title: Effects of blood pressure lowering and intensive glucose control on the incidence and progression of retinopathy in patients with type 2 diabetes mellitus: a randomised controlled trial Tight Glycemic Control in Diabetic Coronary Artery Bypass Graft Patients Improves Perioperative Outcomes and Decreases Recurrent Ischemic Events Effect of blood glucose control on peripheral nerve function in diabetic patients. Effect of intravenous insulin administration on left ventricular performance during non-ST-elevation acute coronary events in patients with diabetes mellitus. 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 Effect of a multifactorial intervention on mortality in type 2 diabetes. [Long-term intensive glycemic and lipid control ameliorates the carotid intima medial thickness in type 2 diabetes mellitus]. The influences of obesity and glycemic control on endothelial activation in patients with type 2 diabetes. Combined Effects of Routine Blood Pressure Lowering and Intensive Glucose Control on Macrovascular and Microvascular Outcomes in Patients With Type 2 Diabetes Effects of Structured Versus Usual Care on Renal Endpoint in Type 2 Diabetes: The SURE Study Severe hypoglycemia and risks of vascular events and death. Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes. Cost-effectiveness of intensive insulin therapy for type 2 diabetes: a 10-year follow-up of the Kumamoto study. A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (U.K. Prospective Diabetes Study 44) Diabetes Care Protocol: effects on patient-important outcomes. A cluster randomized, non-inferiority trial in primary care. Intensive insulin treatment reduces transient ischaemic episodes during acute coronary events in diabetic patients. Quality of Life in Type 2 Diabetic Patients Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VII. Mortality and selected nonfatal events with insulin treatment. Effect of short term intensive multitherapy on carotid intima-media thickness in patients with newly diagnosed type 2 diabetes mellitus. 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. Health-related quality of life in the VA Feasibility Study on glycemic control and complications in type 2 diabetes mellitus. 10-year follow-up of intensive glucose control in type 2 diabetes. Glycaemic separation and risk factor control in the Veterans Affairs Diabetes Trial: an interim report. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial
abstract: Aims /hypothesisThe aim of the present study was to investigate the effect of blood pressure lowering and intensive glucose control on the incidence and progression of retinopathy in type 2 diabetic patients . Methods The Action in Diabetes and Vascular Disease : Preterax and Diamicron MR Controlled Evaluation ( ADVANCE ) Retinal Measurements study , a sub study of ADVANCE , is a r and omised ( using a central , computer-based procedure ) controlled 2 × 2 factorial trial comprising a double-blind comparison of blood pressure lowering with perindopril – indapamide vs placebo , and an open comparison of st and ard vs intensive glucose control targeting a HbA1c of ≤ 6.5 % in 1,602 diabetic patients from ADVANCE centres with access to retinal cameras conducted from 2001 to 2008 . At baseline and the final visit , seven-field stereoscopic retinal photographs were taken and grade d by blinded readers ( grade able baseline and final photographs from 1,241 patients ) . Progression of ≥2 steps in the Early Treatment of Diabetic Retinopathy Study classification ( using the eye with worst grading ) was the primary outcome . Results Retinopathy progressed in 59 ( 4.8 % ) patients and developed in 128 ( 10.3 % ) patients over 4.1 years . Fewer patients on blood pressure-lowering treatment ( n = 623 ) experienced incidence or progression of retinopathy compared with patients on placebo ( n = 618 ) , but the difference was not significant ( OR 0.78 ; 95 % CI 0.57–1.06 ; p = 0.12 ) . Blood pressure-lowering treatment reduced the occurrence of macular oedema ( OR 0.50 ; 95 % CI 0.29–0.88 ; p = 0.016 ) and arteriovenous nicking compared with placebo ( OR 0.60 ; 95 % CI 0.38–0.94 ; p = 0.025 ) . Compared with st and ard glucose control ( n = 611 ) , intensive glucose control ( n = 630 ) did not reduce ( p = 0.27 ) the incidence and progression of retinopathy ( OR 0.84 ; 95 % CI 0.61–1.15 ) . Lower , borderline significant risks of microaneurysms , hard exu date s and macular oedema were observed with intensive glucose control , adjusted for baseline retinal haemorrhages . These effects of the two treatments were independent and additive . Adverse events in the ADVANCE study are reported elsewhere . Conclusions /interpretationBlood pressure lowering or intensive glucose control did not significantly reduce the incidence and progression of retinopathy , although consistent trends towards a benefit were observed , with significant reductions in some lesions observed with both interventions .Trial registration : Clinical Trials.gov ID no. NCT00145925 . Funding : Grants from Servier and the National Health and Medical Research Council of Background —This study sought to determine whether tight glycemic control with a modified glucose-insulin-potassium ( GIK ) solution in diabetic coronary artery bypass graft ( CABG ) patients would improve perioperative outcomes . Methods and Results —One hundred forty-one diabetic patients undergoing CABG were prospect ively r and omized to tight glycemic control ( serum glucose , 125 to 200 mg/dL ) with GIK or st and ard therapy ( serum glucose < 250 mg/dL ) using intermittent subcutaneous insulin beginning before anesthesia and continuing for 12 hours after surgery . GIK patients had lower serum glucose levels ( 138±4 versus 260±6 mg/dL ; P < 0.0001 ) , a lower incidence of atrial fibrillation ( 16.6 % versus 42 % ; P = 0.0017 ) , and a shorter postoperative length of stay ( 6.5±0.1 versus 9.2±0.3 days ; P = 0.003 ) . GIK patients also showed a survival advantage over the initial 2 years after surgery ( P = 0.04 ) and decreased episodes of recurrent ischemia ( 5 % versus 19 % ; P = 0.01 ) and developed fewer recurrent wound infections ( 1 % versus 10 % , P = 0.03 ) . Conclusions —Tight glycemic control with GIK  in diabetic CABG patients  improves perioperative outcomes , enhances survival , and decreases the incidence of ischemic events and wound complications A prospect i ve , stratified , r and omized 3-year clinical trial was conducted on the effect of rigorous versus conventional glucose control on peripheral nerve function in 33 insulin-treated diabetic patients with a duration of diabetes of less than 2 years . The goals for conventional glucose control were the mean of fasting and 80-minute postpr and ial plasma glucose of 150 mg/dl for non-insulin-dependent diabetes and 200 mg/dl for insulin-dependent diabetes . The goal of rigorous glucose control was an approximation of nondiabetic glucose control . No significant difference in glucose control or peripheral nerve function was observed between the rigorously and the conventionally controlled groups . Eight patients in the conventional-control group spontaneously achieved glucose control in the range that was the objective for the rigorous-control group , and five patients in the rigorous-control group never achieved the desired glucose control . In the remaining 20 patients , with similar baseline glucose control and peripheral nerve function characteristics , observed over a median of 2 years , improved blood glucose control ( P less than 0.01 ) was not associated with any significant improvement in peripheral nerve function . Nevertheless , a significant ( P less than 0.05 ) correlation was found between the degree of abnormal nerve function at entry into the study and change in nerve function during the study . If control of hyperglycemia benefits peripheral nerve function of diabetic patients , its demonstration may require a closer approximation of normoglycemia , a larger difference in glucose control between the two study groups , a longer duration of treatment , and the use of patients with more advanced  peripheral nerve function  abnormalities than those in this study maintaining near-normal glycemia . 5 Group B patients were treated using the usual protocol s , with oral hy- poglycemic drugs or 2 daily doses of intermediate- acting insulin . Supplementary small doses of short- acting insulin were administered subcutaneously only if glucose levels were 250 mg/dl . Mean daily plasma glucose levels were assessed in each patient in both groups by employing all the measured glucose values obtained during the study . The mean glucose level in the conservative treatment group was assessed by the 3 st and ard prepr and ial glucose values ( at 7 A.M. , 1 P.M. , 6 P.M. ) , 1 measurement at 12 A.M. hours and any additional measurements that were performed accord- ing to the discretion of the attending physician . All patients were treated with an optimal antianginal reg- imen . Complete 2-dimensional , spectral , and color-fl ow Doppler echocardiographic examinations were per- formed by 2 examiners not involved in the fi nal anal- ysis of data , with a Hewlett-Packard Sonos 1000 Ul- trasound Machine ( And over , Massachusetts ) with a 2.5-MHz transducer , while the patients were asymp- tomatic . Images were obtained within 3 hours from ad- mission and 72 hours later and stored on high- quality videotapes for later blinded analysis . A DI design ed to determine the combined systolic and diastolic myocar- dial performance , and defi ned as the sum of isovolumet- ric contraction time plus isovolumetric relaxation time divided by ejection time , was estimated from LV outfl ow and mitral infl ow velocity patterns ( ( IVCT IVRT)/ ET).6 Videotape recordings were analyzed by 1 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 BACKGROUND Intensified multifactorial intervention - with tight glucose regulation and the use of renin-angiotensin system blockers , aspirin , and lipid-lowering agents - has been shown to reduce the risk of nonfatal cardiovascular disease among patients with type 2 diabetes mellitus and microalbuminuria . We evaluated whether this approach would have an effect on the rates of death from any cause and from cardiovascular causes . METHODS In the Steno-2 Study , we r and omly assigned 160 patients with type 2 diabetes and persistent microalbuminuria to receive either intensive therapy or conventional therapy ;  the mean treatment period was 7.8 years . Patients were subsequently followed observationally for a mean of 5.5 years , until December 31 , 2006 . The primary end point at 13.3 years of follow-up was the time to death from any cause . RESULTS Twenty-four patients in the intensive-therapy group died , as compared with 40 in the conventional-therapy group ( hazard ratio , 0.54 ; 95 % confidence interval [ CI ] , 0.32 to 0.89 ; P=0.02 ) . Intensive therapy was associated with a lower risk of death from cardiovascular causes ( hazard ratio , 0.43 ; 95 % CI , 0.19 to 0.94 ; P=0.04 ) and of cardiovascular events ( hazard ratio , 0.41 ; 95 % CI , 0.25 to 0.67 ; P<0.001 ) . One patient in the intensive-therapy group had progression to end-stage renal disease , as compared with six patients in the conventional-therapy group ( P=0.04 ) . Fewer patients in the intensive-therapy group required retinal photocoagulation ( relative risk , 0.45 ; 95 % CI , 0.23 to 0.86 ; P=0.02 ) . Few major side effects were reported . CONCLUSIONS In at-risk patients with type 2 diabetes , intensive intervention with multiple drug combinations and behavior modification had sustained beneficial effects with respect to vascular complications and on rates of death from any cause and from cardiovascular causes . ( Clinical Trials.gov number , NCT00320008 . OBJECTIVE To investigate whether long-term intensive glycemic and lipid control would ameliorate the carotid intima medial thickness ( IMT ) in patients with type 2 diabetes mellitus ( T2DM ) . METHODS IMT was evaluated on B-mode ultrasonography in 116 patients with T2DM .  Body mass index ( BMI ) , waist-to-hip ratio ( WHR ) , fasting blood glucose ( FBG ) , 2 hour postpr and ial glucose ( 2hPG ) , hemoglobin A(1)c(HbA(1)c ) , total cholesterol(TC ) , triglycerides ( TG ) , low-density lipoprotein cholesterol (LDL-C),high-density lipoprotein cholesterol ( HDL-C ) were also measured . Of all the patients 89 were divided r and omly into group of intensive glycemic and lipid control and group of conventional treatment and underwent 1 year clinical interview . RESULTS ( 1 ) IMT in patients with T2DM was significantly correlated with age(r = 0.515,P = 0.000 ) , SBP ( r = 0.208 , P = 0.025 ) , TC(r = 0.213,P = 0.022 ) , LDL-C(r = 0.253 , P = 0.006 ) and no correlations were found between IMT and BMI , WHR , FBG , 2hPG , HbA(1)c , TG and HDL-C. In multivariate regression analysis , age ( Beta = 0.527 , P = 0.000 ) and TC(Beta = 0.243 , P = 0.002 ) were significant independent determinants for IMT . ( 3 ) After 1 year the change of IMT in the group of intensive glycemic and lipid control was significantly different compared with the group of conventional treatment [ (-0.044+/-0.148)mm vs ( 0.056+/-0.178 ) , P<0.05 ] . The change of IMT was not significantly associated with the use of Metformin , Sulphonylurea and Aspirin , but significantly associated with the use of  statins  . The change of IMT in the group using statins was significantly different compared with that in the group without using statins[(-0.053+/-0.153)mm vs (0.042+/-0.165)mm , P < 0.05 ] . CONCLUSION Carotid IMT appears to be closely related to age and TC in the patients with T2DM . long-term intensive glycemic control and lipid control could ameliorate the IMT in patients with T2DM . The improvement of IMT may be associated with the use of statin drug The aims of this study were to eluci date the factors that contribute to endothelial activation and fibrinolytic abnormalities in patients with poorly controlled type 2 diabetes and to determine whether improved glycemic control reduces endothelial activation . Adhesion molecules [ E-selectin , intracellular adhesion molecule-1 ( ICAM-1 ) , and vascular cell adhesion molecule-1 ] , von Willebr and factor , total nitric oxide ( NO ) , endothelin-1 , tissue plasminogen activator , and plasminogen activator inhibitor-1 were measured in 43 type 2 diabetic subjects with hemoglobin A1c of 9.0 % or more at baseline ( compared with 21 healthy controls ) who after 20 wk had been r and omized to either improved ( IC ) or usual ( UC ) glycemic control . At baseline , type 2 diabetic patients had significant endothelial activation and abnormal fibrinolysis compared with control subjects . Body mass index in the diabetic patients was the only independent predictor of E-selectin ( P = 0.007 ) , ICAM-1 ( P = 0.01 ) , and NO ( P = 0.008 ) concentrations , but not vascular cell adhesion molecule-1 , plasminogen activator inhibitor-1 , or tissue plasminogen activator ( all P > 0.05 ) . Type 2 diabetic patients with a body mass index of 28 kg/m2 or less had concentrations of E-selectin , ICAM-1 , endothelin-1 , and NO similar to those in healthy controls . After 20 wk , hemoglobin A1c was significantly lower in IC vs. UC ( IC , 8.02 + /- 0.25 % ; UC , 10.23 + /- 0.23 % ; P < 0.0001 ) , but there were no significant changes in markers of endothelial activation or indexes of fibrinolysis . Obesity appears to be the most important predictor of endothelial activation in patients with type 2 diabetes . Short-term improvement in glycemic control does not appear to reduce endothelial activation OBJECTIVE To assess the magnitude and independence of the effects of routine blood pressure lowering and intensive glucose control on clinical outcomes in patients with long-st and ing type 2 diabetes . RESEARCH DESIGN AND METHODS This was a multicenter , factorial r and omized trial of perindopril-indapamide versus placebo ( double-blind comparison ) and intensive glucose control with a gliclazide MR – based regimen ( target A1C ≤6.5 % ) versus st and ard glucose control ( open comparison ) in 11,140 participants with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease : Preterax and Diamicron MR Controlled Evaluation ( ADVANCE ) trial .  Annual event rates and risks of major macrovascular and microvascular events considered jointly and separately , renal events , and death during an average 4.3 years of follow-up were assessed , using Cox proportional hazards models . RESULTS There was no interaction between the effects of  routine blood pressure lowering and intensive glucose control for any of the prespecified clinical outcomes ( all P > 0.1 ) : the separate effects of the two interventions for the renal outcomes and death appeared to be additive on the log scale . Compared with neither intervention , combination treatment reduced the risk of new or worsening nephropathy by 33 % ( 95 % CI 12–50 % , P = 0.005 ) , new onset of macroalbuminuria by 54 % ( 35–68 % , P < 0.0001 ) , and new onset of microalbuminuria by 26 % ( 17–34 % ) . Combination treatment was associated with an 18 % reduction in the risk of all-cause death ( 1–32 % , P = 0.04 ) . CONCLUSIONS The effects of routine blood pressure lowering and intensive glucose control were independent of one another . When combined , they produced additional reductions in clinical ly relevant outcomes OBJECTIVE Multifaceted care has been shown to reduce mortality and complications in type 2 diabetes . We hypothesized that structured care would reduce renal complications in type 2 diabetes . RESEARCH DESIGN AND METHODS A total of 205 Chinese type 2 diabetic patients from nine public hospitals who had plasma creatinine levels of 150–350 μmol/l were r and omly assigned to receive structured care ( n = 104 ) or usual care ( n = 101 ) for 2 years . The structured care group was managed according to a prespecified protocol with the following treatment goals : blood pressure < 130/80 mmHg , A1C < 7 % , LDL cholesterol < 2.6 mmol/l , triglyceride < 2 mmol/l , and persistent treatment with renin-angiotensin blockers . The primary end point was death and /or renal end point ( creatinine > 500 μmol/l or dialysis ) . RESULTS Of these 205 patients ( mean ± SD age 65 ± 7.2 years ; disease duration 14 ± 7.9 years ) , the structured care group achieved better control than the usual care group ( diastolic blood pressure 68 ± 12 vs. 71 ± 12 mmHg , respectively , P = 0.02 ; A1C 7.3 ± 1.3 vs. 8.0 ± 1.6 % , P < 0.01 ) . After adjustment for age , sex , and study sites , the structured care ( 23.1 % , n = 24 ) and usual care ( 23.8 % , n = 24 ; NS ) groups had similar end points , but more patients in the structured care group attained ≥3 treatment goals ( 61 % , n = 63 , vs. 28 % , n = 28 ; P < 0.001 ) . Patients who attained ≥3 treatment targets ( n = 91 ) had reduced risk of the primary end point ( 14 vs. 34 ; relative risk 0.43 [ 95 % CI 0.21–0.86 ] compared with that of those who attained ≤2 targets ( n = 114 ) . CONCLUSIONS Attainment of multiple treatment targets reduced the renal end point and death in type 2 diabetes . In addition to protocol , audits and feedback are needed to improve outcomes BACKGROUND Severe hypoglycemia may increase the risk of a poor outcome in patients with type 2 diabetes assigned to an intensive glucose-lowering intervention .  We analyzed data from a large study of intensive glucose lowering to explore the relationship between severe hypoglycemia and adverse clinical outcomes . METHODS We examined the associations between severe hypoglycemia and the risks of macrovascular or microvascular events and death among 11,140 patients with type 2 diabetes , using Cox proportional-hazards models with adjustment for covariates measured at baseline and after r and omization . RESULTS During a median follow-up period of 5 years , 231 patients ( 2.1 % ) had at least one severe hypoglycemic episode ; 150 had been assigned to intensive glucose control ( 2.7 % of the 5571 patients in that group ) , and 81 had been assigned to st and ard glucose control ( 1.5 % of the 5569 patients in that group ) . The median times from the onset of severe hypoglycemia to the first major macrovascular event , the first major microvascular event , and death were 1.56 years ( interquartile range , 0.84 to 2.41 ) , 0.99 years ( interquartile range , 0.40 to 2.17 ) , and 1.05 years ( interquartile range , 0.34 to 2.41 ) , respectively . During follow-up , severe hypoglycemia was associated with a significant increase in the adjusted risks of major macrovascular events ( hazard ratio , 2.88 ; 95 % confidence interval [ CI ] , 2.01 to 4.12 ) , major microvascular events ( hazard ratio , 1.81 ; 95 % CI , 1.19 to 2.74 ) , death from a cardiovascular cause ( hazard ratio , 2.68 ; 95 % CI , 1.72 to 4.19 ) , and death from any cause ( hazard ratio , 2.69 ; 95 % CI , 1.97 to 3.67 ) ( P<0.001 for all comparisons ) . Similar associations were apparent for a range of nonvascular outcomes , including respiratory , digestive , and skin conditions ( P<0.01 for all comparisons ) . No relationship was found between repeated episodes of severe hypoglycemia and vascular outcomes or death . CONCLUSIONS Severe hypoglycemia was strongly associated with increased risks of a range of adverse clinical outcomes . It is possible that severe hypoglycemia contributes to adverse outcomes , but these analyses indicate that hypoglycemia is just as likely to be a marker of vulnerability to such events . ( Funded by Servier and the National Health and Medical Research Council of Australia ; Clinical Trials.gov number , NCT00145925 . ) BACKGROUND The risks and benefits of intensive therapy in non-insulin-dependent diabetes mellitus ( NIDDM ) need to be defined . In preparation for a long-term trial , a feasibility study of 153 men in 5 medical centers compared st and ard vs intensive insulin therapy . OBJECTIVE To assess the rate of development of new cardiovascular events and their correlates . METHODS Patients with a mean + /- SD age of 60 + /- 6 years and diagnosis of NIDDM for 7.8 + /- 4.0 years were r and omly assigned to a st and ard ( 1 insulin injection every morning ) or to an intensive treatment arm ( stepped plan from 1 evening injection of insulin , alone or with glipizide , to multiple daily injections ) design ed to attain near-normal glycemia levels . A 2.07 % separation of glycosylated hemoglobin ( HbA1c ) was sustained for a mean follow-up of 27 months ( P < .001 ) . Predefined cardiovascular events were assessed by a committee unaware of treatment assignment . RESULTS Mild and moderate hypoglycemic events were more frequent in the intensive than in the st and ard treatment arm ( 16.5 vs 1.5 per patient per year , respectively ) . Mean insulin dose was 23 % lower in the st and ard treatment arm ( P < .001 ) . There were 61 new cardiovascular events in 24 patients ( 32 % ) in the intensive treatment arm and in 16 patients ( 20 % ) in the st and ard treatment arm ( P = .10 ) . There was no difference in total and cardiovascular mortality ( n = 5 and n = 3 in the intensive and st and ard treatment arms , respectively ) or in new events in patients with cardiovascular history ( n = 10 in each arm ) . In Cox regression analysis , the only significant correlate for new cardiovascular events was previous cardiovascular disease ( P = .04 ) . Entering in the analysis any baseline cardiovascular abnormality , the regression model indicated a lower HbA1c level prior to the event as the only correlate for new cardiovascular events ( P = .05 ) . CONCLUSION A long-term prospect i ve trial is needed to assess the risk-benefit ratio of intensive insulin therapy for NIDDM in patients who require it To evaluate the cost and effectiveness of intensive insulin therapy for type 2 diabetes on the prevention of diabetes complications in Japan , we performed economic evaluation based on a r and omized controlled trial . A total of 110 patients with type 2 diabetes were r and omly assigned into two groups , a multiple insulin injection therapy ( MIT ) group or a conventional insulin injection therapy ( CIT ) group , and were followed-up for 10 years . Economic evaluation ( cost-consequences analysis ) was applied to evaluate both health and economic outcomes . As outcome measures for effectiveness of intensive insulin therapy , the frequency of complications , such as retinopathy , nephropathy , neuropathy , macrovascular event , and diabetes-related death , was used . For estimating costs , a viewpoint of the payer ( the National Health Insurance ) was adopted . Direct medical costs associated with diabetes care during 10 years were calculated and evaluated . In a base case analysis , all costs were discounted to the present value at an annual rate of 3 % . Sensitivity analyses were carried out to assess the robustness of the results to changes in the values of important variables . MIT reduced the relative risk in the progression of retinopathy by 67 % , photocoagulation by 77 % , progression of nephropathy by 66 % , albuminuria by 100 % and clinical neuropathy by 64 % , relative to CIT . Moreover , MIT prolonged the period in which patients were free of complications , including 2.0 years for progression of retinopathy ( P<0.0001 ) , 0.3 years for photocoagulation ( P<0.05 ) , 1.5 years for progression of nephropathy ( P<0.01 ) and 2.2 years for clinical neuropathy ( P<0.0001 ) . The total cost ( discounted at 3 % ) per patient during the 10-year period for each group was $ 30310 and 31525 , respectively . The reduction of total costs in MIT over CIT was mainly due to reduced costs for management of diabetic complications . Our results show that MIT  is more beneficial than CIT in both cost and effectiveness . Therefore , MIT is recommended for the treatment of type 2 diabetic patients who require insulin therapy as early as possible from the perspective of both patients and health policy OBJECTIVE To determine the degree to which alpha-glucosidase inhibitors , with their unique mode of action primarily reducing postpr and ial hyperglycemia , offer an additional therapeutic approach in the long-term treatment of type 2 diabetes . RESEARCH DESIGN AND METHODS We studied 1,946 patients ( 63 % men ) who were previously enrolled in the U.K. Prospect i ve Diabetes Study ( UKPDS ) . The patients were r and omized to acarbose ( n = 973 ) , titrating to a maximum dose of 100 mg three times per day , or to matching placebo ( n = 973 ) . Mean + /- SD age was 59 + /- 9 years , body weight 84 + /- 17 kg , diabetes duration 7.6 + /- 2.9 years , median ( interquartile range ) HbA1c 7.9 % ( 6.7 - 9.5 ) , and fasting plasma glucose ( FPG ) 8.7 mmol/l ( 6.8 - 11.1 ) . Fourteen percent of patients were treated with diet alone , 52 % with monotherapy , and 34 % with combined therapy . Patients were monitored in UKPDS clinics every 4 months for 3 years . The main outcome measures were HbA1c , FPG , body weight , compliance with study medication , incidence of side effects , and frequency of major clinical events . RESULTS At 3 years , a lower proportion of patients were taking acarbose compared with placebo ( 39 vs. 58 % , P < 0.0001 ) , the main reasons for noncompliance being flatulence ( 30 vs. 12 % , P < 0.0001 ) and diarrhea ( 16 vs. 8 % , P < 0.05 ) . Analysis by intention to treat showed that patients allocated to acarbose , compared with placebo , had 0.2 % significantly lower median HbA1c at 3 years ( P < 0.001 ) . In patients remaining on their allocated therapy , the HbA1c difference at 3 years ( 309 acarbose , 470 placebo ) was 0.5 % lower median HbA1c ( 8.1 vs. 8.6 % , P < 0.0001 ) . Acarbose appeared to be equally efficacious when given in addition to diet alone ; in addition to monotherapy with a sulfonylurea , metformin , or insulin ; or in combination with more complex treatment regimens . No significant differences were seen in FPG , body weight , incidence of hypoglycemia , or frequency of major clinical events . CONCLUSIONS Acarbose significantly improved glycemic control over 3 years in patients with established type 2 diabetes , irrespective of concomitant therapy for diabetes . Careful titration of acarbose is needed in view of the increased noncompliance rate seen secondary to the known side effects AIMS The Diabetes Care Protocol ( DCP ) combines task delegation , intensification of diabetes treatment and feedback . It reduces cardiovascular risk in Type 2 diabetes ( T2DM ) patients . This study determines the effects of DCP on patient-important outcomes . METHODS A cluster r and omized , non-inferiority trial , by self-administered question naires in 55 Dutch primary care practice s : 26 practice s DCP ( 1699 patients ) , 26 usual care ( 1692 patients ) . T2DM patients treated by their general practitioner were included . Main outcome was the 1-year between-group difference in Diabetes Health Profile ( DHP-18 ) total score . SECONDARY OUTCOMES DHP-18 subscales , general perceived health [ Medical Outcomes Study 36-Items Short Form Health Survey ( SF-36 ) , Euroqol 5 Dimensions ( EQ-5D ) and Euroqol visual analogue scale ( EQ-VAS ) ] , treatment satisfaction ( Diabetes Treatment Satisfaction Question naire ; DTSQ status ) and psychosocial self-efficacy ( Diabetes Empowerment Scale Short Form ; DES-SF ) . Per protocol ( PP ) and intention-to-treat ( ITT ) analyses were performed : non-inferiority margin Delta=-2 % . At baseline 2333 question naires were returned and 1437 1 year thereafter . RESULTS Comparing DCP with usual care , DHP-18 total score was non-inferior : PP -0.88 ( 95 % CI -1.94 to 0.12 ) , ITT -0.439 ( 95 % CI -1.01 to 0.08 ) , SF-36 ' health change ' improved : PP 3.51 ( 95 % CI 1.23 to 5.82 ) , ITT 1.91 ( 95 % CI 0.62 to 3.23 ) , SF-36 ' social functioning ' was inconclusive : PP-1.57 ( 95 % CI-4.3 to 0.72 ) , ITT-1.031 ( 95 % CI-2.52 to -0.25 ) . Other DHP and SF-36 scores were inconsistent or non-inferior . DHP-18 ' disinhibited eating ' was significantly worse in PP analyses . For EQ-5D/EQ-VAS , DTSQ and DES-SF , no significant between-group differences were found . CONCLUSION DCP does not seem to influence health status negatively , therefore diabetes care providers should not shrink from intensified treatment . However , they should take possible detrimental effects on ' social functioning ' and  ' disinhibited eating '  into account OBJECTIVES This study tested the impact of intensive metabolic treatment with insulin on transient myocardial ischaemia detected with continuous 12-lead ST-segment monitoring during non-ST segment elevation acute coronary syndromes in type 2 diabetic patients . METHODS AND RESULTS The study included 57 type 2 diabetic patients with non-ST segment elevation acute coronary syndromes . Twenty-eight patients r and omized to conventional treatment plus intensive insulin therapy ( group A ) and twenty-nine to conventional therapy only ( group B ) . Group A patients received insulin by infusion for 48 hours according to a predefined protocol aim ing to maintain normoglycaemia . Group B patients received st and ard coronary care unit treatment . The ST-segment monitoring was performed for 48 hours in the coronary care unit . The two groups were comparable in terms of medical history , clinical and biochemical data . Three patients from both groups were excluded from the analysis because there was objective evidence for evolution in persistent ST-segment elevation acute myocardial infa rct ion . Six patients ( 24 % ) from group A vs. twelve from group B ( 46.2 % ) had evidence of transient ischaemia ( p = 0.098 ) . Group A patients showed significantly lower values in the mean number [ group A vs. group B : 0.4 + /- 0.8 vs. 2 + /- 3.1 , p < 0.01 ] and total duration of ST-episodes [ group A vs. group B : 2.4 + /- 5.1 vs. 21.2 + /- 31 min , p < 0.01 ] . Multivariate analysis revealed that the mean plasma glucose during the study period was a powerful predictor of the presence ( b:0.377,p < 0.01 ) , the number ( b:0.523,p < 0.001 ) and the total duration ( b : 0.686 , p < 0.001 ) of ST-episodes , respectively . CONCLUSIONS ; Intensive insulin treatment considerably decreases the number and the total duration of ST-episodes in type 2 diabetic patients suffering from non-ST segment elevation acute coronary syndromes Summary The presence of diabetes mellitus leads to a decrease in life quality in all domains . The aim of our study was to evaluate the quality of life ( QOL ) in diabetic patients and the factors affecting it in type 2 diabetic mellitus patients . We conducted a cross-sectional study that included 86 patients with type 2 diabetes mellitus , in the territory of the City of Niš .  Health-related QOL of patients was measured using the short form survey ( SF-36 ) that produces an 8-scale health profile . The average duration of diabetes was 12.76±8.08 years . The best QOL in all areas was observed in patients diagnosed with diabetes less than 10 years ago p<0.05 ) and younger than 65 years . Male respondents perceived a better QOL compared to women , especially in the vitality and pain domains . The patients with comorbidity ( 93.64 % ) had lower QOL score in all domains . There was no significant difference in the QOL of patients with diabetes compared to the level of education . High QOL represents an ultimate goal and an important outcome of all medical interventions in diabetic patients . Factors related to lower QOL included : older age , female gender , and existence of comorbidities . Uncontrolled diabetic patients had a lower QOL than controlled diabetics . Sažetak Prisustvo dijabetesa dovodi do pada kvaliteta života u svim domenima . Cilj našeg istraživanja bio je da procenimo kvalitet života bolesnika sa dijabetesom tip 2 i da utvrdimo faktore koji na to utiču . Sprovedena je studija preseka na teritoriji grada Niša kojom je obuhvaćeno 86 bolesnika sa dijabetes melitusom tip 2 . Kvalitet života bolesnika procenjen je pomoću upitnika SF-36 . Prosečna dužina trajanja dijabetesa iznosila je 12.76±8.08 godina . Najbolji kvalitet života u svim domenima uočen je kod bolesnika mlađih od 65 godina i kod onih kod kojih je dijabetes melitus dijagnostikovan pre manje od 10 godina ( p<0.05 ) . Muškarci su prijavili bolji kvalitet života od žena , posebno u oblasti vitalnosti i bolova . Bolesnici sa komorbiditetima ( 93.64 % ) su imali niži kvalitet života u svim domenima . Nije zabeležena značajna razlika u kvalitetu života ispitanika obolelih od dijabetesa u odnosu na stepen obrazovanja . Kvalitet života je važan zdravstveni ishod i predstavlja konačni cilj svih zdravstvenih intervencija . Faktori koji utiču na niži kvalitet života bili su ženski pol , starost i postojanje komorbiditeta The University Group Diabetes Program is a long-term prospect i ve clinical trial design ed to evaluate the effects of various hypoglycemic agents on vascular complications in patients with asymptomatic adult-onset diabetes .  Mortality and blood glucose levels were determined as well as certain nonfatal events for patients assigned to diet alone or to either of two insulin treatment regimens . Lower levels of blood glucose with mean values close to normoglycemia were achieved in the treatment group in which the insulin dosage was adjusted to achieve normoglycemia compared with the levels achieved in patients treated with diet alone or with a fixed dose of insulin . In spite of differences in blood glucose levels among the treatment groups , there were only minor differences in the occurrence of fatal or nonfatal events BACKGROUND Controlling plasma glucose levels , blood pressure and lipid levels is proven to reduce the risk of vascular complications in patients with type 2 diabetes mellitus . This has prompted intensive multitherapy targeted at several macrovascular risk factors . Carotid intima-media thickness ( cIMT ) is a reliable measure of early atherosclerosis . We sought to determine whether a 6-month intensive mutiltherapy program result ed in better goal attainment than usual care and its effect on the development of cIMT among patients with newly diagnosed type 2 diabetes mellitus . METHODS The study r and omly assigned 220 patients with newly diagnosed type 2 diabetes mellitus to intensive or traditional therapy groups . The clinical parameters , such as fasting plasma glucose , total cholesterol , triglyceride , blood pressure , body weight and insulin were assessed at the baseline and after the 6-month therapy . cIMT of the patients was also obtained . RESULTS The average levels of fasting plasma glucose , hemoglobin A1c , total cholesterol ( TC ) and low-density lipoprotein cholesterol ( LDL-C ) in the intensive group were significantly lower than those in the control group at the end of 6-month treatment . By 6 months , a higher proportion of patients in the intensive therapy group than in the control group attained goals for fasting plasma glucose ( FPG ) , TC , LDL-C and hemoglobin A1c . With intensive multherapy the level of carotid intima-media thickness in the intensive therapy group was lower than that in the control group ( ( 0.88 + /- 0.26 ) mm vs ( 0.96 + /- 0.22 ) mm , P < 0.01 ) . CONCLUSIONS The evidence from this clinical trial demonstrates that intensive glucose , lipid and blood pressure control in patients with newly diagnosed type 2 diabetes is associated with diabetic macrovascular benefits . Intensive multitherapy allows more patients to achieve aims of control and may reduce macrovascular complications and delay disease progression 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 OBJECTIVE The Veterans Affairs Cooperative Study in Diabetes Mellitus Type 2 Feasibility Trial ( VA CSDM ) studied st and ard and intensive glycemic treatment groups , achieving and maintaining for 27 months a difference in HbA1c of 2.1 % ( 9.2 % vs. 7.1 % , respectively ) . A sub study planned in advance examined health status as assessed by a health status question naire obtained at baseline and 24 months . DESIGN AND METHODS A r and omized , prospect i ve trial was carried out at five VA Medical Centers from 1990 to 1993 . The sample involved 153 male veterans 40 - 69 years of age and with diabetes duration of 8+/-4 years , who were suboptimally controlled with st and ard glucose lowering treatment .  The participants were r and omized to  intensive and st and ard treatment groups . In addition to a variety of indicators of glycemic control and complications , health-related qualify of life data were assessed using a 20- question version of the Medical Outcome Study instrument . Scores were evaluated at baseline and 24 months for changes between the treatment groups . RESULTS The two groups were similar at baseline with respect to age , duration of diabetes , complications , comorbidities , and reported physical activity . The intensive treatment group had more frequent , m and atory self-glucose monitoring ( vs. occasional measurement in the st and ard ) and received two or more daily insulin injections  ( only one in the st and ard ) . This group had three times the number of clinic visits and 10-fold higher reported incidence of mild/moderate hypoglycemia . There were no significant changes in the health status over time in either the st and ard or intensive treatment groups , nor was there a difference between the two groups . CONCLUSIONS Intensive glucose control in advanced Type 2 diabetes mellitus ( DM ) has no effect on health status over 2 years . The successful lowering of glycemia does not improve health-related quality of life nor do the increased dem and s of an intensive therapy regimen worsen it 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 . OBJECTIVE The Veterans Affairs Diabetes Trial ( VADT ) will assess the effect of intensive ( INT ) vs improved st and ard ( STD ) glycaemic control on major cardiovascular ( CV ) events , treating other risk factors equally in both arms . Four-year results of main metabolic parameters are presented . RESEARCH DESIGN AND METHODS VADT is a 7.5 years prospect i ve r and omized study of 1791 patients , 20 centres , of men and women of age 60.5 + /- 8.7 years , diagnosed for 11.5 + /- 7.5 years . Their body mass index ( BMI ) at baseline was 31 + /- 4 kg/m(2 ) and mean A1C 9.4 + /- 1.5 % after maximum dose of oral agents or insulin treatment . Step treatment consists of glimepiride or metformin , rosiglitazone , insulin and other agents ; A1C goals are 8 - 9 % in STD and < 6 % in INT . Lifestyle , blood pressure and lipids are treated uniformly in both arms . RESULTS A1C improved in both arms . INT kept median A1C < 7 % all years , A1C separation is 1.5 - 1.7 % . From year 1 to 4 , mean blood pressure is < 129/74 mmHg , similar throughout . Median LDL-C was < 97 mg/dl by year 1 and triglycerides 150 or less by 2 years . Triglycerides were lower in INT ( 12 - 16 mg/dl ; p < 0.01 ) . By 4 years , 88 % are on lipid-lowering agents and 93 % are on antiplatelet/anticoagulant agents . BMI is higher in INT every year ( 0.9 - 1.6 kg/m(2 ) ; p < 0.01 ) . CONCLUSION VADT is maintaining the expected A1C in both STD and INT , and LDL-C , triglycerides and blood pressure are at target . The trial is continuing to June 2008 . It will be the first long-term completed type 2 diabetes study of the role of glycaemia on CV disease with modern treatments 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
target: Intensive glycaemic control does not seem to reduce all cause mortality in patients with type 2 diabetes .
background: 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 .