from december 2005 to september 2006 , drug - naive type 2 diabetic patients , aged 1879 years , with a1c 7% and 10% , were recruited at 98 clinical centers in the u.s .
inclusion criteria included fasting c - peptide > 1.0 ng / ml , bmi 40 kg / m , and renal status as follows : glomerular filtration rate > 60 ml / min per 1.73 m , serum creatinine < 1.5 mg / dl ( men)/<1.4 mg / dl ( women ) , and urine microalbumin / creatinine ratio 300 mg / g .
this was a prospective , 12-week , randomized , parallel - group , double - blind , placebo - controlled study , with a 2-week diet / exercise placebo lead - in and 4-week follow - up ( fig .
patients were randomly assigned equally to once - daily dapagliflozin ( 2.5 , 5 , 10 , 20 , or 50 mg ) , metformin xr ( 750 mg force - titrated at week 2 to 1,500 mg ) ( therapeutic benchmark ) , or placebo .
patients with fasting plasma glucose ( fpg ) > 240 mg / dl at weeks 4 and 6 , > 220 mg / dl at week 8 , or > 200 mg / dl at week 10 were discontinued from the study and were eligible to receive additional antidiabetic agents .
the study was conducted pursuant to the declaration of helsinki and was approved by institutional review boards / independent ethics committees at participating sites .
the primary objective was to compare mean a1c change from baseline for each dapagliflozin group versus placebo after 12 weeks .
secondary objectives were comparisons of dapagliflozin versus placebo for fpg change from baseline , dose - dependent trends in glycemic efficacy , proportion of patients achieving a1c < 7% , and change in 24-h urinary glucose - to - creatinine ratio .
study visits occurred at screening ; days 14 and 1 ; weeks 1 , 2 , 4 , 6 , 8 , 10 , and 12 ; and follow - up weeks 14 and 16 . fasting blood and urine samples were collected after a minimum 10-h fast . during oral glucose tolerance testing ,
blood was drawn at 0 , 30 , 60 , 120 , and 180 min after an oral glucose challenge ( 75 g ) .
vital signs , brief physical examination , and adverse event assessment were performed at each visit .
adverse events were summarized by preferred term ( medical dictionary for regulatory activities [ meddra ] , version 10 ) .
fifty patients per treatment group provided 82% power to detect a mean 0.7% difference in a1c between dapagliflozin groups and placebo , assuming 1% sd .
comparisons between dapagliflozin and placebo were performed at the 0.012 level using dunnett 's adjustment so that overall type 1 error rate was controlled at 0.05 significance .
week 12 primary and secondary efficacy analyses for a1c , fpg , and 24-h urinary glucose - to - creatinine ratio were performed by ancova with treatment group as the effect and baseline value as covariate .
linear trend tests were performed to assess dose - response relationships among dapagliflozin groups for a1c change from baseline after 12 weeks .
fisher 's exact test was used to compare the proportion of subjects achieving a1c < 7.0% between dapagliflozin groups and placebo .
study visits occurred at screening ; days 14 and 1 ; weeks 1 , 2 , 4 , 6 , 8 , 10 , and 12 ; and follow - up weeks 14 and 16 .
fasting blood and urine samples were collected after a minimum 10-h fast . during oral glucose tolerance testing ,
blood was drawn at 0 , 30 , 60 , 120 , and 180 min after an oral glucose challenge ( 75 g ) .
vital signs , brief physical examination , and adverse event assessment were performed at each visit .
adverse events were summarized by preferred term ( medical dictionary for regulatory activities [ meddra ] , version 10 ) .
fifty patients per treatment group provided 82% power to detect a mean 0.7% difference in a1c between dapagliflozin groups and placebo , assuming 1% sd .
comparisons between dapagliflozin and placebo were performed at the 0.012 level using dunnett 's adjustment so that overall type 1 error rate was controlled at 0.05 significance .
week 12 primary and secondary efficacy analyses for a1c , fpg , and 24-h urinary glucose - to - creatinine ratio were performed by ancova with treatment group as the effect and baseline value as covariate .
linear trend tests were performed to assess dose - response relationships among dapagliflozin groups for a1c change from baseline after 12 weeks .
fisher 's exact test was used to compare the proportion of subjects achieving a1c < 7.0% between dapagliflozin groups and placebo .
a total of 389 patients were randomly assigned to receive dapagliflozin , metformin , or placebo ( fig .
baseline patient characteristics at week 12 , all dapagliflozin groups achieved significant reductions in mean a1c change from baseline versus placebo ( fig .
adjusted mean reductions ranged from 0.55 to 0.90% ( dapagliflozin ) , 0.18% ( placebo ) , and 0.73% ( metformin ) .
no log - linear dose - response relationship was demonstrated ( ptrend = 0.41 ) .
changes in glycemic parameters . a : adjusted mean change from baseline in a1c at week 12 ( locf ) .
c : adjusted mean change from baseline in postprandial glucose area under the curve ( auc ) during a 75-g oral glucose tolerance test at week 12 ( locf ) .
d : change from baseline in 24-h urinary glucose ( grams ) normalized for urinary creatinine ( grams ) at week 12 ( locf ) . displayed
are means and 95% cis ( a , b , and d ) . when statistical significance was achieved with dapagliflozin groups compared with placebo , dunnett 's multiplicity adjustment was used .
efficacy parameters , adverse events , vital signs , and laboratory parameters data are means  sd or n ( % ) .
missing data imputed by locf ranged from 5.2 to 13.6% ( a1c ) , 11.5 to 26.0% ( fpg ) , 5.2 to 13.6% ( proportion with a1c < 7.0% ) , and 2.0 to 8.2% ( 24-h urinary glucose / creatinine ) .
a1c , fpg , ppg , and 24-h urinary glucose / creatinine represent adjusted mean changes .
infections of the urinary tract  were events of urinary tract infection , cystitis , escherichia urinary tract infection , urinary tract infection fungal , and fungal infection ( verbatim investigator term  yeast infection [ in urine ]  ) .
genital infections  were events of vulvovaginal mycotic infection , vaginal infection , genital herpes , genital infection fungal , penile infection , vaginitis bacterial , and vulvitis .
#  hypotensive events  were events of hypotension , orthostatic hypotension , and syncope . * * change from baseline at week 12 .
fpg reductions were apparent by week 1 in all dapagliflozin groups . by week 12 , adjusted mean fpg reductions were 16 to 31 mg / dl ( dapagliflozin ) , 6 mg / dl ( placebo ) , and 18 mg / dl ( metformin ) , demonstrating dose - related fpg decreases and statistically significant reductions in the 5- to 50-mg dapagliflozin groups versus placebo ( fig .
adjusted mean postprandial plasma glucose ( ppg ) auc reductions from baseline were 7,053 to 10,149 mg  min  dl ( dapagliflozin ) , 3,182 mg  min  dl ( placebo ) , and 5,891 mg  min  dl ( metformin ) ( fig . 2c and table 2 )
. proportions of patients achieving a1c < 7% at week 12 ranged from 40 to 59% ( dapagliflozin ) , 32% ( placebo ) , and 54% ( metformin ) .
the comparison versus placebo was statistically significant only for the 50-mg group ( p < 0.01 ) .
adjusted mean changes in 24-h urinary glucose - to - creatinine ratios at week 12 were 3265 g / g versus 0.2 g / g for placebo ( p < 0.001 for each dapagliflozin group ) ( fig .
total mean urinary glucose excreted per 24 h at week 12 ranged from 52 to 85 g with dapagliflozin ( table 2 ) .
mean percent reductions at week 12 were 2.5 to 3.4% ( dapagliflozin ) , 1.2% ( placebo ) , and 1.7% ( metformin ) ( fig .
more patients achieved > 5% reductions with dapagliflozin ( range 15.329.1% ) than with placebo ( 7.7% ) ; the proportion with metformin was 16.1% .
mean percent changes in waist circumference were 1.6 to 3.5% ( dapagliflozin ) , 1.2% ( placebo ) , and 2.2% ( metformin ) .
a : percent change from baseline in weight over the 12-week treatment period and 4-week follow - up period ( observed values ) .
b : adjusted mean percent change from baseline in weight after 12 weeks of treatment ( locf ) . displayed
generally , adverse events were reported at similar frequencies across all groups ( table 2 ) .
hypoglycemic events were reported in 610% of dapagliflozin - treated patients with no dose relationship , in 4% of placebo - treated patients , and in 9% of metformin - treated patients ( table 2 ) .
events relating to each category were pooled ( e.g. , preferred terms  urinary tract infection  and  cystitis  were pooled as 
infections of the urinary tract were seen in 512% of dapagliflozin - treated patients with no clear dose relationship versus 6% of placebo - treated patients and 9% of metformin - treated patients .
genital infections were seen in 27% of dapagliflozin - treated patients , 0% of placebo - treated patients , and 2% of metformin - treated patients .
hypotensive events were seen in 02% of dapagliflozin - treated patients versus 2% of placebo - treated patients and 4% of metformin - treated patients . decreased blood pressure was observed in all dapagliflozin groups ( table 2 ) .
mean changes from baseline in supine systolic blood pressure ( sbp ) at week 12 ranged from 2.6 to 6.4 mmhg with no clear dose relationship .
changes in diastolic blood pressure ( dbp ) and heart rate were small and inconsistent across dapagliflozin groups .
the diuretic effect of dapagliflozin was assessed by 24-h urine volume , hematocrit , and serum blood urea nitrogen ( bun ) and creatinine ( table 2 ) .
small dose - related increases in 24-h urine volumes ( range 107470 ml above baseline of 1.82.2 l ) were demonstrated at week 12 .
increases in hematocrit were also dose - related ( range 1.52.9% ) . there were small changes from baseline in serum bun and no change in serum creatinine at week 12 across dapagliflozin doses .
mean percent increases at week 12 in the bun - to - creatinine ratio ranged from 10.4 to 18.3% , with no apparent dose relationship .
changes in urine volume , hematocrit , and bun - to - creatinine ratio returned toward baseline during follow - up .
there was no clinically meaningful change in estimated glomerular filtration rate ( modification of diet in renal disease formula ) ( 19 ) in any group .
meq / l above the baseline mean ( 1.7 meq / l ) in serum magnesium and a larger relative decrease of 1.0 mg / dl below the baseline mean ( 5.5 mg / dl ) in serum uric acid were observed , returning toward baseline after discontinuation of dapagliflozin .
serum phosphate increased in a dose - related manner for doses 5 mg ( range 0.01 to + 0.24 mg / dl from baseline of 3.63.8 mg / dl ) , although these changes were not statistically different from placebo ( 0.08 mg / dl ) ( table 2 ) .
there were no clinically relevant mean changes from baseline in serum sodium , potassium , and calcium ( table 2 ) .
with respect to bone metabolism , serum 1,25-dihydroxyvitamin d and 25-hydroxyvitamin d values were unchanged from baseline .
mean changes in the 24-h urinary calcium - to - creatinine ratio were similar to those with placebo .
small increases in mean parathyroid hormone concentrations ( range 0.67.0 pg / ml above baseline of 31.135.0 pg / ml ) were noted , which were generally greater than the 0.8 pg / ml increase for placebo .
there was no clear treatment effect of dapagliflozin on fasting lipid parameters in this 12-week study .
glucose reabsorption by the kidney is necessary from an evolutionary standpoint to retain calories but becomes detrimental in type 2 diabetes by contributing to perpetuation of hyperglycemia and caloric excess .
paradoxically , the glucose resorptive capacity of the kidney may increase in type 2 diabetes ( 20 ) .
therefore , limiting renal glucose reabsorption through the inhibition of sglt2 represents a new approach to treating hyperglycemia in type 2 diabetic patients .
this study provides evidence that inducing controlled glucosuria through selective sglt2 inhibition improves hyperglycemia consistently over 12 weeks of treatment in type 2 diabetic patients .
dapagliflozin produced decreases in a1c , fpg , and ppg after 12 weeks , with reductions in fpg apparent by week 1 .
changes in fpg were dose - related ; however , there was little evidence of a dose response for either ppg or a1c .
the impact of sglt2 inhibition was relatively greater on ppg than on fpg , with renal glucose excretion acting as a relief valve to blunt postprandial hyperglycemia .
even the lowest dapagliflozin dose ( 2.5 mg ) produced a near - maximal effect on ppg , consistent with reductions observed in a clinical ward study ( 16 ) .
in contrast , the effect on fpg , measured at the trough drug concentration , was dose - ordered and corresponded to expected residual trough pharmacodynamic activity ( 16 ) .
dapagliflozin exhibited a diuretic effect , with small dose - dependent increases in urine volume equivalent to 0.31.5 voids / day , small increases in bun , and small dose - dependent increases in hematocrit .
the relevance of this diuresis in type 2 diabetic patients , who often require diuretics for controlling hypertension ( 21 ) , warrants further investigation .
although no effect on renal function was observed , longer - term studies and exploratory renal biomarker assessments are being undertaken .
veterinary literature suggests that chronic administration of phlorizin in lactating cows induces lipolysis ( 22 ) , and dapagliflozin in obese rats induces reduced adiposity ( 23 ) . during treatment ,
weight loss was more pronounced during week 1 with dapagliflozin , particularly at higher doses .
this observation , coupled with a rapid partial rebound in weight after discontinuation of higher doses , suggests that diuresis may contribute to some weight loss .
overall , it appears likely that acute weight reduction during week 1 represents fluid loss , which may also result in lower sbp , whereas continued gradual weight loss represents decreased fat mass .
longer - term clinical and body composition studies will help to establish the relative contribution of diuresis versus adiposity reduction to total weight loss .
daily dapagliflozin was well tolerated with no major difference in adverse events across treatment groups .
the hypoglycemia experience supports the potential for dapagliflozin to achieve meaningful glycemic efficacy with relatively low hypoglycemic risk .
the number of reported urinary tract infections was similar among dapagliflozin , metformin , and placebo groups and is consistent with rates reported in type 2 diabetic patients ( 24 ) .
the incidence of genital infections was higher with dapagliflozin versus placebo , especially at higher doses , but without statistical significance for comparison .
of note is the lower rate of genital infections reported for placebo group patients than previously reported for type 2 diabetic patients ( 25 ) .
dapagliflozin increased serum phosphate at higher doses , and all arms including placebo and metformin demonstrated increased serum parathyroid hormone .
additional data are needed to understand the long - term effects of chronic glucosuria and dapagliflozin treatment on skeletal metabolism .
this study demonstrated the clinical efficacy of inhibiting renal glucose reabsorption with dapagliflozin in type 2 diabetic patients and relative safety across numerous doses .
our results suggest that dapagliflozin , as the first in a new class of sglt inhibitors , can improve glycemic and weight status of type 2 diabetic patients .
although we evaluated monotherapy , the insulin - independent mechanism of dapagliflozin may complement other type 2 diabetes agents that act through insulin signaling pathways and thus enhance combination therapy .
although human genetic case reports are reassuring , the chronic effects of pharmacologically induced glucosuria are unknown and require long - term assessment . on the basis of evidence to date ,
further clinical study of dapagliflozin is warranted to develop a more definitive benefit / risk profile for this novel therapeutic agent .
 objectivedapagliflozin , a novel inhibitor of renal sodium - glucose cotransporter 2 , allows an insulin - independent approach to improve type 2 diabetes hyperglycemia . in this multiple - dose study 
 we evaluated the safety and efficacy of dapagliflozin in type 2 diabetic patients.research design and methodstype 2 diabetic patients were randomly assigned to one of five dapagliflozin doses , metformin xr , or placebo for 12 weeks . 
 the primary objective was to compare mean change from baseline in a1c . 
 other objectives included comparison of changes in fasting plasma glucose ( fpg ) , weight , adverse events , and laboratory measurements.resultsafter 12 weeks , dapagliflozin induced moderate glucosuria ( 5285 g urinary glucose / day ) and demonstrated significant glycemic improvements versus placebo ( a1c 0.55 to 0.90% and fpg 16 to 31 mg / dl ) . 
 weight loss change versus placebo was 1.3 to 2.0 kg . there was no change in renal function . 
 serum uric acid decreased , serum magnesium increased , serum phosphate increased at higher doses , and dose - related 24-h urine volume and hematocrit increased , all of small magnitude . 
 treatment - emergent adverse events were similar across all groups.conclusionsdapagliflozin improved hyperglycemia and facilitates weight loss in type 2 diabetic patients by inducing controlled glucosuria with urinary loss of 200300 kcal / day . 
 dapagliflozin treatment demonstrated no persistent , clinically significant osmolarity , volume , or renal status changes . 
RESEARCH DESIGN AND METHODS
Measurements
Statistical analyses
RESULTS
CONCLUSIONS