***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 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 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 Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more 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 Chronic hyperglycemia impairs insulin action , result ing in glucotoxicity , which can be ameliorated in animal models by inducing glucosuria with renal glucose transport inhibitors . Here , we examined whether reduction of plasma glucose with a sodium-glucose cotransporter 2 ( SGLT2 ) inhibitor could improve insulin-mediated tissue glucose disposal in patients with type 2 diabetes . Eighteen diabetic men were r and omized to receive either dapagliflozin ( n = 12 ) or placebo ( n = 6 ) for 2 weeks . We measured insulin-mediated whole body glucose uptake and endogenous glucose production ( EGP ) at baseline and 2 weeks after treatment using the euglycemic hyperinsulinemic clamp technique . Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose . Insulin-mediated tissue glucose disposal increased by approximately 18 % after 2 weeks of dapagliflozin treatment , while placebo-treated subjects had no change in insulin sensitivity . Surprisingly , following dapagliflozin treatment , EGP increased substantially and was accompanied by an increase in fasting plasma glucagon concentration . Together , our data indicate that reduction of plasma glucose with an agent that works specifically on the kidney to induce glucosuria improves muscle insulin sensitivity . However , glucosuria induction following SGLT2 inhibition is associated with a paradoxical increase in EGP . These results provide support for the glucotoxicity hypothesis , which suggests that chronic hyperglycemia impairs insulin action in individuals with type 2 diabetes AIMS To evaluate the effects of the sodium glucose cotransporter 2 ( SGLT2 ) inhibitor empagliflozin added to metformin for 12 weeks in patients with type 2 diabetes . METHODS This dose-ranging , double-blind , placebo-controlled trial r and omized 495 participants with type 2 diabetes inadequately controlled on metformin [ haemoglobin A1c ( HbA1c ) > 7 to ≤10 % ] to receive 1 , 5 , 10 , 25 , or 50 mg empagliflozin once daily ( QD ) , or placebo , or open-label sitagliptin ( 100 mg QD ) , added to metformin for 12 weeks . The primary endpoint was change in HbA1c from baseline to week 12 ( empagliflozin groups versus placebo ) . RESULTS Reductions in HbA1c of -0.09 to -0.56 % were observed with empagliflozin after 12 weeks , versus an increase of 0.15 % with placebo ( baseline : 7.8 - 8.1 % ) . Compared with placebo , empagliflozin doses from 5 to 50 mg result ed in reductions in fasting plasma glucose ( -2 to -28 mg/dl vs. 5 mg/dl with placebo ; p < 0.0001 ) and body weight ( -2.3 to -2.9 kg vs. -1.2 kg ; p < 0.01 ) . Frequency of adverse events was generally similar with empagliflozin ( 29.6 - 48.6 % ) , placebo ( 36.6 % ) and sitagliptin ( 35.2 % ) . Hypoglycaemia rates were very low and balanced among groups . Most frequent adverse events with empagliflozin  were urinary tract infections ( 4.0 % vs. 2.8 % with placebo ) and pollakiuria ( 2.5 % vs. 1.4 % with placebo ) . Genital infections were reported only with empagliflozin ( 4.0 % ) . CONCLUSIONS Once daily empagliflozin as add-on therapy to metformin was well tolerated except for increased genital infections and result ed in reductions in HbA1c , fasting plasma glucose and body weight in patients with type 2 diabetes inadequately controlled on metformin monotherapy To investigate the long‐term efficacy and safety of 
    Output:
    
In addition , EMPA as add-on to MET also had a favourable effect on body weight and blood pressure .
Conclusions EMPA as add-on to MET was well tolerated and provided additional benefits beyond glucose lowering , such as weight loss and blood pressure reduction .