***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: Composite outcomes , in which multiple end points are combined , are frequently used as primary outcome measures in r and omized trials and are often associated with increased statistical efficiency . However , such measures may prove challenging for the interpretation of results . In this article , we examine the use of composite outcomes in major clinical trials , assess the arguments for and against them , and provide guidance on their application and reporting . To assess incidence and quality of reporting , we systematic ally review ed the use of composite end points in clinical trials in Annals of Internal Medicine , BMJ , Circulation , Clinical Infectious Diseases , Journal of the American College of Cardiology , JAMA , Lancet , New Engl and Journal of Medicine , and Stroke from 1997 through 2001 using a sensitive search strategy . We selected for review 167 original reports of r and omized trials ( with a total of 300 276 patients ) that included a composite primary outcome that incorporated all-cause mortality .  Sixty-three trials ( 38 % ) were neutral both for the primary end point and the mortality component . Sixty trials ( 36 % ) reported significant results for the primary outcome measure but not for the mortality component . Only 6 trials ( 4 % ) were significant for the mortality component but not for the primary composite outcome , whereas 19 trials ( 11 % ) were significant for both . Twenty-two trials ( 13 % ) were inadequately reported . Our review suggests that reporting of composite outcomes is generally inadequate , implying that the results apply to the individual components of the composite outcome rather than only to the overall composite . Current guidelines for the undertaking and reporting of clinical trials could be revised to reflect the common use of composite outcomes in clinical trials BACKGROUND In the Action in Diabetes and Vascular Disease : Preterax and Diamicron Modified Release Controlled Evaluation ( ADVANCE ) factorial trial , the combination of perindopril and indapamide reduced mortality among patients with type 2 diabetes , but intensive glucose control , targeting a glycated hemoglobin level of less than 6.5 % , did not . We now report results of the 6-year post-trial follow-up . METHODS We invited surviving participants , who had previously been assigned to perindopril-indapamide or placebo and to intensive or st and ard glucose control ( with the glucose-control comparison extending for an additional 6 months ) , to participate in a post-trial follow-up evaluation . The primary end points were death from any cause and major macrovascular events . RESULTS The baseline characteristics were similar among the 11,140 patients who originally underwent r and omization and the 8494 patients who participated in the post-trial follow-up for a median of 5.9 years ( blood-pressure-lowering comparison ) or 5.4 years ( glucose-control comparison ) . Between-group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit . The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood-pressure-lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up ; the hazard ratios were 0.91 ( 95 % confidence interval [ CI ] , 0.84 to 0.99 ; P=0.03 ) and 0.88 ( 95 % CI , 0.77 to 0.99 ; P=0.04 ) , respectively . No differences were observed during follow-up in the risk of death from any cause or major macrovascular events between the intensive-glucose-control group and the st and ard-glucose-control group ; the hazard ratios were 1.00 ( 95 % CI , 0.92 to 1.08 ) and 1.00 ( 95 % CI , 0.92 to 1.08 ) , respectively . CONCLUSIONS The benefits with respect to mortality that had been observed among patients originally assigned to blood-pressure-lowering therapy were attenuated but still evident at the end of follow-up . There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events . ( Funded by the National Health and Medical Research Council of Australia and others ; ADVANCE-ON Clinical Trials.gov number , NCT00949286 . ) Much of the controversy at the American Diabetes Association Scientific Sessions , held 6–10 June 2008 in San Francisco , California , pertained to questions raised about the benefits of intensive glycemic control by three large clinical studies : the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial , the Action in Diabetes and Vascular Disease ( ADVANCE ) trial , and the Veterans ’ Administration Diabetes Trial ( VADT ) . All three presented somewhat negative study results . David Goff ( Winston-Salem , NC ) discussed the ACCORD study design . The goal of ACCORD was to determine whether cardiovascular disease ( CVD ) event rates could be reduced by intensively treating three important risk factors ( hyperglycemia , dyslipidemia , and high blood pressure ) in a double 2 × 2 factorial design . For glycemia , the question of A1C < 6 vs. 7–7.9 % was addressed . Goff review ed previous studies that led to the decision to aim for the low A1C target . In the UK Prospect i ve Diabetes Study ( UKPDS ) , insulin and sulfonylurea treatment achieved a mean A1C level of 7 % , with 7.9 % in a control group . The 16 % CVD reduction just missed statistical significance . Metformin treatment in this study achieved a mean A1C level of 7.4 % with 8 % in a control group , associated with a significant 39 % CVD reduction . ( Goff did not mention that , compared with sulfonylureas alone , the other UKPDS metformin sub study showed that metformin with a sulfonylurea was associated with 96 , 60 , and 9 % increases in diabetes-related and all-cause mortality and in myocardial infa rct ion [ 1 ] . ) A nonsignificant CVD risk reduction of ∼50 % was seen in the Kumamoto study , while there was also a nonsignificant CVD risk increase of ∼50 % in the Veterans ’ Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes ( VACSDM ) ; both studies showed A1C 7.1 % in the treatment group and 9.3–9.4 % in the control group . Analysis of a number of observational studies 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 BACKGROUND Improved blood-glucose control decreases the progression of diabetic microvascular disease , but the effect on macrovascular complications is unknown . There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation . We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a r and omised controlled trial . METHODS 3867 newly diagnosed patients with type 2 diabetes , median age 54 years ( IQR 48 - 60 years ) , who after 3 months ' diet treatment had a mean of two fasting plasma glucose ( FPG ) concentrations of 6.1 - 15.0 mmol/L were r and omly assigned intensive policy with a sulphonylurea ( chlorpropamide , glibenclamide , or glipizide ) or with insulin , or conventional policy with diet . The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group , the aim was the best achievable FPG with diet alone ; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment :  any diabetes-related endpoint ( sudden death , death from hyperglycaemia or hypoglycaemia , fatal or non-fatal myocardial infa rct ion , angina , heart failure , stroke , renal failure , amputation [ of at least one digit ] , vitreous haemorrhage , retinopathy requiring photocoagulation , blindness in one eye , or cataract extraction ) ; diabetes-related death ( death from myocardial infa rct ion , stroke , peripheral vascular disease , renal disease , hyperglycaemia or hypoglycaemia , and sudden death ) ; all-cause mortality . Single clinical endpoints and surrogate sub clinical endpoints were also assessed . All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy . FINDINGS Over 10 years , haemoglobin A1c ( HbA1c ) was 7.0 % ( 6.2 - 8.2 ) in the intensive group compared with 7.9 % ( 6.9 - 8.8 ) in the conventional group -- an 11 % reduction . There was no difference in HbA1c among agents in the intensive group . Compared with the conventional group , the risk in the intensive group was 12 % lower ( 95 % CI 1 - 21 , p=0.029 ) for any diabetes-related endpoint ; 10 % lower ( -11 to 27 , p=0.34 ) for any diabetes-related death ; and 6 % lower ( -10 to 20 , p=0.44 ) for all-cause mortality . Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25 % risk reduction ( 7 - 40 , p=0.0099 ) in microvascular endpoints , including the need for retinal photocoagulation . There was no difference for any of the three aggregate endpoints between the three intensive agents ( chlorpropamide , glibenclamide , or insulin ) . Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis ( both p<0.0001 ) . The rates of major hypoglycaemic episodes per year were 0.7 % with conventional treatment , 1.0 % with chlorpropamide , 1.4 % with glibenclamide , and 1.8 % with insulin .  Weight gain was significantly higher in the intensive group ( mean 2.9 kg ) than in the conventional group ( p<0.001 ) , and patients assigned insulin had a greater gain in weight ( 4.0 kg ) than those assigned chlorpropamide ( 2.6 kg ) or glibenclamide ( 1.7 kg ) . INTERPRETATION Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications , but not macrovascular disease , in patients with type 2 diabetes . ( ABSTRACT TRUNCATED Abstract Objective : To estimate the cost effectiveness of conventional versus intensive blood glucose control in patients with type 2 diabetes . Design : Incremental cost effectiveness analysis alongside r and omised controlled trial . Setting : 23 UK hospital clinic based study centres . Participants : 3867 patients with newly diagnosed type 2 diabetes ( mean age 53 years ) . Interventions : Conventional ( primarily diet ) glucose control policy versus intensive control policy with a sulphonylurea or insulin . Main outcome measures : Incremental cost per event-free year gained within the trial period . Results : Intensive glucose control  increased trial treatment 
    Output:
    
This evidence reported no significant impact of tight glycemic control on the risk of dialysis/transplantation/renal death , blindness , or neuropathy .
Discordance exists between the research evidence and academic and clinical policy statements about the value of tight glycemic control to reduce micro- and macrovascular complications .