***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: ABSTRACT Review of : Neal B , Perkovic V , Mahaffey K , et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes . N Engl J Med . 2017;377:644–657 . The report combines the data from two trials , CANVAS and CANVAS-Renal , which were design ed to evaluate the safety and effect of canagliflozin , an SGLT-2 inhibitor , on the appearance of cardiovascular and renal events in patients with type 2 diabetes . Enrollees were patients with type 2 diabetes of at least 30 years of age , with a glycated hemoglobin of > or equal to 7.0 % and < or equal to 10.5 % . Patients either had to have preexisting cardiovascular disease or to be at elevated risk for cardiovascular disease , and to have an estimated glomerular filtration rate ( eGFR ) of > 30 ml/min . Patients were r and omized to canagliflozin at doses of either 100 mg or 300 mg or matching placebo in CANVAS , and to canagliflozin 100 mg with a possible increase to 300 mg , or placebo , in CANVAS-Renal . Physicians were instructed to continue appropriate diabetic management and other therapies in accordance with the best practice s in their community . There was a significant 14 % reduction in the combined endpoint of cardiovascular events of death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke in the canagliflozin treated patients . There was also a pattern of improvement in markers of renal disease , including the change in the level and nature of albuminuria , a 40 % decrease in the glomerular filtration rate , the need for renal replacement therapy , or death from renal causes . This study exp and s the scope of SGLT-2 inhibitor therapy to prevent cardiovascular disease in diabetic patients beyond those with preexisting cardiovascular disease studied in the previous empagliflozin study , raising the question as to whether SGLT-2 inhibitor therapy should be considered appropriate for most , if not all , type 2 diabetes patients , not only to control hyperglycemia but also to reduce cardiovascular and renal events Abstract Introduction To evaluate the pharmacodynamics , pharmacokinetics , safety and tolerability of empagliflozin in Japanese patients with type 2 diabetes mellitus . Material s and methods In this 4‐week , multiple dose , r and omized , parallel‐group , double‐blind , placebo‐controlled trial , patients ( n = 100 ) were r and omized to receive 1 , 5 , 10 or 25 mg of empagliflozin , or placebo once daily . Key end‐points were urinary glucose excretion ( UGE ) , fasting plasma glucose ( FPG ) and eight‐point glucose profile . Results Data are presented for 1 , 5 , 10 , 25 mg of empagliflozin and placebo groups , respectively . Adjusted mean changes from baseline to day 27 in UGE were 40.8 , 77.1 , 80.9 , 93.0 and −2.1 g ( P < 0.0001 for all empagliflozin groups vs placebo ) . Adjusted mean changes from baseline to day 28 in FPG were −1.56 , −1.96 , −2.31 , −2.37 and −0.86 mmol/L ( P < 0.01 for all empagliflozin groups vs placebo ) . Adjusted mean changes from baseline to day 27 in eight‐point glucose profile were −1.96 , −2.21 , −2.42 , −2.54 and −0.97 mmol/L ( P < 0.01 for all empagliflozin groups vs placebo ) . Empagliflozin  reached peak plasma concentration 1.5–2 h after dosing . Mean steady state terminal elimination half‐lives ranged from 13.2 to 18.0 h. Of 100 patients , 25 experienced an adverse event , occurring more frequently for empagliflozin ( 29.1 % ) than placebo ( 9.5 % ) ; frequency was not dose related . Conclusions In Japanese patients with type 2 diabetes mellitus , empagliflozin at doses up to 25 mg once daily for 4 weeks was well tolerated and result ed in significant improvements in glycemic control compared with placebo . This trial was registered with Clinical Trials.gov ( no. NCT00885118 ) Introduction Canagliflozin is a sodium glucose co-transporter 2 inhibitor approved worldwide for the treatment of patients with type 2 diabetes mellitus ( T2DM ) . The present study evaluated pharmacokinetics , pharmacodynamics , and safety of canagliflozin in Japanese patients with T2DM . Methods Canagliflozin , at doses of 25 , 100 , 200 , or 400 mg , was administered as a single dose and , after a washout of 1 day , in repeated doses for 14 consecutive days to 61 subjects in a r and omized , double-blind ,  placebo-controlled  study . Plasma concentrations of canagliflozin and urinary glucose excretion ( UGE ) were measured , and renal threshold for glucose excretion ( RTG ) was calculated . Safety was evaluated on the basis of adverse event ( AE ) reports , blood and urine laboratory parameters , and vital signs . Results Plasma canagliflozin maximum concentration and area under the concentration – time curve ( AUC ) values increased in a dose-dependent manner with the time to maximum concentration ( tmax ) of 1.0 h and elimination half-life ( t1/2 ) of 10.22–13.26 h on Day 1 . No significant changes in tmax and t1/2 were observed after multiple-dose administration . The linearity factors , as calculated from the ratios of AUC0–24h on Day 16 to AUC0–∞ on Day 1 , were close to 1 in all canagliflozin groups . Canagliflozin  increased UGE0–24h ( 80–110 g/day with canagliflozin ≥100 mg ) and decreased RTG from the first day of treatment ; these effects were sustained during the entire period of multiple administration . No significant AEs were noted . Urine volume was slightly increased on Day 1 , but subsequent changes after repeated doses for 14 days were small . Urinary sodium tended to be higher in the early treatment period , whereas no particular change was observed in serum osmolality and hematocrit . Conclusion Canagliflozin  increased UGE , decreased RTG , and was well tolerated throughout the entire period of multiple administrations in Japanese patients with T2DM . Funding Mitsubishi Tanabe Pharma Corporation . Trial registration Clinical Trials.gov#NCT00707954 BACKGROUND Combining metformin ( XR ) with dapagliflozin to initiate pharmacotherapy in patients with type 2 diabetes ( T2D ) and high baseline HbA1c may be advantageous . We conducted two r and omised , double-blind , three-arm 24-week trials in treatment-naïve patients to compare dapagliflozin plus metformin , dapagliflozin alone and metformin alone . METHODS Eligible patients had baseline HbA1c 7.5 - 12 % . Each trial had three arms : dapagliflozin plus metformin , dapagliflozin monotherapy and metformin monotherapy . Dapagliflozin in combination and as monotherapy was dosed at 5 mg ( Study 1 ) and 10 mg ( Study 2 ) . Metformin in combination and as monotherapy was titrated to 2000 mg . The primary endpoint was HbA1c change from baseline ; secondary endpoints included change in fasting plasma glucose ( FPG ) and weight . RESULTS In both trials , combination therapy led to significantly greater reductions in HbA1c compared with either monotherapy : -2.05 for dapagliflozin + metformin , -1.19 for dapagliflozin , and -1.35 for metformin ( p < 0.0001 ) ( Study 1 ) ; -1.98 for dapagliflozin + metformin , -1.45 for dapagliflozin and -1.44 for metformin ( p < 0.0001 ) ( Study 2 ) . Combination therapy was statistically superior to monotherapy in reduction of FPG ( p < 0.0001 for both studies ) ; combination therapy was more effective than metformin for weight reduction ( p < 0.0001 ) . Dapagliflozin 10 mg was non-inferior to metformin in reducing HbA1c ( Study 2 ) . Events suggestive of genital infection were reported in 6.7 % , 6.9 % and 2.0 % ( Study 1 ) and 8.5 % , 12.8 % and 2.4 % ( Study 2 ) of patients in combination , dapagliflozin and metformin groups ; events suggestive of urinary tract infection were reported in 7.7 % , 7.9 % and 7.5 % ( Study 1 ) and 7.6 % , 11.0 % and 4.3 % ( Study 2 ) of patients in the respective groups . No major hypoglycaemia was reported . CONCLUSION In treatment-naïve patients with T2D , dapagliflozin plus metformin was generally well tolerated and effective in reducing HbA1c , FPG and weight .  Dapagliflozin-induced glucosuria led to an increase in events suggestive of urinary tract and genital infections OBJECTIVE To investigate the long-term safety and efficacy of empagliflozin , a sodium glucose cotransporter 2 inhibitor ; sitagliptin ; and metformin in patients with type 2 diabetes . RESEARCH DESIGN AND METHODS In this r and omized , open-label , 78-week extension study of two 12-week , blinded , dose-finding studies of empagliflozin ( monotherapy and add-on to metformin ) with open-label comparators , 272 patients received 10 mg empagliflozin ( 166 as add-on to metformin ) , 275 received 25 mg empagliflozin ( 166 as add-on to metformin ) , 56 patients received metformin , and 56 patients received sitagliptin as add-on to metformin . RESULTS Changes from baseline in HbA1c at week 90 were −0.34 to −0.63 % ( −3.7 to −6.9 mmol/mol ) with empagliflozin , −0.56 % ( −6.1 mmol/mol ) with metformin , and −0.40 % ( −4.4 mmol/mol ) with sitagliptin . Changes from baseline in weight at week 90 were −2.2 to −4.0 kg with empagliflozin , −1.3 kg with metformin , and −0.4 kg with sitagliptin  . Adverse events ( AEs ) were reported in 63.2–74.1 % of patients on empagliflozin and 69.6 % on metformin or sitagliptin ; most AEs were mild or moderate in intensity . Hypoglycemic events were rare in all treatment groups , and none required assistance . AEs consistent with genital infections were reported in 3.0–5.5 % of patients on empagliflozin , 1.8 % on metformin , and none on sitagliptin . AEs consistent with urinary tract infections were reported in 3.8–12.7 % of patients on empagliflozin , 3.6 % on metformin , and 12.5 % on sitagliptin . CONCLUSIONS Long-term empagliflozin treatment provided sustained glycemic and weight control and was well tolerated with a low risk of hypoglycemia in patients with type 2 diabetes OBJECTIVE To assess the dose-ranging efficacy and safety of LX4211 , a dual inhibitor of sodium – glucose cotransporter ( SGLT ) 1 and SGLT2 , in type 2 diabetes . RESEARCH DESIGN AND METHODS Type 2 diabetic patients inadequately controlled on metformin were r and omly assigned to 75 mg once daily , 200 mg once daily , 200 mg twice daily , or 400 mg once daily of LX4211 or placebo . Primary end point was A1C change from baseline to week 12 . Secondary end points included changes in blood pressure ( BP ) and body weight . RESULTS Baseline characteristics in 299 patients r and omly assigned to LX4211 or placebo in this 12-week dose-ranging study were similar : mean age 55.9 years , A1C 8.1 % ( 65 mmol/mol ) , BMI 33.1 kg/m2 , and BP 124/79 mmHg .  LX4211 significantly reduced A1C to week 12 in a dose-dependent manner by 0.42 % ( 4.6 mmol/mol ) , 0.52 % ( 5.7 mmol/mol ) 
    Output:
    
INTERPRETATION Current RCT evidence does not suggest a dose-response relation between most SGLT2 inhibitors and UTIs , with the exception of dapagliflozin .