WITHDRAWN: Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. Development and validation of Risk Equations for Complications Of type 2 Diabetes (RECODe) using individual participant data from randomised trials. Blood pressure and glucose control in subjects with diabetes: new analyses from ADVANCE Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study Long-term effects of intensive glucose lowering on cardiovascular outcomes. Effects of insulin treatment on cause-specific one-year mortality and morbidity in diabetic patients with acute myocardial infarction. DIGAMI Study Group. Diabetes Insulin-Glucose in Acute Myocardial Infarction. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Validation of Risk Equations for Complications of Type 2 Diabetes (RECODe) Using Individual Participant Data From Diverse Longitudinal Cohorts in the U.S. Oral Antidiabetic Agents High apolipoprotein AI concentrations are associated with lower mortality and myocardial infarction five years after coronary artery bypass graft surgery Prognostic implications of glucose-lowering treatment in patients with acute myocardial infarction and diabetes: experiences from an extended follow-up of the Diabetes Mellitus Insulin–Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 Study Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial 10-year follow-up of intensive glucose control in type 2 diabetes. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial--clinical implications. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study Compliance and adverse event withdrawal: their impact on the West of Scotland Coronary Prevention Study. Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/beta-blocker-based treatment regimen: a subanalysis of the Captopril Prevention Project. Inverse relation of body weight and weight change with mortality and morbidity in patients with type 2 diabetes and cardiovascular co-morbidity: an analysis of the PROactive study population. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial
Background Patients with type 2 diabetes mellitus ( T2D ) have an increased risk of cardiovascular disease and mortality compared to the background population . Observational studies report an association between reduced blood glucose and reduced risk of both micro- and macrovascular complications in patients with T2D . Our previous systematic review of intensive glycaemic control versus conventional glycaemic control was based on 20 r and omised clinical trials that r and omised 29 , 986 participants with T2D . We now report our up date d review . Objectives To assess the effects of targeted intensive glycaemic control compared with conventional glycaemic control in patients with T2D . Search methods Trials were obtained from search es of The Cochrane Library , MEDLINE , EMBASE , Science Citation Index Exp and ed , LILACS , and CINAHL ( all until December 2012 ) . Selection criteria We included r and omised clinical trials that prespecified targets of intensive glycaemic control versus conventional glycaemic control targets in adults with T2D . Data collection and analysis Two authors independently assessed the risk of bias and extracted data . Dichotomous outcomes were assessed by risk ratios ( RR ) and 95 % confidence intervals ( CI ) . Health-related quality of life and costs of intervention were assessed with st and ardized mean differences ( SMD ) and 95 % Cl . Main results Twenty-eight trials with 34,912 T2D participants r and omised 18,717 participants to intensive glycaemic control  versus 16,195 participants to  conventional glycaemic control . Only two trials had low risk of bias on all risk of bias domains assessed . The duration of the intervention ranged from three days to 12.5 years . The number of participants in the included trials ranged from 20 to 11,140 . There were no statistically significant differences between targeting intensive versus conventional glycaemic control for all-cause mortality ( RR 1.00 , 95 % CI 0.92 to 1.08 ; 34,325 participants , 24 trials ) or cardiovascular mortality ( RR 1.06 , 95 % CI 0.94 to 1.21 ; 34,177 participants , 22 trials ) . Trial sequential analysis showed that a 10 % relative risk reduction could be refuted for all-cause mortality . Targeting intensive glycaemic control did not show a statistically significant effect on the risks of macrovascular complications as a composite outcome in the r and om-effects model , but decreased the risks in the fixed-effect model ( r and om RR 0.91 , 95 % CI 0.82 to 1.02 ; and fixed RR 0.93 , 95 % CI 0.87 to 0.99 ; P = 0.02 ; 32,846 participants , 14 trials ) . Targeting intensive versus conventional glycaemic control seemed to reduce the risks of non-fatal myocardial infa rct ion ( RR 0.87 , 95 % CI 0.77 to 0.98 ; P = 0.02 ; 30,417 participants , 14 trials ) , amputation of a lower extremity ( RR 0.65 , 95 % CI 0.45 to 0.94 ; P = 0.02 ; 11,200 participants , 11 trials ) , as well as the risk of developing a composite outcome of microvascular diseases ( RR 0.88 , 95 % CI 0.82 to 0.95 ; P = 0.0008 ; 25,927 participants , 6 trials ) , nephropathy ( RR 0.75 , 95 % CI 0.59 to 0.95 ; P = 0.02 ; 28,096 participants , 11 trials ) , retinopathy ( RR 0.79 , 95 % CI 0.68 to 0.92 ; P = 0.002 ; 10,300 participants , 9 trials ) , and the risk of retinal photocoagulation ( RR 0.77 , 95 % CI 0.61 to 0.97 ; P = 0.03 ; 11,212 participants , 8 trials ) . No statistically significant effect of targeting intensive glucose control could be shown on non-fatal stroke , cardiac revascularization , or peripheral revascularization . Trial sequential analyses did not confirm a reduction of the risk of non-fatal myocardial infa rct ion but confirmed a 10 % relative risk reduction in favour of intensive glycaemic control on the composite outcome of microvascular diseases . For the remaining microvascular outcomes , trial sequential analyses could not establish firm evidence for a 10 % relative risk reduction . Targeting intensive glycaemic control significantly increased the risk of mild hypoglycaemia , but substantial heterogeneity was present ; severe hypoglycaemia ( RR 2.18 , 95 % CI 1.53 to 3.11 ; 28,794 participants , 12 trials ) ; and serious adverse events ( RR 1.06 , 95 % CI 1.02 to 1.10 ; P = 0.007 ; 24,280 participants , 11 trials ) . Trial sequential analysis for a 10 % relative risk increase showed firm evidence for mild hypoglycaemia and serious adverse events and a 30 % relative risk increase for severe hypoglycaemia when targeting intensive versus conventional glycaemic control . Overall health-related quality of life , as well as the mental and the physical components of health-related quality of life did not show any statistical significant differences . Authors ' conclusions Although we have been able to exp and the number of participants by 16 % in this up date , we still find paucity of data on outcomes and the bias risk of the trials was mostly considered high . Targeting intensive glycaemic control compared with conventional glycaemic control did not show significant differences for all-cause mortality and cardiovascular mortality . Targeting intensive glycaemic control seemed to reduce the risk of microvascular complications , if we disregard the risks of bias , but increases the risk of hypoglycaemia and serious adverse events 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 AIMS Hypoglycaemia caused by glucose-lowering therapy has been linked to cardiovascular ( CV ) events . The ORIGIN trial provides an opportunity to further assess this relationship . METHODS AND RESULTS A total of 12 537 participants with dysglycaemia and high CV-risk were r and omized to basal insulin glargine titrated to a fasting glucose of ≤ 5.3 mmol/L ( 95 mg/dL ) or st and ard glycaemic care . Non-severe hypoglycaemia was defined as symptoms confirmed by glucose ≤ 54 mg/dL and severe hypoglycaemia as a requirement for assistance or glucose ≤ 36 mg/dL. Outcomes were : ( i ) the composite of CV death , non-fatal myocardial infa rct ion or stroke ; ( ii ) mortality ; ( iii ) CV mortality ; and ( iv ) arrhythmic death . Hazards were estimated before and after adjustment for a hypoglycaemia propensity score . During a median of 6.2 years ( IQR : 5.8 - 6.7 ) , non-severe hypoglycaemic episodes occurred in 41.7 and 14.4 % glargine and st and ard group participants , respectively , while severe episodes occurred in 5.7 and 1.8 % , respectively . Non-severe hypoglycaemia was not associated with any outcome following adjustment . Conversely , severe hypoglycaemia was associated with a greater risk for the primary outcome ( HR : 1.58 ; 95 % CI : 1.24 - 2.02 , P < 0.001 ) , mortality ( HR : 1.74 ; 95 % CI : 1.39 - 2.19 , P < 0.001 ) , CV death ( HR : 1.71 ; 95 % CI : 1.27 - 2.30 , P < 0.001 ) and arrhythmic death ( HR : 1.77 ; 95 % CI : 1.17 - 2.67 , P = 0.007 ) . Similar findings were noted for severe nocturnal hypoglycaemia for the primary outcome and mortality . The severe hypoglycaemia hazard for all four outcomes was higher with st and ard care than with insulin glargine . CONCLUSION Severe hypoglycaemia is associated with an increased risk for CV outcomes in people at high CV risk and dysglycaemia . Although allocation to insulin glargine vs. st and ard care was associated with an increased risk of severe and non-severe hypoglycaemia , the relative risk of CV outcomes with hypoglycaemia was lower with insulin glargine-based glucose-lowering therapy than with the st and ard glycaemic control . Trial Registration ( ORIGIN Clinical Trials.gov number NCT00069784 ) BACKGROUND In view of substantial mis-estimation of risks of diabetes complications using existing equations , we sought to develop up date d Risk Equations for Complications Of type 2 Diabetes ( RECODe ) . METHODS To develop and vali date these risk equations , we used data from the Action to Control Cardiovascular Risk in Diabetes study ( ACCORD , n=9635 ; 2001 - 09 ) and vali date d the equations for microvascular events using data from the Diabetes Prevention Program Outcomes Study ( DPPOS , n=1018 ; 1996 - 2001 ) , and for cardiovascular events using data from the Action for Health in Diabetes ( Look AHEAD , n=4760 ; 2001 - 12 ) . Microvascular outcomes were nephropathy , retinopathy , and neuropathy . Cardiovascular outcomes were myocardial infa rct ion , stroke , congestive heart failure , and cardiovascular mortality . We also included all-cause mortality as an outcome . We used a cross-validating machine learning method to select predictor variables from demographic characteristics , clinical variables , comorbidities , medications , and biomarkers into Cox proportional hazards models for each outcome . The new equations were compared to older risk equations by assessing model discrimination , calibration , and the net reclassification index . FINDINGS All equations had moderate internal and external discrimination ( C-statistics 0·55 - 0·84 internally , 0·57 - 0·79 externally ) and high internal and external calibration ( slopes 0·71 - 1·31 between observed and estimated risk ) . Our equations had better discrimination and calibration than the UK Prospect i ve Diabetes Study Outcomes Model 2 ( for microvascular and cardiovascular outcomes , C-statistics 0·54 - 0·62 , slopes 0·06 - 1·12 ) and the American College of Cardiology/American Heart Association Pooled Cohort Equations ( for fatal or non-fatal myocardial infa rct ion or stroke , C-statistics 0·61 - 0·66 , slopes 0·30 - 0·39 ) . INTERPRETATION RECODe might improve estimation of risk of complications for patients with type 2 diabetes . FUNDING National Institute for Diabetes and Digestive and Kidney Disease , National Heart , Lung and Blood Institute , and National Institute on Minority Health and Health Disparities , National Institutes of Health , and US Department of Veterans Affairs Objectives To evaluate among individuals with diabetes whether major microvascular and macrovascular events are reduced by : ( 1 ) blood pressure lowering with a perindopril/indapamide combination compared with placebo ; ( 2 ) intensive glucose control ( targeting a haemoglobin A1c level of ≤6.5 % ) with a gliclazide MR-based regimen , compared with usual care . Methods Participants with diabetes aged 55 years and older with at least one additional vascular risk factor were r and omly assigned , using a 2 × 2 factorial design , to additional blood pressure lowering versus placebo and intensive versus st and ard glucose control . The primary outcomes were macrovascular ( cardiovascular death , non-fatal myocardial infa rct ion or non-fatal stroke ) and microvascular ( new or worsening nephropathy or retinopathy ) events jointly and separately . Results A total of 11 140 participants were r and omly assigned to the blood pressure and glucose-lowering arms , which ended after 4.3 and 5.5 years , respectively . The effects of the two interventions were independent and additive on prespecified endpoints . Compared with placebo , additional blood pressure lowering of 5.6/2.2 mmHg was associated with reductions of 9 % in the primary endpoint ( P = 0.041 ) , 18 % in cardiovascular death ( P = 0.027 ) , 14 % in total mortality ( P = 0.025 ) , and 21 % in total renal events ( P < 0.01 ) . Compared with st and ard glucose control , intensive control ( mean in-trial 0.67 percentage point reduction in haemoglobin A1c level ) was associated with reductions of 10 % in the primary endpoint ( P = 0.013 ) , 14 % in major microvascular events ( P = 0.01 ) and 11 % in total renal events ( P < 0.001 ) . Conclusion Additional blood pressure lowering and intensive glucose control , as achieved in ADVANCE , produce independent benefits and , when combined , substantially reduced cardiovascular mortality and all-cause mortality and improved renal outcomes BACKGROUND Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infa rct ion and stroke . There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma ( PPAR gamma ) could reduce macrovascular complications . Our aim , therefore , was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes . METHODS We did a prospect i ve , r and omised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease .  We recruited patients from primary -care practice s and hospitals . We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg ( n=2605 ) or matching placebo ( n=2633 ) , to be taken in addition to their glucose-lowering drugs and other medications . Our primary endpoint was the composite of all-cause mortality , non fatal myocardial infa rct ion ( including silent myocardial infa rct ion ) , stroke , acute coronary syndrome , endovascular or surgical intervention in the coronary or leg arteries , and amputation above the ankle . Analysis was by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N NCT00174993 . FINDINGS Two patients were lost to follow-up , but were included in analyses . The average time of observation was 34.5 months . 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint ( HR 0.90 , 95 % CI 0.80 - 1.02 , p=0.095 ) . The main secondary endpoint was the composite of all-cause mortality , non-fatal myocardial infa rct ion , and stroke . 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint ( 0.84 , 0.72 - 0.98 , p=0.027 ) . Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified . 6 % ( 149 of 2065 ) and 4 % ( 108 of 2633 ) of those in the pioglitazone and placebo groups , respectively , were admitted to hospital with heart failure ; mortality rates from heart failure did not differ between groups . INTERPRETATION Pioglitazone reduces the composite of all-cause mortality , non-fatal myocardial infa rct ion , and stroke in patients with type 2 diabetes who have a high risk of macrovascular events Abstract Objective : To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes . Design : Prospect i ve observational study . Setting : 23 hospital based clinics in Engl and , Scotl and , and Northern Irel and . Participants : 4585 white , Asian Indian , and Afro-Caribbean UKPDS patients , whether r and omised or not to treatment , were included in analyses of incidence ; of these , 3642 were included in analyses of relative risk . Outcome measures : Primary predefined aggregate clinical outcomes : any end point or deaths related to diabetes and all cause mortality . Secondary aggregate outcomes : myocardial infa rct ion , stroke , amputation ( including death from peripheral vascular disease ) , and microvascular disease ( predominantly retinal photo-coagulation ) . Single end points : non-fatal heart failure and cataract extraction . Risk reduction associated with a 1 % reduction in up date d mean HbA1c adjusted for possible confounders at diagnosis of diabetes . Results : The incidence of clinical complications was significantly associated with glycaemia . Each 1 % reduction in up date d mean HbA1c was associated with reductions in risk of 21 % for any end point related to diabetes ( 95 % confidence interval 17 % to 24 % , P<0.0001 ) , 21 % for deaths related to diabetes ( 15 % to 27 % , P<0.0001 ) , 14 % for myocardial infa rct ion ( 8 % to 21 % , P<0.0001 ) , and 37 % for microvascular complications ( 33 % to 41 % , P<0.0001 ) . No threshold of risk was observed for any end point . Conclusions : In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia . Any reduction in HbA1c is likely to reduce the risk of complications , with the lowest risk being in those with HbA1c values in the normal range ( < 6.0 % ) BACKGROUND Intensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease . This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events . METHODS We r and omly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy ( targeting a glycated hemoglobin level below 6.0 % ) or st and ard therapy ( targeting a level of 7 to 7.9 % ) . After termination of the intensive therapy , due to higher mortality in the intensive-therapy group , the target glycated hemoglobin level was 7 to 7.9 % for all participants , who were followed until the planned end of the trial . RESULTS Before the intensive therapy was terminated , the intensive-therapy group did not differ significantly from the st and ard-therapy group in the rate of the primary outcome ( a composite of nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes ) ( P=0.13 ) but had more deaths from any cause ( primarily cardiovascular ) ( hazard ratio , 1.21 ; 95 % confidence interval [ CI ] , 1.02 to 1.44 ) and fewer nonfatal myocardial infa rct ions ( hazard ratio , 0.79 ; 95 % CI , 0.66 to 0.95 ) . These trends persisted during the entire follow-up period ( hazard ratio for death , 1.19 ; 95 % CI , 1.03 to 1.38 ; and hazard ratio for nonfatal myocardial infa rct ion , 0.82 ; 95 % CI , 0.70 to 0.96 ) . After the intensive intervention was terminated , the median glycated hemoglobin level in the intensive-therapy group rose from 6.4 % to 7.2 % , and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups . CONCLUSIONS As compared with st and ard therapy , the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6 % reduced 5-year nonfatal myocardial infa rct ions but increased 5-year mortality . Such a strategy can not be recommended for high-risk patients with advanced type 2 diabetes . ( Funded by the National Heart , Lung and Blood Institute ; Clinical Trials.gov number , NCT00000620 . ) Diabetic patients with acute myocardial infa rct ion have a poor prognosis , which has been attributed to a higher incidence of congestive heart failure and fatal reinfa rct ion . This study reports on the one-year morbidity and mortality in a r and omized study with the aim of testing whether insulin-glucose infusion initiated as soon as possible after onset of myocardial infa rct ion and followed by long-term subcutaneous insulin treatment may have a beneficial effect on outcome in diabetic patients . In all , 306 patients were recruited to the insulin-treated group , while 314 patients served as controls .  The overall mortality after one year was 19 % in the insulin group compared to 26 % among controls ( P < 0.05 ) . The treatment effect was most pronounced in patients without prior insulin medication and at low cardiovascular risk . In this stratum the in-hospital mortality was reduced by 58 % ( P < 0.05 ) and the one-year mortality by 52 % ( P < 0.02 ) . The most frequent cause of death in all patients was congestive heart failure ( 66 % ) , but cardiovascular mortality ( congestive heart failure , fatal reinfa rct ion , sudden death and stroke ) tended to be decreased in insulin-treated patients . However , this difference did not reach the level of statistical significance . The number of reinfa rct ions was 53 ( 28 % fatal ) in the insulin group compared to 55 ( 45 % fatal ) in the control group . The two groups did not differ as regards need for hospital care or coronary revascularization during the year of follow-up . In summary , left ventricular failure and fatal reinfa rct ions contribute to increased mortality in diabetic patients following acute myocardial infa rct ion . Intensive insulin treatment lowered this mortality during one year of follow-up Abstract Objective : To determine the relation between  systolic blood pressure  over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes . Design : Prospect i ve observational study . Setting : 23 hospital based clinics in Engl and , Scotl and , and Northern Irel and . Participants : 4801 white , Asian Indian , and Afro-Caribbean UKPDS patients , whether r and omised or not to treatment , were included in analyses of incidence ; of these , 3642 were included in analyses of relative risk . Outcome measures : Primary predefined aggregate clinical outcomes : any complications or deaths related to diabetes and all cause mortality . Secondary aggregate outcomes : myocardial infa rct ion , stroke , lower extremity amputation ( including death from peripheral vascular disease ) , and microvascular disease ( predominantly retinal photocoagulation ) . Single end points : non-fatal heart failure and cataract extraction . Risk reduction associated with a 10 mm Hg decrease in up date d mean systolic blood pressure adjusted for specific confounders Results : The incidence of clinical complications was significantly associated with systolic blood pressure , except for cataract extraction . Each 10 mm Hg decrease in up date d mean systolic blood pressure was associated with reductions in risk of 12 % for any complication related to diabetes ( 95 % confidence interval 10 % to 14 % , P<0.0001 ) , 15 % for deaths related to diabetes ( 12 % to 18 % , P<0.0001 ) , 11 % for myocardial infa rct ion ( 7 % to 14 % , P<0.0001 ) , and 13 % for microvascular complications ( 10 % to 16 % , P<0.0001 ) . No threshold of risk was observed for any end point . Conclusions : In patients with type 2 diabetes the risk of diabetic complications was strongly associated with raised blood pressure . Any reduction in blood pressure is likely to reduce the risk of complications , with the lowest risk being in those with systolic blood pressure less than 120 mm Hg BACKGROUND The beneficial effects of beta-blockers on long-term outcome after acute myocardial infa rct ion were shown before the introduction of thrombolysis and angiotensin-converting-enzyme ( ACE ) inhibitors . Generally , the patients recruited to these trials were at low risk : few had heart failure , and none had measurements of left-ventricular function taken . We investigated the long-term efficacy of carvedilol on morbidity and mortality in patients with left-ventricular dysfunction after acute myocardial infa rct ion treated according to current evidence -based practice . METHODS In a multicentre , r and omised , placebo-controlled trial , 1959 patients with a proven acute myocardial infa rct ion and a left-ventricular ejection fraction of < /=40 % were r and omly assigned 6.25 mg carvedilol ( n=975 ) or placebo ( n=984 ) . Study medication was progressively increased to a maximum of 25 mg twice daily during the next 4 - 6 weeks , and patients were followed up until the requisite number of primary endpoints had occurred . The primary endpoint was all-cause mortality or hospital admission for cardiovascular problems . Analysis was by intention to treat . FINDINGS Although there was no difference between the carvedilol and placebo groups in the number of patients with the primary endpoint ( 340 [ 35 % ] vs 367 [ 37 % ] , hazard ratio 0.92 [ 95 % CI 0.80 - 1.07 ] ) , all-cause mortality alone was lower in the carvedilol group than in the placebo group ( 116 [ 12 % ] vs 151 [ 15 % ] , 0.77 [ 0.60 - 0.98 ] , p=0.03 ) . Cardiovascular mortality , non-fatal myocardial infa rct ions , and all-cause mortality or non-fatal myocardial infa rct ion were also lower on carvedilol than on placebo . INTERPRETATION In patients treated long-term after an acute myocardial infa rct ion complicated by left-ventricular systolic dysfunction , carvedilol reduced the frequency of all-cause and cardiovascular mortality , and recurrent , non-fatal myocardial infa rct ions . These beneficial effects are additional to those of evidence -based treatments for acute myocardial infa rct ion including ACE inhibitors OBJECTIVE We sought to vali date Risk Equations for Complications of Type 2 Diabetes ( RECODe ) among diverse population s. RESEARCH DESIGN AND METHODS We compared risk predictions from RECODe equations and from two alternative risk models ( UK Prospect i ve Diabetes Study Outcomes Model 2 [ UKPDS OM2 ] and American College of Cardiology/American Heart Association Pooled Cohort Equations ) to observed outcomes in two studies : the Multi-Ethnic Study of Atherosclerosis ( MESA , n = 1,555 adults with type 2 diabetes , median follow-up 9.1 years ) and the Jackson Heart Study ( JHS , n = 1,746 adults with type 2 diabetes , median follow-up 8.0 years ) . Outcomes included nephropathy by multiple measures ( microalbuminuria , macroalbuminuria , renal failure , end-stage renal disease , and reduction in glomerular filtration rate ) , moderate to severe diabetic retinopathy by Airlie House classification , fatal or nonfatal myocardial infa rct ion , fatal or nonfatal stroke , congestive heart failure , and all-cause mortality . RESULTS RECODe equations for microvascular and cardiovascular outcomes had C-statistics for discrimination ranging from 0.71 to 0.85 in MESA and 0.64 to 0.91 in JHS for alternative outcomes . Calibration slopes in MESA ranged from 0.62 for a composite nephropathy outcome , 0.83–1.04 for individual nephropathy outcomes , 1.07 for retinopathy , 1.00–1.05 for cardiovascular outcomes , and 1.03 for all-cause mortality . Slopes in JHS ranged from 0.47 for retinopathy , 0.97–1.16 for nephropathy , 0.72–1.05 for cardiovascular outcomes , and 1.01 for all-cause mortality . The alternative models had C-statistics 0.50–0.72 and calibration slopes 0.07–0.60 . CONCLUSIONS RECODe equations improved risk estimation for diverse patients with type 2 diabetes , as compared with two commonly used alternatives Type 2 diabetes mellitus is a progressive and complex disorder that is difficult to treat effectively in the long term . The majority of patients are overweight or obese at diagnosis and will be unable to achieve or sustain near normoglycaemia without oral antidiabetic agents ; a sizeable proportion of patients will eventually require insulin therapy to maintain long-term glycaemic control , either as monotherapy or in conjunction with oral antidiabetic therapy . The frequent need for escalating therapy is held to reflect progressive loss of islet β-cell function , usually in the presence of obesity-related insulin resistance . Today ’s clinicians are presented with an extensive range of oral antidiabetic drugs for type 2 diabetes . The main classes are heterogeneous in their modes of action , safety profiles and tolerability . These main classes include agents that stimulate insulin secretion ( sulphonylureas and rapid-acting secretagogues ) , reduce hepatic glucose production ( biguanides ) , delay digestion and absorption of intestinal carbohydrate ( α-glucosidase inhibitors ) or improve insulin action (thiazolidinediones).The UKPDS ( United Kingdom Prospect i ve Diabetes Study ) demonstrated the benefits of intensified glycaemic control on microvascular complications in newly diagnosed patients with type 2 diabetes . However , the picture was less clearcut with regard to macrovascular disease , with neither sulphonylureas nor insulin significantly reducing cardiovascular events . The impact of oral antidiabetic agents on atherosclerosis — beyond expected effects on glycaemic control — is an increasingly important consideration . In the UKPDS , overweight and obese patients r and omised to initial monotherapy with metformin experienced significant reductions in myocardial infa rct ion and diabetes-related deaths .  Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors . Accordingly , metformin is widely regarded as the drug of choice for most patients with type 2 diabetes . Concern about cardiovascular safety of sulphonylureas has largely dissipated with generally reassuring results from clinical trials , including the UKPDS . Encouragingly , the recent Steno-2 Study showed that intensive target-driven , multifactorial approach to management , based around a sulphonylurea , reduced the risk of both micro- and macrovascular complications in high-risk patients . Theoretical advantages of selectively targeting postpr and ial hyperglycaemia require confirmation in clinical trials of drugs with preferential effects on this facet of hyperglycaemia are currently in progress . The insulin-sensitising thiazolidinedione class of antidiabetic agents has potentially advantageous effects on multiple components of the metabolic syndrome ; the results of clinical trials with cardiovascular endpoints are awaited . The selection of initial monotherapy is based on a clinical and biochemical assessment of the patient , safety considerations being paramount . In some circumstances , for example pregnancy or severe hepatic or renal impairment , insulin may be the treatment of choice when nonpharmacological measures prove inadequate . Insulin is also required for metabolic decompensation , that is , incipient or actual diabetic ketoacidosis , or non-ketotic hyperosmolar hyperglycaemia . Certain comorbidities , for example presentation with myocardial infa rct ion during other acute intercurrent illness , may make insulin the best option . Oral antidiabetic agents should be initiated at a low dose and titrated up according to glycaemic response , as judged by measurement of  glycosylated haemoglobin  ( HbA1c ) concentration , supplemented in some patients by self monitoring of capillary blood glucose . The average glucose-lowering effect of the major classes of oral antidiabetic agents is broadly similar ( averaging a 1–2 % reduction in HbA1c ) , α-glucosidase inhibitors being rather less effective . Tailoring the treatment to the individual patient is an important principle . Doses are gradually titrated up according to response . However , the maximal glucose-lowering action for sulphonylureas is usually attained at appreciably lower doses ( approximately 50 % ) than the manufacturers ’ recommended daily maximum . Combinations of certain agents , for example a secretagogue plus a biguanide or a thiazolidinedione , are logical and widely used , and combination preparations are now available in some countries . While the benefits of metformin added to a sulphonylurea were initially less favourable in the UKPDS , longer-term data have allayed concern . When considering long-term therapy , issues such as tolerability and convenience are important additional considerations . Neither sulphonylureas nor biguanides are able to appreciably alter the rate of progression of hyperglycaemia in patients with type 2 diabetes . Preliminary data suggesting that thiazolidinediones may provide better long-term glycaemic stability are currently being tested in clinical trials ; current evidence , while encouraging , is not conclusive . Delayed progression from glucose intolerance to type 2 diabetes in high-risk individuals with glucose intolerance has been demonstrated with troglitazone , metformin and acarbose . However , intensive lifestyle intervention can be more effective than drug therapy , at least in the setting of interventional clinical trials . No antidiabetic drugs are presently licensed for use in prediabetic individuals OBJECTIVE To examine mortality and myocardial infa rct ion  five years after coronary artery bypass graft ( CABG ) surgery  and the association with different lipid fractions and haemostatic , glycaemic , and demographic risk factors . SETTING A regional cardiothoracic centre , Freeman Hospital , and the University Clinical Investigation Unit , Royal Victoria Infirmary , Newcastle upon Tyne , UK . DESIGN 353 consecutive patients ( 297 male , mean age 57.2 years ) undergoing first time CABG for stable angina were recruited to a prospect i ve cohort study and studied to five years . MAIN OUTCOME MEASURES All cause mortality , late cardiac mortality ( beyond 30 days ) alone and in combination with non-fatal myocardial infa rct ion . Risk factor assessment s before operation and 3 , 6 , 12 , 24 , and 60 months after surgery . For each laboratory variable a weighted mean for the period of exposure was calculated from the concentration at each time interval and the time between measurements . The distribution was divided into tertiles . RESULTS 41 patients died ( 16 late cardiac deaths ) and eight had a myocardial infa rct . An adverse outcome occurred more frequently in the lower tertile of weighted apolipoprotein AI compared with the upper tertile . An adverse outcome was also more common in patients in the upper tertile of weighted total white blood cell count and less consistently so in patients in the upper tertile of the haemostatic covariates , factor VIIc and factor VIIIc . There was no association with other lipid fractions except for total mortality and apolipoprotein B ( owing to low levels in five patients with carcinoma ) . CONCLUSIONS Low apolipoprotein AI concentrations , but no other markers of an adverse lipid profile , were associated with mortality and myocardial infa rct ion five years after CABG . Apolipoprotein AI is associated with paraoxonase , an enzyme located on high density lipoprotein , which may limit the oxidation of low density lipoprotein . An association between outcome and other covariates such as white cell count provides a credible pointer to inflammation mediating a component of cardiovascular risk Aims /hypothesisThis post hoc analysis from the Diabetes Mellitus Insulin – Glucose Infusion in Acute Myocardial Infa rct ion ( DIGAMI ) 2 trial reports on extended long-term outcome in relation to glucose-lowering agents in patients with myocardial infa rct ion and type 2 diabetes . Methods Patients were r and omised as follows : group 1 , insulin-based treatment ; group 2 , insulin during hospitalisation followed by conventional glucose control ; and group 3 , conventional treatment .  Treatment according to the above protocol lasted 2.1 years . Using the total DIGAMI 2 cohort as an epidemiological data base , this study presents mortality rates in the r and omised groups , and mortality and morbidity rates by glucose-lowering treatment during an extended period of follow-up ( median 4.1 and max 8.1 years ) . Results Follow-up data were available in 1,145 of the 1,253 patients . The mortality rate was 31 % ( 72 % cardiovascular ) without significant differences between treatment groups . The total number of fatal malignancies was 37 , with a trend towards a higher risk in group 1 . The HR for death from malignant disease , compared with group 2 , was 1.77 ( 95 % CI 0.87–3.61 ; p = 0.11 ) and 3.60 ( 95 % CI 1.24–10.50 ; p = 0.02 ) compared with group 3 . Insulin treatment was associated with non-fatal cardiovascular events ( OR 1.89 95 % CI 1.35–2.63 ; p = 0.0002 ) , but not with mortality ( OR 1.30 , 95 % CI 0.93–1.81 ; p = 0.13 ) . Metformin was associated with a lower mortality rate ( HR 0.65 , 95 % CI 0.47–0.90 ; p = 0.01 ) and a lower risk of death from malignancies ( HR 0.25 , 95 % CI 0.08–0.83 ; p = 0.02 ) . Conclusions /interpretation Patients with type 2 diabetes and myocardial infa rct ion have a poor prognosis . Glucose-lowering drugs appear to be of prognostic importance . Insulin may be associated with an increased risk of non-fatal cardiac events , while metformin seems to be protective against risk of death BACKGROUND Intensive diabetes therapy aim ed at achieving near normoglycemia reduces the risk of microvascular and neurologic complications of type 1 diabetes . We studied whether the use of intensive therapy as compared with conventional therapy during the Diabetes Control and Complications Trial ( DCCT ) affected the long-term incidence of cardiovascular disease . METHODS The DCCT r and omly assigned 1441 patients with type 1 diabetes to intensive or conventional therapy , treating them for a mean of 6.5 years between 1983 and 1993 . Ninety-three percent were subsequently followed until February 1 , 2005 , during the observational Epidemiology of Diabetes Interventions and Complications study . Cardiovascular disease ( defined as nonfatal myocardial infa rct ion , stroke , death from cardiovascular disease , confirmed angina , or the need for coronary-artery revascularization ) was assessed with st and ardized measures and classified by an independent committee . RESULTS During the mean 17 years of follow-up , 46 cardiovascular disease events occurred in 31 patients who had received intensive treatment in the DCCT , as compared with 98 events in 52 patients who had received conventional treatment . Intensive treatment reduced the risk of any cardiovascular disease event by 42 percent ( 95 percent confidence interval , 9 to 63 percent ; P=0.02 ) and the risk of nonfatal myocardial infa rct ion , stroke , or death from cardiovascular disease by 57 percent ( 95 percent confidence interval , 12 to 79 percent ; P=0.02 ) . The decrease in glycosylated hemoglobin values during the DCCT was significantly associated with most of the positive effects of intensive treatment on the risk of cardiovascular disease . Microalbuminuria and albuminuria were associated with a significant increase in the risk of cardiovascular disease , but differences between treatment groups remained significant ( P < or = 0.05 ) after adjusting for these factors . CONCLUSIONS Intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease in patients with type 1 diabetes BACKGROUND Hyperglycaemia is associated with increased risk of cardiovascular complications in people with type 2 diabetes . We investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in people with type 2 diabetes . METHODS ACCORD was a parallel-group , r and omised trial done in 77 clinical sites in North America . People with diabetes , high HbA(1c ) concentrations ( > 7.5 % ) , and cardiovascular disease ( or > or=2 cardiovascular risk factors ) were r and omly assigned by central r and omisation to intensive ( target haemoglobin A(1c ) [ HbA(1c ) ] of < 6.0 % ) or st and ard ( 7.0 - 7.9 % ) glycaemic therapy . In this analysis , the prespecified composite outcomes were : dialysis or renal transplantation , high serum creatinine ( > 291.7 micromol/L ) , or retinal photocoagulation or vitrectomy ( first composite outcome ) ; or peripheral neuropathy plus the first composite outcome ( second composite outcome ) . 13 prespecified secondary measures of kidney , eye , and peripheral nerve function were also assessed . Investigators and participants were aware of treatment group assignment . Analysis was done for all patients who were assessed for microvascular outcomes , on the basis of treatment assignment , irrespective of treatments received or compliance to therapies . ACCORD is registered with Clinical Trials.gov , number NCT00000620 . FINDINGS 10 251 patients were r and omly assigned , 5128 to the intensive glycaemia control group and 5123 to st  and ard group . Intensive therapy was stopped before study end because of higher mortality in that group , and patients were transitioned to st and ard therapy . At transition , the first composite outcome was recorded in 443 of 5107 patients in the intensive group versus 444 of 5108 in the st and ard group ( HR 1.00 , 95 % CI 0.88 - 1.14 ; p=1.00 ) , and the second composite outcome was noted in 1591 of 5107 versus 1659 of 5108 ( 0.96 , 0.89 - 1.02 ; p=0.19 ) . Results were similar at study end ( first composite outcome 556 of 5119 vs 586 of 5115 [ HR 0.95 , 95 % CI 0.85 - 1.07 , p=0.42 ] ; and second 1956 of 5119 vs 2046 of 5115 , respectively [ 0.95 , 0.89 - 1.01 , p=0.12 ] ) . Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes , but delayed the onset of albuminuria and some measures of eye complications and neuropathy . Seven secondary measures at study end favoured intensive therapy ( p<0.05 ) . INTERPRETATION Microvascular benefits of intensive therapy should be weighed against the increase in total and cardiovascular disease-related mortality , increased weight gain , and high risk for severe hypoglycaemia . FUNDING US National Institutes of Health ; National Heart , Lung , and Blood Institute ; National Institute of Diabetes and Digestive and Kidney Diseases ; National Institute on Aging ; National Eye Institute ; Centers for Disease Control and Prevention ; and General Clinical Research Centers BACKGROUND During the United Kingdom Prospect i ve Diabetes Study ( UKPDS ) , patients with type 2 diabetes mellitus who received intensive glucose therapy  had a lower risk of microvascular complications than did those receiving conventional dietary therapy . We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes . METHODS Of 5102 patients with newly diagnosed type 2 diabetes , 4209 were r and omly assigned to receive either conventional therapy ( dietary restriction ) or intensive therapy ( either sulfonylurea or insulin or , in overweight patients , metformin ) for glucose control . In post-trial monitoring , 3277 patients were asked to attend annual UKPDS clinics for 5 years , but no attempts were made to maintain their previously assigned therapies . Annual question naires were used to follow patients who were unable to attend the clinics , and all patients in years 6 to 10 were assessed through question naires . We examined seven prespecified aggregate clinical outcomes from the UKPDS on an intention-to-treat basis , according to previous r and omization categories . RESULTS Between-group differences in glycated hemoglobin levels were lost after the first year . In the sulfonylurea-insulin group , relative reductions in risk persisted at 10 years for any diabetes-related end point ( 9 % , P=0.04 ) and microvascular disease ( 24 % , P=0.001 ) , and risk reductions for myocardial infa rct ion ( 15 % , P=0.01 ) and death from any cause ( 13 % , P=0.007 ) emerged over time , as more events occurred . In the metformin group , significant risk reductions persisted for any diabetes-related end point ( 21 % , P=0.01 ) , myocardial infa rct ion ( 33 % , P=0.005 ) , and death from any cause ( 27 % , P=0.002 ) . CONCLUSIONS Despite an early loss of glycemic differences , a continued reduction in microvascular risk and emergent risk reductions for myocardial infa rct ion and death from any cause were observed during 10 years of post-trial follow-up . A continued benefit after metformin therapy was evident among overweight patients . ( UKPDS 80 ; Current Controlled Trials number , IS RCT N75451837 . Patients with type 2 diabetes are at high risk for several serious health problems , including premature death , cardiovascular disease (CVD),2 blindness , and kidney failure . Moreover , there is a strong positive association between the degree of glycemia , measured as plasma glucose or glycated hemoglobin ( Hb A1c ) , and the above outcomes . Hence , it has been hypothesized that the mortality and morbidity of type 2 diabetes can be reduced with intensive control of glycemia . The Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial tested this hypothesis by determining whether a therapeutic strategy that targeted a typical Hb A1c value of < 6.0 % , compared with a strategy that targeted an Hb A1c value of 7.0%–7.9 % , would reduce CVD ( 1 ) . The primary outcome was a composite of CVD death , nonfatal myocardial infa rct ion , and nonfatal stroke . Secondary outcomes included all-cause mortality , development and progression of microvascular disease , frequency of severe hypoglycemia , and progression of retinopathy . The trial also tested the effects of intensive blood pressure ( BP ) control and the addition of a fibrate in selected patients . The study r and omized 10 251 participants with well-established type 2 diabetes . Entry criteria included a history of a cardiovascular event or at least 2 risk factors for CVD , and a normal serum creatinine concentration . The trial was not design ed to test the efficacy of any particular medication or combination of medications . What differed between the 2 arms was the glycemic target and consequently the frequency of use of glycemia medications and , to a lesser extent , the dosage . All participants made frequent clinic visits , during which lifestyle education and hypoglycemia prevention were emphasized . Within 8 months after enrollment , the median Hb A1c values in the intensive and st and ard glycemia arms reached 6.4 % and 7.5 % , respectively , and remained stable with a difference between the medians of 1.1 % BACKGROUND The efficacy of new antihypertensive drugs has been question ed . We compared the effects of conventional and newer antihypertensive drugs on cardiovascular mortality and morbidity in elderly patients . METHODS We did a prospect i ve , r and omised trial in 6614 patients aged 70 - 84 years with hypertension ( blood pressure > or = 180 mm Hg systolic , > or = 105 mm Hg diastolic , or both ) . Patients were r and omly assigned conventional antihypertensive drugs ( atenolol 50 mg , metoprolol 100 mg , pindolol 5 mg , or hydrochlorothiazide 25 mg plus amiloride 2.5 mg daily ) or newer drugs ( enalapril 10 mg or lisinopril 10 mg , or felodipine 2.5 mg or isradipine 2 - 5 mg daily ) . We assessed fatal stroke , fatal myocardial infa rct ion , and other fatal cardiovascular disease . Analysis was by intention to treat . FINDINGS Blood pressure was decreased similarly in all treatment groups . The primary combined endpoint of fatal stroke , fatal myocardial infa rct ion , and other fatal cardiovascular disease occurred in 221 of 2213 patients in the conventional drugs group ( 19.8 events per 1000 patient-years ) and in 438 of 4401 in the newer drugs group ( 19.8 per 1000 ; relative risk 0.99 [ 95 % CI 0.84 - 1.16 ] , p=0.89 ) . The combined endpoint of fatal and non-fatal stroke , fatal and non-fatal myocardial infa rct ion , and other cardiovascular mortality occurred in 460 patients taking conventional drugs and in 887 taking newer drugs ( 0.96 [ 0.86 - 1.08 ] , p=0.49 ) . INTERPRETATION Old and new antihypertensive drugs were similar in prevention of cardiovascular mortality or major events . Decrease in blood pressure was of major importance for the prevention of cardiovascular events AIMS To assess the additional benefit gained from high  compliance in the West of Scotl and Coronary Prevention Study and to examine cases where withdrawal from trial medication was due to an adverse event . METHODS The incidence of definite coronary heart disease or non-fatal myocardial infa rct ion , cardiovascular mortality , definite or suspect coronary heart disease death or non-fatal myocardial infa rct ion , the need for coronary revascularization procedures , all-cause mortality and incident cancers were measured in the entire cohort and compared with the high compliance group . The adverse events associated with withdrawal were coded by body system . RESULTS In subjects with compliance > or = 75 % , treatment with pravastatin result ed in a 38 % risk reduction for definite coronary heart disease death or non-fatal myocardial infa rct ion and for cardiovascular mortality , a 46 % reduction in risk or coronary revascularization and a 32 % risk reduction ( P = 0.015 ) for all-cause mortality . CONCLUSIONS The analysis of the effect of pravastatin in the subgroup of high compliers to r and omized medication demonstrated a substantial increase in the estimated risk reductions in comparison with that achieved in the intention-to-treat analysis . This result has significant implication s for the motivation of high compliance among patients and for the assessment of the cost-effectiveness of treatment OBJECTIVE The Captopril Prevention Project ( CAPPP ) evaluated the effects of an ACE inhibitor-based therapeutic regimen on  cardiovascular mortality and morbidity in hypertension .  One planned sub analysis of the CAPPP was to evaluate the outcome in the diabetic patient group . RESEARCH DESIGN AND METHODS In the CAPPP , 572 ( 4.9 % of 10,985 hypertensive patients ) had diabetes at baseline and were studied according to a prospect i ve , r and omized , open , blinded , end point trial design . Patients aged 25 - 66 years with diastolic blood pressure > or = 100 mmHg were included and r and omized to receive either captopril or conventional antihypertensive treatment ( diuretics and /or beta-blockers ) . RESULTS The primary end point , fatal and nonfatal myocardial infa rct ion and stroke as well as other cardiovascular deaths , was markedly lower in the captopril than in the conventional therapy group ( relative risk [ RR ] = 0.59 ; P = 0.018 ) . Specifically , cardiovascular mortality , defined as fatal stroke and myocardial infa rct ion , sudden death , and other cardiovascular death , tended to be lower in the captopril group ( RR = 0.48 ; P = 0.084 ) , and no difference was observed between the study groups for stroke ( RR = 1.02 ; P = 0.96 ) . Myocardial infa rct ions were less frequent in the captopril group than in the conventional therapy group ( RR = 0.34 ; P = 0.002 ) . Furthermore , total mortality was lower in the captopril as compared with the conventional therapy group ( RR = 0.54 ; P = 0.034 ) . Patients with impaired metabolic control seemed to benefit the most from ACE inhibitor-based therapy . CONCLUSIONS Captopril is superior to a diuretic/beta-blocker antihypertensive treatment regimen in preventing cardiovascular events in hypertensive diabetic patients , especially in those with metabolic decompensation CONTEXT Although weight reduction is a recommended goal in type 2 diabetes mellitus ( T2DM ) , weight loss is linked to impaired survival in patients with some chronic cardiovascular diseases . OBJECTIVE To assess the association of weight and weight change with mortality and non-fatal cardiovascular outcomes ( hospitalisation , myocardial infa rct ion and stroke ) in T2DM patients with cardiovascular co-morbidity and the effect of pioglitazone-induced weight change on mortality . SETTING AND PARTICIPANTS We assessed in a post hoc analysis body weight and weight change in relation to outcome in 5202 patients from the PROactive trial population who had T2DM and evidence of pre-existing cardiovascular disease . Patients were r and omized to treatment with pioglitazone or placebo in addition to their concomitant glucose-lowering and cardiovascular medication . Mean follow up was 34.5 months . MAIN OUTCOME MEASURE The impact of body weight and body weight change on all-cause mortality , cardiovascular mortality , on non-fatal cardiovascular events and on hospitalisation . RESULTS The lowest mortality was seen in patients with BMI 30 - 35 kg/m(2 ) at baseline . In comparison to this ( reference group ) , patients in the placebo group with BMI < 22 kg/m(2 ) ( Hazard Ratio ( 95 % confidence intervals ) 2.96 [ 1.27 to 6.86 ] ; P=0.012 ) and BMI 22 to 25 kg/m(2 ) ( HR 1.88 [ 1.11 to 3.21 ] ; P=0.019 ) had a higher all-cause mortality . Weight loss was associated with increased total mortality ( HR per 1 % body weight : 1.13 [ 1.11 to 1.16 ] ; P<0.0001 ) , with increased cardiovascular mortality , all-cause hospitalisation and the composite of death , myocardial infa rct ion and stroke . Weight loss of ≥7.5 % body weight ( seen in 18.3 % of patients ) was the strongest cut-point to predict impaired survival ( multivariable adjusted HR 4.42 [ 3.30 to 5.94 ] . Weight gain was not associated with increased mortality . Weight gain in patients treated with pioglitazone ( mean+4.0±6.1 kg ) predicted a better prognosis ( HR per 1 % weight gain : 0.96 [ 0.92 to 1.00 ] P=0.037 ) compared to patients without weight gain . CONCLUSION Among patients with T2DM and cardiovascular co-morbidity , overweight and obese patients had a lower mortality compared to patients with normal weight .  Weight loss  but not  weight gain  was associated with increased mortality and morbidity . There may be an " obesity paradox " in patients with type 2 diabetes and cardiovascular risk . The original PROactive trial is registered as an International St and ard R and omized Controlled Trial ( Number IS RCT N NCT00174993 ) BACKGROUND Despite treatment , there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals . Inadequate reduction of their blood pressure is a likely cause , but the optimum target blood pressure is not known . The impact of acetylsalicylic acid ( aspirin ) has never been investigated in patients with hypertension . We aim ed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension . METHODS 18790 patients , from 26 countries , aged 50 - 80 years ( mean 61.5 years ) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg ( mean 105 mm Hg ) were r and omly assigned a target diastolic blood pressure . 6264 patients were allocated to the target pressure < or = 90 mm Hg , 6264 to < or = 85 mm Hg , and 6262 to < or = 80 mm Hg . Felodipine was given as baseline therapy with the addition of other agents , according to a five-step regimen . In addition , 9399 patients were r and omly assigned 75 mg/day acetylsalicylic acid ( Bamycor , Astra ) and 9391 patients were assigned  placebo . FINDINGS Diastolic blood pressure was reduced by 20.3 mm Hg , 22.3 mm Hg , and 24.3 mm Hg , in the < or = 90 mm Hg , < or = 85 mm Hg , and < or = 80 mm Hg target groups , respectively . The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg ; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg . Further reduction below these blood pressures was safe .  In patients with diabetes mellitus there was a 51 % reduction in major cardiovascular events in target group < or = 80 mm Hg compared with target group < or = 90 mm Hg ( p for trend=0.005 ) . Acetylsalicylic acid reduced major cardiovascular events by 15 % ( p=0.03 ) and all myocardial infa rct ion by 36 % ( p=0.002 ) , with no effect on stroke . There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group , and 129 versus 70 non-fatal major bleeds in the two groups , respectively ( p<0.001 ) . INTERPRETATION Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events . The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg . Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infa rct ion . There was no effect on the incidence of stroke or fatal bleeds , but non-fatal major bleeds were twice as common
Intensive glycaemic control does not seem to reduce all cause mortality in patients with type 2 diabetes .
OBJECTIVE To assess the effect of targeting intensive glycaemic control versus conventional glycaemic control on  all cause mortality and cardiovascular mortality , non-fatal myocardial infa rct ion , microvascular complications , and severe hypoglycaemia in patients with type 2 diabetes .