title: Outcomes With Nifedipine GITS or Co-Amilozide in Hypertensive Diabetics and Nondiabetics in Intervention as a Goal in Hypertension (INSIGHT) Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people Reductions in the risks of recurrent stroke in patients with and without diabetes: The PROGRESS Trial 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. Uniformity of captopril benefit in the SAVE Study: subgroup analysis. Survival and Ventricular Enlargement Study. Randomised trial of effects of calcium antagonists compared with diuretics and β-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. Swiss Hypertension and Risk Factor Program (SHARP): Cardiovascular risk factors management in patients with type 2 diabetes in Switzerland Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39 Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study) Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study The Anglo-Scandinavian Cardiac Outcomes Trial: blood pressure-lowering limb: effects in patients with type II diabetes Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial Cardiorenal end points in a trial of aliskiren for type 2 diabetes. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. Is a systolic blood pressure target <140 mmHg indicated in all hypertensives? Subgroup analyses of findings from the randomized FEVER trial. Effects of medical therapies on retinopathy progression in type 2 diabetes. Mortality findings for stepped-care and referred-care participants in the hypertension detection and follow-up program, stratified by other risk factors. The Hypertension Detection and Follow-up Program Cooperative Research Group. Five-year findings of the Hypertension Detection and Follow-up Program Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial of Patients with Type 2 Diabetes and Overt Nephropathy The effect of diabetes on outcomes of patients with advanced heart failure in the BEST trial. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial Nifedipine retard was as effective as angiotensin converting enzyme inhibitors in preventing cardiac events in high-risk hypertensive patients with diabetes and coronary artery disease: the Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) subgroup analysis. Timolol Treatment After Myocardial Infarction in Diabetic Patients The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF) Lowering blood pressure reduces renal events in type 2 diabetes. Comparison of antihypertensive treatments in preventing cardiovascular events in elderly diabetic patients: results from the Swedish Trial in Old Patients with Hypertension–2 The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The role of antihypertensive therapy in reducing vascular complications of type 2 diabetes. Findings from the DIabetic REtinopathy Candesartan Trials-Protect 2 study Effects of intensive blood-pressure control in type 2 diabetes mellitus. The Study on COgnition and Prognosis in the Elderly (SCOPE) – Major CV events and stroke in subgroups of patients Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. Efficacy, safety and tolerability of metoprolol CR/XL in patients with diabetes and chronic heart failure: experiences from MERIT-HF. Combined angiotensin inhibition for the treatment of diabetic nephropathy.
abstract: Abstract —To investigate the impact of treatment on cardiovascular mortality and morbidity , we assessed outcomes in patients with hypertension and diabetes who received co-amilozide or nifedipine in the International Nifedipine GITS Study : Intervention as a Goal in Hypertension . Participants had to be 55 to 80 years of age , with hypertension ( ≥150/95 or ≥160 mm Hg ) and at least one additional cardiovascular risk factor . Patients received 30 mg nifedipine once daily or co-amilozide ( 25 mg hydrochlorothiazide and 2.5 mg amiloride ) daily . Doses were doubled if target blood pressures ( < 140/90 mm Hg ) were not achieved . Primary ( composite of cardiovascular death , myocardial infa rct ion , heart failure , and stroke ) and secondary outcomes ( composite of primary outcomes , including all-cause mortality and death from vascular and nonvascular causes ) were assessed by means of intent-to-treat analyses . There was no significant difference in the incidence of primary outcomes between nifedipine-treated and  co-amilozide – treated patients with diabetes at baseline ( n=1302 ) ( 8.3 % versus 8.4 % ; relative risk , 0.99 , 95 % CI , 0.69 to 1.42;P = 1.00 ) . A significant benefit for nifedipine-treated patients was seen for the composite secondary outcome ( 14.2 % versus 18.7 % ; relative risk , 0.76 , 95 % CI , 0.59 to 0.97;P = 0.03 ) . Among patients without diabetes at baseline ( n=5019 ) , there was a significant difference in the incidence of new diabetes ( nifedipine 4.3 % versus co-amilozide 5.6 % , P = 0.023 ) . Nifedipine GITS once daily is as effective as  diuretic therapy in reducing cardiovascular complications in hypertensive diabetics . Nifedipine-treated patients were also less likely to have diabetes or have secondary events ( a composite of all-cause mortality , death from a vascular cause , and death from a nonvascular cause ) than co-amilozide recipients . Our results suggest that nifedipine could be considered as first-line therapy for hypertensive diabetics BACKGROUND The most suitable antihypertensive drug to reduce the risk of cardiovascular disease in patients with hypertension and diabetes is unclear . In prespecified analyses , we compared the effects of losartan and atenolol on cardiovascular morbidity and mortality in diabetic patients . METHODS As part of the LIFE study , in a double-masked , r and omised , parallel-group trial , we assigned a group of 1195 patients with diabetes , hypertension , and signs of left-ventricular hypertrophy ( LVH ) on electrocardiograms losartan-based or atenolol-based treatment . Mean age of patients was 67 years ( SD 7 ) and mean blood pressure 177/96 mm Hg ( 14/10 ) after placebo run-in . We followed up patients for at least 4 years ( mean 4.7 years [ 1.1 ] ) . We used Cox regression analysis with baseline Framingham risk score and electrocardiogram-LVH as covariates to compare the effects of the drugs on the primary composite endpoint of cardiovascular morbidity and mortality ( cardiovascular death , stroke , or myocardial infa rct ion ) . FINDINGS Mean blood pressure fell to 146/79 mm Hg ( 17/11 ) in losartan patients and 148/79 mm Hg ( 19/11 ) in atenolol patients . The primary endpoint occurred in 103 patients assigned losartan ( n=586 ) and 139 assigned atenolol ( n=609 ) ; relative risk 0.76 ( 95 % CI 0.58-.98 ) , p=0.031 . 38 and 61 patients in the losartan and atenolol groups , respectively , died from cardiovascular disease ; 0.63 ( 0.42 - 0.95 ) , p=0.028 . Mortality from all causes was 63 and 104 in losartan and atenolol groups , respectively ; 0.61 ( 0.45 - 0.84 ) , p=0.002 . INTERPRETATION Losartan was more effective than atenolol in reducing cardiovascular morbidity and mortality as well as mortality from all causes in patients with hypertension , diabetes , and LVH . Losartan seems to have benefits beyond blood pressure reduction BACKGROUND Diabetes mellitus is a strong risk factor for cardiovascular and renal disease . We investigated whether the angiotensin-converting-enzyme ( ACE ) inhibitor ramipril can lower these risks in patients with diabetes . METHODS 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study , aged 55 years or older , who had a previous cardiovascular event or at least one other cardiovascular risk factor , no clinical proteinuria , heart failure , or low ejection fraction , and who were not taking ACE inhibitors , were r and omly assigned ramipril ( 10 mg/day ) or placebo , and vitamin E or placebo , according to a two-by-two factorial design . The combined primary outcome was myocardial infa rct ion , stroke , or cardiovascular death . Overt nephropathy was a main outcome in a sub study . FINDINGS The study was stopped 6 months early ( after 4.5 years ) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo . Ramipril lowered the risk of the combined primary outcome by 25 % ( 95 % CI 12 - 36 , p=0.0004 ) , myocardial infa rct ion by 22 % ( 6 - 36 ) , stroke by 33 % ( 10 - 50 ) , cardiovascular death by 37 % ( 21 - 51 ) , total mortality by 24 % ( 8 - 37 ) , revascularisation by 17 % ( 2 - 30 ) , and overt nephropathy by 24 % ( 3 - 40 , p=0.027 ) . After adjustment for the changes in systolic ( 2.4 mm Hg ) and diastolic ( 1.0 mm Hg ) blood pressures , ramipril still lowered the risk of the combined primary outcome by 25 % ( 12 - 36 , p=0.0004 ) . INTERPRETATION Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes . The cardiovascular benefit was greater than that attributable to the decrease in blood pressure . This treatment represents a vasculoprotective and renoprotective effect for people with diabetes Summary Background The associations of blood pressure with the different manifestations of incident cardiovascular disease in a contemporary population have not been compared . In this study , we aim ed to analyse the associations of blood pressure with 12 different presentations of cardiovascular disease . Methods We used  linked electronic health records from 1997 to 2010 in the CALIBER ( CArdiovascular research using LInked Bespoke studies and Electronic health Records ) programme to assemble a cohort of 1·25 million patients , 30 years of age or older and initially free from cardiovascular disease , a fifth of whom received blood pressure-lowering treatments . We studied the heterogeneity in the age-specific associations of clinical ly measured blood pressure with 12 acute and chronic cardiovascular diseases , and estimated the lifetime risks ( up to 95 years of age ) and cardiovascular disease-free life-years lost adjusted for other risk factors at index ages 30 , 60 , and 80 years . This study is registered at Clinical Trials.gov , number NCT01164371 . Findings During 5·2 years median follow-up , we recorded 83 098 initial cardiovascular disease presentations . In each age group , the lowest risk for cardiovascular disease was in people with systolic blood pressure of 90–114 mm Hg and diastolic blood pressure of 60–74 mm Hg , with no evidence of a J-shaped increased risk at lower blood pressures . The effect of high blood pressure varied by cardiovascular disease endpoint , from strongly positive to no effect . Associations with high systolic blood pressure were strongest for intracerebral haemorrhage ( hazard ratio 1·44 [ 95 % CI 1·32–1·58 ] ) , subarachnoid haemorrhage ( 1·43 [ 1·25–1·63 ] ) , and stable angina ( 1·41 [ 1·36–1·46 ] ) , and weakest for abdominal aortic aneurysm ( 1·08 [ 1·00–1·17 ] ) . Compared with diastolic blood pressure , raised systolic blood pressure had a greater effect on angina , myocardial infa rct ion , and peripheral arterial disease , whereas raised diastolic blood pressure had a greater effect on abdominal aortic aneurysm than did raised systolic pressure . Pulse pressure associations were inverse for abdominal aortic aneurysm ( HR per 10 mm Hg 0·91 [ 95 % CI 0·86–0·98 ] ) and strongest for peripheral arterial disease ( 1·23 [ 1·20–1·27 ] ) . People with  hypertension ( blood pressure ≥140/90 mm Hg or those receiving blood pressure-lowering drugs ) had a lifetime risk of overall cardiovascular disease at 30 years of age of 63·3 % ( 95 % CI 62·9–63·8 ) compared with 46·1 % ( 45·5–46·8 ) for those with normal blood pressure , and developed cardiovascular disease 5·0 years earlier ( 95 % CI 4·8–5·2 ) . Stable and unstable angina accounted for most ( 43 % ) of the cardiovascular disease-free years of life lost associated with hypertension from index age 30 years , whereas heart failure and stable angina accounted for the largest proportion ( 19 % each ) of years of life lost from index age 80 years . Interpretation The widely held assumptions that blood pressure has strong associations with the occurrence of all cardiovascular diseases across a wide age range , and that diastolic and systolic associations are concordant , are not supported by the findings of this high-resolution study . Despite modern treatments , the lifetime burden of hypertension is substantial . These findings emphasise the need for new  blood pressure-lowering strategies , and will help to inform the design of r and omised trials to assess them . Funding Medical Research Council , National Institute for Health Research , and Wellcome Trust Background : Analyses of the risks of stroke were conducted for subjects with and without diabetes , participating in a r and omized , double‐blind , placebo‐controlled  trial of a perindopril‐based blood pressure lowering regimen in 6105 people with prior stroke or transient ischaemic attack ( TIA ) , followed for a median of 3.9 years . Findings : Seven hundred and sixty‐one patients had diabetes at baseline . Diabetes increased the risk of recurrent stroke by 35 % ( 95 % CI 10–65 % ) principally through an effect on ischaemic stroke ( 1.53 , 95 % CI 1.23–1.90 ) . Active treatment reduced blood pressure by 9.5/4.6 mmHg in patients with diabetes and by 8.9/3.9 mmHg in patients without diabetes . The proportional risk reductions achieved for stroke in patients with diabetes , 38 % ( 95 % CI 8–58 % ) , and patients without diabetes , 28 % ( 95 % CI 16–39 % ) , were not significantly different ( p homogeneity = 0.5 ) . The absolute reduction in the risk of recurrent stroke in the patients with diabetes was equivalent to one stroke avoided among every 16 ( 95 % CI 9–111 ) patients treated for 5 years . Conclusions : Diabetes is an important risk factor for stroke in patients with established cerebrovascular disease . Treatment with the ACE inhibitor perindopril with discretionary use of the diuretic indapamide produced reductions in the risk of recurrent stroke in patients with diabetes that were at least as great as those achieved in patients without diabetes 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 The Survival and Ventricular Enlargement ( SAVE ) Study demonstrated that long-term administration of the angiotensin-converting enzyme inhibitor captopril to recent survivors of myocardial infa rct ion with left ventricular dysfunction result ed in a reduction in cardiovascular mortality and morbidity . Analysis of multiple subgroups demonstrated that baseline demographics ( older age ) and clinical characteristics ( such as prior MI , history of diabetes or hypertension ) , that have previously been associated with a higher risk of cardiovascular events , were associated with greater end point event rates in SAVE regardless of therapy assignment at the time of r and omization . The effectiveness of captopril therapy in reducing cardiovascular mortality and morbidity was examined in multiple subgroups . Although not all subgroups provided adequate statistical power , the benefits of captopril therapy were relatively uniform in the SAVE study . This indicates that the benefits were not confined to one particular subgroup and conversely that targeting of captopril therapy should be to the broadest group , as defined by SAVE entry criteria , to result in a reduction in cardiovascular mortality and morbidity BACKGROUND Calcium antagonists are a first-line treatment for hypertension . The effectiveness of diltiazem , a non-dihydropyridine calcium antagonist , in reducing cardiovascular morbidity or mortality is unclear . We compared the effects of diltiazem with that of diuretics , beta-blockers , or both on cardiovascular morbidity and mortality  in hypertensive patients . METHODS In a prospect i ve , r and omised , open , blinded endpoint study , we enrolled 10,881 patients , aged 50 - 74 years , at health centres in Norway and Sweden , who had diastolic blood pressure of 100 mm Hg or more . We r and omly assigned patients diltiazem , or diuretics , beta-blockers , or both . The combined primary endpoint was fatal and non-fatal stroke , myocardial infa rct ion , and other cardiovascular death . Analysis was done by intention to treat . FINDINGS Systolic and diastolic blood pressure were lowered effectively in the diltiazem and diuretic and beta-blocker groups ( reduction 20.3/18.7 vs 23.3/18.7 mm Hg ; difference in systolic reduction p<0.001 ) . A primary endpoint occurred in 403 patients in the diltiazem group and in 400 in the diuretic and beta-blocker group ( 16.6 vs 16.2 events per 1000 patient-years ; relative risk 1.00 [ 95 % CI 0.87 - 1.15 ] , p=0.97 ) . Fatal and non-fatal stroke occurred in 159 patients in the diltiazem group and in 196 in the diuretic and beta-blocker group ( 6.4 vs 7.9 events per 1000 patient-years ; 0.80 [ 0.65 - 0.99 ] , p=0.04 ) and fatal and non-fatal myocardial infa rct ion in 183 and 157 patients ( 7.4 vs 6.3 events per 1000 patient-years ; 1.16 [ 0.94 - 1.44 ] , p=0.17 ) . INTERPRETATION Diltiazem was as effective as treatment based on diuretics , beta-blockers , or both in preventing the combined primary endpoint of all stroke , myocardial infa rct ion , and other cardiovascular death BACKGROUND It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure . METHODS We r and omly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan ( 300 mg daily ) , amlodipine ( 10 mg daily ) , or  placebo .  The target blood pressure was 135/85 mm Hg or less in all groups . We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration , the development of end-stage renal disease , or death from any cause . We also compared them with regard to the time to a secondary , cardiovascular composite end point . RESULTS The mean duration of follow-up was 2.6 years . Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group ( P=0.02 ) and 23 percent lower than that in the amlodipine group ( P=0.006 ) . The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group ( P=0.003 ) and 37 percent lower in the irbesartan group than in the amlodipine group ( P<0.001 ) . Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups ( P=0.07 for both comparisons ) . These differences were not explained by differences in the blood pressures that were achieved . The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group ( P=0.008 ) and 21 percent more slowly than in the amlodipine group ( P=0.02 ) . There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point . CONCLUSIONS The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes . This protection is independent of the reduction in blood pressure it causes The prevalence of hypertension in type 2 diabetics is high , though there is no published data for Switzerl and . This prospect i ve cohort survey determined the frequency of type 2 diabetes mellitus associated with hypertension from medical practitioners in Switzerl and , and collected data on the diagnostic and therapeutic work‐up for cardiovascular risk patients . The Swiss Hypertension And Risk Factor Program ( SHARP ) is a two‐part survey : The first part , I‐SHARP , was a survey among 1040 Swiss physicians to assess what are the target blood pressure ( BP ) values and preferred treatment for their patients . The second part , SHARP , collected data from 20,956 patients treated on any of 5 consecutive days from 188 participating physicians . In I‐SHARP , target BP⩽135/85 mmHg , as recommended by the Swiss Society of Hypertension , was the goal for 25 % of physicians for hypertensives , and for 60 % for hypertensive diabetics ; values > 140/90 mmHg were targeted by 19 % for hypertensives , respectively 9 % for hypertensive diabetics . In SHARP , 30 % of the 20,956 patients enrolled were hypertensive ( as defined by the doctors ) and 10 % were diabetic ( 67 % of whom were also hypertensive ) . Six per cent of known hypertensive patients and 4 % of known hypertensive diabetics did not receive any antihypertensive treatment . Diabetes was not treated pharmacologically in 20 % of diabetics . Proteinuria was not screened for in 45 % of known hypertensives and in 29 % of known hypertensive diabetics . In Switzerl and , most physicians set target BP levels higher than recommended in published guidelines . In this country with easy access to medical care , high medical density and few financial constraints , appropriate detection and treatment for cardiovascular risk factors remain highly problematic Abstract Objective : To determine whether tight control of blood pressure with either a β blocker or an angiotensin converting enzyme inhibitor has a specific advantage or disadvantage in preventing the macrovascular and microvascular complications of type 2 diabetes . Design : R and omised controlled trial comparing an angiotensin converting enzyme inhibitor ( captopril ) with a β blocker ( atenolol ) in patients with type 2 diabetes aim ing at a blood pressure of < 150/<85 mm Hg . Setting : 20 hospital based clinics in Engl and , Scotl and , and Northern Irel and . Subjects : 1148 hypertensive patients with type 2 diabetes ( mean age 56 years , mean blood pressure 160/94 mm Hg ) . Of the 758 patients allocated to tight control of blood pressure , 400 were allocated to captopril and 358 to atenolol . 390 patients were allocated to less tight control of blood pressure . Main outcome measures : Predefined clinical end points , fatal and non-fatal , related to diabetes , death related to diabetes , and all cause mortality . Surrogate measures of microvascular and macrovascular disease included urinary albumin excretion and retinopathy assessed by retinal photography . Results : Captopril and atenolol were equally effective in reducing blood pressure to a mean of 144/83 mm Hg and 143/81 mm Hg respectively , with a similar proportion of patients ( 27 % and 31 % ) requiring three or more antihypertensive treatments . More patients in the captopril group than the atenolol group took the allocated treatment : at their last clinic visit , 78 % of those allocated captopril and 65 % of those allocated atenolol were taking the drug ( P<0.0001 ) . Captopril and atenolol were equally effective in reducing the risk of macrovascular end points . Similar proportions of patients in the two groups showed deterioration in retinopathy by two grade s after nine years ( 31 % in the captopril group and 37 % in the atenolol group ) and developed clinical grade albuminuria ≥300 mg/l ( 5 % and 9 % ) . The proportion of patients with hypoglycaemic attacks was not different between groups , but mean weight gain in the atenolol group was greater ( 3.4 kg v 1.6 kg ) . Conclusion : Blood pressure lowering with captopril or atenolol was similarly effective in reducing the incidence of diabetic complications . This study provided no evidence that either drug has any specific beneficial or deleterious effect , suggesting that blood pressure reduction in itself may be more important than the treatment used OBJECTIVE The Appropriate Blood Pressure Control in Diabetes ( ABCD ) Trial is a prospect i ve r and omized blinded clinical trial that compares the effects of intensive versus moderate blood pressure control on the incidence and progression of type 2 diabetic complications . The current article discusses the results of 5.3 years of follow-up of 470 patients with hypertension and evaluates the effects of intensive and moderate blood pressure therapy using nisoldipine versus enalapril as the initial antihypertensive medication for nephropathy , retinopathy , and neuropathy . RESEARCH DESIGN AND METHODS The 470 hypertensive subjects , defined as having a baseline diastolic blood pressure of > or = 90 mmHg , were r and omized to intensive blood pressure control ( diastolic blood pressure goal of 75 mmHg ) versus moderate blood pressure control ( diastolic blood pressure goal of 80 - 89 mmHg ) . RESULTS The mean blood pressure achieved was 132/78 mmHg in the intensive group and 138/86 mmHg in the moderate control group . During the 5-year follow-up period , no difference was observed between intensive versus moderate blood pressure control and those r and omized to nisoldipine versus enalapril with regard to the change in creatinine clearance . After the first year of antihypertensive treatment , creatinine clearance stabilized in both the intensive and moderate blood pressure control groups in those patients with baseline normo- or microalbuminuria . In contrast , patients starting with overt albuminuria demonstrated a steady decline in creatinine clearance of 5 - 6 ml.min-1.1.73 m-2 per year throughout the follow-up period whether they were on intensive or moderate therapy . There was also no difference between the interventions with regard to individuals progressing from normoalbuminuria to microalbuminuria ( 25 % intensive therapy vs. 18 % moderate therapy , P = 0.20 ) or microalbuminuria to overt albuminuria ( 16 % intensive therapy vs. 23 % moderate therapy , P = 0.28 ) . Intensive therapy demonstrated a lower overall incidence of deaths , 5.5 vs. 10.7 % , P = 0.037 . Over a 5-year follow-up period , there was no difference between the intensive and moderate groups with regard to the progression of diabetic retinopathy and neuropathy . In addition , the use of nisoldipine versus enalapril had no differential effect on diabetic retinopathy and neuropathy . CONCLUSIONS Blood pressure control of 138/86 or 132/78 mmHg with either nisoldipine or enalapril as the initial antihypertensive medication appeared to stabilize renal function in hypertensive type 2 diabetic patients without overt albuminuria over a 5-year period . The more intensive blood pressure control decreased all-cause mortality Abstract Objective To investigate whether a low dose of the angiotensin converting enzyme ( ACE ) inhibitor ramipril lowers cardiovascular and renal events in patients with type 2 diabetes who have microalbuminuria or proteinuria . Design R and omised , double blind , parallel group trial comparing ramipril ( 1.25 mg/day ) with placebo ( on top of usual treatment ) for cardiovascular and renal outcomes for at least three years . Setting Multicentre , primary care study conducted mostly by general practitioners in 16 European and north African countries . Participants 4912 patients with type 2 diabetes aged > 50 years who use oral antidiabetic drugs and have persistent microalbuminuria or proteinuria ( urinary albumin excretion 20 mg/l in two consecutive sample s ) , and serum creatinine ≤ 150 μmol/l . Main outcome measures The primary outcome measure was the combined incidence of cardiovascular death , non-fatal myocardial infa rct ion , stroke , heart failure leading to hospital admission , and end stage renal failure . Results Participants were followed for 3 to 6 ( median 4 ) years . There were 362 primary events among the 2443 participants taking ramipril ( 37.8 per 1000 patient years ) and 377 events among the 2469 participants taking placebo ( 38.8 per 1000 patient years ; hazard ratio 1.03 ( 95 % confidence interval 0.89 to 1.20 , P = 0.65 ) ) . None of the components of the primary outcome was reduced . Ramipril  lowered systolic and diastolic blood pressures ( by 2.43 and 1.06 mm Hg respectively after two years ) and favoured regression from microalbuminuria ( 20 - 200 mg/l ) or proteinuria ( > 200mg/l ) to normal level ( < 20 mg/l ) or microalbuminuria ( P < 0.07 ) in 1868 participants who completed the study . Conclusions Low dose ( 1.25 mg ) ramipril once daily has no effect on cardiovascular and renal outcomes of patients with type 2 diabetes and albuminuria , despite a slight decrease in blood pressure and urinary albumin . The cardiovascular benefits of a daily higher dose ( 10 mg ) ramipril observed elsewhere are not found with an eightfold lower daily dose BACKGROUND Angiotensin-converting-enzyme ( ACE ) inhibitors have been used for more than a decade to treat high blood pressure  , despite the lack of data from r and omised intervention trials to show that such treatment affects cardiovascular morbidity and mortality . The Captopril Prevention Project ( CAPPP ) is a r and omised intervention trial to compare the effects of ACE inhibition and conventional therapy on cardiovascular morbidity and mortality in patients with hypertension . METHODS CAPPP was a prospect i ve , r and omised , open trial with blinded endpoint evaluation . 10,985 patients were enrolled at 536 health centres in Sweden and Finl and . Patients aged 25 - 66 years with a measured diastolic blood pressure of 100 mm Hg or more on two occasions were r and omly assigned captopril or conventional antihypertensive treatment ( diuretics , beta-blockers ) . Analysis was by intention-to-treat . The primary endpoint was a composite of fatal and non-fatal myocardial infa rct ion , stroke , and other cardiovascular deaths . FINDINGS Of 5492 patients assigned captopril and 5493 assigned conventional therapy , 14 and 13 , respectively , were lost to follow-up . Primary endpoint events occurred in 363 patients in the captopril group ( 11.1 per 1000 patient-years ) and 335 in the conventional-treatment group ( 10.2 per 1000 patient-years ; relative risk 1.05 [ 95 % CI 0.90 - 1.22 ] , p=0 - 52 ) . Cardiovascular mortality was lower with captopril than with conventional treatment ( 76 vs 95 events ; relative risk 0.77 [ 0.57 - 1 - 04 ] , p=0.092 ) , the rate of fatal and non-fatal myocardial infa rct ion was similar ( 162 vs 161 ) , but fatal and non-fatal stroke was more common with captopril ( 189 vs 148 ; 1.25 [ 1 - 01 - 1 - 55 ] . p=0.044 ) . INTERPRETATION Captopril and conventional treatment did not differ in efficacy in preventing cardiovascular morbidity and mortality . The difference in stroke risk is probably due to the lower levels of blood pressure obtained initially in previously treated patients r and omised to conventional therapy BACKGROUND Diabetic retinopathy remains a leading cause of visual loss in people of working age . We examined whether c and esartan treatment could slow the progression and , secondly , induce regression of retinopathy in people with type 2 diabetes . METHODS We did a r and omised , double-blind , parallel-group , placebo-controlled trial in 309 centres worldwide . We recruited normoalbuminuric , normotensive , or treated hypertensive people with type 2 diabetes with mild to moderately severe retinopathy and assigned them to c and esartan 16 mg once a day or placebo . After a month , the dose was doubled to 32 mg once per day . Investigators and patients were unaware of the treatment allocation status . Progression of retinopathy was the primary endpoint , and regression was a secondary endpoint . Analysis was by intention to treat . The trial is registered with Clinical Trials.gov , number NCT00252694 . FINDINGS 1905 participants ( aged 37 - 75 years ) were r and omised to c and esartan ( n=951 ) or placebo ( n=954 ) . 161 ( 17 % ) patients in the c and esartan group and 182 ( 19 % ) in the placebo group had progression of retinopathy by three steps or more on the Early Treatment Diabetic Retinopathy Study scale . The risk of progression of retinopathy was non-significantly reduced by 13 % in patients on c and esartan compared with those on placebo ( hazard ratio [ HR ] 0.87 , 95 % CI 0.70 - 1.08 , p=0.20 ) . Regression on active treatment was increased by 34 % ( 1.34 , 1.08 - 1.68 , p=0.009 ) . HRs were not attenuated by adjustment for baseline risk factors or changes in blood pressure during the trial . An overall change towards less severe retinopathy by the end of the trial was observed in the c and esartan group ( odds 1.17 , 95 % CI 1.05 - 1.30 , p=0.003 ) . Adverse events did not differ between the treatment groups . INTERPRETATION Treatment with c and esartan in type 2 diabetic patients with mild to moderate retinopathy might induce improvement of retinopathy 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 Objective To compare the effects of two antihypertensive treatment strategies for the prevention of coronary heart disease and other cardiovascular events in the large sub population ( n = 5137 ) with diabetes mellitus in the blood pressure-lowering arm of the Anglo-Sc and inavian Cardiac Outcomes Trial . Methods Patients had either untreated hypertension or treated hypertension . For those with type II diabetes mellitus , inclusion criteria required at least two additional risk factors . Patients were r and omized to amlodipine with addition of perindopril as required ( amlodipine-based ) or atenolol with addition of thiazide as required ( atenolol-based ) . Therapy was titrated to achieve a target blood pressure of less than 130/80 mmHg . Results The trial was terminated early due to significant benefits on mortality and stroke associated with the amlodipine-based regimen . In patients with diabetes mellitus , the amlodipine-based treatment reduced the incidence of the composite endpoint – total cardiovascular events and procedures – compared with the atenolol-based regimen ( hazard ratio 0.86 , confidence interval 0.76–0.98 , P = 0.026 ) . Fatal and nonfatal strokes were reduced by 25 % ( P = 0.017 ) , peripheral arterial disease by 48 % ( P = 0.004 ) and noncoronary revascularization procedures by 57 % ( P < 0.001 ) . For the other endpoints included in the composite , the endpoint differences were less clear including coronary heart disease deaths and nonfatal myocardial infa rct ions ( the primary endpoint ) , which were reduced nonsignificantly by 8 % ( hazard ratio 0.92 , confidence interval 0.74–1.15 ) . Conclusion In the large diabetic subgroup in the blood pressure-lowering arm of the Anglo-Sc and inavian Cardiac Outcomes Trial , the benefits of amlodipine-based treatment , compared with atenolol-based treatment , on the incidence of total cardiovascular events and procedures was significant ( 14 % reduction ) and similar to that observed in the total trial population ( 16 % reduction ) BACKGROUND Microalbuminuria in diabetes is strongly predictive of nephropathy , end-stage renal disease , and premature cardiovascular morbidity and mortality . Effective preventive therapies are therefore a clinical priority . OBJECTIVE To determine whether the angiotensin-receptor blocker c and esartan compared with placebo affects microalbuminuria incidence or rate of change in albuminuria in type 1 and type 2 diabetes . DESIGN 3 r and omized trials of the DIRECT ( Diabetic Retinopathy C and esartan Trials ) Program . SETTING 309 secondary care centers . PATIENTS 3326 and 1905 patients with type 1 and type 2 diabetes , respectively . Most were normotensive , and all had normoalbuminuria ( median urinary albumin excretion rate , 5.0 microg/min ) . INTERVENTION C and esartan , 16 mg/d increasing to 32 mg/d , versus placebo . Assignment was done central ly using an interactive voice-response system . Patients , caregivers , and research ers were blinded to treatment assignment . During a median follow-up of 4.7 years , 793 patients discontinued therapy and 63 were lost to follow-up . MEASUREMENTS Urinary albumin excretion rate , assessed annually by 2 overnight collection s ; if it was 20 microg/min or greater , then 2 further collection s were done . The primary end point was new microalbuminuria ( 3 or 4 collection s of urinary albumin excretion rate > or=20 microg/min ) . The secondary end point was rate of change in albuminuria . RESULTS Individual and pooled results of the 3 trials showed that c and esartan had little effect on risk for microalbuminuria ( pooled hazard ratio , 0.95 [ 95 % CI , 0.78 to 1.16 ] ; P = 0.60 ) . Pooled results showed that the annual rate of change in albuminuria was 5.53 % lower ( CI , 0.73 % to 10.14 % ; P = 0.024 ) with c and esartan than with placebo . LIMITATIONS Investigators recruited mainly normotensive patients or patients with well-controlled hypertension who were at low overall vascular risk , which result ed in a low rate of microalbuminuria . Studies were powered for retinal and not renal end points . CONCLUSION C and esartan , 32 mg/d , for 4.7 years did not prevent microalbuminuria in mainly normotensive patients with type 1 or type 2 diabetes BACKGROUND Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown . We investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke . METHODS In this r and omised open-label trial , eligible patients lived in North America , Latin America , and Spain and had recent , MRI-defined symptomatic lacunar infa rct ions . Patients were recruited between March , 2003 , and April , 2011 , and r and omly assigned , according to a two-by-two multifactorial design , to a systolic-blood-pressure target of 130 - 149 mm Hg or less than 130 mm Hg . The primary endpoint was reduction in all stroke ( including ischaemic strokes and intracranial haemorrhages ) . Analysis was done by intention to treat . This study is registered with Clinical Trials.gov , number NCT 00059306 . FINDINGS 3020 enrolled patients , 1519 in the higher-target group and 1501 in the lower-target group , were followed up for a mean of 3·7 ( SD 2·0 ) years . Mean age was 63 ( SD 11 ) years . After 1 year , mean systolic blood pressure was 138 mm Hg ( 95 % CI 137 - 139 ) in the higher-target group and 127 mm Hg ( 95 % CI 126 - 128 ) in the lower-target group . Non-significant rate reductions were seen for all stroke ( hazard ratio 0·81 , 95 % CI 0·64 - 1·03 , p=0·08 ) , disabling or fatal stroke ( 0·81 , 0·53 - 1·23 , p=0·32 ) , and the composite outcome of myocardial infa rct ion or vascular death ( 0·84 , 0·68 - 1·04 , p=0·32 ) with the lower target . The rate of intracerebral haemorrhage was reduced significantly ( 0·37 , 0·15 - 0·95 , p=0·03 ) . Treatment-related serious adverse events were infrequent . INTERPRETATION Although the reduction in stroke was not significant , our results support that in patients with recent lacunar stroke , the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial . FUNDING National Institutes of Health-National Institute of Neurological Disorders and Stroke ( NIH-NINDS ) BACKGROUND This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease , cardiovascular disease , or both . METHODS In a double-blind fashion , we r and omly assigned 8561 patients to aliskiren ( 300 mg daily ) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker . The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation ; nonfatal myocardial infa rct ion ; nonfatal stroke ; unplanned hospitalization for heart failure ; end-stage renal disease , death attributable to kidney failure , or the need for renal-replacement therapy with no dialysis  or transplantation available or initiated ; or doubling of the baseline serum creatinine level . RESULTS The trial was stopped prematurely after the second interim efficacy analysis . After a median follow-up of 32.9 months , the primary end point had occurred in 783 patients ( 18.3 % ) assigned to aliskiren as compared with 732 ( 17.1 % ) assigned to placebo ( hazard ratio , 1.08 ; 95 % confidence interval [ CI ] , 0.98 to 1.20 ; P=0.12 ) . Effects on secondary renal end points were similar . Systolic and diastolic blood pressures were lower with aliskiren ( between-group differences , 1.3 and 0.6 mm Hg , respectively ) and the mean reduction in the urinary albumin-to-creatinine ratio was greater ( between-group difference , 14 percentage points ; 95 % CI , 11 to 17 ) . The proportion of patients with hyperkalemia ( serum potassium level , ≥6 mmol per liter ) was significantly higher in the aliskiren group than in the placebo group ( 11.2 % vs. 7.2 % ) , as was the proportion with reported hypotension ( 12.1 % vs. 8.3 % ) ( P<0.001 for both comparisons ) . CONCLUSIONS The addition of aliskiren to st and ard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful . ( Funded by Novartis ; ALTITUDE Clinical Trials.gov number , NCT00549757 . ) BACKGROUND Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease . We investigated whether treatment with an angiotensin-receptor blocker ( ARB ) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria . METHODS In a r and omized , double-blind , multicenter , controlled trial , we assigned 4447 patients with type 2 diabetes to receive olmesartan ( at a dose of 40 mg once daily ) or placebo for a median of 3.2 years . Additional antihypertensive drugs ( except angiotensin-converting-enzyme inhibitors or ARBs ) were used as needed to lower blood pressure to less than 130/80 mm Hg . The primary outcome was the time to the first onset of microalbuminuria . The times to the onset of renal and cardiovascular events were analyzed as secondary end points . RESULTS The target blood pressure ( < 130/80 mm Hg ) was achieved in nearly 80 % of the patients taking olmesartan and 71 % taking placebo ;  blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group . Microalbuminuria developed in 8.2 % of the patients in the olmesartan group ( 178 of 2160 patients who could be evaluated ) and 9.8 % in the placebo group ( 210 of 2139 ) ; the time to the onset of microalbuminuria was increased by 23 % with olmesartan ( hazard ratio for onset of microalbuminuria , 0.77 ; 95 % confidence interval , 0.63 to 0.94 ; P=0.01 ) . The serum creatinine level doubled in 1 % of the patients in each group . Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events--81 of 2232 patients ( 3.6 % ) as compared with 91 of 2215 patients ( 4.1 % ) (P=0.37)--but a greater number had fatal cardiovascular events--15 patients ( 0.7 % ) as compared with 3 patients ( 0.1 % ) ( P=0.01 ) , a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease ( 11 of 564 patients [ 2.0 % ] vs. 1 of 540 [ 0.2 % ] , P=0.02 ) . CONCLUSIONS Olmesartan was associated with a delayed onset of microalbuminuria , even though blood-pressure control in both groups was excellent according to current st and ards . The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern . ( Funded by Daiichi Sankyo ; Clinical Trials.gov number , NCT00185159 . ) AIMS Major guidelines recommend lowering systolic blood pressure ( SBP ) to < 140 mmHg in all hypertensives , but evidence is missing whether this is beneficial in ( i ) uncomplicated hypertensives , ( ii ) grade 1 hypertensives , and ( iii ) elderly hypertensives . Providing this missing evidence is important to justify efforts and costs of aggressive therapy in all hypertensives . METHODS AND RESULTS Felodipine Event Reduction ( FEVER ) was a double-blind , r and omized trial on 9711 Chinese hypertensives , in whom cardiovascular outcomes  were significantly reduced by more intense therapy ( low-dose hydrochlorothiazide and low-dose felodipine ) achieving a mean of 138 mmHg SBP compared with less-intense therapy ( low-dose hydrochlorothiazide and placebo ) achieving a mean of 142 mmHg . FEVER included older and younger patients , and patients with and without diabetes or cardiovascular disease . In the analyses here reported , Cox regression models assessed outcome differences between more and less-intense treatments in groups of patients with different baseline characteristics . Significant reductions in stroke were found in uncomplicated hypertensives ( -39 % , P = 0.002 ) , in hypertensives with r and omization SBP < 153 mmHg ( -29 % , P = 0.03 ) , and in elderly hypertensives ( -44 % , P < 0.001 ) , when their SBP was lowered by more intense treatment . Significant reductions ( between -29 and -47 % , P = 0.02 to < 0.001 ) were also found in all cardiovascular events and all deaths . Achieving mean SBP values < 140 mmHg by adding a small dose of a generic drug prevented 2.1 ( uncomplicated hypertensives ) and 5.2 ( elderly ) cardiovascular events every 100 patients treated for 3.3 years . CONCLUSIONS These analyses provide strong support , missing so far , to guidelines recommending goal SBP < 140 mmHg in uncomplicated hypertensives , individuals with moderately elevated BP and elderly hypertensives BACKGROUND We investigated whether intensive glycemic control , combination therapy for dyslipidemia , and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes . Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy . METHODS In a r and omized trial , we enrolled 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive or st and ard treatment for glycemia ( target glycated hemoglobin level , < 6.0 % or 7.0 to 7.9 % , respectively ) and also for dyslipidemia ( 160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin ) or for systolic blood-pressure control ( target , < 120 or < 140 mm Hg ) . A subgroup of 2856 participants was evaluated for the effects of these interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale ( as assessed from seven-field stereoscopic fundus photographs , with 17 possible steps and a higher number of steps indicating greater severity ) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy . RESULTS At 4 years , the rates of progression of diabetic retinopathy were 7.3 % with intensive glycemia treatment , versus 10.4 % with st and ard therapy ( adjusted odds ratio , 0.67 ; 95 % confidence interval [ CI ] , 0.51 to 0.87 ; P=0.003 ) ; 6.5 % with fenofibrate for intensive dyslipidemia therapy , versus 10.2 % with placebo ( adjusted odds ratio , 0.60 ; 95 % CI , 0.42 to 0.87 ; P=0.006 ) ; and 10.4 % with intensive blood-pressure therapy , versus 8.8 % with st and ard therapy ( adjusted odds ratio , 1.23 ; 95 % CI , 0.84 to 1.79 ; P=0.29 ) . CONCLUSIONS Intensive glycemic control and intensive combination treatment of dyslipidemia , but not intensive blood-pressure control , reduced the rate of progression of diabetic retinopathy . ( Funded by the National Heart , Lung , and Blood Institute and others ; Clinical Trials.gov numbers , NCT00000620 for the ACCORD study and NCT00542178 for the ACCORD Eye study . Analyses of 5-year mortality data from the  Hypertension Detection and Follow-up Program ( HDFP )  were performed with stratification according to several baseline traits . The HDFP participants were 10,940 white and black men and women ages 30 - 69 at baseline who were r and omized to either stepped-care ( SC ) or referred-care  ( RC ) groups . All-causes mortality rates were lower for the SC than the RC group , both overall and for the 90 - 104 mm Hg stratum , for both cigarette smokers and nonsmokers , and for persons with and without hypercholesterolemia , hyperglycemia , diagnosed diabetes , hyperuricemia , or rapid pulse rate . The SC group also fared better than RC for all strata of body mass index , with an apparent trend toward an inverse relationship between body mass index and degree of benefit . Several of the traits -- cigarette smoking , fasting hyperglycemia , and hyperuricemia -- were associated with significantly higher 5-year mortality rates in both SC and RC participants , in both univariate and multivariate analyses , and a significant U-shaped relationship was recorded between body mass index and mortality for both SC and RC groups . These findings indicate the broad benefit of vigorous antihypertensive stepped-care treatment for hypertensive patients regardless of the presence or absence of the other major risk factors . They also underscore the need for comprehensive management of persons with high blood pressure to control not only their hypertension but also other risk factors associated with negative impact on long-term prognosis The Hypertension Detection and Follow-up Program ( HDFP ) data are reported by diastolic blood pressure ( DBP ) stratum for four race-sex subgroups . For Stratum I ( entry DBP 90–104 mm Hg ) in each of the race-sex subgroups ( black male , black female , white male , and white female ) , Stepped Care ( SC ) participants experienced a reduced mortality as compared to Referred Care ( RC ) . For black males and females in all three entry DBP strata , mortality was lower in the SC than RC . Only in three subgroups did the SC mortality exceed RC : Stratum II ( entry DBP 105–114 mm Hg ) white females and Stratum III ( entry DBP 115 + mm Hg ) white males and females . Possible explanations for these deviant findings are discussed . The HDFP was design ed to determine the difference in total 5-year mortality between SC and RC ; subgroup analyses may be subject to large chance variation and must be interpreted with great caution . The value of vigorous treatment of “ mild ” hypertension ( Stratum I ) in males and females , black and white , and the value of treatment for all blood pressure strata in blacks are confirmed by this analysis BACKGROUND It is not known whether the treatment of patients with asymptomatic left ventricular dysfunction reduces mortality and morbidity . We studied the effect of an angiotensin-converting -- enzyme inhibitor , enalapril , on total mortality and mortality from cardiovascular causes , the development of heart failure , and hospitalization for heart failure among patients with ejection fractions of 0.35 or less who were not receiving drug treatment for heart failure . METHODS Patients were r and omly assigned to receive either placebo ( n = 2117 ) or enalapril ( n = 2111 ) at doses of 2.5 to 20 mg per day in a double-blind trial . Follow-up averaged 37.4 months . RESULTS There were 334 deaths in the placebo group , as compared with 313 in the enalapril group ( reduction in risk , 8 percent by the log-rank test ; 95 percent confidence interval , -8 percent [ an increase of 8 percent ] to 21 percent ; P = 0.30 ) . The reduction in mortality from cardiovascular causes was larger but was not statistically significant ( 298 deaths in the placebo group vs. 265 in the enalapril group ; risk reduction , 12 percent ; 95 percent confidence interval , -3 to 26 percent ; P = 0.12 ) . When we combined patients in whom heart failure developed and those who died , the total number of deaths and cases of heart failure was lower in the enalapril group than in the placebo group ( 630 vs. 818 ; risk reduction , 29 percent ; 95 percent confidence interval , 21 to 36 percent ; P less than 0.001 ) . In addition , fewer patients given enalapril  died or were hospitalized for heart failure ( 434 in the enalapril group ; vs. 518 in the placebo group ; risk reduction , 20 percent ; 95 percent confidence interval , 9 to 30 percent ; P less than 0.001 ) . CONCLUSIONS The angiotensin-converting -- enzyme inhibitor enalapril significantly reduced the incidence of heart failure and the rate of related hospitalizations , as compared with the rates in the group given placebo , among patients with asymptomatic left ventricular dysfunction . There was also a trend toward fewer deaths due to cardiovascular causes among the patients who received enalapril BACKGROUND It has recently been reported that the use of calcium-channel blockers for hypertension may be associated with an increased risk of cardiovascular complications . Because this issue remains controversial , we studied the incidence of such complications in patients with non-insulin-dependent diabetes mellitus and hypertension who were r and omly assigned to treatment with either the calcium-channel blocker nisoldipine or the angiotensin-converting-enzyme inhibitor enalapril as part of a larger study . METHODS The Appropriate Blood Pressure Control in Diabetes ( ABCD ) Trial is a prospect i ve , r and omized , blinded trial comparing the effects of moderate control of blood pressure ( target diastolic pressure , 80 to 89 mm Hg ) with those of intensive control of blood pressure ( diastolic pressure , 75 mm Hg ) on the incidence and progression of complications of diabetes . The study also compared nisoldipine with enalapril as a first-line antihypertensive agent in terms of the prevention and progression of complications of diabetes . In the current study , we analyzed data on a secondary end point ( the incidence of myocardial infa rct ion ) in the subgroup of patients in the ABCD Trial who had hypertension . RESULTS Analysis of the 470 patients in the trial who had hypertension ( base-line diastolic blood pressure , > or = 90 mm Hg ) showed similar control of blood pressure , blood glucose and lipid concentrations , and smoking behavior in the nisoldipine group ( 237 patients ) and the enalapril group ( 233 patients ) throughout five years of follow-up . Using a multiple logistic-regression model with adjustment for cardiac risk factors , we found that nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infa rct ions ( a total of 24 ) than enalapril ( total , 4 ) ( risk ratio , 9.5 ; 95 percent confidence interval , 2.7 to 33.8 ) . CONCLUSIONS In this population of patients with diabetes and hypertension , we found a significantly higher incidence of fatal and nonfatal myocardial infa rct ion among those assigned to therapy with the calcium-channel blocker nisoldipine than among those assigned to receive enalapril . Since our findings are based on a secondary end point , they will require confirmation Context Previously published results of this r and omized , double-blind trial showed that high-risk patients with type 2 diabetic nephropathy had better renal protection if they were treated with irbesartan rather than amlodipine in addition to conventional antihypertensive therapy . Contribution These detailed analyses showed no differences in overall cardiovascular outcomes between patients given irbesartan or amlodipine .  Fewer patients given irbesartan had heart failure and fewer patients given amlodipine had heart attacks . Caution s The trial had limited power to detect important differences between groups in mortality or strokes , and most patients received several antihypertensive agents . The Editors Patients with diabetes have an increased risk for cardiovascular complications and death ( 1 ) . Studies that analyzed the effects of inhibition of the reninangiotensin system on the risk for cardiovascular complications included a substantial number of patients with diabetes ( 2 - 5 ) or were done exclusively in patients with diabetes ( 6 - 8 ) . The meta- analysis of these studies ( 9 ) , the analysis of the diabetic cohorts in the Heart Outcomes Prevention Evaluation ( HOPE ) study ( 2 ) , and the Losartan Intervention for Endpoint Reduction in Hypertension ( LIFE ) trial ( 5 ) demonstrated that angiotensin-converting enzyme ( ACE ) inhibitors ( 2 , 9 ) and angiotensin-receptor blockers ( 5 ) had a statistically significant advantage over placebo or alternative agents in decreasing the risk for several cardiovascular events . These studies r and omly assigned few patients with renal involvement and overt proteinuria . Overt proteinuria occurred in fewer than 20 % of the 470 patients in the Appropriate Blood Pressure Control in Diabetes ( ABCD ) trial ( 6 ) , and only 11 % of the 1195 patients in the LIFE trial ( 5 ) . The Captopril Prevention Project ( CAPP ) ( 3 ) and the Swedish Trial in Old Patients with Hypertension-2 ( STOP Hypertension-2 ) ( 4 ) did not state the number of patients with diabetes and overt proteinuria . There were no such patients in the Fosinopril versus Amlodipine Cardiovascular Events Trial ( FACET ) ( 7 ) , and patients with dipstick-positive albuminuria were excluded from the HOPE trial ( 2 ) . Since proteinuria is an independent risk factor for cardiovascular disease ( 10 , 11 ) , the data obtained in the aforementioned trials can not be extrapolated to patients with type 2 diabetes and overt nephropathy . Trials performed in such patients have reported a blood pressureindependent effect of two different angiotensin-receptor blocker agents to protect against nephropathy ( 12 , 13 ) without a change in all-cause mortality . Apart from studies in heart failure , few cardiovascular data exist for receptor blockers compared with either placebo or calcium-channel blockers . We report on the analysis of the cardiovascular end points that were monitored as secondary end points in the Irbesartan Diabetic Nephropathy Trial ( IDNT ) ( 12 ) and assess whether an angiotensin II receptor blocker or a calcium-channel blocker alters the risk for cardiovascular events beyond those observed by blood pressure reduction alone without such agents . Methods Patients The IDNT was a r and omized , double-blind study on the effect of treatment with irbesartan or amlodipine compared with placebo in patients with type 2 diabetic nephropathy . The protocol of this study has been published ( 12 , 14 ) . Entry criteria required that patients be between 30 and 70 years of age and have type 2 diabetes mellitus and overt nephropathy , as evidence d by current treatment for hypertension or by a protein excretion rate of 900 mg/d or greater , serum creatinine level of 89 mol/L ( 1.0 mg/dL ) to 266 mol/L ( 3.0 mg/dL ) in women or of 106 mol/L ( 1.2 mg/dL ) to 266 mol/L ( 3.0 mg/dL ) in men , and baseline seated blood pressure greater than 135/85 mm Hg . The institutional review boards of each center approved the protocol . All patients gave written informed consent . Treatment and R and omization Patients were r and omly assigned central ly by computer to receive treatment with irbesartan , 300 mg/d ( Avapro , Bristol-Myers Squibb , Princeton , New Jersey ) ; amlodipine , 10 mg/d ( Norvasc , Pfizer , New York ) ; or matched placebo . To minimize any center effect , r and omization was blocked by center . All patients had blood pressure controlled to the same blood pressure goal of less than 135/85 mm Hg by using antihypertensive agents other than ACE inhibitors , angiotensin II receptor blocking agents , or calcium-channel blockers . For the analysis of cardiovascular end points , patients were followed to initiation of treatment for end-stage renal failure ( dialysis or renal transplantation ) , reaching a serum creatinine level of 530.4 mol/L ( 6.0 mg/dL ) or higher , death , or administrative censoring in December 2000 . Outcomes We prospect ively established cardiovascular outcomes , defined in the Appendix Table . Appendix Table . Classification for Fatal and Nonfatal Cardiovascular Events Ascertainment of Cardiovascular Events Information about hospitalizations and adverse events were screened at Bristol-Myers Squibb , Princeton , New Jersey , by trained , blinded clinical research associates to identify potential cardiovascular events . Investigators used study forms to report and characterize all cardiovascular outcomes . For all potential events , records , including laboratory values , electrocardiograms , and radiographic reports were obtained for clarification . Since myocardial infa rct ions may go unrecognized , a central electrocardiogram reading center was established at Brigham and Women 's Hospital , Boston , Massachusetts , where two cardiologists review ed every electrocardiogram . Electrocardiography was performed at baseline , 6 months , 12 months , and annually thereafter . A total of 5698 electrocardiograms were review ed at the center . When a new Q-wave infa rct ion was found , the cardiologists asked whether a clinical myocardial infa rct ion was reported . Even when myocardial infa rct ions were not clinical ly reported , these Q-wave infa rct ions were adjudicated as myocardial infa rct ions . Adjudication of Cardiovascular Events Investigators at each center reported cardiovascular events , defined in the Appendix Table . The information on all potential events was referred to one member of the Outcomes Confirmation and Classification Committee ( Appendix ) . If the committee member agreed with the judgment of the center investigator , their combined judgment was accepted . If the center investigator and the committee member differed , the case material was review ed by the membership of the committee , whose decision was accepted . Deaths were adjudicated by a Mortality Committee ( Appendix ) . Each death was review ed by two members of the committee and presented to the membership , whose decision was accepted as final . Statistical Analysis For graphical presentation ( Figure ) and overall testing for statistically significant differences among the three treatment groups , time to the first occurrence of either a specific cardiovascular outcome or one of the composite outcomes was analyzed by product-limit survival curves and the log-rank test ( 15 ) . We used proportional hazards modeling to determine hazard ratios . For the cardiovascular death outcome , which could occur only once , we used the st and ard proportional hazards model ( 16 ) , with treatment assignment as the only independent covariate . For other cardiovascular outcomes , which could occur more than once , we used the And ersonGill formulation of the proportional hazards model ( 17 ) , in which patients are considered at risk for the first event from r and omization to the first event , at risk for the second event from the day following the first event to the second event , and so forth , permitting use of all the data . In accordance with the method of Lee and colleagues ( 18 ) , we used a robust variance estimate that accounts for the possibility of correlation of risk for several events within a patient . We believed that occurrence of a first event of a given type increases the likelihood of a subsequent similar event . Therefore , both treatment assignment and a time-dependent covariate indicating whether the event was the first of its type or a subsequent event were included in these analyses . The time-dependent covariate was statistically significant in each case , confirming the above assumption . There was no statistically significant interaction between treatment and the time-dependent covariatethe effects of treatment assignment were similar for first and subsequent events and inclusion of the time-dependent covariate did not change either the estimates of the treatment effect or their statistical significance s. Figure . Time to first cardiovascular composite event as a function of treatment assignment . P Data management and computations were done by using SAS software for Windows , version 8 ( SAS Institute , Inc. , Cary , North Carolina ) , or S-Plus for Windows , version 6.0 ( Insightful Corp. , Seattle , Washington ) . Statistical tests were two sided . A P value of 0.05 or less , unadjusted for the multiple comparisons , was considered statistically significant . Role of the Funding Sources The funding sources were involved in the data collection but not in the analysis or interpretation or the decision to su bmi t the manuscript for publication . Results The baseline characteristics of the three groups are shown in Table 1 . A flow diagram of the study is shown in the Appendix Figure . Table 1 . Baseline Characteristics Appendix Figure . Flow diagram for the Irbesartan Diabetic Nephropathy Trial . Clinical Management During the study , the blood pressure decreased from the baseline values to 140/77 mm Hg in the irbesartan group , 141/77 mm Hg in the amlodipine group , and 144/80 mm Hg in the placebo group . Blood pressure in the two active treatment groups did not differ ; values in both groups were statistically significantly lower than in the placebo group ( P = 0.001 ) . The distribution of non study drugs used to achieve the target blood pressure was similar OBJECTIVES This was a retrospective analysis to determine the effect of diabetes on outcome in patients with advanced heart failure ( HF ) , and to determine the effect of beta-blockade in patients with HF with and without diabetes mellitus . BACKGROUND In chronic HF the impact on clinical outcomes and therapeutic response of the prevalent comorbid condition diabetes mellitus has not been extensively investigated . METHODS We assessed the impact of diabetes on prognosis and effectiveness of beta-blocker therapy with bucindolol in patients with HF enrolled in the Beta-Blocker Evaluation of Survival Trial ( BEST ) . We conducted a retrospective analysis to examine the prognosis of patients with advanced HF with and without diabetes , and the effect of beta-blocker therapy on mortality and HF progression or myocardial infa rct ion ( MI ) . The data base was the 2,708 patients with advanced HF ( 36 % with diabetes and 64 % without diabetes ) who were r and omized to the beta-blocker bucindolol or placebo in BEST and followed for mortality , hospitalization , and MI for an average of two years . RESULTS Patients with diabetes had more severe chronic HF  and more coronary risk factors than patients without diabetes . Diabetes was independently associated with increased mortality in patients with ischemic cardiomyopathy ( adjusted hazard ratio 1.33 , 95 % confidence interval 1.12 to 1.58 , p = 0.001 ) , but not in those with a nonischemic etiology ( adjusted hazard ratio 0.98 , 95 % confidence interval 0.74 to 1.30 , p = 0.89 ) . Compared with patients without diabetes , in diabetic patients beta-blocker therapy was at least as effective in reducing death or HF hospitalizations , total hospitalizations , HF hospitalizations , and MI . Ventricular function and physiologic responses to beta-blockade were similar in patients with and without diabetes . CONCLUSIONS Diabetes worsens prognosis in patients with advanced HF , but this worsening appears to be limited to patients with ischemic cardiomyopathy . In advanced HF beta-blockade is effective in reducing major clinical end points in patients with and without diabetes 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 We stratified findings from the Japan Multicenter Investigation for Cardiovascular Diseases-B according to whether or not the patients had diabetes and compared the incidence of cardiac events occurring over a 3-year period between treatment with nifedipine retard and angiotensin converting enzyme ( ACE ) inhibitor . The primary endpoint was the overall incidence of cardiac events ( cardiac death or sudden death , myocardial infa rct ion , hospitalization for angina pectoris or heart failure , serious arrhythmia , and coronary interventions ) , and the secondary endpoints were a composite of other events ( cerebrovascular accidents , worsening of renal dysfunction , non-cardiovascular events , and total mortality ) . The results showed no significant difference in the incidence of the primary endpoint between the nifedipine group ( n=199 ) and the ACE inhibitor group ( n=173 ) in diabetic patients : 15.08 % vs. 15.03 % , relative risk 1.06 , p=0.838 . Also in nondiabetic patients , no significant difference was observed between the former ( n=629 ) and the latter ( n=649 ) : 13.67 % vs. 12.33 % , relative risk 1.04 , p=0.792 . Similar results were obtained for the incidence of the secondary endpoints : in diabetic patients , 5.03 % vs. 5.20 % , relative risk 0.89 , p=0.799 ; in nondiabetic patients , 2.70 % vs. 2.47 % , relative risk 1.07 , p=0.842 . Achieved blood pressure levels were 138/76 and 136/77 mmHg in the nifedipine group and 140/78 and 138/79 mmHg in the ACE inhibitor group in diabetic and nondiabetic patients , respectively . This study showed that nifedipine retard was as effective as ACE inhibitors in reducing the incidence of cardiac events in extremely high-risk hypertensive patients with complications of diabetes and coronary artery disease In diabetic patients long-term treatment with timolol after myocardial infa rct ion was related to a reduction in overall mortality , total cardiac death , sudden death , and nonfatal reinfa rct ion , compared with patients in a placebo group . The analyses were based on 99 diabetic patients in the Norwegian timolol multicenter study . The dosage of timolol was 10 mg twice daily and the follow-up period was 12–33 mo ( mean : 17 mo ) . When analyzing all r and omized patients , there were 14 deaths in the placebo group and 6 deaths in the timolol group , a reduction of 62.8 % ( P < 0.05 ) . The number of nonfatal reinfa rct ions was 10 in the placebo group and 2 in the timolol group , a reduction of 82.7 % ( P < 0.05 ) . With regard to inclusion rate , side effects , withdrawals , and timolol-related reduction in mortality and reinfa rct ion , the diabetic patients basically behaved like nondiabetic patients . The data were analyzed retrospectively and should be confirmed by a prospect i ve study . The study also indicates that long-term treatment with timolol may induce slight carbohydrate intolerance BACKGROUND Microalbuminuria and hypertension are risk factors for diabetic nephropathy . Blockade of the renin-angiotensin system slows the progression to diabetic nephropathy in patients with type 1 diabetes , but similar data are lacking for hypertensive patients with type 2 diabetes . We evaluated the renoprotective effect of the angiotensin-II-receptor antagonist irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria . METHODS A total of 590 hypertensive patients with type 2 diabetes and microalbuminuria were enrolled in this multinational , r and omized , double-blind , placebo-controlled study of irbesartan , at a dose of either 150 mg daily or 300 mg daily , and were followed for two years . The primary outcome was the time to the onset of diabetic nephropathy , defined by persistent albuminuria in overnight specimens , with a urinary albumin excretion rate that was greater than 200 microg per minute and at least 30 percent higher than the base-line level . RESULTS The base-line characteristics in the three groups were similar . Ten of the 194 patients in the 300-mg group ( 5.2 percent ) and 19 of the 195 patients in the 150-mg group ( 9.7 percent ) reached the primary end point , as compared with 30 of the 201 patients in the placebo group ( 14.9 percent ) ( hazard ratios , 0.30 [ 95 percent confidence interval , 0.14 to 0.61 ; P < 0.001 ] and 0.61 [ 95 percent confidence interval , 0.34 to 1.08 ; P=0.081 for the two irbesartan groups , respectively ) . The average blood pressure during the course of the study was 144/83 mm Hg in the placebo group , 143/83 mm Hg in the 150-mg group , and 141/83 mm Hg in the 300-mg group ( P=0.004 for the comparison of systolic blood pressure between the placebo group and the combined irbesartan groups ) . Serious adverse events were less frequent among the patients treated with irbesartan ( P=0.02 ) . CONCLUSIONS Irbesartan is renoprotective independently of its blood-pressure-lowering effect in patients with type 2 diabetes and microalbuminuria CONTEXT Antihypertensive therapy is well established to reduce hypertension-related morbidity and mortality , but the optimal first-step therapy is unknown . OBJECTIVE To determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease ( CHD ) or other cardiovascular disease ( CVD ) events vs treatment with a diuretic . DESIGN The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) , a r and omized , double-blind , active-controlled clinical trial conducted from February 1994 through March 2002 . SETTING AND PARTICIPANTS A total of 33 357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor from 623 North American centers . INTERVENTIONS Participants were r and omly assigned to receive chlorthalidone , 12.5 to 25 mg/d ( n = 15 255 ) ; amlodipine , 2.5 to 10 mg/d ( n = 9048 ) ; or lisinopril , 10 to 40 mg/d ( n = 9054 ) for planned follow-up of approximately 4 to 8 years . MAIN OUTCOME MEASURES The primary outcome was combined fatal CHD or nonfatal myocardial infa rct ion , analyzed by intent-to-treat . Secondary outcomes were all-cause mortality , stroke , combined CHD ( primary outcome , coronary revascularization , or angina with hospitalization ) , and combined CVD ( combined CHD , stroke , treated angina without hospitalization , heart failure [ HF ] , and peripheral arterial disease ) . RESULTS Mean follow-up was 4.9 years . The primary outcome occurred in 2956 participants , with no difference between treatments . Compared with chlorthalidone ( 6-year rate , 11.5 % ) , the relative risks ( RRs ) were 0.98 ( 95 % CI , 0.90 - 1.07 ) for amlodipine ( 6-year rate , 11.3 % ) and 0.99 ( 95 % CI , 0.91 - 1.08 ) for lisinopril ( 6-year rate , 11.4 % ) . Likewise , all-cause mortality did not differ between groups . Five-year systolic blood pressures were significantly higher in the amlodipine ( 0.8 mm Hg , P = .03 ) and lisinopril ( 2 mm Hg , P<.001 ) groups compared with chlorthalidone , and 5-year diastolic blood pressure was significantly lower with amlodipine ( 0.8 mm Hg , P<.001 ) . For amlodipine vs chlorthalidone , secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine ( 10.2 % vs 7.7 % ; RR , 1.38 ; 95 % CI , 1.25 - 1.52 ) . For lisinopril vs chlorthalidone , lisinopril had higher 6-year rates of combined CVD ( 33.3 % vs 30.9 % ; RR , 1.10 ; 95 % CI , 1.05 - 1.16 ) ; stroke ( 6.3 % vs 5.6 % ; RR , 1.15 ; 95 % CI , 1.02 - 1.30 ) ; and HF ( 8.7 % vs 7.7 % ; RR , 1.19 ; 95 % CI , 1.07 - 1.31 ) . CONCLUSION Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive . They should be preferred for first-step antihypertensive therapy BACKGROUND Long-term administration of angiotensin-converting -- enzyme ( ACE ) inhibitors has been shown to improve survival in patients with symptomatic left ventricular failure and to attenuate left ventricular dilatation in patients with myocardial infa rct ion . We studied whether mortality could be reduced during the 6 months after an acute myocardial infa rct ion with use of the ACE inhibitor enalapril . METHODS At 103 Sc and inavian centers patients with acute myocardial infa rct ions and blood pressure above 100/60 mm Hg were r and omly assigned to treatment with either enalapril or placebo , in addition to conventional therapy . Therapy was initiated with an intravenous infusion of enalapril ( enalaprilat ) within 24 hours after the onset of chest pain , followed by administration of oral enalapril . RESULTS Of the 6090 patients enrolled , 3046 were assigned to  placebo and 3044 to enalapril . The life-table mortality rates in the two groups at one and six months were not significantly different ( 6.3 and 10.2 percent in the placebo group vs. 7.2 and 11.0 percent in the enalapril group , P = 0.26 ) . The relative risk of death in the enalapril group was 1.10 ( 95 percent confidence interval , 0.93 to 1.29 ) . Death due to progressive heart failure occurred in 104 patients ( 3.4 percent ) in the placebo group and 132 ( 4.3 percent ) in the enalapril group ( P = 0.06 ) . Therapy had to be changed because of worsening heart failure in 30 percent of the placebo group and 27 percent of the enalapril group ( P less than 0.006 ) . Early hypotension ( systolic pressure less than 90 mm Hg or diastolic pressure less than 50 mm Hg ) occurred in 12 percent of the enalapril group and 3 percent of the placebo group ( P less than 0.001 ) . CONCLUSIONS Enalapril therapy started within 24 hours of the onset of acute myocardial infa rct ion does not improve survival during the 180 days after infa rct ion BACKGROUND Metoprolol can improve haemodynamics in chronic heart failure , but survival benefit has not been proven . We investigated whether metoprolol controlled release/extended release ( CR/XL ) once daily , in addition to st and ard therapy , would lower mortality in patients with decreased ejection fraction and symptoms of heart failure . METHODS We enrolled 3991 patients with chronic heart failure in New York Heart Association ( NYHA ) functional class II-IV and with ejection fraction of 0.40 or less , stabilised with optimum st and ard therapy , in a double-blind r and omised controlled study . R and omisation was preceded by a 2-week single-blind placebo run-in period . 1990 patients were r and omly assigned  metoprolol CR/XL 12.5 mg ( NYHA III-IV ) or 25.0 mg once daily ( NYHA II ) and 2001 were assigned  placebo .  The target dose was 200 mg once daily and doses were up-titrated over 8 weeks . Our primary endpoint was all-cause mortality , analysed by intention to treat . FINDINGS The study was stopped early on the recommendation of the independent safety committee . Mean follow-up time was 1 year . All-cause mortality was lower in the metoprolol CR/XL group than in the placebo group ( 145 [ 7.2 % , per patient-year of follow-up ] ) vs 217 deaths [ 11.0 % ] , relative risk 0.66 [ 95 % CI 0.53 - 0.81 ] ; p=0.00009 or adjusted for interim analyses p=0.0062 ) . There were fewer sudden deaths in the metoprolol CR/XL group than in the placebo group ( 79 vs 132 , 0.59 [ 0.45 - 0.78 ] ; p=0.0002 ) and deaths from worsening heart failure ( 30 vs 58 , 0.51 [ 0.33 - 0.79 ] ; p=0.0023 ) . INTERPRETATION Metoprolol CR/XL once daily in addition to optimum st and ard therapy improved survival . The drug was well tolerated BP is an important determinant of kidney disease among patients with diabetes . The recommended thresholds to initiate treatment to lower BP are 130/80 and 125/75 mmHg for people with diabetes and nephropathy , respectively . We sought to determine the effects of lowering BP below these currently recommended thresholds on renal outcomes among 11,140 patients who had type 2 diabetes and participated in the Action in Diabetes and Vascular disease : preterAx and diamicroN-MR Controlled Evaluation ( ADVANCE ) study . Patients were r and omly assigned to fixed combination perindopril-indapamide or placebo , regardless of their BP at entry . During a mean follow-up of 4.3 yr , active treatment reduced the risk for renal events by 21 % ( P < 0.0001 ) , which was driven by reduced risks for developing microalbuminuria and macroalbuminuria ( both P < 0.003 ) . Effects of active treatment were consistent across subgroups defined by baseline systolic or diastolic BP . Lower systolic BP levels during follow-up , even to < 110 mmHg , was associated with progressively lower rates of renal events . In conclusion , BP-lowering treatment with perindopril-indapamide administered routinely to individuals with type 2 diabetes provides important renoprotection , even among those with initial BP < 120/70 mmHg . We could not identify a BP threshold below which renal benefit is lost Background The benefits of treating hypertension in elderly diabetic patients , in terms of achieving reductions in cardiovascular morbidity and mortality , have been documented in several recent prospect i ve trials . There has , however , been some controversy regarding the effect of different antihypertensive drugs on the frequency of myocardial infa rct ion in this group of patients . Design STOP Hypertension-2 was a prospect i ve , r and omized , open trial with blinded endpoint evaluation . Methods We studied 6614 elderly patients aged 70–84 years ; 719 of them had diabetes mellitus at the start of the study ( mean age 75.8 years ) . Patients were r and omly assigned to one of three treatment strategies : conventional antihypertensive drugs ( diuretics or β-blockers ) , calcium antagonists , or angiotensin converting enzyme ( ACE ) inhibitors . Results Reduction in blood pressure was similar in the three treatment groups of diabetics . The prevention of cardiovascular mortality was also similar ; the frequency of this primary endpoint did not differ significantly between the three groups . There were , however , significantly fewer ( P = 0.025 ) myocardial infa rct ions during ACE inhibitor treatment ( n = 17 ) than during calcium antagonist treatment ( n = 32 ; relative risk 0.51 , 95 % confidence interval 0.28–0.92 ) ; but a ( non-significant ) tendency to more strokes during ACE inhibitor treatment ( n = 34 compared with n = 29 ; relative risk 1.16 , 95 % confidence interval 0.71–1.91 ) . Conclusion Treatment of hypertensive diabetic patients with conventional antihypertensive drugs ( diuretics , β-blockers , or both ) seemed to be as effective as treatment with newer drugs such as calcium antagonists or ACE inhibitors AIMS The aim of this study was to assess the effect of the angiotensin converting enzyme inhibitor perindopril on cardiovascular events in diabetic patients with coronary artery disease . METHODS AND RESULTS A total of 1502 diabetic patients with known coronary artery disease and without heart failure of 12 218 overall in the EUropean trial on Reduction Of cardiac events with Perindopril  in stable coronary Artery ( EUROPA ) disease were r and omized in a double-blinded manner to perindopril 8 mg once daily or placebo . Follow-up was for a median of 4.3 years . The primary end point was cardiovascular death , non-fatal myocardial infa rct ion , and resuscitated cardiac arrest .  Perindopril treatment was associated with a non-significant reduction in the primary endpoint in the diabetic population , 12.6 vs. 15.5 % , relative risk reduction 19 % [ ( 95 % CI , -7 to 38 % ) , P=0.13 ] . This was of similar relative magnitude to the 20 % risk reduction observed in the main EUROPA population . CONCLUSION Perindopril tends to reduce major cardiovascular events in diabetic patients with coronary disease in addition to other preventive treatments and the trend towards reduction was of a similar relative magnitude to that observed the general population with coronary artery disease BACKGROUND Although several important studies have been performed in hypertensive type 2 diabetic patients , it is not known whether lowering blood pressure in normotensive ( BP < 140/90 mm Hg ) patients offers any beneficial results on vascular complications . The current study evaluated the effect of intensive versus moderate diastolic blood pressure ( DBP ) control on diabetic vascular complications in 480 normotensive type 2 diabetic patients . METHODS The current study was a prospect i ve , r and omized controlled trial in normotensive type 2 diabetic subjects . The subjects were r and omized to intensive ( 10 mm Hg below the baseline DBP ) versus moderate ( 80 to 89 mm Hg ) DBP control . Patients in the moderate therapy group were given placebo , while the patients r and omized to intensive therapy received either nisoldipine or enalapril in a blinded manner as the initial antihypertensive medication . The primary end point evaluated was the change in creatinine clearance with the secondary endpoints consisting of change in urinary albumin excretion , progression of retinopathy and neuropathy and the incidence of cardiovascular disease . RESULTS The mean follow-up was 5.3 years . Mean BP in the intensive group was 128 + /- 0.8/75 + /- 0.3 mm Hg versus 137 + /- 0.7/81 + /- 0.3 mm Hg in the moderate group , P < 0.0001 . Although no difference was demonstrated in creatinine clearance ( P = 0.43 ) , a lower percentage of patients in the intensive group progressed from normoalbuminuria to microalbuminuria ( P = 0.012 ) and microalbuminuria to overt albuminuria ( P = 0.028 ) . The intensive BP control group also demonstrated less progression of diabetic retinopathy ( P = 0.019 ) and a lower incidence of strokes ( P = 0.03 ) . The results were the same whether enalapril or nisoldipine was used as the initial antihypertensive agent . CONCLUSION Over a five-year follow-up period , intensive ( approximately 128/75 mm Hg ) BP control in normotensive type 2 diabetic patients : ( 1 ) slowed the progression to incipient and overt diabetic nephropathy ; ( 2 ) decreased the progression of diabetic retinopathy ; and ( 3 ) diminished the incidence of stroke BACKGROUND Patients with congestive heart failure have a high mortality rate and are also hospitalized frequently . We studied the effect of an angiotensin-converting-enzyme inhibitor , enalapril , on mortality and hospitalization in patients with chronic heart failure and ejection fractions less than or equal to 0.35 . METHODS Patients receiving conventional treatment for heart failure were r and omly assigned to receive either placebo ( n = 1284 ) or enalapril ( n = 1285 ) at doses of 2.5 to 20 mg per day in a double-bind trial . Approximately 90 percent of the patients were in New York Heart Association functional classes II and III . The follow-up averaged 41.4 months . RESULTS There were 510 deaths in the placebo group ( 39.7 percent ) , as compared with 452 in the enalapril group ( 35.2 percent ) ( reduction in risk , 16 percent ; 95 percent confidence interval , 5 to 26 percent ; P = 0.0036 ) . Although reductions in mortality were observed in several categories of cardiac deaths , the largest reduction occurred among the deaths attributed to progressive heart failure ( 251 in the placebo group vs. 209 in the enalapril group ; reduction in risk , 22 percent ; 95 percent confidence interval , 6 to 35 percent ) . There was little apparent effect of treatment on deaths classified as due to arrhythmia without pump failure . Fewer patients died or were hospitalized for worsening heart failure ( 736 in the placebo group and 613 in the enalapril group ; risk reduction , 26 percent ; 95 percent confidence interval , 18 to 34 percent ; P less than 0.0001 ) . CONCLUSIONS The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and reduced ejection fractions Background Recent trials question previously accepted low blood pressure targets in type 2 diabetes to reduce complication risk . We explored this question in the DIabetic REtinopathy C and esartan Trials-Protect 2 clinical trial . Methods A total of 1905 normoalbuminuric participants with type 2 diabetes and mild-moderate retinopathy were r and omized to c and esartan or placebo .  Participants were normotensive [ untreated , blood pressure ( BP ) < 130/85 mmHg ] or treated hypertensive [ ( 62 % ) , BP < 160/90 mmHg ] . The effects of c and esartan on microvascular and macrovascular endpoints alone and in combination were analysed , including subgroup analyses by baseline hypertension status . Results Mean age was 57 ± 8 years , 50 % were men , mean diabetes duration was 9 ± 5 years and baseline HbA1c was 8.2 ± 1.6 % . Mean r and omization BP was 123/75 mmHg in the normotensive , and 139/79 mmHg in the treated hypertensive subgroups . During the median 4.7-year follow-up , achieved systolic pressure on c and esartan was 128 mmHg in baseline normotensive individuals , and 136 mmHg in treated hypertensive patients . C and esartan reduced combined macrovascular and microvascular complication risk ; the age and baseline SBP overall adjusted hazard ratio for c and esartan vs. placebo was 0.85 [ 95 % confidence interval ( CI ) 0.72–0.99 ] , P = 0.040 , reflecting hazard ratios of 0.86 ( 0.66–1.13 ) for baseline normotensive individuals and 0.83 ( 0.68–1.02 ) for hypertensive patients . Hazard ratios were 0.87 ( 0.74–1.04 ) for microvascular and 0.84 ( 0.57–1.25 ) for macrovascular complications , when analysed separately . However , an interaction ( P = 0.06 ) between hypertensive [ hazard ratio 0.67 ( 0.42–1.07 ) ] and normotensive ( 1.45 , 0.71–2.94 ) subgroups was observed for macrovascular events . Conclusion C and esartan modestly reduces vascular complication risk in treated hypertensive diabetic individuals at low risk of cardiovascular disease . Separate analyses of microvascular and macrovascular events suggest that c and esartan may not reduce macrovascular events in normotensive persons with type 2 diabetes . Clinical trial registration : http:// clinical trials.gov/ct2/show/NCT00252694 BACKGROUND There is no evidence from r and omized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus . We investigated whether therapy targeting normal systolic pressure ( i.e. , < 120 mm Hg ) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events . METHODS A total of 4733 participants with type 2 diabetes were r and omly assigned to intensive therapy , targeting a systolic pressure of less than 120 mm Hg , or st and ard therapy , targeting a systolic pressure of less than 140 mm Hg . The primary composite outcome was nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes . The mean follow-up was 4.7 years . RESULTS After 1 year , the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the st and ard-therapy group . The annual rate of the primary outcome was 1.87 % in the intensive-therapy group and 2.09 % in the st and ard-therapy group ( hazard ratio with intensive therapy , 0.88 ; 95 % confidence interval [ CI ] , 0.73 to 1.06 ; P=0.20 ) . The annual rates of death from any cause were 1.28 % and 1.19 % in the two groups , respectively ( hazard ratio , 1.07 ; 95 % CI , 0.85 to 1.35 ; P=0.55 ) . The annual rates of stroke , a prespecified secondary outcome , were 0.32 % and 0.53 % in the two groups , respectively ( hazard ratio , 0.59 ; 95 % CI , 0.39 to 0.89 ; P=0.01 ) . Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group ( 3.3 % ) and 30 of the 2371 participants in the st and ard-therapy group ( 1.3 % ) ( P<0.001 ) . CONCLUSIONS In patients with type 2 diabetes at high risk for cardiovascular events , targeting a systolic blood pressure of less than 120 mm Hg , as compared with less than 140 mm Hg , did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events . ( Clinical Trials.gov number , NCT00000620 . The Study on COgnition and Prognosis in the Elderly ( SCOPE ) assessed the effect of c and esartan on cardiovascular outcomes in elderly patients with mild to moderate hypertension . Patients were r and omized to c and esartan 8–16 mg daily ( n = 2477 ) or placebo ( n = 2460 ) . Due to extensive add‐on therapy , blood pressure reduction was only about 3/2 mmHg greater in the c and esartan group than in the control group . Nevertheless , non‐fatal stroke was reduced by 28 % ( p = 0.04 ) in the c and esartan group compared to the control group , and there was a non‐significant 11 % reduction in major cardiovascular events ( p = 0.19 ) . This report provides results in pre‐specified subgroups of patients ( age , gender , diabetes , history of stroke , smoking and cardiovascular risk at r and omization ) . Reductions in major cardiovascular events and stroke  with c and esartan‐based therapy were indicated in all subgroups . A significant interaction between treatment and subgroups was found for one pair of subgroups only ; the reduction in major cardiovascular events with c and esartan  was greater in patients with a previous stroke ( 64 % reduction , p = 0.004 ) than in those without ( 5 % reduction , p>0.20 ) . In conclusion , this analysis indicates consistent favourable effects of c and esartan‐based  therapy on major cardiovascular events and stroke across the different subgroups of patients . However , the benefit was particularly pronounced in patients who entered the study with a previous stroke BACKGROUND Left ventricular dilatation and dysfunction after myocardial infa rct ion are major predictors of death . In experimental and clinical studies , longterm therapy with the angiotensin-converting -- enzyme inhibitor captopril attenuated ventricular dilatation and remodeling . We investigated whether captopril could reduce morbidity and mortality in patients with left ventricular dysfunction after a myocardial infa rct ion . METHODS Within 3 to 16 days after myocardial infa rct ion , 2231 patients with ejection fractions of 40 percent or less but without overt heart failure or symptoms of myocardial ischemia were r and omly assigned to receive doubleblind treatment with either placebo ( 1116 patients ) or captopril ( 1115 patients ) and were followed for an average of 42 months . RESULTS Mortality from all causes was significantly reduced in the captopril group ( 228 deaths , or 20 percent ) as compared with the placebo group ( 275 deaths , or 25 percent ) ; the reduction in risk was 19 percent ( 95 percent confidence interval , 3 to 32 percent ; P = 0.019 ) . In addition , the incidence of both fatal and nonfatal major cardiovascular events was consistently reduced in the captopril group . The reduction in risk was 21 percent ( 95 percent confidence interval , 5 to 35 percent ; P = 0.014 ) for death from cardiovascular causes , 37 percent ( 95 percent confidence interval , 20 to 50 percent ; P less than 0.001 ) for the development of severe heart failure , 22 percent ( 95 percent confidence interval , 4 to 37 percent ; P = 0.019 ) for congestive heart failure requiring hospitalization , and 25 percent ( 95 percent confidence interval , 5 to 40 percent ; P = 0.015 ) for recurrent myocardial infa rct ion . CONCLUSIONS In patients with asymptomatic left ventricular dysfunction after myocardial infa rct ion , long-term administration of captopril was associated with an improvement in survival and reduced morbidity and mortality due to major cardiovascular events . These benefits were observed in patients who received thrombolytic therapy , aspirin , or beta-blockers , as well as those who did not , suggesting that treatment with captopril leads to additional improvement in outcome among selected survivors of myocardial infa rct ion BACKGROUND The objective of the current study was to examine the efficacy and tolerability of the beta-blocker metoprolol succinate controlled release/extended release ( CR/XL ) in patients with diabetes in the Metoprolol CR/XL R and omized Intervention Trial in Chronic Heart Failure ( MERIT-HF ) . METHODS The Cox proportional hazards model was used to calculate hazard ratios ( HR ) for convenience expressed as relative risks ( risk reduction = 1-HR ) , and 95 % confidence intervals ( CI ) . RESULTS The risk of hospitalization for heart failure was 76 % higher in diabetics compared to non-diabetics ( 95 % CI 38 % to 123 % ) . Metoprolol CR/XL was well tolerated and reduced the risk of hospitalization for heart failure by 37 % in the diabetic group ( 95 % CI 53 % to 15 % ) , and by 35 % in the non-diabetic group ( 95 % CI 48 % to 19 % ) . Pooling of mortality data from the Cardiac Insufficiency Bisoprolol Study II ( CIBIS II ) , MERIT-HF , and the Carvedilol Prospect i ve R and omized Cumulative Survival Study ( COPERNICUS ) showed similar survival benefits in patients with diabetes ( 25 % ; 95 % CI 40 % to 4 % ) and without diabetes ( 36 % ; 95 % CI 44 % to 27 % ) ; test of diabetes by treatment interaction was non-significant . Adverse events were reported more often on placebo than on metoprolol CR/XL . CONCLUSIONS Patients with heart failure and diabetes have a much higher risk of hospitalization than patients without diabetes . Regardless of diabetic status , a highly significant reduction in hospitalizations for heart failure was observed with metoprolol CR/XL therapy , which was very well tolerated also by patients with diabetes . Furthermore , the pooled data showed a statistically significant survival benefit in patients with diabetes BACKGROUND Combination therapy with angiotensin-converting-enzyme ( ACE ) inhibitors and angiotensin-receptor blockers ( ARBs ) decreases proteinuria ; however , its safety and effect on the progression of kidney disease are uncertain . Methods We provided losartan ( at a dose of 100 mg per day ) to patients with type 2 diabetes , a urinary albumin-to-creatinine ratio ( with albumin measured in milligrams and creatinine measured in grams ) of at least 300 , and an estimated glomerular filtration rate ( GFR ) of 30.0 to 89.9 ml per minute per 1.73 m(2 ) of body-surface area and then r and omly assigned them to receive lisinopril ( at a dose of 10 to 40 mg per day ) or placebo . The primary end point was the first occurrence of a change in the estimated GFR ( a decline of ≥ 30 ml per minute per 1.73 m(2 ) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2 ) or a decline of ≥ 50 % if the initial estimated GFR was < 60 ml per minute per 1.73 m(2 ) ) , end-stage renal disease ( ESRD ) , or death . The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD . Safety outcomes included mortality , hyperkalemia , and acute kidney injury . Results The study was stopped early owing to safety concerns . Among 1448 r and omly assigned patients with a median follow-up of 2.2 years , there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group ( hazard ratio with combination therapy , 0.88 ; 95 % confidence interval [ CI ] , 0.70 to 1.12 ; P=0.30 ) . A trend toward a benefit from combination therapy with respect to the secondary end point ( hazard ratio , 0.78 ; 95 % CI , 0.58 to 1.05 ; P=0.10 ) decreased with time ( P=0.02 for nonproportionality ) . There was no benefit with respect to mortality ( hazard ratio for death , 1.04 ; 95 % CI , 0.73 to 1.49 ; P=0.75 ) or cardiovascular events . Combination therapy increased the risk of hyperkalemia ( 6.3 events per 100 person-years , vs. 2.6 events per 100 person-years with monotherapy ; P<0.001 ) and acute kidney injury ( 12.2 vs. 6.7 events per 100 person-years , P<0.001 ) . Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events  among patients with diabetic nephropathy . ( Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development ; VA NEPHRON-D Clinical Trials.gov number , NCT00555217 . )
target: The associations between BP-lowering treatments and outcomes were not significantly different , irrespective of drug class , except for stroke and heart failure .
  AND RELEVANCE Among patients with type 2 diabetes , BP lowering was associated with improved mortality and other clinical outcomes with lower RRs observed among those with baseline BP of 140 mm Hg and greater .
  These findings support the use of medications for BP lowering in these patients
background: IMPORTANCE Lowering blood pressure ( BP ) is widely used to reduce vascular risk in individuals with diabetes .
  OBJECTIVE To determine the associations between BP-lowering treatment and vascular disease in type 2 diabetes .