant differences in bmi change for patients in the det - s and gla - c subgroups after follow - up ( figure 4a ) .
the 1-year follow - up weight was similar for the det - s and gla - c subgroups ( 99.3 vs. 99.4  kg ; p  =  0.881 ) , with similar weight changes between patients in the det - s subgroup and those in the gla - c subgroup ( figure 4b ) .
changes in ( a ) body mass index ( bmi ) and ( b ) body weight at 1-year follow - up .
det , insulin detemir ; gla , insulin glargine ; det - s , patients previously treated with gla who switched to det ; gla - c , patients who remained on gla ; gla - s , patients previously treated with det who switched to gla ; det - c , patients who remained on det . in cohort 2 , at the end of 1-year follow - up , patients in the gla - s subgroup had a higher bmi ( 36.3 vs. 35.5  kg / m ; p  =  0.052 ) , but this was not statistically significant . change in bmi was significantly different ( figure 4a ) .
there were no significant differences at 1-year follow - up for body weight between patients in the gla - s and det - c subgroups ( 102.2 vs. 100.9  kg ; p  =  0.299 ) ; however , patients in the gla - s subgroup had a greater change from baseline in body weight compared with those in the det - c subgroup ( figure 4b ) .
sensitivity analyses using ordinary least squares regressions yielded similar results : adjusted weight change : cohort 1 det - s versus gla - c subgroup , 0.18 versus + 0.10  kg ( p  =  0.329 ) ; cohort 2 gla - s versus det - c subgroup , + 1.48 versus + 0.02  kg ( p  < 
0.001 ) ; adjusted bmi change : cohort 1 gla - c versus det - s subgroup , 0.18 versus 0.04  kg ( p  =  0.122 ) ; cohort 2 gla - s versus det - c subgroup , + 0.48 versus    0.05  kg ( p  <  0.001 ) .
the aim of the present study was to evaluate retrospectively the real - world clinical outcomes of switching between basal insulin analogues , compared with continuing on previous basal insulin , among patients with t2 dm identified from the us ge centricity emr database .
overall , contrasting findings were observed when patients switched from gla to det , as compared with switching from det to gla . in cohort 1 ,
compared with patients in the det - s subgroup , patients in the gla - c subgroup had better clinical outcomes at 1-year follow - up , including lower hba1c levels and significantly higher hba1c reductions .
in addition , significantly more patients in the gla - c subgroup achieved the targeted hba1c levels of  < 7.0% or  < 8.0% and those in the det - s subgroup had significantly higher rapid - acting insulin use .
in addition , no significant differences in hypoglycaemia rates and weight / bmi were observed between the two groups .
these results could be attributable to lower persistence / adherence as patients might not be taking their full medication . in cohort 2 , however , patients in the gla - s subgroup had lower hba1c levels and a numerically higher ( but non - significant ) hba1c reduction ; similar proportions of patients achieved hba1c levels of < 7.0 or < 8.0% , and similar hypoglycaemia rates were seen in the two groups .
although 1-year follow - up body weight and bmi were similar , patients in the det - c subgroup had a decreased bmi and a lower body weight increase , whereas patients in the gla - s subgroup had increased bmi and significantly greater body weight increase .
although the patients in the gla - s subgroup gained weight , the increase was  < 1% which ,
it is suggested , is not clinically relevant 22 , and may reflect differences in follow - up plasma glucose levels or other factors . furthermore , the increase in weight with gla could be taken to be a sign of better compliance .
if a switch between insulin analogues is of a  disruptive nature , it will result in decreased compliance .
for example , if a regimen becomes more complex ( from once daily to twice daily , adding a rapid - acting insulin etc . ) , it could lead to less of the typical weight gain associated with insulin treatment . in cohort 1 ,
the patients in the det - s subgroup , who switched from gla to det , had lower persistence than those who remained on gla ( robust in sensitivity analyses ) . this could be attributable to the fact that most patients on det administer twice daily , whereas most patients on gla administer once daily 13,23 . unfortunately , this information is not captured in the ge centricity emr database . by contrast , in cohort 2 , data on patients in the gla - s subgroup switching from det to gla suggested similar overall persistence with treatment .
approximately 27% of the patients in the det - s subgroup restarted gla during the follow - up period . of patients in the gla - s subgroup
although the reasons for restarting the former insulin are not captured in the ge centricity emr database , these findings are consistent with a previous impact and humana database study 14 .
unlike randomized controlled trials , where patients are required to be  persistent with their therapy , real - world patients and physicians do not follow a stringent protocol and , therefore , any differences in patients ' persistence with their insulin treatment can translate into differences in clinical and economic  outcomes 17 .
overall , contrasting outcomes were observed when patients were switched from gla to det , when compared with switching from det to gla .
this raises questions about the therapeutic interchangeability of these two basal analogue insulins in clinical practice , although further studies are required to confirm this non - interchangeability .
the results of the present ge centricity emr switching analysis , however , were highly consistent with the previously performed claims database analysis 14 .
the ge centricity emr database is a large and comprehensive source of data to understand clinical practice and outcomes in the real - world setting .
this database contains rich clinical information , such as hba1c level , weight and bmi , that is not available in insurance claim databases .
overall 25  000 patients were identified in this study , and almost 15  000 were propensity - score - matched and analysed , including those switching from det to gla and those switching from gla to det during the same time period . in previous observational studies on switching from gla to det 11,13,24 ,
conflicting results were shown with relatively low numbers of patients included ( 301300 patients ) and including either only patients with t1 dm , or a mixed group of patients with t1 dm and t2 dm .
our previous study used administrative claims data 14 , and the results described in the present study not only validate our previous findings with a different data source but also strengthen them with additional data on weight .
one of the key limitations of the present study , however , is that the emr analysis was carried out on primary care physician prescription data , rather than on claims databases .
prescription orders do not necessarily mean that the prescriptions were filled and taken as directed .
in addition , certain data were not available , including glucose levels , the duration of treatment with the initial insulin , the duration of t2 dm , and the reason for switching insulin ( e.g. insurance required switching to other insulin ) . although propensity - score matching was used to balance the baseline data between treatment groups , the differences between the groups were quite significant ( table s1 ) and the potential residual confounding might therefore still be present , particularly unobserved selection bias . in a real - world setting ,
switching patients to another treatment regimen may introduce confounding by indication , an important limitation to observational studies reporting on patients changing their treatment regimens , including the study described here .
other potential sources of bias and confounding include the range of time from measurement of hba1c to index date , differences in time for follow - up hba1c and follow - up bmi , and patient / physician preference .
in addition , the dose of insulin at the time of switching was not available in the ge centricity emr database and might have impacted on clinical outcomes , especially in patients who had recently switched insulin analogues and had not had the opportunity to titrate their dosage . specifically , the present study was designed to compare between patients who switched to a different basal insulin and those who continued on the previous basal insulin . in the case of comparing patients in the det - s with those in the gla - c subgroup ,
patients in the latter subgroup may already be fully titrated , while it takes time for patients switching to det to titrate .
this may lead to an overestimation of the benefits of gla compared with det , representing a further limitation of this analysis .
the same limitation applies to the comparison of the gla - s with the det - c subgroup .
one approach to account for confounding by indication is to compare patients in the gla - s subgroup with those in the det - s subgroup directly ; however , these patients had different baseline doses of basal insulin , and based on a real - world study among us patients initiating gla or det , it may be that higher insulin doses were used in the det - treated patients 6 .
it is not possible to establish causality from the differences in outcomes , nor are the data necessarily representative of all patients with t2 dm .
patients could drop out for various reasons and thus selection may occur . in the present study ,
more patients treated with det than those treated with gla dropped out from the study population ( 56 vs. 35% ) when 6-month baseline and 12-month follow - up were required .
similarly , only 8% of patients on det treatment compared with 40% on gla , dropped out when being aged > 18  years was required ( figure 1 ) .
sufficient data on hba1c levels and bmi were missing for half of the patients in this analysis , and this lack of completeness should be considered as a major limitation of emr databases . when interpreting the findings of the present study , it should be remembered that , because of its limitations , the methodology used may have introduced bias or affected the 
because of the real - world nature of the present study , patients did not have their hba1c levels or bmi evaluated regularly and thus were excluded if they did not have baseline and/or follow - up hba1c / bmi values .
overall , recognizing the inherent limitations of real - world data analyses , the findings of the present study alone should not be used to guide clinicians in the decision to switch insulin , but the findings do merit further investigation .
future studies should look more closely at a number of other factors , including the dose , duration of treatment , reasons for and cost - effectiveness of switching in patients with t2 dm .
in addition , although previous studies have suggested that in patients with t1 dm det was associated with a higher dose and more frequent twice - daily dosing than gla 13,24 , large cohort comparative studies in patients with t1 dm should be conducted to confirm these findings . in conclusion ,
the results of the present study suggest that switching patients with t2 dm from gla to det might lead to decreases in treatment persistence alongside having a negative effect on glycaemic outcomes .
maintaining patients on gla or switching from det to gla , however , might be beneficial , although may result in minor weight gain .
this suggests that the two basal insulin analogues might not be therapeutically interchangeable , and further studies are required to investigate this hypothesis .
p. l. is a member of the advisory panel for sanofi us , inc . and
, has received research support from eli lilly and co. , sanofi us , inc . , novo nordisk , inc . , amylin pharmaceuticals , inc . and boehringer ingelheim pharmaceuticals , inc . , and serves on speaker 's bureaus for eli lilly and co. , novo nordisk , inc . , amylin pharmaceuticals , inc . and boehringer ingelheim pharmaceuticals , inc .
w. w. , r. m. , f. y. and j. g. are employees of sanofi us , inc .
l. x. and o. b. are employees of statinmed , which received funding to carry out this work from sanofi us , inc .
p. l. co - developed the concept , interpreted the results of the analyses , reviewed manuscript outline and drafts and provided comments .
w. w. proposed and co - developed the concept , co - developed the analysis plan , interpreted the results of the analyses , reviewed manuscript outline and drafts and provided comments .
r. m. co - developed the concept , co - developed the analysis plan , interpreted the results of the analyses , reviewed manuscript outline and drafts and provided comments .
f. y. collected the data , co - developed the analysis plan , conducted statistical analyses and interpreted the results , reviewed manuscript outline and drafts and provided comments .
l. x. collected the data , co - developed the analysis plan , conducted statistical analyses and interpreted the results , reviewed manuscript outline and drafts and provided comments .
o. b. interpreted the results of the analyses , reviewed manuscript outline and drafts and provided comments .
j. g. developed the concept , co - developed the analysis plan , interpreted the results of the analyses , reviewed manuscript outline and drafts and provided comments .
additional supporting informationmay be found in the online version of this article : baseline characteristics among prematched patients of cohorts 1 and 2 .
 aimsto evaluate real - world clinical outcomes for switching basal insulin analogues [ insulin glargine ( gla ) and insulin detemir ( det ) ] among us patients with type 2 diabetes mellitus ( t2dm).methodsusing the ge centricity electronic medical records database , this retrospective study examined two cohorts : cohort 1 , comprising patients previously on gla and then either switching to det ( det - s ) or continuing with gla ( gla - c ) ; and cohort 2 , comprising patients previously on det and then either switching to gla ( gla - s ) or continuing with det ( det - c ) . within each cohort , 
 treatment groups were propensity - score - matched on baseline characteristics . at 1-year follow - up , insulin treatment patterns , glycated haemoglobin ( hba1c ) levels , hypoglycaemic events , weight and body mass index ( bmi ) were evaluated.resultsthe analysis included 13  942 patients : cohort 1 : 
 n  =  10  657 ( det - s , n  =  1797 matched to gla - c , n  =  8860 ) and cohort 2 : n  =  3285 ( gla - s , n  =  858 matched to det - c , n  =  2427 ) . 
 baseline characteristics were similar between the treatment groups in each cohort . at 1-year follow - up , in cohort 1 , patients in the det - s subgroup were significantly less persistent with treatment , more likely to use a rapid - acting insulin analogue , had higher hba1c values , lower hba1c reductions and lower proportions of patients achieving hba1c < 7.0 or < 8.0% compared with patients in the gla - c subgroup , while hypoglycaemia rates and bmi / weight values and change from baseline were similar in the two subgroups . in cohort 2 , 
 overall , there were contrasting findings between patients in the gla - s and those in the det - c subgroup.conclusionsthis study showed contrasting results when patients with t2 dm switched between basal insulin analogues , although these preliminary results may be subject to limitations in the analysis . 
 nevertheless , this study calls into question the therapeutic interchangeability of gla and det , and this merits further investigation . 