***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 The cardiovascular effects of adding once‐weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown . METHODS We r and omly assigned patients with type 2 diabetes , with or without previous cardiovascular disease , to receive subcutaneous injections of extended‐release exenatide at a dose of 2 mg or matching placebo once weekly . The primary composite outcome was the first occurrence of death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke . The co primary hypotheses were that exenatide , administered once weekly , would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy . RESULTS In all , 14,752 patients ( of whom 10,782 [ 73.1 % ] had previous cardiovascular disease ) were followed for a median of 3.2 years ( interquartile range , 2.2 to 4.4 ) . A primary composite outcome event occurred in 839 of 7356 patients ( 11.4 % ; 3.7 events per 100 person‐years ) in the exenatide group and in 905 of 7396 patients ( 12.2 % ; 4.0 events per 100 person‐years ) in the placebo group ( hazard ratio , 0.91 ; 95 % confidence interval [ CI ] , 0.83 to 1.00 ) , with the intention‐to‐treat analysis indicating that exenatide , administered once weekly , was noninferior to placebo with respect to safety ( P<0.001 for noninferiority ) but was not superior to placebo with respect to efficacy ( P=0.06 for superiority ) . The rates of death from cardiovascular causes , fatal or nonfatal myocardial infa rct ion , fatal or nonfatal stroke , hospitalization for heart failure , and hospitalization for acute coronary syndrome , and the incidence of acute pancreatitis , pancreatic cancer , medullary thyroid carcinoma , and serious adverse events did not differ significantly between the two groups . CONCLUSIONS Among patients with type 2 diabetes with or without previous cardiovascular disease , the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo . ( Funded by Amylin Pharmaceuticals ; EXSCEL Clinical Trials.gov number , NCT01144338 . BACKGROUND R and omized trials demonstrated a lower risk of cardiovascular ( CV ) events with sodium-glucose cotransporter-2 inhibitors ( SGLT-2i ) in patients with type 2 diabetes ( T2D ) at high CV risk . Prior real-world data suggested similar SGLT-2i effects in T2D patients with a broader risk profile , but these studies focused on heart failure and death and were limited to the United States and Europe . OBJECTIVES The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs ( oGLDs ) across 6 countries in the Asia Pacific , the Middle East , and North American regions . METHODS New users of SGLT-2i and oGLDs were identified via cl aims , medical records , and national registries in South Korea , Japan , Singapore , Israel , Australia , and Canada . Propensity scores for SGLT-2i initiation were developed in each country , with 1:1 matching . Hazard ratios ( HRs ) for death , hospitalization for heart failure ( HHF ) , death or HHF , MI , and stroke were assessed by country and pooled using weighted meta- analysis . RESULTS After propensity-matching , there were 235,064 episodes of treatment initiation in each group ; ∼27 % had established CV disease . Patient characteristics were well-balanced between groups  . Dapagliflozin , empagliflozin , ipragliflozin , canagliflozin , tofogliflozin , and luseogliflozin  accounted for 75 % , 9 % , 8 % , 4 % , 3 % , and 1 % of exposure time in the SGLT-2i group , respectively . Use of SGLT-2i versus oGLDs was associated with a lower risk of death ( HR : 0.51 ; 95 % confidence interval [ CI ] : 0.37 to 0.70 ; p < 0.001 ) , HHF ( HR : 0.64 ; 95 % CI : 0.50 to 0.82 ; p = 0.001 ) , death or HHF ( HR : 0.60 ; 95 % CI : 0.47 to 0.76 ; p < 0.001 ) , MI ( HR : 0.81 ; 95 % CI : 0.74 to 0.88 ; p < 0.001 ) , and stroke ( HR : 0.68 ; 95 % CI : 0.55 to 0.84 ; p < 0.001 ) . Results were directionally consistent across both countries and patient subgroups , including those with and without CV disease . CONCLUSIONS In this large , international study of patients with T2D from the Asia Pacific , the Middle East , and North America , initiation of SGLT-2i was associated with a lower risk of CV events across a broad range of outcomes and patient characteristics . ( Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [ CVD-REAL ] ; NCT02993614 ) 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 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 CONTEXT Mortality from coronary heart disease has declined substantially in the United States during the past 30 years . However , it is unknown whether patients with diabetes have also experienced a decline in heart disease mortality . OBJECTIVE To compare adults with diabetes with those without diabetes for time trends in mortality from all causes , heart disease , and ischemic heart disease . DESIGN , SETTING , AND PARTICIPANTS Representative cohorts of subjects with and without diabetes were derived from the First National Health and Nutrition Examination Survey ( NHANES I ) conducted between 1971 and 1975 ( n = 9639 ) and the NHANES I Epidemiologic Follow-up Survey conducted between 1982 and 1984 ( n = 8463 ) . The cohorts were followed up prospect ively for mortality for an average of 8 to 9 years . MAIN OUTCOME MEASURE Changes in mortality rates per 1000 person-years for all causes , heart disease , and ischemic heart disease for the 1982 - 1984 cohort compared with the 1971 - 1975 cohort . RESULTS For the 2 periods , nondiabetic men experienced a 36.4 % decline in age-adjusted heart disease mortality compared with a 13.1 % decline for diabetic men . Age-adjusted heart disease mortality declined 27 % in nondiabetic women but increased 23 % in diabetic women . These patterns were also found for all-cause mortality and ischemic heart disease mortality . CONCLUSIONS The decline in heart disease mortality in the general US population has been attributed to reduction in cardiovascular risk factors and improvement in treatment of heart disease . The smaller declines in mortality for diabetic subjects in the present study indicate that these changes may have been less effective for people with diabetes , particularly women ABBREVIATIONS A1C = hemoglobin A1C ; AACE = American Association of Clinical Endocrinologists ; ACCORD = Action to Control Cardiovascular Risk in Diabetes ; ACCORD BP = Action to Control Cardiovascular Risk in Diabetes Blood Pressure ; ACEI = angiotensin-converting enzyme inhibitor ; ADVANCE = Action in Diabetes and Vascular Disease : Preterax and Diamicron MR Controlled Evaluation ; AGI = alpha-glucosidase inhibitor ; apo B = apolipoprotein B ; ASCVD = atherosclerotic cardiovascular disease ; BAS = bile acid sequestrant ; BCR-QR = bromocriptine quick release ; BMI = body mass index ; BP = blood pressure ; CCB = calcium channel blocker ; CHD = coronary heart disease ; CKD = chronic kidney disease ; CVD = cardiovascular disease ; DASH = Dietary Approaches to Stop Hypertension ; DPP4 = dipeptidyl peptidase 4 ; eGFR = estimated glomerular filtration rate ; ER = extended release ; FDA = Food and Drug Administration ; GLP1 = glucagon-like peptide 1 ;  HDL-C = high-density lipoprotein cholesterol ; IMPROVE-IT = Improved Reduction of Outcomes : Vytorin Efficacy International Trial ; LDL-C = low-density lipoprotein cholesterol ; LDL-P = low-density lipoprotein particle ; Look AHEAD = Look Action for Health in Diabetes ; NPH = neutral protamine Hagedorn ; OSA = obstructive sleep apnea ; RCT = r and omized controlled trial ; SU = sulfonylurea ; SGLT2 = sodium glucose cotransporter-2 ; SMBG = self-monitoring of blood glucose ; T2D = type 2 diabetes ; TZD = thiazolidinedione ; VADT = Veterans Affairs Diabetes Trial BACKGROUND Glucagon-like peptide 1 receptor agonists differ in chemical structure , duration of action , and in their effects on clinical outcomes . The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown . We aim ed to determine the safety and efficacy of albiglutide in preventing cardiovascular death , myocardial infa rct ion , or stroke . METHODS We did a double-blind , r and omised , placebo-controlled trial in 610 sites across 28 countries . We r and omly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease ( at a 1:1 ratio ) to groups that either received a subcutaneous injection of albiglutide ( 30 - 50 mg , based on glycaemic response and tolerability ) or of a matched volume of placebo once a week , in addition to their st and ard care . Investigators used an interactive voice or web response system to obtain treatment assignment , and patients and all study investigators were masked to their treatment allocation . We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death , myocardial infa rct ion , or stroke , which was assessed in the intention-to-treat population . If non-inferiority was confirmed by an upper limit of the 95 % CI for a hazard ratio of less than 1·30 , closed testing for superiority was prespecified . This study is registered with Clinical Trials.gov , number NCT02465515 . FINDINGS Patients were screened between July 1 , 2015 , and Nov 
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CONCLUSIONS SGLT2 inhibitors and GLP-1RAs reduced the three-point major adverse cardiovascular event risk compared to placebo , with no differences between them .
Compared with GLP-1RAs and placebo , SGLT2 inhibitors led to a larger reduction in hospital admission for heart failure risk