this was a randomized , placebo - controlled , double - blind phase iii study conducted from july 2010 to february 2012 in 148 centers in 12 countries ( canada , china , france , germany , india , korea , mexico , slovakia , slovenia , taiwan , turkey , and the u.s . ) .
the clinical trial protocol was approved by the institutional review boards and independent ethics committees and competent authorities of the participating centers , and the trial complied with the declaration of helsinki , in accordance with the international conference on harmonization harmonized tripartite guideline for good clinical practice .
this study enrolled patients ( aged 18 years ; bmi 45 kg / m ) with inadequately controlled type 2 diabetes ( hba1c 7 to 10% ) despite a diet and exercise program and a stable regimen ( unchanged for 12 weeks prior to randomization ) of metformin immediate release plus a sulfonylurea .
patients with hba1c > 10% were eligible to participate in an open - label treatment arm .
exclusion criteria included uncontrolled hyperglycemia ( glucose level > 13.3 mmol / l ) after an overnight fast , confirmed by a second measurement ) , acute coronary syndrome , stroke or transient ischemic attack within 3 months prior to consent , indication of liver disease , impaired kidney function ( estimated glomerular filtration rate [ egfr ] < 30 ml / min/1.73 m ) during screening or run - in , contraindications to metformin or sulfonylurea according to the local label , gastrointestinal surgeries that induce chronic malabsorption , history of cancer ( except basal cell carcinoma ) or treatment for cancer within 5 years , blood dyscrasias or any disorders causing hemolysis or unstable erythrocytes , treatment with antiobesity drugs 3 months prior to consent , use of any treatment at screening that leads to unstable body weight , treatment with systemic steroids at time of consent , change in dosage of thyroid hormones within 6 weeks of consent , alcohol or drug abuse within 3 months of consent , and investigational drug intake within 30 days of the trial .
after a 2-week open - label placebo run - in period , eligible patients were randomized ( 1:1:1 ) to receive once - daily ( in the morning with water ) empagliflozin 10 mg , empagliflozin 25 mg , or placebo as add - on therapy to metformin ( 1,500 mg / day or maximum tolerated dose or maximum dose according to local label ) plus a sulfonylurea ( greater than or equal to half the maximum recommended dose , or the maximum tolerated dose , or the maximum dose according to local label ) for 24 weeks .
randomization was performed using a third - party interactive voice and web response system and was stratified by hba1c ( < 8.5 and 8.5% ) , egfr ( 90 , 6089 , and 3059 ml / min/1.73 m ; modification of diet in renal disease equation ) , and region ( europe , asia , north america , and latin america ) .
patients allocated to the open - label arm received empagliflozin 25 mg for 24 weeks without run - in .
study visits were scheduled at screening ; at the start of the placebo run - in period ( randomized patients only ) ; and at weeks 0 , 6 , 12 , 18 , and 24 .
rescue medication was initiated during the treatment period if , between weeks 1 and 12 , a patient had a glucose level > 13.3
mmol / l after an overnight fast or , between weeks 12 and 24 , a patient had a glucose level > 11.1 mmol / l after an overnight fast or hba1c > 8.5% .
the initiation , choice , and dosage of rescue medication were at the investigator s discretion , according to local prescribing information . in cases of hypoglycemia ,
rescue medication was reduced or discontinued . where hyper- or hypoglycemia could not be controlled , the patient was discontinued from the trial .
key secondary end points were change from baseline to week 24 in body weight and mean daily glucose ( mdg ) using an 8-point blood glucose profile .
exploratory end points included the following : percentage of patients with baseline hba1c 7.0% who had hba1c < 7% at week 24 ; change from baseline in fasting plasma glucose ( fpg ) , waist circumference , and systolic and diastolic blood pressure ( sbp and dbp ) at week 24 ; percentage of patients with > 5% reduction in body weight at week 24 ; and use of rescue medication .
change from baseline in 2-h postprandial glucose ( ppg ) was assessed in a subset of patients based on a meal tolerance test ( mtt ) performed at baseline and week 24 .
safety end points included vital signs , clinical laboratory parameters , 12-lead electrocardiogram , and adverse events ( aes ; preferred terms coded according to the medical dictionary for drug regulatory activities version 14.1 ) .
aes included all events with an onset after the first dose of trial medication up to a period of 7 days after the last dose .
mmol / l and/or requiring assistance ) and events consistent with urinary tract infection ( uti ) and genital infection .
events consistent with uti and genital infection were identified from aes reported spontaneously by the investigator using prospectively defined search categories based on 67 and 87 preferred terms , respectively .
efficacy analysis was performed on the full analysis set ( fas ) , which included all randomized patients treated with one or more doses of study drug who had a baseline hba1c value .
two - hour ppg was analyzed in the mtt set ( patients in the fas with valid baseline and one or more on - treatment mtt measurements ) .
safety and lipid parameters were analyzed in the treated set ( patients treated with one or more doses of study drug ) .
the last observation carried forward ( locf ) approach was used to impute missing continuous efficacy data .
locf - ir imputation ( i.e. , locf without setting values after rescue therapy to missing ) was used for analysis of lipid parameters .
analyses of efficacy end points in the open - label set were based on oc .
the primary end point was assessed using an ancova model , with treatment , region , and egfr at baseline as fixed effects and baseline hba1c as a linear covariate .
key secondary and continuous exploratory end points were analyzed using the statistical model described for the primary end point , with the baseline value for the end point in question as an additional linear covariate .
changes over time in hba1c , fpg , and blood pressure were analyzed using restricted maximum likelihood  based mixed model repeated measures .
categorical change in hba1c and the proportion of patients with > 5% weight loss were analyzed using logistic regression .
treatment differences versus placebo in primary and key secondary end points were tested using a hierarchical testing approach for each dose at a significance level of 2.5% ( two sided ) to maintain the overall type i error at 5% .
all other exploratory tests were two sided at a 5% level ( no multiplicity adjustment ) .
safety analyses and analyses of efficacy end points in the open - label group were descriptive .
further details on statistical analysis including sample size calculation are given in supplementary section 1 .
this was a randomized , placebo - controlled , double - blind phase iii study conducted from july 2010 to february 2012 in 148 centers in 12 countries ( canada , china , france , germany , india , korea , mexico , slovakia , slovenia , taiwan , turkey , and the u.s . ) .
the clinical trial protocol was approved by the institutional review boards and independent ethics committees and competent authorities of the participating centers , and the trial complied with the declaration of helsinki , in accordance with the international conference on harmonization harmonized tripartite guideline for good clinical practice .
this study enrolled patients ( aged 18 years ; bmi 45 kg / m ) with inadequately controlled type 2 diabetes ( hba1c 7 to 10% ) despite a diet and exercise program and a stable regimen ( unchanged for 12 weeks prior to randomization ) of metformin immediate release plus a sulfonylurea .
patients with hba1c > 10% were eligible to participate in an open - label treatment arm .
exclusion criteria included uncontrolled hyperglycemia ( glucose level > 13.3 mmol / l ) after an overnight fast , confirmed by a second measurement ) , acute coronary syndrome , stroke or transient ischemic attack within 3 months prior to consent , indication of liver disease , impaired kidney function ( estimated glomerular filtration rate [ egfr ] < 30 ml / min/1.73 m ) during screening or run - in , contraindications to metformin or sulfonylurea according to the local label , gastrointestinal surgeries that induce chronic malabsorption , history of cancer ( except basal cell carcinoma ) or treatment for cancer within 5 years , blood dyscrasias or any disorders causing hemolysis or unstable erythrocytes , treatment with antiobesity drugs 3 months prior to consent , use of any treatment at screening that leads to unstable body weight , treatment with systemic steroids at time of consent , change in dosage of thyroid hormones within 6 weeks of consent , alcohol or drug abuse within 3 months of consent , and investigational drug intake within 30 days of the trial .
after a 2-week open - label placebo run - in period , eligible patients were randomized ( 1:1:1 ) to receive once - daily ( in the morning with water ) empagliflozin 10 mg , empagliflozin 25 mg , or placebo as add - on therapy to metformin ( 1,500 mg / day or maximum tolerated dose or maximum dose according to local label ) plus a sulfonylurea ( greater than or equal to half the maximum recommended dose , or the maximum tolerated dose , or the maximum dose according to local label ) for 24 weeks .
randomization was performed using a third - party interactive voice and web response system and was stratified by hba1c ( < 8.5 and 8.5% ) , egfr ( 90 , 6089 , and 3059 ml / min/1.73 m ; modification of diet in renal disease equation ) , and region ( europe , asia , north america , and latin america ) .
patients allocated to the open - label arm received empagliflozin 25 mg for 24 weeks without run - in .
study visits were scheduled at screening ; at the start of the placebo run - in period ( randomized patients only ) ; and at weeks 0 , 6 , 12 , 18 , and 24 .
rescue medication was initiated during the treatment period if , between weeks 1 and 12 , a patient had a glucose level > 13.3 mmol / l after an overnight fast or , between weeks 12 and 24 , a patient had a glucose level > 11.1 mmol / l after an overnight fast or hba1c > 8.5% .
the initiation , choice , and dosage of rescue medication were at the investigator s discretion , according to local prescribing information . in cases of hypoglycemia ,
rescue medication was reduced or discontinued . where hyper- or hypoglycemia could not be controlled , the patient was discontinued from the trial .
key secondary end points were change from baseline to week 24 in body weight and mean daily glucose ( mdg ) using an 8-point blood glucose profile .
exploratory end points included the following : percentage of patients with baseline hba1c 7.0% who had hba1c < 7% at week 24 ; change from baseline in fasting plasma glucose ( fpg ) , waist circumference , and systolic and diastolic blood pressure ( sbp and dbp ) at week 24 ; percentage of patients with > 5% reduction in body weight at week 24 ; and use of rescue medication .
change from baseline in 2-h postprandial glucose ( ppg ) was assessed in a subset of patients based on a meal tolerance test ( mtt ) performed at baseline and week 24 .
safety end points included vital signs , clinical laboratory parameters , 12-lead electrocardiogram , and adverse events ( aes ; preferred terms coded according to the medical dictionary for drug regulatory activities version 14.1 ) .
aes included all events with an onset after the first dose of trial medication up to a period of 7 days after the last dose .
aes of special interest included confirmed hypoglycemic aes ( plasma glucose 3.9 mmol / l and/or requiring assistance ) and events consistent with urinary tract infection ( uti ) and genital infection .
events consistent with uti and genital infection were identified from aes reported spontaneously by the investigator using prospectively defined search categories based on 67 and 87 preferred terms , respectively .
efficacy analysis was performed on the full analysis set ( fas ) , which included all randomized patients treated with one or more doses of study drug who had a baseline hba1c value .
two - hour ppg was analyzed in the mtt set ( patients in the fas with valid baseline and one or more on - treatment mtt measurements ) .
safety and lipid parameters were analyzed in the treated set ( patients treated with one or more doses of study drug ) .
the last observation carried forward ( locf ) approach was used to impute missing continuous efficacy data .
locf - ir imputation ( i.e. , locf without setting values after rescue therapy to missing ) was used for analysis of lipid parameters .
analyses of efficacy end points in the open - label set were based on oc .
the primary end point was assessed using an ancova model , with treatment , region , and egfr at baseline as fixed effects and baseline hba1c as a linear covariate .
key secondary and continuous exploratory end points were analyzed using the statistical model described for the primary end point , with the baseline value for the end point in question as an additional linear covariate .
changes over time in hba1c , fpg , and blood pressure were analyzed using restricted maximum likelihood  based mixed model repeated measures .
categorical change in hba1c and the proportion of patients with > 5% weight loss were analyzed using logistic regression .
treatment differences versus placebo in primary and key secondary end points were tested using a hierarchical testing approach for each dose at a significance level of 2.5% ( two sided ) to maintain the overall type i error at 5% .
all other exploratory tests were two sided at a 5% level ( no multiplicity adjustment ) .
safety analyses and analyses of efficacy end points in the open - label group were descriptive .
further details on statistical analysis including sample size calculation are given in supplementary section 1 .
a total of 669 patients were randomized , of whom 666 patients were treated double blind with study medication and comprised the fas .
overall , 91.3% of randomized and treated patients completed the treatment period . a further 101 patients with hba1c > 10% were treated with open - label empagliflozin 25 mg , and 84.2% of these patients completed the treatment period .
two - hour ppg was evaluated in a subset of 124 patients ( placebo , n = 35 ; empagliflozin 10 mg , n = 43 ; empagliflozin 25 mg , n = 46 ) .
the mean ( sd ) age of randomized patients was 57.1 years ( 9.2 ) ; mean ( sd ) bmi was 28.2 kg / m ( 5.3 ) .
mean ( sd ) baseline hba1c in the randomized groups was 8.10% ( 0.83 ) , 49.1% had a baseline hba1c < 8.0% , and 16.4% had a baseline hba1c 9.0% .
patient demographics and baseline characteristics adjusted mean hba1c levels over the 24-week treatment period are shown in fig .
reductions in hba1c after 24 weeks were significantly greater in empagliflozin groups than in the placebo group , with adjusted mean ( se ) changes of 0.17% ( 0.05 ) for placebo , compared with 0.82% ( 0.05 ) for empagliflozin 10 mg and 0.77% ( 0.05 ) for empagliflozin 25 mg ( differences of adjusted means vs. placebo were 0.64% [ 95% ci 0.77 to 0.51 ] for empagliflozin 10 mg and 0.59% [ 0.73 to 0.46 ] for empagliflozin 25 mg ; p < 0.001 for both doses ) ( fig .
, a greater proportion of patients treated with empagliflozin 10 and 25 mg reached hba1c < 7.0% at week 24 ( 26.3 and 32.2% , respectively ) compared with placebo ( 9.3% ) ; odds ratios versus placebo were 3.85 ( 95% ci 2.176.85 ) for empagliflozin 10 mg and 5.22 ( 2.959.24 ) for empagliflozin 25 mg ; p < 0.001 for both doses
1a , and supplementary table 1 ) . in the subgroups of patients with normal renal function ( egfr 90 ml / min/1.73 m ) ,
mild renal impairment ( egfr 60 to < 90 ml / min/1.73 m ) , and moderate renal impairment ( egfr 30 to < 60 ml / min/1.73 m ) , empagliflozin reduced hba1c at week 24 versus placebo ( p < 0.01 for each renal function subgroup ) ( supplementary table 2 )
a : hba1c over time in randomized groups ( mixed model repeated measures , fas , and oc ) .
b : change from baseline in hba1c at week 24 in randomized groups ( ancova , fas , and locf imputation ) .
c : hba1c over time in the open - label treatment group ( oc and descriptive statistics ) .
d : change from baseline in mdg at week 24 in randomized groups ( ancova , fas , and oc ) .
e : change from baseline in weight at week 24 ( ancova , fas , and locf ) .
f : change from baseline in sbp at week 24 ( ancova , fas , and locf ) .
g : change from baseline in dbp at week 24 ( ancova , fas , and locf ) .
data are adjusted mean ( se ) for randomized groups and mean ( se ) for open - label treatment group . *
p < 0.001 vs. placebo ; p = 0.032 vs. placebo ; p = 0.005 vs. placebo ; 
p = 0.557 vs. placebo ; p = 0.534 vs. placebo . adjusted mean ( se ) changes in mdg from baseline to week 24 using locf imputation
mmol / l ( 0.10 ) for empagliflozin 10 mg and 0.72 mmol / l ( 0.11 ) for empagliflozin 25 mg ( differences of adjusted means vs. placebo were 0.56
mmol / l [ 95% ci 0.83 to 0.28 ] for empagliflozin 10 mg and 0.72
mmol / l [ 1.02 to 0.43 ] for empagliflozin 25 mg ; p < 0.001 for both doses ) ( supplementary table 1 ) . as 46.9% of analyzed patients
had missing or invalid mdg measurements at week 24 and therefore had their baseline values carried forward according to the locf imputation method , results based on the prespecified oc analysis may more accurately reflect the treatment effect of empagliflozin on mdg . here , the adjusted mean ( se ) changes from baseline to week 24 were 0.03 mmol / l ( 0.17 ) with placebo vs. 1.05 mmol / l ( 0.15 ) with empagliflozin 10 mg ( p < 0.001 ) and 1.14
mmol / l ( 0.16 ) with empagliflozin 25 mg ( differences of adjusted means vs. placebo were 1.08
mmol / l [ 95% ci 1.53 to 0.62 ] for empagliflozin 10 mg and 1.17
mmol / l [ 1.64 to 0.70 ] for empagliflozin 25 mg ; p < 0.001 for both doses ) ( fig .
1d ) were significantly greater in the empagliflozin 10 and 25 mg groups than in the placebo group at week 24 ( supplementary table 1 ) .
further data on the effect of empagliflozin and placebo on these end points are given in supplementary section 2 .
treatment with empagliflozin resulted in a significantly greater reduction in body weight compared with placebo at week 24 , with adjusted mean ( se ) changes from baseline of 0.39 kg ( 0.15 ) with placebo compared with 2.16 kg ( 0.15 ) with empagliflozin 10 mg and 2.39 kg ( 0.16 ) with empagliflozin 25 mg ( differences of adjusted means vs. placebo were 1.76 kg [ 95% ci 2.19 to 1.34 ] for empagliflozin 10 mg and 1.99 kg [ 2.42 to 1.56 ] for empagliflozin 25 mg ; p < 0.001 for both doses ) ( fig
the proportion of patients with > 5% reduction in body weight at week 24 was significantly greater with empagliflozin 10 mg ( 27.6% ) and empagliflozin 25 mg ( 23.6% ) than with placebo ( 5.8% ; odds ratios vs. placebo were 6.36 [ 95% ci 3.3612.02 ] for empagliflozin 10 mg and 5.19 [ 2.729.91 ] for empagliflozin 25 mg ; p < 0.001 for both doses ) ( supplementary fig
the reduction in body weight in patients on empagliflozin 10 and 25 mg was accompanied by significant decreases in waist circumference at week 24 ( adjusted mean [ se ] changes of 1.46 cm [ 0.27 ] and 1.48 cm [ 0.28 ] , respectively ) versus placebo ( 0.31 cm [ 0.28 ] ; differences of adjusted means vs. placebo were 1.15 cm [ 95% ci 1.92 to 0.39 ] for empagliflozin 10 mg and 1.17 cm [ 1.94 to 0.40 ] for empagliflozin 25 mg ; p = 0.003 for both doses ) ( supplementary fig
the adjusted mean ( se ) change from baseline at week 24 was 1.4 mmhg ( 0.7 ) with placebo compared with 4.1 mmhg ( 0.7 ) with empagliflozin 10 mg ( difference vs. placebo : 2.7 mmhg [ 95% ci 4.6 to 0.8 ] ; p = 0.005 ) and 3.5 mmhg ( 0.7 ) with empagliflozin 25 mg ( difference vs. placebo : 2.1 mmhg [ 4.0 to 0.2 ] ; p = 0.032 ) ( fig .
changes from baseline in dbp with empagliflozin were not significant at week 24 compared with placebo ( fig . 2 g and supplementary table 4 ) . in total , 33 patients ( 5.0% ) in the randomized groups received rescue therapy .
more patients received rescue therapy in the placebo group ( 26 patients [ 11.6% ] ) than in the randomized empagliflozin groups ( 5 patients [ 2.2% ] on 10 mg , 2 patients [ 0.9% ] on 25 mg ) .
of the seven patients who required rescue medication while receiving empagliflozin , five patients received a thiazolidinedione ( four patients on empagliflozin 10 mg and one patient on empagliflozin 25 mg ) and two patients received an -glucosidase inhibitor ( one patient on each dose ) .
the changes in hba1c over time in the open - label group ( baseline hba1c > 10% ) are given in fig .
the mean ( se ) change from baseline in hba1c at week 24 was 2.89% ( 0.16 ) .
a total of 8.9% of patients achieved hba1c < 7.0% at week 24 ( supplementary table 1 ) . at week 24 , the mean ( se ) changes from baseline in mdg and fpg were 3.39
mmol / l ( 0.58 ) and 3.02 mmol / l ( 0.37 ) , respectively ; mean ( se ) change in body weight was 1.76 kg ( 0.40 ) , and mean ( se ) change in waist circumference was 1.36 cm ( 0.54 ) . a total of 18.8% of patients achieved a > 5% reduction in body weight at week 24 .
changes ( se ) from baseline in sbp and dbp were 4.3 mmhg ( 1.2 ) and 3.4 mmhg ( 1.0 ) , respectively .
most ( 96% ) of patients with one or more ae reported only events of mild or moderate intensity .
one patient in the empagliflozin 10 mg group died during the study due to an acute myocardial infarction , which was assessed as not being related to the study drug by the investigator . confirmed hypoglycemic aes were reported by more patients in the empagliflozin 10 mg ( n = 36 ; 16.1% ) and 25 mg ( n = 25 ; 11.5% ) groups than with placebo ( n = 19 ; 8.4% ) .
events consistent with uti were reported in 8.0% of patients on placebo , similar to the proportion on empagliflozin 25 mg ( 8.3% ) and slightly lower than the proportion on empagliflozin 10 mg ( 10.3% ) .
the majority of events consistent with uti were mild in intensity , none was severe , and only one such event led to study discontinuation .
most patients who reported any events consistent with uti reported just one event ; two patients in the empagliflozin 10 mg group and two patients in the empagliflozin 25 mg group reported two events .
events consistent with uti were reported considerably more frequently in female patients ( 13.318.0% ) than in male patients ( 0.02.7% ) .
the proportion of patients who reported events consistent with genital infection was low , but higher with empagliflozin than with placebo ( 2.32.7 vs. 0.9% ) .
all but one patient ( in the placebo group ) who reported any events consistent with genital infection reported just one event .
events consistent with genital infection were reported more frequently in female patients ( 0.94.5% ) than in male patients ( 0.9% ) . in the open - label group , confirmed hypoglycemic events were reported for seven patients ( 6.9% ) .
events consistent with uti were reported for three patients ( 3.0% ) , and events consistent with genital infection were reported for two patients ( 2.0% ) .
changes in laboratory values ( electrolytes , hematocrit , and lipid parameters ) are presented in supplementary table 5 .
there were small increases in hematocrit and small decreases in uric acid levels in the randomized empagliflozin groups .
there was a small increase from baseline in hdl cholesterol with empagliflozin 10 and 25 mg ( mean [ se ] , 0.05 mmol / l [ 0.01 ] for both doses ) compared with placebo ( 0.02
no major differences in mean ( se ) changes from baseline in ldl cholesterol or triglycerides were noted between placebo and empagliflozin .
a total of 669 patients were randomized , of whom 666 patients were treated double blind with study medication and comprised the fas .
overall , 91.3% of randomized and treated patients completed the treatment period . a further 101 patients with hba1c > 10% were treated with open - label empagliflozin 25 mg , and 84.2% of these patients completed the treatment period .
two - hour ppg was evaluated in a subset of 124 patients ( placebo , n = 35 ; empagliflozin 10 mg , n = 43 ; empagliflozin 25 mg , n = 46 ) .
the mean ( sd ) age of randomized patients was 57.1 years ( 9.2 ) ; mean ( sd ) bmi was 28.2 kg / m ( 5.3 ) .
mean ( sd ) baseline hba1c in the randomized groups was 8.10% ( 0.83 ) , 49.1% had a baseline hba1c < 8.0% , and 16.4% had a baseline hba1c 9.0% .
reductions in hba1c after 24 weeks were significantly greater in empagliflozin groups than in the placebo group , with adjusted mean ( se ) changes of 0.17% ( 0.05 ) for placebo , compared with 0.82% ( 0.05 ) for empagliflozin 10 mg and 0.77% ( 0.05 ) for empagliflozin 25 mg ( differences of adjusted means vs. placebo were 0.64% [ 95% ci 0.77 to 0.51 ] for empagliflozin 10 mg and 0.59% [ 0.73 to 0.46 ] for empagliflozin 25 mg ; p < 0.001 for both doses ) ( fig .
, a greater proportion of patients treated with empagliflozin 10 and 25 mg reached hba1c < 7.0% at week 24 ( 26.3 and 32.2% , respectively ) compared with placebo ( 9.3% ) ; odds ratios versus placebo were 3.85 ( 95% ci 2.176.85 ) for empagliflozin 10 mg and 5.22 ( 2.959.24 ) for empagliflozin 25 mg ; p < 0.001 for both doses
1a , and supplementary table 1 ) . in the subgroups of patients with normal renal function ( egfr 90 ml / min/1.73 m ) ,
mild renal impairment ( egfr 60 to < 90 ml / min/1.73 m ) , and moderate renal impairment ( egfr 30 to < 60 ml / min/1.73 m ) , empagliflozin reduced hba1c at week 24 versus placebo ( p < 0.01 for each renal function subgroup ) ( supplementary table 2 )
a : hba1c over time in randomized groups ( mixed model repeated measures , fas , and oc ) .
b : change from baseline in hba1c at week 24 in randomized groups ( ancova , fas , and locf imputation ) .
c : hba1c over time in the open - label treatment group ( oc and descriptive statistics ) .
d : change from baseline in mdg at week 24 in randomized groups ( ancova , fas , and oc ) .
e : change from baseline in weight at week 24 ( ancova , fas , and locf ) .
f : change from baseline in sbp at week 24 ( ancova , fas , and locf ) .
g : change from baseline in dbp at week 24 ( ancova , fas , and locf ) .
data are adjusted mean ( se ) for randomized groups and mean ( se ) for open - label treatment group .
* p < 0.001 vs. placebo ; p = 0.032 vs. placebo ; p = 0.005 vs. placebo ;  p = 0.557 vs. placebo ; p = 0.534 vs. placebo .
adjusted mean ( se ) changes in mdg from baseline to week 24 using locf imputation were 0.00 mmol / l ( 0.10 ) for placebo , compared with 0.56
mmol / l ( 0.10 ) for empagliflozin 10 mg and 0.72 mmol / l ( 0.11 ) for empagliflozin 25 mg ( differences of adjusted means vs. placebo were 0.56
mmol / l [ 95% ci 0.83 to 0.28 ] for empagliflozin 10 mg and 0.72
mmol / l [ 1.02 to 0.43 ] for empagliflozin 25 mg ; p < 0.001 for both doses ) ( supplementary table 1 ) . as 46.9% of analyzed patients
had missing or invalid mdg measurements at week 24 and therefore had their baseline values carried forward according to the locf imputation method , results based on the prespecified oc analysis may more accurately reflect the treatment effect of empagliflozin on mdg . here
, the adjusted mean ( se ) changes from baseline to week 24 were 0.03 mmol / l ( 0.17 ) with placebo vs. 1.05 mmol / l ( 0.15 ) with empagliflozin 10 mg ( p < 0.001 ) and 1.14
mmol / l ( 0.16 ) with empagliflozin 25 mg ( differences of adjusted means vs. placebo were 1.08
mmol / l [ 95% ci 1.53 to 0.62 ] for empagliflozin 10 mg and 1.17 mmol / l [ 1.64 to 0.70 ] for empagliflozin 25 mg ; p < 0.001 for both doses ) ( fig .
reductions in fpg ( supplementary fig . 1b and c ) and 2-h ppg ( supplementary fig .
1d ) were significantly greater in the empagliflozin 10 and 25 mg groups than in the placebo group at week 24 ( supplementary table 1 ) .
further data on the effect of empagliflozin and placebo on these end points are given in supplementary section 2 .
treatment with empagliflozin resulted in a significantly greater reduction in body weight compared with placebo at week 24 , with adjusted mean ( se ) changes from baseline of 0.39 kg ( 0.15 ) with placebo compared with 2.16 kg ( 0.15 ) with empagliflozin 10 mg and 2.39 kg ( 0.16 ) with empagliflozin 25 mg ( differences of adjusted means vs. placebo were 1.76 kg [ 95% ci 2.19 to 1.34 ] for empagliflozin 10 mg and 1.99 kg [ 2.42 to 1.56 ] for empagliflozin 25 mg ; p < 0.001 for both doses ) ( fig .
the proportion of patients with > 5% reduction in body weight at week 24 was significantly greater with empagliflozin 10 mg ( 27.6% ) and empagliflozin 25 mg ( 23.6% ) than with placebo ( 5.8% ; odds ratios vs. placebo were 6.36 [ 95% ci 3.3612.02 ] for empagliflozin 10 mg and 5.19 [ 2.729.91 ] for empagliflozin 25 mg ; p < 0.001 for both doses ) ( supplementary fig
the reduction in body weight in patients on empagliflozin 10 and 25 mg was accompanied by significant decreases in waist circumference at week 24 ( adjusted mean [ se ] changes of 1.46 cm [ 0.27 ] and 1.48 cm [ 0.28 ] , respectively ) versus placebo ( 0.31 cm [ 0.28 ] ; differences of adjusted means vs. placebo were 1.15 cm [ 95% ci 1.92 to 0.39 ] for empagliflozin 10 mg and 1.17 cm [ 1.94 to 0.40 ] for empagliflozin 25 mg ; p = 0.003 for both doses ) ( supplementary fig
the adjusted mean ( se ) change from baseline at week 24 was 1.4 mmhg ( 0.7 ) with placebo compared with 4.1 mmhg ( 0.7 ) with empagliflozin 10 mg ( difference vs. placebo : 2.7 mmhg [ 95% ci 4.6 to 0.8 ] ; p = 0.005 ) and 3.5 mmhg ( 0.7 ) with empagliflozin 25 mg ( difference vs. placebo : 2.1 mmhg [ 4.0 to 0.2 ] ; p = 0.032 ) ( fig .
changes from baseline in dbp with empagliflozin were not significant at week 24 compared with placebo ( fig . 2 g and supplementary table 4 ) . in total , 33 patients ( 5.0% ) in the randomized groups received rescue therapy .
more patients received rescue therapy in the placebo group ( 26 patients [ 11.6% ] ) than in the randomized empagliflozin groups ( 5 patients [ 2.2% ] on 10 mg , 2 patients [ 0.9% ] on 25 mg ) .
of the seven patients who required rescue medication while receiving empagliflozin , five patients received a thiazolidinedione ( four patients on empagliflozin 10 mg and one patient on empagliflozin 25 mg ) and two patients received an -glucosidase inhibitor ( one patient on each dose ) .
the changes in hba1c over time in the open - label group ( baseline hba1c > 10% ) are given in fig .
the mean ( se ) change from baseline in hba1c at week 24 was 2.89% ( 0.16 ) .
a total of 8.9% of patients achieved hba1c < 7.0% at week 24 ( supplementary table 1 ) . at week 24 , the mean ( se ) changes from baseline in mdg and fpg were 3.39
mmol / l ( 0.58 ) and 3.02 mmol / l ( 0.37 ) , respectively ; mean ( se ) change in body weight was 1.76 kg ( 0.40 ) , and mean ( se ) change in waist circumference was 1.36 cm ( 0.54 ) .
a total of 18.8% of patients achieved a > 5% reduction in body weight at week 24 .
changes ( se ) from baseline in sbp and dbp were 4.3 mmhg ( 1.2 ) and 3.4 mmhg ( 1.0 ) , respectively .
reductions in hba1c after 24 weeks were significantly greater in empagliflozin groups than in the placebo group , with adjusted mean ( se ) changes of 0.17% ( 0.05 ) for placebo , compared with 0.82% ( 0.05 ) for empagliflozin 10 mg and 0.77% ( 0.05 ) for empagliflozin 25 mg ( differences of adjusted means vs. placebo were 0.64% [ 95% ci 0.77 to 0.51 ] for empagliflozin 10 mg and 0.59% [ 0.73 to 0.46 ] for empagliflozin 25 mg ; p < 0.001 for both doses ) ( fig .
, a greater proportion of patients treated with empagliflozin 10 and 25 mg reached hba1c < 7.0% at week 24 ( 26.3 and 32.2% , respectively ) compared with placebo ( 9.3% ) ; odds ratios versus placebo were 3.85 ( 95% ci 2.176.85 ) for empagliflozin 10 mg and 5.22 ( 2.959.24 ) for empagliflozin 25 mg ; p < 0.001 for both doses
1a , and supplementary table 1 ) . in the subgroups of patients with normal renal function ( egfr 90 ml / min/1.73 m ) ,
mild renal impairment ( egfr 60 to < 90 ml / min/1.73 m ) , and moderate renal impairment ( egfr 30 to < 60 ml / min/1.73 m ) , empagliflozin reduced hba1c at week 24 versus placebo ( p < 0.01 for each renal function subgroup ) ( supplementary table 2 )
a : hba1c over time in randomized groups ( mixed model repeated measures , fas , and oc ) .
b : change from baseline in hba1c at week 24 in randomized groups ( ancova , fas , and locf imputation ) .
c : hba1c over time in the open - label treatment group ( oc and descriptive statistics ) .
d : change from baseline in mdg at week 24 in randomized groups ( ancova , fas , and oc ) .
e : change from baseline in weight at week 24 ( ancova , fas , and locf ) .
f : change from baseline in sbp at week 24 ( ancova , fas , and locf ) .
g : change from baseline in dbp at week 24 ( ancova , fas , and locf ) .
data are adjusted mean ( se ) for randomized groups and mean ( se ) for open - label treatment group .
* p < 0.001 vs. placebo ; p = 0.032 vs. placebo ; p = 0.005 vs. placebo ;  p = 0.557 vs. placebo ; p = 0.534 vs. placebo .
adjusted mean ( se ) changes in mdg from baseline to week 24 using locf imputation were 0.00 mmol / l ( 0.10 ) for placebo , compared with 0.56
mmol / l ( 0.10 ) for empagliflozin 10 mg and 0.72 mmol / l ( 0.11 ) for empagliflozin 25 mg ( differences of adjusted means vs. placebo were 0.56
mmol / l [ 95% ci 0.83 to 0.28 ] for empagliflozin 10 mg and 0.72
mmol / l [ 1.02 to 0.43 ] for empagliflozin 25 mg ; p < 0.001 for both doses ) ( supplementary table 1 ) . as 46.9% of analyzed patients
had missing or invalid mdg measurements at week 24 and therefore had their baseline values carried forward according to the locf imputation method , results based on the prespecified oc analysis may more accurately reflect the treatment effect of empagliflozin on mdg . here
, the adjusted mean ( se ) changes from baseline to week 24 were 0.03 mmol / l ( 0.17 ) with placebo vs. 1.05 mmol / l ( 0.15 ) with empagliflozin 10 mg ( p < 0.001 ) and 1.14
mmol / l ( 0.16 ) with empagliflozin 25 mg ( differences of adjusted means vs. placebo were 1.08
mmol / l [ 95% ci 1.53 to 0.62 ] for empagliflozin 10 mg and 1.17 mmol / l [ 1.64 to 0.70 ] for empagliflozin 25 mg ; p < 0.001 for both doses ) ( fig .
reductions in fpg ( supplementary fig . 1b and c ) and 2-h ppg ( supplementary fig .
1d ) were significantly greater in the empagliflozin 10 and 25 mg groups than in the placebo group at week 24 ( supplementary table 1 ) .
further data on the effect of empagliflozin and placebo on these end points are given in supplementary section 2 .
treatment with empagliflozin resulted in a significantly greater reduction in body weight compared with placebo at week 24 , with adjusted mean ( se ) changes from baseline of 0.39 kg ( 0.15 ) with placebo compared with 2.16 kg ( 0.15 ) with empagliflozin 10 mg and 2.39 kg ( 0.16 ) with empagliflozin 25 mg ( differences of adjusted means vs. placebo were 1.76 kg [ 95% ci 2.19 to 1.34 ] for empagliflozin 10 mg and 1.99 kg [ 2.42 to 1.56 ] for empagliflozin 25 mg ; p < 0.001 for both doses ) ( fig .
the proportion of patients with > 5% reduction in body weight at week 24 was significantly greater with empagliflozin 10 mg ( 27.6% ) and empagliflozin 25 mg ( 23.6% ) than with placebo ( 5.8% ; odds ratios vs. placebo were 6.36 [ 95% ci 3.3612.02 ] for empagliflozin 10 mg and 5.19 [ 2.729.91 ] for empagliflozin 25 mg ; p < 0.001 for both doses ) ( supplementary fig
the reduction in body weight in patients on empagliflozin 10 and 25 mg was accompanied by significant decreases in waist circumference at week 24 ( adjusted mean [ se ] changes of 1.46 cm [ 0.27 ] and 1.48 cm [ 0.28 ] , respectively ) versus placebo ( 0.31 cm [ 0.28 ] ; differences of adjusted means vs. placebo were 1.15 cm [ 95% ci 1.92 to 0.39 ] for empagliflozin 10 mg and 1.17 cm [ 1.94 to 0.40 ] for empagliflozin 25 mg ; p = 0.003 for both doses ) ( supplementary fig
the adjusted mean ( se ) change from baseline at week 24 was 1.4 mmhg ( 0.7 ) with placebo compared with 4.1 mmhg ( 0.7 ) with empagliflozin 10 mg ( difference vs. placebo : 2.7 mmhg [ 95% ci 4.6 to 0.8 ] ; p = 0.005 ) and 3.5 mmhg ( 0.7 ) with empagliflozin 25 mg ( difference vs. placebo : 2.1 mmhg [ 4.0 to 0.2 ] ; p = 0.032 ) ( fig .
changes from baseline in dbp with empagliflozin were not significant at week 24 compared with placebo ( fig . 2 g and supplementary table 4 ) . in total , 33 patients ( 5.0% ) in the randomized groups received rescue therapy .
more patients received rescue therapy in the placebo group ( 26 patients [ 11.6% ] ) than in the randomized empagliflozin groups ( 5 patients [ 2.2% ] on 10 mg , 2 patients [ 0.9% ] on 25 mg ) .
of the seven patients who required rescue medication while receiving empagliflozin , five patients received a thiazolidinedione ( four patients on empagliflozin 10 mg and one patient on empagliflozin 25 mg ) and two patients received an -glucosidase inhibitor ( one patient on each dose ) .
the changes in hba1c over time in the open - label group ( baseline hba1c > 10% ) are given in fig .
a total of 8.9% of patients achieved hba1c < 7.0% at week 24 ( supplementary table 1 ) . at week 24 , the mean ( se ) changes from baseline in mdg and fpg were 3.39 mmol / l ( 0.58 ) and 3.02 mmol / l ( 0.37 ) , respectively ; mean ( se ) change in body weight was 1.76 kg ( 0.40 ) , and mean ( se ) change in waist circumference was 1.36 cm ( 0.54 ) .
a total of 18.8% of patients achieved a > 5% reduction in body weight at week 24 .
changes ( se ) from baseline in sbp and dbp were 4.3 mmhg ( 1.2 ) and 3.4 mmhg ( 1.0 ) , respectively .
most ( 96% ) of patients with one or more ae reported only events of mild or moderate intensity .
one patient in the empagliflozin 10 mg group died during the study due to an acute myocardial infarction , which was assessed as not being related to the study drug by the investigator . confirmed hypoglycemic aes were reported by more patients in the empagliflozin 10 mg ( n = 36 ; 16.1% ) and 25 mg ( n = 25 ; 11.5% ) groups than with placebo ( n = 19 ; 8.4% ) .
events consistent with uti were reported in 8.0% of patients on placebo , similar to the proportion on empagliflozin 25 mg ( 8.3% ) and slightly lower than the proportion on empagliflozin 10 mg ( 10.3% ) .
the majority of events consistent with uti were mild in intensity , none was severe , and only one such event led to study discontinuation .
most patients who reported any events consistent with uti reported just one event ; two patients in the empagliflozin 10 mg group and two patients in the empagliflozin 25 mg group reported two events
. events consistent with uti were reported considerably more frequently in female patients ( 13.318.0% ) than in male patients ( 0.02.7% ) .
the proportion of patients who reported events consistent with genital infection was low , but higher with empagliflozin than with placebo ( 2.32.7 vs. 0.9% ) .
all but one patient ( in the placebo group ) who reported any events consistent with genital infection reported just one event .
events consistent with genital infection were reported more frequently in female patients ( 0.94.5% ) than in male patients ( 0.9% ) . in the open - label group ,
events consistent with uti were reported for three patients ( 3.0% ) , and events consistent with genital infection were reported for two patients ( 2.0% ) .
changes in laboratory values ( electrolytes , hematocrit , and lipid parameters ) are presented in supplementary table 5 .
there were small increases in hematocrit and small decreases in uric acid levels in the randomized empagliflozin groups .
there was a small increase from baseline in hdl cholesterol with empagliflozin 10 and 25 mg ( mean [ se ] , 0.05 mmol / l [ 0.01 ] for both doses ) compared with placebo ( 0.02 mmol / l [ 0.01 ] ; p < 0.001 ) .
no major differences in mean ( se ) changes from baseline in ldl cholesterol or triglycerides were noted between placebo and empagliflozin .
the current study was undertaken to establish the efficacy and safety of empagliflozin 10 and 25 mg once daily for 24 weeks in patients with type 2 diabetes who had inadequate glycemic control on metformin and sulfonylurea .
both doses led to clinically meaningful improvements in glycemic control , body weight , and sbp ( but not dbp ) with a good tolerability and safety profile .
guidelines recommend that patients who fail to achieve adequate glycemic control with metformin monotherapy receive an additional agent such as sulfonylurea , a glucagon - like peptide-1 ( glp-1 ) receptor agonist , a dipeptidyl peptidase-4 ( dpp4 ) inhibitor , a thiazolidinedione , or basal insulin .
when combination therapy fails to achieve adequate glycemic control , insulin therapy is usually the most appropriate third - line treatment ( 1,14 ) .
although efficacious , insulin is associated with side effects such weight gain and hypoglycemia ( 1,14 ) . in this trial ,
the addition of empagliflozin to metformin and sulfonylurea led to significant reductions in hba1c , with 2632% of patients reaching hba1c < 7.0% at week 24 compared with only 9% in the placebo group . improved glucose control
was further demonstrated by significant reductions in mdg , fpg , and 2-h ppg with empagliflozin compared with placebo .
changes in mdg , assessed based on oc analysis , corresponded well with changes in hba1c ( 15 ) . a beneficial effect of empagliflozin on glucose control
was also observed in patients with very poor glycemic control at baseline , in whom hba1c was reduced from a mean of 11.28.2% at week 24 .
further , empagliflozin was shown to be efficacious in a patient population that included a substantial number of patients with a long duration of type 2 diabetes ( 77% of randomized patients had been diagnosed > 5 years before the trial ) .
significant reductions in body weight and waist circumference were observed with empagliflozin compared with placebo , and 2428% of patients on empagliflozin had a > 5% reduction in weight at week 24 , compared with only 6% on placebo .
weight control is important for patients with type 2 diabetes to help improve glycemic control ( 16,17 ) and improve cardiovascular risk factors ( 1,18,19 ) , and is particularly pertinent for patients taking a sulfonylurea .
treatment with sulfonylurea is associated with weight gain , a side effect that has been shown to reduce patient satisfaction and adherence to medication ( 20,21 ) .
hypertension is an important cardiovascular risk factor associated with type 2 diabetes ( 22,23 ) . in this study , a significant reduction in sbp
this may reflect osmotic diuresis associated with urinary glucose excretion ( 24 ) , which may also explain the small increase in hematocrit .
unexpectedly , no reduction in dbp was observed at week 24 . as a limitation of the study ,
changes in antihypertensive medication were allowed , possibly diluting the effect of empagliflozin versus placebo on blood pressure . a reduction in uric acid levels
was observed in patients treated with empagliflozin , compared with an increase in patients on placebo . in many epidemiological studies , lower uric acid levels
empagliflozin was well tolerated when used as add - on therapy to metformin plus sulfonylurea for 24 weeks .
more patients reported serious aes with placebo than empagliflozin , and the number of patients who discontinued due to aes was similar between the randomized empagliflozin groups and the placebo group .
this suggests that empagliflozin in combination with sulfonylurea may increase the risk of hypoglycemia , whereas empagliflozin alone has a low risk of hypoglycemia ( 11 ) .
importantly , empagliflozin as add - on to on metformin plus sulfonylurea did not cause any hypoglycemic events that required assistance .
patients with type 2 diabetes , particularly female patients , are at increased risk of utis ( 27,28 ) ; however , the reported incidence varies between trials due to different reporting methods . in this trial ,
the proportion of patients with events consistent with uti was slightly higher with empagliflozin 10 mg than with empagliflozin 25 mg or placebo , and the proportion of patients reporting genital infections was higher with empagliflozin than with placebo .
this is consistent with data on other sglt2 inhibitors , which show that a higher proportion of patients report genital infections with the sglt2 inhibitor versus placebo , but the proportion of patients who report utis is similar or only slightly higher with sglt2 inhibitor versus placebo ( 29,30 ) .
empagliflozin 10 and 25 mg showed no difference in efficacy or tolerability in this trial , even though a dose - dependent increase in urinary glucose excretion and a dose - dependent decrease in hba1c have been reported in phase i / ii studies ( 11,12,31,32 ) .
dose dependency of empagliflozin will be evaluated based on the totality of data from phase iii trials comprising more than 10,000 patients . to conclude , in this trial , empagliflozin at doses of 10 and 25 mg led to clinically meaningful improvements in glycemic control in patients with inadequate control on metformin plus sulfonylurea , led to significant reductions in body weight and sbp , and was well tolerated over 24 weeks .
these results demonstrate the potential of empagliflozin as a third - line therapy in patients inadequately controlled with metformin plus a sulfonylurea .
 objectiveto investigate the efficacy and tolerability of empagliflozin as add - on to metformin and sulfonylurea in patients with type 2 diabetes.research design and methodspatients inadequately controlled on metformin and sulfonylurea ( hba1c 7 to 10% ) were randomized and treated with once - daily empagliflozin 10 mg ( n = 225 ) , empagliflozin 25 mg ( n = 216 ) , or placebo ( n = 225 ) for 24 weeks . 
 the primary end point was change from baseline in hba1c at week 24 . 
 key secondary end points were changes from baseline in weight and mean daily glucose ( mdg ) at week 24.resultsat week 24 , adjusted mean ( se ) changes from baseline in hba1c were 0.17% ( 0.05 ) for placebo vs. 0.82% ( 0.05 ) and 0.77% ( 0.05 ) for empagliflozin 10 and 25 mg , respectively ( both p < 0.001 ) . 
 empagliflozin significantly reduced mdg , weight , and systolic ( but not diastolic ) blood pressure versus placebo . 
 adverse events were reported in 62.7 , 67.9 , and 64.1% of patients on placebo and empagliflozin 10 and 25 mg , respectively . 
 events consistent with urinary tract infection were reported in 8.0 , 10.3 , and 8.3% of patients on placebo and empagliflozin 10 and 25 mg , respectively ( females : 13.3 , 18.0 , and 17.5% , respectively ; males : 2.7 , 2.7 , and 0% , respectively ) . 
 events consistent with genital infection were reported in 0.9 , 2.7 , and 2.3% of patients on placebo and empagliflozin 10 and 25 mg , respectively ( females : 0.9 , 4.5 , and 3.9% , respectively ; males : 0.9% in each group).conclusionsempagliflozin 10 and 25 mg for 24 weeks as add - on to metformin plus sulfonylurea improved glycemic control , weight , and systolic blood pressure and were well tolerated . 
RESEARCH DESIGN AND METHODS
Study design
Inclusion and exclusion criteria
Treatment and interventions
End points and assessments
Statistical analysis
RESULTS
Patients
Efficacy
Randomized groups.
Open-label group.
Safety
CONCLUSIONS
Supplementary Material