***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: Background — Diabetes mellitus and heart failure frequently coexist . However , few diabetes mellitus trials have prospect ively evaluated and adjudicated heart failure as an end point . Methods and Results — A total of 16 492 patients with type 2 diabetes mellitus and a history of , or at risk of , cardiovascular events were r and omized to saxagliptin or placebo  ( mean follow-up , 2.1 years ) . The primary end point was the composite of cardiovascular death , myocardial infa rct ion , or ischemic stroke . Hospitalization for heart failure was a predefined component of the secondary end point . Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients . More patients treated with saxagliptin ( 289 , 3.5 % ) were hospitalized for heart failure compared with placebo ( 228 , 2.8 % ; hazard ratio , 1.27 ; 95 % confidence intercal , 1.07–1.51 ; P=0.007 ) . Corresponding rates at 12 months were 1.9 % versus 1.3 % ( hazard ratio , 1.46 ; 95 % confidence interval , 1.15–1.88 ; P=0.002 ) , with no significant difference thereafter ( time-varying interaction , P=0.017 ) . Subjects at greatest risk of hospitalization for heart failure had previous heart failure , an estimated glomerular filtration rate ⩽60 mL/min , or elevated baseline levels of N-terminal pro B-type natriuretic peptide . There was no evidence of heterogeneity between N-terminal pro B-type natriuretic peptide and saxagliptin ( P for interaction=0.46 ) , although the absolute risk excess for heart failure with saxagliptin was greatest in the highest N-terminal pro B-type natriuretic peptide quartile ( 2.1 % ) . Even in patients at high risk of hospitalization for heart failure , the risk of the primary and secondary end points were similar between treatment groups . Conclusions — In the context of balanced primary and secondary end points , saxagliptin treatment was associated with an increased risk or hospitalization for heart failure . This increase in risk was highest among patients with elevated levels of natriuretic peptides , previous heart failure , or chronic kidney disease . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT01107886 Abbreviations ACCORD Action to Control Cardiovascular Risk in Diabetes ADVANCE Action in Diabetes and Vascular Disease : Preterax and Diamicron Modified-Release Controlled Evaluation AGI α-Glucosidase inhibitor  CAD Coronary artery disease CKD Chronic kidney disease CVD Cardiovascular disease DPP-4 Dipeptidyl peptidase IV GIP Glucose-dependent insulinotropic peptide GLP-1 Glucagon-like peptide 1 NPH Neutral protamine Hagedorn TZD Thiazolidinedione UKPDS UK Prospect i ve Diabetes Study VADT Veterans Affairs Diabetes Background In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes , treatment with sitagliptin  , a dipeptidyl peptidase-4 ( DPP-4 ) inhibitor , was shown to be generally well tolerated compared with treatment with control agents . As clinical development of sitagliptin continues , additional studies have been completed , and more patients have been exposed to sitagliptin . The purpose of the present analysis is to up date the safety and tolerability assessment of sitagliptin by pooling data from 19 double-blind clinical studies . Methods The present analysis included data from 10,246 patients with type 2 diabetes who received either sitagliptin 100 mg/day ( N = 5,429 ; sitagliptin group ) or a comparator agent ( placebo or an active comparator ) ( N = 4,817 ; non-exposed group ) . The 19 studies from which this pooled population was drawn represent the double-blind , r and omized studies that included patients treated with the usual clinical dose of sitagliptin ( 100 mg/day ) for between 12 weeks and 2 years and for which results were available as of July 2009 . These 19 studies assessed sitagliptin taken as monotherapy , initial combination therapy with metformin or pioglitazone , or as add-on combination therapy with other antihyperglycemic agents ( metformin , pioglitazone , a sulfonylurea ± metformin , insulin ± metformin , or rosiglitazone + metformin ) . Patients in the non-exposed group were taking placebo , metformin , pioglitazone , a sulfonylurea ± metformin , insulin ± metformin , or rosiglitazone + metformin . The analysis used patient-level data from each study to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events . Results Summary measures of overall adverse events were similar in the sitagliptin and non-exposed groups , except for an increased incidence of drug-related adverse events in the non-exposed group . Incidence rates of specific adverse events were also generally similar between the two groups , except for increased incidence rates of hypoglycemia , related to the greater use of a sulfonylurea , and diarrhea , related to the greater use of metformin , in the non-exposed group and constipation in the sitagliptin group . Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events . Conclusions In this up date d pooled safety analysis of data from 10,246 patients with type 2 diabetes  , sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration 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 R and omized treatment comparing an intensive glycemic treatment strategy with a st and ard strategy in the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial was ended early because of an unexpected excess of mortality in the intensive arm . As part of ongoing post hoc analyses of potential mechanisms for this finding , we explored whether on-treatment A1C itself had an independent relationship with mortality . RESEARCH DESIGN AND METHODS Participants with type 2 diabetes ( n = 10,251 with mean age 62 years , median duration of diabetes 10 years , and median A1C 8.1 % ) were r and omly assigned to treatment strategies targeting either A1C < 6.0 % ( intensive ) or A1C 7.0–7.9 % ( st and ard ) . Data obtained during 3.4 ( median ) years of follow-up before cessation of intensive treatment were analyzed using several multivariable models . RESULTS Various characteristics of the participants and the study sites at baseline had significant associations with the risk of mortality . Before and after adjustment for these covariates , a higher average on-treatment A1C was a stronger predictor of mortality than the A1C for the last interval of follow-up or the decrease of A1C in the first year . Higher average A1C was associated with greater risk of death . The risk of death with the intensive strategy increased approximately linearly from 6–9 % A1C and appeared to be greater with the intensive than with the st and ard strategy only when average A1C was > 7 % . CONCLUSIONS These analyses implicate factors associated with persisting higher A1C levels , rather than low A1C per se , as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD OBJECTIVE To examine the safety and cardiovascular ( CV ) effects of saxagliptin in the predefined elderly ( ≥65 years ) and very elderly ( ≥75 years ) sub population s of the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infa rct ion 53 ( SAVOR-TIMI 53 ) trial . RESEARCH DESIGN AND METHODS Individuals ≥40 years ( n = 16,492 ; elderly , n = 8,561 ; very elderly , n = 2,330 ) with HbA1c ≥6.5 % ( 47.5 mmol/mol ) and ≤12.0 % ( 107.7 mmol/mol ) were r and omized ( 1:1 ) to saxagliptin  ( 5 or 2.5 mg daily ) or placebo in a double-blind trial for a median follow-up of 2.1 years . RESULTS The hazard ratio ( HR ) for the comparison of saxagliptin versus placebo for the primary end 
    Output:
    
Over the short term ( up to 4 years ) , patients with T2DM exposed to a DPP-4 inhibitor or GLP-1 receptor agonist were not at increased risk for MACE ( or its component endpoints ) compared with those who received comparator agents .
In four RCTs that evaluated alogliptin , saxagliptin , sitagliptin , or lixisenatide , there was no overall increased risk for MACE relative to placebo in T2DM patients at high risk for CV events or with established CV disease , although there was an increased rate of hospitalization for heart failure associated with saxagliptin .
Conclusion Overall , incretin therapy does not appear to increase risk for MACE in the short term