***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: CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes ( NCT01243424 ) is an ongoing , r and omized trial in subjects with early type 2 diabetes and increased cardiovascular risk or established complications that will determine the long-term cardiovascular impact of linagliptin versus the sulphonylurea glimepiride .  Eligible patients were sulphonylurea-naïve with HbA1c 6.5%–8.5 % or previously exposed to sulphonylurea ( in monotherapy or in a combination regimen < 5 years ) with HbA1c 6.5%–7.5 % . Primary outcome is time to first occurrence of cardiovascular death , non-fatal myocardial infa rct ion , non-fatal stroke or hospitalization for unstable angina .  A total of 631 patients with primary outcome events will be required to provide 91 % power to demonstrate non-inferiority in cardiovascular safety by comparing the upper limit of the two-sided 95 % confidence interval as being below 1.3 for a given hazard ratio . Hierarchical testing for superiority will follow , and the trial has 80 % power to demonstrate a 20 % relative cardiovascular risk reduction . A total of 6041 patients were treated with median type 2 diabetes duration 6.2 years , 40.0 % female , mean HbA1c 7.2 % , 66 % on 1 and 24 % on 2 glucose-lowering agents and 34.5 % had previous cardiovascular complications . The results of CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes may influence the decision-making process for selecting a second glucose-lowering agent after metformin in type 2 diabetes BACKGROUND The cardiovascular safety and efficacy of many current antihyperglycemic agents , including saxagliptin , a dipeptidyl peptidase 4 ( DPP-4 ) inhibitor , are unclear . METHODS We r and omly assigned 16,492 patients with type 2 diabetes who had a history of , or were at risk for , cardiovascular events to receive saxagliptin or placebo and followed them for a median of 2.1 years . Physicians were permitted to adjust other medications , including antihyperglycemic agents . The primary end point was a composite of cardiovascular death , myocardial infa rct ion , or ischemic stroke . RESULTS A primary end-point event occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group ( 7.3 % and 7.2 % , respectively , according to 2-year Kaplan-Meier estimates ; hazard ratio with saxagliptin , 1.00 ; 95 % confidence interval [ CI ] , 0.89 to 1.12 ; P=0.99 for superiority ; P<0.001 for noninferiority ) ; the results were similar in the " on-treatment " analysis ( hazard ratio , 1.03 ; 95 % CI , 0.91 to 1.17 ) . The major secondary end point of a composite of cardiovascular death , myocardial infa rct ion , stroke , hospitalization for unstable angina , coronary revascularization , or heart failure occurred in 1059 patients in the saxagliptin group and in 1034 patients in the placebo group ( 12.8 % and 12.4 % , respectively , according to 2-year Kaplan-Meier estimates ; hazard ratio , 1.02 ; 95 % CI , 0.94 to 1.11 ; P=0.66 ) . More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure ( 3.5 % vs. 2.8 % ; hazard ratio , 1.27 ; 95 % CI , 1.07 to 1.51 ; P=0.007 ) . Rates of adjudicated cases of acute and chronic pancreatitis were similar in the two groups ( acute pancreatitis , 0.3 % in the saxagliptin group and 0.2 % in the placebo group ; chronic pancreatitis , < 0.1 % and 0.1 % in the two groups , respectively ) . CONCLUSIONS DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events , though the rate of hospitalization for heart failure was increased . Although saxagliptin improves glycemic control , other approaches are necessary to reduce cardiovascular risk in patients with diabetes . ( Funded by AstraZeneca and Bristol-Myers Squibb ; SAVOR-TIMI 53 Clinical Trials.gov number , NCT01107886 . ) OBJECTIVE The epidemic of type 2 diabetes ( T2DM ) threatens to become the major public health problem of this century . However , a comprehensive comparison of the long-term effects of medications to treat T2DM has not been conducted . GRADE , a pragmatic , unmasked clinical trial , aims to compare commonly used diabetes medications , when combined with metformin , on glycemia-lowering effectiveness and patient-centered outcomes . RESEARCH DESIGN AND METHODS GRADE was design ed with support from a U34 planning grant from the National Institute of Diabetes and Digestive and Kidney Diseases ( NIDDK ) . The consensus protocol was approved by NIDDK and the GRADE Research Group . Eligibility criteria for the 5,000 metformin-treated subjects include < 5 years ' diabetes duration , ≥30 years of age at time of diagnosis , and baseline hemoglobin A1c ( A1C ) of 6.8–8.5 % ( 51–69 mmol/mol ) . Medications representing four classes ( sulfonylureas , dipeptidyl peptidase 4 inhibitors , glucagon-like peptide 1 receptor agonists , and insulin ) will be r and omly assigned and added to metformin ( minimum – maximum 1,000–2,000 mg/day ) . The primary metabolic outcome is the time to primary failure defined as an A1C ≥7 % ( 53 mmol/mol ) , subsequently confirmed , over an anticipated mean observation period of 4.8 years ( range 4–7 years ) . Other long-term metabolic outcomes include the need for the addition of basal insulin after a confirmed A1C > 7.5 % ( 58 mmol/mol ) and , ultimately , the need to implement an intensive basal/bolus insulin regimen . The four drugs will also be compared with respect to selected microvascular complications , cardiovascular disease risk factors , adverse effects , tolerability , quality of life , and cost-effectiveness . CONCLUSIONS GRADE will compare the long-term effectiveness of major glycemia-lowering medications and provide guidance to clinicians about the most appropriate medications to treat T2DM . GRADE begins recruitment at 37 centers in the U.S. in 2013 Aims /hypothesisThe aims of this work were to assess glycaemic control in  metformin users receiving their first add-on glucose-lowering therapy and to examine the real-life effectiveness of different add-on drugs . Methods We carried out a population -based cohort study using healthcare data bases in northern Denmark during 2000–2012 . We included 4,734 persons who initiated metformin monotherapy and added another glucose-lowering drug within 3 years . Attainment of recommended HbA1c goals within 6 months of add-on was investigated , using Poisson regression analysis adjusted for age , sex , baseline HbA1c , diabetes duration , complications and Charlson Comorbidity Index . Results Median  metformin treatment duration at intensification was 12 months ( interquartile range [ IQR ] 4–23 months ) and pre-intensification HbA1c was 8.0 % ( IQR 7.2–9.2 % ) ( 64 [ IQR 55–77 ] mmol/mol ) . Median HbA1c dropped 1.2 % ( 13 mmol/mol ) with a sulfonylurea ( SU ) add-on , 0.8 % ( 9 mmol/mol ) with a dipeptidyl peptidase-4 ( DPP-4 ) inhibitor , 1.3 % ( 14 mmol/mol ) with a glucagon-like peptide-1 ( GLP-1 ) receptor agonist , 0.9 % ( 10 mmol/mol ) with other non-insulin drugs and 2.4 % ( 26 mmol/mol ) with insulin . Compared with SU add-on , attainment of HbA1c < 7 % ( < 53 mmol/mol ) was higher with GLP-1 receptor agonists ( adjusted RR [ aRR ] 1.10 ; 95 % CI 1.01 , 1.19 ) and lower with DPP-4 inhibitors ( aRR 0.94 ; 95 % CI 0.89 , 0.99 ) , other drugs ( aRR 0.86 ; 95 % CI 0.77 , 0.96 ) and insulin ( aRR 0.88 ; 95 % CI 0.77 , 0.99 ) . The proportion of metformin add-on users who attained HbA1c < 7 % ( < 53 mmol/mol ) increased from 46 % in 2000–2003 to 59 % in 2010–2012 , whereas attainment of HbA1c < 6.5 % ( < 48 mmol/mol ) remained 30 % among patients aged < 65 years without comorbidities . Conclusions /interpretationAmong early type 2 diabetes patients receiving their first metformin add-on treatment , HbA1c reduction with different non-insulin drugs is similar to , and comparable with , that observed in r and omised trials , yet 41 % do not achieve HbA1c < 7 % ( < 53 mmol/mol ) within 6 months OBJECTIVE To compare the efficacy and safety of weekly albiglutide with daily sitagliptin , daily glimepiride , and placebo . Research Design And Methods Patients with type 2 diabetes receiving metformin were r and omized to albiglutide ( 30 mg ) , sitagliptin ( 100 mg ) , glimepiride ( 2 mg ) , or placebo . Blinded dose titration for albiglutide ( to 50 mg ) and glimepiride ( to 4 mg ) was based on predefined hyperglycemia criteria . The primary end point was change in HbA1c from baseline at week 104 . Secondary end points included fasting plasma glucose ( FPG ) , weight , and time to hyperglycemic rescue . RESULTS Baseline characteristics were similar among the albiglutide ( n = 302 ) , glimepiride ( n = 307 ) , sitagliptin ( n = 302 ) , and placebo ( n = 101 ) groups .  Baseline HbA1c was 8.1 % ( 65.0 mmol/mol ) ; mean age was 54.5 years . The mean doses for albiglutide and glimepiride at week 104 were 40.5 and 3.1 mg , respectively . At week 104 , albiglutide significantly reduced HbA1c compared with placebo ( −0.9 % [ −9.8 mmol/mol ] ; P < 0.0001 ) , sitagliptin ( −0.4 % [ −4.4 mmol/mol ] ; P = 0.0001 ) , and glimepiride ( −0.3 % [ −3.3 mmol/mol ] ; P = 0.0033 ) . Outcomes for FPG and HbA1c were similar . Weight change from baseline for each were as follows : albiglutide −1.21 kg ( 95 % CI −1.68 to −0.74 ) , placebo −1.00 kg ( 95 % CI −1.81 to −0.20 ) , sitagliptin −0.86 kg ( 95 % CI −1.32 to −0.39 ) , glimepiride 1.17 kg ( 95 % CI 0.70–1.63 ) . The difference between albiglutide and glimepiride was statistically significant ( P < 0.0001 ) . Hyperglycemic rescue rate at week 104 was 25.8 % for albiglutide compared with 59.2 % ( P < 0.0001 ) , 36.4 % ( P = 0.0118 ) , and 32.7 % ( P = 0.1504 ) for placebo , sitagliptin , and glimepiride , respectively . Rates of serious adverse events in the albiglutide group were similar to comparison groups . Diarrhea ( albiglutide 12.9 % , other groups 8.6–10.9 % ) and nausea ( albiglutide 10.3 % , other groups 6.2–10.9 % ) were generally the most frequently reported gastrointestinal events . CONCLUSIONS Added to metformin , albiglutide was well tolerated ; produced superior reductions in HbA1c and FPG at week 104 compared with placebo , sitaglipt 
    Output:
    
Similar change was observed across most other effectiveness outcomes reported .