this randomized , double - blind , placebo - controlled , parallel group , 24-week study with a subsequent 24-week extension enrolled male and female patients with type 2 diabetes between 29 july 2008 and 4 july 2009 .
the study took place at 105 sites in argentina , canada , india , mexico , peru , philippines , taiwan , and united states and was completed on 15 june 2010 .
institutional review boards or independent ethics committees approved this protocol , and each patient provided written informed consent .
patients 18 years old having fasting c - peptide 1.0 ng / ml and bmi 45.0 kg / m entered group a or b. group a patients had received 12 weeks of pioglitazone 30 or 45 mg / day and had hba1c 7.0 and 10.5% .
group b patients were drug naive for the previous 10 weeks with hba1c 8.0 and 11.0% or had received pioglitazone 15 mg / day or any dose of rosiglitazone with hba1c 8.0 and 11.0% or had received 8 weeks of metformin 1700 mg / day or sulfonylurea less than or equal to half the maximal dose with hba1c 7.0 and 11.0% .
group b patients could not be on > 1 oral antidiabetic medication , and patients on more than half the maximum dose of sulfonylurea or metformin were excluded .
group b patients underwent a 10-week dose - optimization period in which their initial therapy was discontinued , and pioglitazone 30 mg / day was started and increased to 45 mg / day if possible .
group b patients were discontinued if their fasting plasma glucose ( fpg ) was > 270 mg / dl ( 15.0 mmol / l ) after 3 weeks or after 6 weeks with hba1c < 7.0 or > 11.0% .
exclusion criteria included aspartate or alanine aminotransferases > 2.5 times the upper limit of normal , total bilirubin > 2.0 mg / dl , serum creatinine 2.0 mg / dl , urine albumin / creatinine ratio > 1,800 mg / g , calculated creatinine clearance < 50 ml / min , and congestive heart failure class iii and iv .
patients with prerandomization hba1c 7.0 and 10.5% entered the 2-week , single - blind lead - in period and received diet and exercise counseling .
randomized patients received double - blind dapagliflozin 5 or 10 mg or placebo every day ( oral administration ) with open - label pioglitazone 30 or 45 mg / day , stratified by pre - enrollment diabetes treatment group a and b. to ensure adequate representation from group a , randomization was set to recruit at least one - third of the patients from this group .
the primary objective compared the change at 24 weeks from baseline in hba1c with each dose of dapagliflozin plus pioglitazone versus placebo plus pioglitazone .
secondary objectives included change from baseline in fpg , postprandial glucose ( ppg ) measured by 120-min postchallenge response to an oral glucose tolerance test , and total body weight . if fpg was > 270 mg / dl ( 15.0 mmol / l ) ( week 48 ) , > 240 mg / dl ( 13.3 mmol / l ) ( week 812 ) , or > 200 mg / dl ( 11.1
mmol / l ) ( week 1224 ) , then patients were eligible to receive open - label rescue medication ( metformin or sulfonylurea ) .
patients completing the first 24 weeks of the study were eligible for an additional 24 weeks . during weeks 24 to 48 , if hba1c was > 8.0 ( week 2536 ) or > 7.5% ( week 3647 ) , patients were eligible to receive open - label rescue medication .
data obtained after rescue were excluded from the efficacy analysis but included in safety analysis .
adverse events , laboratory abnormalities , and vital signs were assessed for the safety and tolerability of treatment .
hypoglycemia definitions are in the supplementary appendix and were documented for any event the investigator considered to be a hypoglycemic event , regardless of blood glucose measurement .
signs , symptoms , and events suggestive of urinary tract infection ( uti ) and genital infection were solicited at every visit .
preferred term lists included a broad spectrum of signs and symptoms of utis and genital infections in addition to specific diagnoses .
seated blood pressure was determined after 5 min of rest followed by the orthostatic blood pressure measurements .
average blood pressure was determined from three replicate measurements taken at least 1 min apart in each position ( seated , supine , and standing ) .
statistical analyses at week 24 ( last observation carried forward ) including changes from baseline in hba1c , fpg , ppg , and body weight were performed using ancova with treatment group as an effect and baseline value and strata based on pre - enrollment antidiabetic therapy as covariates in the model .
secondary end points were tested for significance sequentially . at week 48 , analyses of change from baseline in hba1c , fpg , ppg , and body weight were performed using longitudinal repeated - measures analysis over time including the fixed categorical effects of strata based on pre - enrollment antidiabetic therapy , treatment , week , and treatment - by - week interaction as well as the continuous fixed covariates of baseline measurement and baseline measurement - by - week interaction .
rescue was added as an additional effect to the mixed model when the analysis was performed on data regardless of rescue .
statistical analyses at week 24 ( last observation carried forward ) including changes from baseline in hba1c , fpg , ppg , and body weight were performed using ancova with treatment group as an effect and baseline value and strata based on pre - enrollment antidiabetic therapy as covariates in the model .
secondary end points were tested for significance sequentially . at week 48 , analyses of change from baseline in hba1c , fpg , ppg , and body weight were performed using longitudinal repeated - measures analysis over time including the fixed categorical effects of strata based on pre - enrollment antidiabetic therapy , treatment , week , and treatment - by - week interaction as well as the continuous fixed covariates of baseline measurement and baseline measurement - by - week interaction .
rescue was added as an additional effect to the mixed model when the analysis was performed on data regardless of rescue .
of the 972 enrolled patients , 558 met the entrance criteria , and 480 entered the lead - in phase with pioglitazone .
almost equal numbers of patients came from group a ( 48% , 200 out of 420 ) and group b ( 52% , 220 out of 420 ) ( supplementary fig .
the proportion of patients who were discontinued or rescued for lack of glycemic control was less with dapagliflozin ( 1118% ) than with placebo ( 34% ) .
demographics and baseline characteristics treatment with dapagliflozin 5 and 10 mg added on to pioglitazone resulted in statistically significant mean reductions in hba1c , fpg , and ppg when compared with placebo at week 24 ( table 2 ) and were maintained through week 48 ( table 2 ) . the mean reduction from baseline in hba1c with dapagliflozin plus pioglitazone ranged from 0.82 to 0.97% compared with 0.42% with the placebo plus pioglitazone at week 24 ( p = 0.0007 and p < 0.0001 for dapagliflozin 5- and 10-mg groups , respectively . ) at 48 weeks , the mean reductions in hba1c were maintained , and dapagliflozin groups ranged from 0.95 to 1.21% compared with 0.54% with the placebo plus pioglitazone .
1a ) and similar between groups a and b over time ( data not shown ) .
1b ) in the dapagliflozin groups and significant at week 24 ( table 2 ) . at week 48 , a greater reduction in mean change from baseline in ppg was observed with dapagliflozin plus pioglitazone ( 60.4 to 80.9 mg / dl [ 3.35 to 4.49 mmol / l ] ) than with placebo plus pioglitazone ( 25.4 mg / dl [ 1.41 mmol / l ] ) ( table 2 ) .
change from baseline at weeks 24 and 48 in efficacy parameters , vital signs , and laboratory values changes in glycemic parameters for placebo ( circles ) , dapagliflozin 5 mg ( squares ) , and dapagliflozin 10 mg ( triangles ) all plus pioglitazone 30 mg . a : mean change from baseline in hba1c after adjustment for baseline value over time .
b : mean change from baseline in fpg after adjustment for baseline value over time .
d : mean change from baseline in total body weight after adjustment for baseline value over time . includes patients who took at least one dose of double - blind study medication .
the increase in mean urinary glucose to creatinine ratio from baseline was maintained in the dapagliflozin groups over time ( fig .
the placebo group experienced a mean increase in body weight of 3.0 kg through week 48 .
dapagliflozin groups had a slight weight reduction initially , followed by gradual weight gain toward the baseline values at week 24 and gains of 1.4 and 0.7 kg for 5 and 10 mg , respectively , at week 48 ( table 2 and fig .
these changes for the dapagliflozin groups were significant at week 24 compared with placebo , maintained throughout 48 weeks ( table 2 ) , and appeared to be dose - dependent over time ( fig .
the placebo group experienced a mean increase in seated blood pressure at weeks 24 and 48 , whereas both dapagliflozin groups experienced mean decreases ( table 2 ) .
small mean increases in hematocrit occurred in both dapagliflozin treatment groups ( 1.362.04% ) , whereas the placebo showed 0.44% change at week 48 .
small changes were observed on mean fasting ldl cholesterol ( 1.13.4% for dapagliflozin and 4.5% for placebo ) , total cholesterol ( 0.02.0% for dapagliflozin and 1.9% for placebo ) , triglycerides ( 3.74.2% for dapagliflozin and 13.5% for placebo ) , and hdl cholesterol ( 4.17.2% for dapagliflozin and 1.3% for placebo ) at week 48 .
no clinically relevant changes in calcium , magnesium , phosphorous , or serum 25 hydroxyvitamin d concentrations were apparent in any treatment group throughout the study ( data not shown ) .
there were small increases within the normal limits for parathyroid hormone and small mean changes in bone markers ( serum procollagen type 1 n - propeptide , cooh - terminal telopeptide of type 1 collagen , n - terminal telopeptide of type 1 collagen , and osteocalcin ) compared with placebo , which were unlikely to be clinically significant .
the proportion of patients who reported at least one adverse event was similar for dapagliflozin ( 68.170.7% ) and placebo ( 66.9% ) through week 48 .
one death due to septic shock was reported on day 117 in the dapagliflozin 5-mg group within 2 days of presenting with acute cholecystitis .
discontinuations were low and similar between the dapagliflozin and the placebo groups , none due to hypoglycemia .
adverse and special interest events through week 48 all of the renal events listed in table 3 occurred during the first 24-week period , and no additional events occurred during the second 24-week period .
they included serum creatinine increase ( four events ) , creatinine renal clearance decrease ( one event ) , glomerular filtration rate decrease ( one event ) , and abnormal renal function test ( one event ) .
the proportion of patients with an event suggestive of uti was 7.9 , 8.5 , and 5.0% with placebo , dapagliflozin 5 mg , and 10 mg , respectively , through week 48 .
signs , symptoms , and other events suggestive of genital infection were more common in both dapagliflozin treatment groups ( 8.69.2% ) than in the placebo group ( 2.9% ) through week 48 .
most events suggestive of uti or genital infection were of mild or moderate intensity ; none of these events were serious or led to withdrawal from the study except for one patient ( dapagliflozin 5 mg ) with recurrent utis .
patients treated with pioglitazone plus dapagliflozin 5 or 10 mg had a lower rate of peripheral edema ( 4.3 and 2.1% , respectively ) compared with pioglitazone plus placebo ( 6.5% ) ( table 3 ) . two patients ( one female and one male ) from the dapagliflozin 5-mg group experienced limb fractures ( one foot and one hand , respectively ) during the first 24-week period .
one patient on placebo had an event of heart failure , and one patient on dapagliflozin 5 mg had urothelial bladder cancer detected on day 144 .
in this study , the addition of dapagliflozin to pioglitazone lowered hba1c levels and attenuated the pioglitazone - related weight gain in patients with type 2 diabetes inadequately controlled on pioglitazone alone .
dapagliflozin acts in the kidney by inhibiting the reabsorption of glucose ( 15,16 ) and is not only capable of reducing fpg but also reabsorption of higher glucose load postprandially as shown in this study .
these beneficial effects of dapagliflozin on hyperglycemia were maintained for almost 1 year and were consistent with sustained pharmacodynamic activity on glycosuria .
the glucosuria induced by sglt-2 inhibition might be suspected to lead to hypoglycemia , utis , and genital infections . however , hypoglycemia events were rare in this study .
no clear relationship to dapagliflozin was observed for events suggestive of utis , although one patient withdrew from the trial due to recurring utis .
consistent with previous reports ( 5,6,8 ) , events suggestive of genital infections were higher in patients on dapagliflozin than on placebo .
urinary excretion of glucose also leads to caloric loss and the addition of dapagliflozin to pioglitazone can potentially mitigate weight gain due to pioglitazone .
the differences between placebo and dapagliflozin - treated groups in weight were mainly driven by continuous weight gain in the placebo group , reflecting probably that pioglitazone was initiated or optimized during the prerandomization period , whereas no meaningful changes from baseline occurred in dapagliflozin groups .
dapagliflozin , acting as a mild diuretic , may also mitigate the fluid retaining effects of pioglitazone as evidenced by fewer reports of edema .
some studies suggest that pioglitazone may modestly lower blood pressure ( 17 ) , a beneficial effect for patients with diabetes .
when dapagliflozin was used as monotherapy ( 5 ) or in combination therapy ( 6,8 ) , there was also some suggestive mild lowering of blood pressure .
in this study , addition of dapagliflozin to pioglitazone was associated with a modest further decrease in blood pressure beyond the effect of pioglitazone alone in the absence of any ill effects such as hypotensive events or measured orthostatic hypotension .
thus , along with effects on weight , dapagliflozin may add to the blood pressure benefit of pioglitazone .
congestive heart failure , bladder cancer , or bone fractures , known side effects of long - term use of pioglitazone , were rare events ; too rare at this stage to infer any effect on the risk of these events with the addition of dapagliflozin ( 13,14,18 ) .
two fractures did occur in the dapagliflozin 5-mg group , but all patients received pioglitazone , and thiazolidinediones are known to increase the risk of fractures ( 19 ) .
dapagliflozin added on to pioglitazone resulted in sustained glycemic benefits in both fasting and postprandial plasma glucose concentrations .
as a possible mild diuretic and consistent glucouretic , dapagliflozin mitigated the weight gain and fluid retention due to pioglitazone . even though more genital infections occurred with dapagliflozin than placebo , dapagliflozin added on to pioglitazone was effective and well - tolerated .
the direct removal of glucose by dapagliflozin complements the insulin - sensitizing action of pioglitazone , providing a potential combination that balances well the benefits and risks of therapy for some patients with type 2 diabetes .
 objectiveto examine the safety and efficacy of dapagliflozin , a sodium - glucose cotransporter-2 inhibitor , added on to pioglitazone in type 2 diabetes inadequately controlled on pioglitazone.research design and methodstreatment - naive patients or those receiving metformin , sulfonylurea , or thiazolidinedione entered a 10-week pioglitazone dose - optimization period with only pioglitazone . 
 they were then randomized , along with patients previously receiving pioglitazone 30 mg , to 48 weeks of double - blind dapagliflozin 5 ( n = 141 ) or 10 mg ( n = 140 ) or placebo ( n = 139 ) every day plus open - label pioglitazone . 
 the primary objective compared hba1c change from baseline with dapagliflozin plus pioglitazone versus placebo plus pioglitazone at week 24 . 
 primary analysis was based on ancova model using last observation carried forward ; all remaining analyses used repeated - measures analysis.resultsat week 24 , the mean reduction from baseline in hba1c was 0.42% for placebo versus 0.82 and 0.97% for dapagliflozin 5 and 10 mg groups , respectively ( p = 0.0007 and p < 0.0001 versus placebo ) . 
 patients receiving pioglitazone alone had greater weight gain ( 3 kg ) than those receiving dapagliflozin plus pioglitazone ( 0.71.4 kg ) at week 48 . through 48 weeks : hypoglycemia was rare ; more events suggestive of genital infection were reported with dapagliflozin ( 8.69.2% ) than placebo ( 2.9% ) ; events suggestive of urinary tract infection showed no clear drug effect ( 5.08.5% for dapagliflozin and 7.9% for placebo ) ; dapagliflozin plus pioglitazone groups had less edema ( 2.14.3% ) compared with placebo plus pioglitazone ( 6.5% ) ; and congestive heart failure and fractures were rare.conclusionsin patients with type 2 diabetes inadequately controlled on pioglitazone , the addition of dapagliflozin further reduced hba1c levels and mitigated the pioglitazone - related weight gain without increasing hypoglycemia risk . 