***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: OBJECTIVE This open-label study investigated potential drug-drug interactions between empagliflozin and metformin . METHODS 16 healthy men received treatment A ( empagliflozin 50 mg q.d . for 5 days ) , treatment B ( empagliflozin 50 mg q.d . for 4 days with metformin 1,000 mg b.i.d . for 3 days and 1,000 mg q.d . on Day 4 ) and treatment C ( metformin 1,000 mg b.i.d . for 3 days and 1,000 mg q.d .on Day 4 ) in the sequence AB then C , or C then AB . RESULTS Metformin had no clinical ly relevant effect on the area under the steady state plasma concentration-time curve ( AUC(τ , ss ) geometric mean ratio ( GMR ) : 96.9 ; 90 % CI : 92.3 - 101.7 ) or the maximum plasma concentration at steady state ( C(max , ss ) GMR : 100.5 ; 90 % CI : 88.8 - 113.7 ) of empagliflozin . Similarly , empagliflozin had no clinical ly relevant effect on AUC(τ , ss ) ( GMR : 100.7 ; 90 % CI : 95.9 - 105.6 ) or C(max , ss ) ( GMR : 103.6 ; 90 % CI : 96.5 - 111.2 ) of metformin . The renal  clearance of empagliflozin and metformin were unaffected by co-administration . Both drugs were well tolerated alone and in combination and did not cause hypoglycemia . CONCLUSIONS These data support co-administration of empagliflozin and metformin without dose adjustment BACKGROUND Ipragliflozin ( ASP1941 ) is a selective sodium glucose cotransporter 2 inhibitor in clinical development for the treatment of patients with type 2 diabetes mellitus ( T2DM ) . OBJECTIVES The primary objective was to evaluate the safety profile and tolerability of ipragliflozin as a glucose-lowering agent in combination with stable metformin therapy in patients with T2DM . A secondary objective was to evaluate the effect of ipragliflozin on the pharmacokinetic ( PK ) properties of metformin . METHODS Thirty-six patients with T2DM stable on metformin therapy ( 850 , 1000 , or 1500 mg bid ) were r and omized in a double-blind manner to receive ipragliflozin ( 300 mg qd ; n = 18 ) or matching placebo ( n = 18 ) for 14 days . Safety profiles , including monitoring of hypoglycemic events , treatment-emergent adverse events ( TEAEs ) , laboratory measurements , and vital signs were assessed throughout the study . The PK properties of metformin and ipragliflozin were determined in plasma . The geometric mean ratio and its 90 % CI for the maximum plasma concentration and AUC(0 - 10 ) were calculated for metformin + ipragliflozin ( day 14 ) versus metformin alone ( day -1 ) . Pharmacodynamic properties were assessed by measurement of urinary glucose excretion over 24 hours ( UGE(0 - 24 ) ) . RESULTS All the TEAEs , except 1 , were mild . Fifteen TEAEs were observed in the ipragliflozin group ( 7 of 18 patients [ 38.9 % ] ) , and 19 TEAEs were observed in the placebo group in ( 8 of 18 patients [ 44.4 % ] ) . Treatment-related TEAEs were reported by 3 of 18 patients ( 16.7 % ) receiving metformin + ipragliflozin and by 5 of 18 patients ( 27.8 % ) receiving metformin + placebo . No hypoglycemic events ( blood glucose level < 54 mg/L [ to convert to millimoles per liter , multiply by 0.0555 ] ) were observed . The geometric mean ratios for C(max ) and AUC(0 - 10 ) of metformin + ipragliflozin versus metformin alone were 1.11 ( 90 % CI , 1.03 - 1.19 ) and 1.18 ( 90 % CI , 1.08 - 1.28 ) , respectively . After ipragliflozin treatment , UGE(0 - 24 ) on day 14 ( 74.9 g ) was significantly higher than that in the placebo group ( 3.6 g ) and at baseline ( 3.3 g ) . CONCLUSIONS Combination treatment for 14 days with ipragliflozin and metformin was well tolerated  in patients withT2DM without hypoglycemia . The addition of ipragliflozin ( 300 mg qd ) to metformin therapy did not result in a clinical ly relevant change in the PK properties of metformin . Clinical Trials.gov identifier : NCT01302145 OBJECTIVE To evaluate the effects of canagliflozin , a sodium-glucose cotransporter 2 inhibitor , in type 2 diabetes mellitus inadequately controlled with metformin monotherapy . RESEARCH DESIGN AND METHODS This was a double-blind , placebo-controlled , parallel-group , multicenter , dose-ranging study in 451 subjects r and omized to canagliflozin 50 , 100 , 200 , or 300 mg once daily ( QD ) or 300 mg twice daily ( BID ) , sitagliptin 100 mg QD , or placebo . Primary end point was change in A1C from baseline through week 12 . Secondary end points included change in fasting plasma glucose ( FPG ) , body weight , and overnight urinary glucose-to-creatinine ratio . Safety and tolerability were also assessed . RESULTS Canagliflozin was associated with significant reductions in A1C from baseline ( 7.6–8.0 % ) to week 12 : −0.79 , −0.76 , −0.70 , −0.92 , and −0.95 % for canagliflozin 50 , 100 , 200 , 300 mg QD and 300 mg BID , respectively , versus −0.22 % for placebo ( all P < 0.001 ) and −0.74 % for sitagliptin . FPG was reduced by −16 to −27 mg/dL , and body weight was reduced by −2.3 to −3.4 % , with significant increases in urinary glucose-to-creatinine ratio . Adverse events were transient , mild to moderate , and balanced across arms except for a non – dose-dependent increase in symptomatic genital infections with canagliflozin ( 3–8 % ) versus placebo and sitagliptin ( 2 % ) . Urinary tract infections were reported without dose dependency in 3–9 % of canagliflozin , 6 % of placebo , and 2 % of sitagliptin  arms . Overall incidence of hypoglycemia was low . CONCLUSIONS Canagliflozin added onto metformin significantly improved glycemic control in type 2 diabetes and was associated with low incidence of hypoglycemia and significant weight loss . The safety/tolerability profile of canagliflozin was favorable except for increased frequency of genital infections in females CONTEXT Dapagliflozin , a selective sodium-glucose cotransporter 2 ( SGLT2 ) inhibitor , reduces hyperglycemia in patients with type 2 diabetes mellitus ( T2DM ) by increasing urinary glucose excretion , and weight loss is a consistent associated finding . OBJECTIVES Our objectives were to confirm weight loss with dapagliflozin and establish through body composition measurements whether weight loss is accounted for by changes in fat or fluid components . DESIGN AND SETTING This was a 24-wk , international , multicenter , r and omized , parallel-group , double-blind , placebo-controlled study with ongoing 78-wk site- and patient-blinded extension period at 40 sites in five countries . PATIENTS Included were 182 patients with T2DM ( mean values : women 63.3 and men 58.6 yr of age ; hemoglobin A1c 7.17 % , body mass index 31.9 kg/m2 , and body weight 91.5 kg ) inadequately controlled on metformin . INTERVENTION Dapagliflozin 10 mg/d or placebo was added to open-label metformin for 24 wk . MAIN OUTCOME MEASURES Primary endpoint was total body weight ( TBW ) change from baseline at wk 24 . Key secondary endpoints were waist circumference and dual-energy x-ray absorptiometry total-body fat mass ( FM ) changes from baseline at wk 24 , and patient proportion achieving body weight reduction of at least 5 % at wk 24 . In a subset of patients , magnetic resonance assessment of visceral adipose tissue ( VAT ) and sc adipose tissue ( SAT ) volume and hepatic lipid content were also evaluated . RESULTS At wk 24 , placebo-corrected changes with dapagliflozin were as follows : TBW , -2.08 kg [ 95 % confidence interval (CI)=-2.84 to -1.31 ; P<0.0001 ] ; waist circumference , -1.52 cm ( 95 % CI=-2.74 to -0.31 ; P=0.0143 ) ; FM , -1.48 kg ( 95 % CI=-2.22 to -0.74 ; P=0.0001 ) ; proportion of patients achieving weight reduction of at least 5 % , + 26.2 % ( 95 % CI=15.5 to 36.7 ; P<0.0001 ) ; VAT , -258.4 cm3 ( 95 % CI=-448.1 to -68.6 ; nominal P=0.0084 ) ; SAT , -184.9 cm3 ( 95 % CI=-359.7 to -10.1 ; nominal P=0.0385 ) . In the dapagliflozin vs. placebo groups , respectively , serious adverse events were reported in 6.6 vs. 1.1 % ; events suggestive of vulvovaginitis , balanitis , and related genital infection in 3.3 vs. 0 % ; and lower urinary tract infections in 6.6 vs. 2.2 % . CONCLUSIONS Dapagliflozin reduces TBW , predominantly by reducing FM , VAT and SAT in T2DM inadequately controlled with metformin Background Despite the number of medications for type 2 diabetes , many people with the condition do not achieve good glycaemic control . Some existing glucose-lowering agents have adverse effects such as weight gain or hypoglycaemia . Type 2 diabetes tends to be a progressive disease , and most patients require treatment with combinations of glucose-lowering agents . The sodium glucose co-transporter 2 ( SGLT2 ) receptor inhibitors are a new class of glucose-lowering agents . Objective To assess the clinical effectiveness and safety of the SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes . Data sources MEDLINE , Embase , Cochrane Library ( all sections ) ; Science Citation Index ; trial registries ; conference abstract s ; drug regulatory authorities ; bibliographies of retrieved papers . Inclusion criteria R and omised controlled trials of SGLT2 receptor inhibitors compared with placebo or active comparator in type 2 diabetes in dual or combination therapy . Methods Systematic review . Quality assessment used the Cochrane risk of bias score . Results Seven trials , published in full , assessed dapagliflozin and one assessed canagliflozin . Trial quality appeared good . Dapagliflozin 10 mg reduced HbA1c by −0.54 % ( weighted mean differences ( WMD ) , 95 % CI −0.67 to −0.40 ) compared to placebo , but there was no difference compared to glipizide . Canagliflozin  reduced HbA1c slightly more than sitagliptin ( up to −0.21 % vs sitagliptin ) . Both dapagliflozin and canagliflozin  led to weight loss  ( dapagliflozin WMD −1.81 kg ( 95 % CI −2.04 to −1.57 ) , canagliflozin up to −2.3 kg compared to placebo ) . Limitations Long-term trial extensions suggested that effects were maintained over time . Data on canagliflozin are currently available from only one paper . Costs of the drugs are not known so cost-effectiveness can not be assessed . More data on safety are needed , with the Food and Drug Administration having concerns about breast and bladder cancers . Conclusions Dapagliflozin appears effective in reducing HbA1c and weight in type 2 diabetes , although more safety data are needed Aims /hypothesisThe aim of this work was to evaluate the efficacy and safety of canagliflozin vs placebo and sitagliptin in patients with type 2 diabetes who were being treated with background metformin . Methods This r and omised , double-blind , four-arm , parallel-group , Phase 3 study was conducted at 169 centres in 22 countries between April 2010 and 
    Output:
    
Incidence of suspected genital infections was slightly more in SGLT-2 inhibitor-MET group .