***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 Abstract Background Diabetes is associated closely with an increased risk of cardiovascular events , including diastolic dysfunction and heart failure that leads to a shortening of life expectancy . It is therefore extremely valuable to evaluate the impact of antidiabetic agents on cardiac function . However , the influence of dipeptidyl peptidase 4 inhibitors on cardiac function is controversial and a major matter of clinical concern . We therefore evaluated the effect of sitagliptin on echocardiographic parameters of diastolic function in patients with type 2 diabetes as a sub- analysis of the PROLOGUE study . Methods Patients in the PROLOGUE study were assigned r and omly to either add-on sitagliptin treatment or conventional antidiabetic treatment . Of the 463 patients in the overall study , 115 patients ( 55 in the sitagliptin group and 60 in the conventional group ) who had complete echocardiographic data of the ratio of peak early diastolic transmitral flow velocity ( E ) to peak early diastolic mitral annular velocity ( e′ ) at baseline and after 12 and 24 months were included in this study . The primary endpoint of this post hoc sub- analysis was a comparison of the changes in the ratio of E to e′ ( E/e′ ) between the two groups from baseline to 24 months . Results The baseline-adjusted change in E/e′ during 24 months was significantly lower in the sitagliptin group than in the conventional group ( −0.18 ± 0.55 vs. 1.91 ± 0.53 , p = 0.008 ) , irrespective of a higher E/e′ value at baseline in the sitagliptin group . In analysis of covariance , sitagliptin treatment was significantly associated with change in E/e′ over 24 months ( β = −9.959 , p = 0.001 ) , independent of other clinical variables at baseline such as blood pressure , HbA1c , and medications for diabetes . Changes in other clinical variables including blood pressure and glycemic parameters , and echocardiographic parameters , such as cardiac structure and systolic function , were comparable between the two groups . There was also no significant difference in the serum levels of N-terminal-pro brain natriuretic peptide and high-sensitive C-reactive protein between the two groups during the study period . Conclusions Adding sitagliptin to conventional antidiabetic regimens in patients with T2DM for 24 months attenuated the annual exacerbation in the echocardiographic parameter of diastolic dysfunction ( E/e′ ) independent of other clinical variables such as blood pressure and glycemic control . Trial registration UMIN000004490 ( University Hospital Medical Information Network Clinical Trials ) . https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000005356 ; registered November 1 , BACKGROUND An association between dipeptidyl peptidase-IV ( DPP-IV ) inhibitors with worse prognosis in HF has been suggested . We aim ed to assess the  serum DPP-IV levels in chronic stable HF patients and determine their association with prognosis . METHODS AND RESULTS Chronic stable HF patients with optimized prognostic-modifying therapy were prospect ively recruited . EXCLUSION CRITERIA 1 ) ejection fraction>50 % , 2 ) hospitalizations or therapeutic adjustments in the previous 2months ; 3 ) patients on renal replacement therapy , and 4 ) use of DPP-IV inhibitors .  A fasting venous blood sample was collected and DPP-IV was measured . Patients were followed-up for 3years and the endpoint studied was all-cause death . Patients ' characteristics were compared according to DPP-IV quartiles . A Cox regression analysis was performed and multivariate models were built . The 3rd DPP-IV quartile was the reference category . We studied 264 patients . Mean age : 69 (±13)years , 70.5 % were male and 33.7 % diabetic . Median ( IQR ) serum DPP-IV levels were 455.6 (350.0 - 625.5)ng/mL. DPP-IV had an inverse relationship with age . Patients in 3rd DPP-IV quartile were in lower NYHA classes and had the lowest 3years all-cause mortality . Patients in the 1st DPP-IV quartile had a multivariate adjusted HR of 3-year mortality of 2.62 ( 95%CI : 1.15 - 5.95 ) when compared with reference category and the HR for the 4th quartile was of 3.79 ( 95%CI : 1.68 - 8.54 ) . CONCLUSIONS There is a U-shaped association of serum DPP-IV with mortality in chronic systolic HF patients . Patients in the 3rd DPP-IV quartile have the best multivariate adjusted 3-year survival  . DPP-IV inhibition might be harmful in patients with low DPP-IV 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 . ) IMPORTANCE Abnormal cardiac metabolism contributes to the pathophysiology of advanced heart failure with reduced left ventricular ejection fraction ( LVEF ) .  Glucagon-like peptide 1 ( GLP-1 ) agonists have shown cardioprotective effects in early clinical studies of patients with advanced heart failure , irrespective of type 2 diabetes status . OBJECTIVE To test whether therapy with a GLP-1 agonist improves clinical stability following hospitalization for acute heart failure . DESIGN , SETTING , AND PARTICIPANTS Phase 2 , double-blind , placebo-controlled r and omized clinical trial of patients with established heart failure and reduced LVEF who were recently hospitalized . Patients were enrolled between August 2013 and March 2015 at 24 US sites . INTERVENTIONS The GLP-1 agonist liraglutide ( n = 154 ) or placebo ( n = 146 ) via a daily subcutaneous injection ; study drug was advanced to a dosage of 1.8 mg/d during the first 30 days as tolerated and continued for 180 days . MAIN OUTCOMES AND MEASURES The primary end point was a global rank score in which all patients , regardless of treatment assignment , were ranked across 3 hierarchical tiers : time to death , time to rehospitalization for heart failure , and time-averaged proportional change in N-terminal pro-B-type natriuretic peptide level from baseline to 180 days . Higher values indicate better health ( stability ) . Exploratory secondary outcomes included primary end point components , cardiac structure and function , 6-minute walk distance , quality of life , and combined events . RESULTS Among the 300 patients who were r and omized ( median age , 61 years [ interquartile range { IQR } , 52 - 68 years ] ; 64 [ 21 % ] women ; 178 [ 59 % ] with type 2 diabetes ; median LVEF of 25 % [ IQR , 19%-33 % ] ; median N-terminal pro-B-type natriuretic peptide level of 2049 pg/mL [ IQR , 1054 - 4235 pg/mL ] ) , 271 completed the study . Compared with placebo , liraglutide had no significant effect on the primary end point ( mean rank of 146 for the liraglutide group vs 156 for the placebo group , P = .31 ) . There were no significant between-group differences in the number of deaths ( 19 [ 12 % ] in the liraglutide group vs 16 [ 11 % ] in the placebo group ; hazard ratio , 1.10 [ 95 % CI , 0.57 - 2.14 ] ; P = .78 ) or rehospitalizations for heart failure ( 63 [ 41 % ] vs 50 [ 34 % ] , respectively ; hazard ratio , 1.30 [ 95 % CI , 0.89 - 1.88 ] ; P = .17 ) or for the exploratory secondary end points . Prespecified subgroup analyses in patients with diabetes 
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The results suggested that targeting the DPP-4-GLP-1 pathway can improve exercise tolerance in heart failure patients [ MD 24.88 ( 95 % CI 5.45 , 44.31 ) , P = 0.01 ] without decreasing QoL [ SMD -0.51 ( 95 % CI -1.13 , 0.10 ) , P = 0.10 ] ; additionally , targeting the DPP-4-GLP-1 pathway did not show signs of increasing the incidence of serious AEs or mortality .
Conclusion Our results suggest that DPP-4 inhibitors or GLP-1 RAs improve exercise tolerance in heart failure patients .
Although the use of these drugs for heart failure has not been approved by any organization , they may be a better choice for type 2 diabetes mellitus patients with heart failure .