***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: Patients with type 2 diabetes mellitus ( T2DM ) with a glycated haemoglobin ( HbA1c ) level ≥7 and ≤10 % were r and omized to receive empagliflozin 12.5 mg twice daily ( n = 219 ) , 25 mg once daily ( n = 218 ) , 5 mg twice daily ( n = 219 ) or 10 mg once daily ( n = 220 ) , or placebo ( n = 107 ) as add‐on to stable‐dose metformin immediate release ( IR ) twice daily for 16 weeks . The primary endpoint was change from baseline in HbA1c at week 16 . At week 16 , change from baseline in HbA1c  with empagliflozin twice daily was non‐inferior to empagliflozin once daily and vice versa . The adjusted mean ( 95 % confidence interval ) difference in change from baseline in HbA1c with empagliflozin 12.5 mg twice daily versus 25 mg once daily was −0.11 % ( −0.26 , 0.03 ) , and with empagliflozin 5 mg twice daily versus 10 mg once daily it was −0.02 % ( −0.16 , 0.13 ) . All empagliflozin regimens were well tolerated ; thus , when used as add‐on to metformin IR in patients with T2DM , the therapeutic effect of empagliflozin twice‐daily and once‐daily regimens can be considered equivalent OBJECTIVE This study compared the efficacy and safety of initial combinations of empagliflozin + metformin with empagliflozin and metformin monotherapy in patients with type 2 diabetes . RESEARCH DESIGN AND METHODS The study r and omized 1,364 drug-naïve patients ( HbA1c > 7.5 to ≤12 % [ > 58 to ≤108 mmol/mol ] ) for 24 weeks to empagliflozin 12.5 mg b.i.d . + metformin 1,000 mg b.i.d . , empagliflozin 12.5 mg b.i.d . + metformin 500 mg b.i.d . , empagliflozin 5 mg b.i.d + metformin 1,000 mg b.i.d . , empagliflozin 5 mg b.i.d . + metformin 500 mg b.i.d . , empagliflozin 25 mg q.d . , empagliflozin 10 mg q.d . , metformin 1,000 mg b.i.d . , or metformin 500 mg b.i.d . The primary end point was change from baseline in HbA1c at week 24 . RESULTS At week 24 , reductions in HbA1c ( mean baseline 8.6–8.9 % [ 70–73 mmol/mol ] ) were −1.9 to −2.1 % with empagliflozin + metformin twice-daily regimens , −1.4 % with both empagliflozin once-daily regimens , and −1.2 to −1.8 % with metformin twice-daily regimens . Reductions in HbA1c were significantly greater with empagliflozin + metformin twice-daily regimens than with empagliflozin once-daily regimens ( P < 0.001 ) and with metformin twice-daily regimens ( P < 0.01 ) . Reductions in weight at week 24 were significantly greater with empagliflozin + metformin twice-daily regimens ( range −2.8 to −3.8 kg ) than with metformin twice-daily regimens ( −0.5 to −1.3 kg ) ( P < 0.001 for all ) . Adverse event ( AE ) rates were similar across groups ( 56.7–66.3 % ) . No hypoglycemic AEs required assistance . CONCLUSIONS Initial combinations of empagliflozin + metformin for 24 weeks significantly reduced HbA1c versus empagliflozin once daily and metformin twice daily , without increased hypoglycemia , reduced weight versus metformin twice daily , and were well tolerated 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 OBJECTIVE To evaluate the efficacy and safety of combinations of empagliflozin/linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin . RESEARCH DESIGN AND METHODS Subjects were r and omized to a combination of empagliflozin 25 mg/linagliptin 5 mg ( n = 137 ) , empagliflozin 10 mg/linagliptin 5 mg ( n = 136 ) , empagliflozin 25 mg ( n = 141 ) , empagliflozin 10 mg ( n = 140 ) , or linagliptin 5 mg ( n = 132 ) as add-on to metformin for 52 weeks . The primary end point was change from baseline in HbA1c at week 24 . RESULTS At week 24 , reductions in HbA1c ( mean baseline 7.90–8.02 % [ 62.8–64.1 mmol/mol ] ) with empagliflozin/linagliptin were superior to those with empagliflozin or linagliptin alone as add-on to metformin ; adjusted mean ( SE ) changes from baseline were −1.19 % ( 0.06 ) ( −13.1 mmol/mol [ 0.7 ] ) with empagliflozin 25 mg/linagliptin 5 mg , −1.08 % ( 0.06 ) ( −11.8 mmol/mol [ 0.7 ] ) with empagliflozin 10 mg/linagliptin 5 mg , −0.62 % ( 0.06 ) ( −6.8 mmol/mol [ 0.7 ] ) with empagliflozin 25 mg , −0.66 % ( 0.06 ) ( −7.2 mmol/mol [ 0.7 ] ) with empagliflozin 10 mg , and −0.70 % ( 0.06 ) ( −7.6 mmol/mol [ 0.7 ] ) with linagliptin 5 mg ( P < 0.001 for all comparisons ) . In these groups , respectively , 61.8 , 57.8 , 32.6 , 28.0 , and 36.1 % of subjects with baseline HbA1c ≥7 % ( ≥53 mmol/mol ) had HbA1c < 7 % ( < 53 mmol/mol ) at week 24 . Efficacy was maintained at week 52 . The proportion of subjects with adverse events ( AEs ) over 52 weeks was similar across treatment arms ( 68.6–73.0 % ) , with no hypoglycemic AEs requiring assistance . CONCLUSIONS Combinations of empagliflozin/linagliptin as second-line therapy for 52 weeks significantly reduced HbA1c compared with the individual components and were well tolerated OBJECTIVE To investigate the efficacy , safety , and tolerability of empagliflozin in patients with type 2 diabetes and hypertension . RESEARCH DESIGN AND METHODS Patients ( N = 825 ) with type 2 diabetes and hypertension ( mean seated systolic blood pressure [ SBP ] 130–159 mmHg and diastolic blood pressure [ DBP ] 80–99 mmHg ) were r and omized ( double blind ) to 10 mg or 25 mg empagliflozin or placebo once daily for 12 weeks . RESULTS At week 12 , adjusted mean difference versus placebo in change from baseline in mean 24-h SBP ( ambulatory blood pressure monitoring [ ABPM ] ) was −3.44 mmHg ( 95 % CI −4.78 , −2.09 ) with 10 mg empagliflozin and −4.16 mmHg ( −5.50 , −2.83 ) with 25 mg empagliflozin ( both P < 0.001 ) . At week 12 , adjusted mean difference versus placebo in change from baseline in mean 24-h DBP ( ABPM ) was −1.36 mmHg ( 95 % CI −2.15 , −0.56 ) with 10 mg empagliflozin and −1.72 mmHg ( 95 % CI −2.51 , −0.93 ) with 25 mg empagliflozin ( both P < 0.001 ) . Changes in office BP were consistent with ABPM . Adjusted mean difference versus placebo in change from baseline in HbA1c at week 12 was −0.62 % ( 95 % CI −0.72 , −0.52 ) ( −6.8 mmol/mol [ 95 % CI −7.9 , −5.7 ] ) with 10 mg empagliflozin and −0.65 % ( 95 % CI −0.75 , −0.55 ) ( −7.1 mmol/mol [ 95 % CI −8.2 , −6.0 ] ) with 25 mg empagliflozin ( both P < 0.001 )  . Empagliflozin was well tolerated . One patient on placebo and one patient on 10 mg empagliflozin reported events consistent with volume depletion . CONCLUSIONS Empagliflozin was associated with significant and clinical ly meaningful reductions in BP and HbA1c versus placebo and was well tolerated in patients with type 2 diabetes and hypertension This r and omized , double-blind , placebo-controlled study evaluated the early effects of canagliflozin on blood pressure ( BP ) in patients with type 2 diabetes mellitus ( T2DM ) and hypertension . Patients were r and omized to canagliflozin 300 mg , canagliflozin 100 mg , or placebo for 6 weeks and underwent 24-hour ambulatory BP monitoring before r and omization , on day 1 of treatment , and after 6 weeks . The primary endpoint was change in mean 24-hour systolic BP ( SBP ) from baseline to week 6 . Overall , 169 patients were included ( mean age , 58.6 years ; glycated hemoglobin , 8.1 % ; seated BP 138.5/82.7 mm Hg ) . At week 6 , canagliflozin 300 mg provided greater reductions in mean 24-hour SBP than placebo ( least squares mean -6.2 vs -1.2 mm Hg , respectively ; P=.006 ) . Numerical reductions in SBP were observed with canagliflo 
    Output:
    
No increased risk for either outcome was found when compared with active controls .
Subgroup analysis did show an increased risk of UTI  with dapagliflozin only ( RR 1.21 ; 95 % CI 1.02 to 1.43 , I2=0.0 % ) , but no other analysis supported an increased risk of AKI , DKA , UTI or fracture .
CONCLUSIONS Current evidence from RCTs does not suggest an increased risk of harm with SGLT2 inhibitors as a class over placebo or active comparators with respect to AKI , DKA , UTI or fracture .
Dapagliflozin , appears to independently increase the risk of UTI , although the mechanism for this intraclass variation in risk is unclear .