Lowering blood pressure reduces renal events in type 2 diabetes. Examination of lower targets for low-density lipoprotein cholesterol and blood pressure in diabetes--the Stop Atherosclerosis in Native Diabetics Study (SANDS). The effects of 12-week psyllium fibre supplementation or healthy diet on blood pressure and arterial stiffness in overweight and obese individuals. The effect of vitamin E on blood pressure in individuals with type 2 diabetes: a randomized, double-blind, placebo-controlled trial Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Vasodilatory effects of troglitazone improve blood pressure at rest and during mental stress in type 2 diabetes mellitus. Functional Vascular Study in Hypertensive Subjects with Type 2 Diabetes Using Losartan or Amlodipine Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective. Pistachio Nut Consumption Modifies Systemic Hemodynamics, Increases Heart Rate Variability, and Reduces Ambulatory Blood Pressure in Well‐Controlled Type 2 Diabetes: a Randomized Trial A Summary of the ADVANCE Trial The role of antihypertensive therapy in reducing vascular complications of type 2 diabetes. Findings from the DIabetic REtinopathy Candesartan Trials-Protect 2 study [ADVANCE study: objectives, design and current status]. Cost-effectiveness of lowering blood pressure with a fixed combination of perindopril and indapamide in type 2 diabetes mellitus: an ADVANCE trial-based analysis. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes Oral Arginine Reduces Systemic Blood Pressure in Type 2 Diabetes: Its Potential Role in Nitric Oxide Generation Effect of Intensive Versus Usual Blood Pressure Control on Kidney Function Among Individuals With Prior Lacunar Stroke: A Post Hoc Analysis of the Secondary Prevention of Small Subcortical Strokes (SPS3) Randomized Trial Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes. Vascular function and atherosclerosis progression after 1 y of flavonoid intake in statin-treated postmenopausal women with type 2 diabetes: a double-blind randomized controlled trial. Average Daily Blood Pressure, Not Office Blood Pressure, Is Associated With Progression of Cerebrovascular Disease and Cognitive Decline in Older People The combined use of aspirin, a statin, and blood pressure-lowering agents (polypill components) and the risk of vascular morbidity and mortality in patients with coronary artery disease. Predictors of adverse outcome among patients with hypertension and coronary artery disease. Modest Salt Reduction Lowers Blood Pressure and Albumin Excretion in Impaired Glucose Tolerance and Type 2 Diabetes Mellitus: A Randomized Double-Blind Trial CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM - 2018 EXECUTIVE SUMMARY.
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 Diabetes incidence is increasing rapidly in the United States . Diabetes increases the risk for cardiovascular disease , the major cause of death in diabetic individuals . The conventional cardiovascular risk factors of hyperlipidemia and hypertension worsen diabetic vascular disease . Treatment targets for low-density lipoprotein cholesterol ( LDL-C ) and blood pressure in diabetic individuals are being debated . The S AND S is a r and omized , open-label , 3-year trial to examine the effects of aggressive LDL-C ( goal < 70 mg/dL ) and blood pressure ( BP ) ( goal < 115/75 mm Hg ) reduction versus the st and ard goals of < 100 mg/dL for LDL-C and < 130/85 mm Hg for BP .  Five hundred forty-nine American-Indian men and women > 40 years old with type 2 diabetes were r and omized to 1 of 2 groups . Lipids and BP are managed using Food and Drug Administration-approved medications in an algorithmic approach . The presence and progression of atherosclerosis are evaluated by carotid ultrasonography ; echocardiography assesses cardiac function . The primary end point is the composite outcome of change in carotid artery intimal medial thickness and fatal/nonfatal cardiovascular events . These outcomes are combined by using a ranked analysis for carotid thickness and assigning a " worst rank " for a cardiovascular event . Secondary end points include carotid plaque score , left ventricular geometry and function , serum C-reactive protein , and safety measures . Unique aspects of the study design and analysis plan involve the use of a composite outcome and changes during the trial of LDL-C treatment goals for participants with baseline or incident cardiovascular disease in the conventional group because of changes in the st and ard of care . Study results will further underst and ing of the effects of aggressive risk factor reduction on atherosclerosis burden and cardiac function in diabetic individuals in US population s and will help determine optimal LDL-C and BP treatment goals for diabetic patients Endothelial dysfunction and increased arterial stiffness occur early in the pathogenesis of the metabolic syndrome and they are both powerful independent predictors of cardiovascular risk . A high-fibre diet has been correlated with lower BMI and a lower incidence of hyperlipidaemia , CVD , hypertension and diabetes . The present r and omised , parallel- design study compared the effects of fibre intake from a healthy diet v. fibre supplement diets on blood pressure ( BP ) and vascular function over 12 weeks . Overweight and obese adults were r and omised to one of three groups : control ( with placebo ) , fibre supplement ( FIB ) or healthy eating group with placebo ( HLT ) . Systolic blood pressure ( SBP ) was lower in the FIB group compared with the control group at week 6 , but not at week 12 . However , SBP was lower in the HLT group compared with control group at week 12 . At week 6 , the FIB group presented lower diastolic blood pressure and augmentation index compared with the control group , but this result did not persist to the end of the study . The present study did not show any improvements in BP or vascular function in overweight and obese individuals with psyllium fibre supplementation over 12 weeks of intervention . However , a healthy diet provided the greatest improvements in BP in overweight and obese subjects . Further research with hypertensive individuals is necessary to eluci date whether increased fibre consumption in the form of psyllium supplementation may provide a safe and acceptable means to reduce BP , vascular function and the risk of developing CVD Objective Oxidative stress has been suggested to play a role in the development of diabetes , hypertension and vascular dysfunction . Vitamin E , a major lipid-soluble dietary antioxidant , has two major dietary forms , α-tocopherol and γ-tocopherol . The potential importance of γ-tocopherol has largely been overlooked . Our aim was to investigate the effect of α-tocopherol and γ-tocopherol supplementation on 24-h ambulatory blood pressure ( BP ) and heart rate , vascular function and oxidative stress in individuals with type 2 diabetes . Method Fifty-eight individuals with type 2 diabetes were r and omized in a double-blind , placebo-controlled trial . Participants were r and omized to a daily dose of 500 mg/day RRR-α-tocopherol , 500 mg/day mixed tocopherols ( 60 % γ-tocopherol ) or placebo for 6 weeks . Primary endpoints were 24-h ambulatory BP and heart rate , endothelium-dependent and independent vasodilation and plasma and urinary F2-isoprostanes . Results Treatment with α-tocopherol significantly increased systolic BP [ 7.0 ( 5.2 , 8.8 ) mmHg , P < 0.0001 ] , diastolic BP [ 5.3 ( 4.0 , 6.5 ) mmHg , P < 0.0001 ] , pulse pressure [ 1.8 ( 0.6 , 3.0 ) mmHg , P < 0.005 ] and heart rate [ 2.0 ( 0.6 , 3.3 ) bpm , P < 0.005 ] versus placebo . Treatment with mixed tocopherols  significantly increased systolic BP [ 6.8 ( 4.9 , 8.6 ) mmHg , P < 0.0001 ] , diastolic BP [ 3.6 ( 2.3 , 4.9 ) mmHg , P < 0.0001 ] , pulse pressure [ 3.2 ( 2.0 , 4.4 ) mmHg , P < 0.0001 ] and heart rate [ 1.8 ( 0.5 , 3.2 ) bpm , P < 0.01 ] versus placebo . Treatment with α-tocopherol or mixed tocopherols  significantly reduced plasma F2-isoprostanes versus placebo , but had no effect on urinary F2-isoprostanes . Endothelium-dependent and independent vasodilation was not affected by either treatment . Conclusion In contrast to our initial hypothesis , treatment with either α- or mixed tocopherols  significantly increased BP , pulse pressure and heart rate in individuals with type 2 diabetes 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 The present study examined the hemodynamic mechanisms of blood pressure ( BP ) lowering by troglitazone in patients with type 2 diabetes mellitus ( DM ) at rest and during a mental arithmetic test ( MAT ) . Twenty-two patients with DM with normal to high-normal BP and 12 controls matched for age , gender , glucose tolerance , and BP were studied . DM subjects showed significantly higher systolic BP response during MAT than controls ( 157 versus 139 mm Hg ; P<0.01 ) . All 22 DM patients and 5 of 12 controls had systolic BP > 140 mm Hg during MAT . Heart rate and diastolic BP were not significantly different between the 2 groups . The DM group was then r and omized to receive troglitazone ( n=10 ; 400 mg/d ) or glyburide ( n=12 ; 20 mg/d ) . MAT was repeated after 6 months of treatment . Both treatments reduced glucose equally ( -1.7 mmol/L for troglitazone and -1.5 mmol/L for glyburide ) , but only troglitazone reduced insulin ( -15 microU/mL ; P<0.001 ) and C-peptide ( -0.9 ng/mL ; P<0.02 ) levels . Troglitazone significantly reduced BP at baseline ( P<0.05 ) and systolic BP response to MAT ( P<0.01 ) , whereas glyburide did not affect BP at baseline or during MAT . Stroke volume and cardiac output did not change with either drug , but troglitazone decreased peripheral vascular resistance ( -112 dyne . s. cm(-5 ) ; P<0.05 ) . Improved insulin resistance rather than an improved glycemic control is associated with lower resting and stress BP values in patients with DM . A reduction in vascular resistance may be a primary hemodynamic mechanism of the manner in which troglitazone lowers BP . Insulin sensitizers may offer potential therapeutic advantage in subjects with DM with elevated BP Background Antihypertensive drugs are used to control blood pressure ( BP ) and reduce macro- and microvascular complications in hypertensive patients with diabetes . Objectives The present study aim ed to compare the functional vascular changes in hypertensive patients with type 2 diabetes mellitus after 6 weeks of treatment with amlodipine or losartan . Methods Patients with a previous diagnosis of hypertension and type 2 diabetes mellitus were r and omly divided into 2 groups and evaluated after 6 weeks of treatment with amlodipine ( 5 mg/day ) or losartan ( 100 mg/day ) . Patient evaluation included BP measurement , ambulatory BP monitoring , and assessment of vascular parameters using applanation tonometry , pulse wave velocity ( PWV ) , and flow-mediated dilation ( FMD ) of the brachial artery . Results A total of 42 patients were evaluated ( 21 in each group ) , with a predominance of women ( 71 % ) in both groups . The mean age of the patients in both groups was similar ( amlodipine group : 54.9 ± 4.5 years ; losartan group : 54.0 ± 6.9 years ) , with no significant difference in the mean BP  [ amlodipine group : 145 ± 14 mmHg ( systolic ) and 84 ± 8 mmHg ( diastolic ) ; losartan group : 153 ± 19 mmHg ( systolic ) and 90 ± 9 mmHg ( diastolic ) ] . The augmentation index ( 30 % ± 9 % and 36 % ± 8 % , p = 0.025 ) and augmentation pressure ( 16 ± 6 mmHg and 20 ± 8 mmHg , p = 0.045 ) were lower in the amlodipine group when compared with the losartan group . PWV and FMD were similar in both groups . Conclusions Hypertensive patients with type 2 diabetes mellitus treated with amlodipine exhibited an improved pattern of pulse wave reflection in comparison with those treated with losartan . However , the use of losartan may be associated with independent vascular reactivity to the pressor effect We described the characteristics in a referred cohort of type II diabetic patients in the Developing Education on Microalbuminuria for Awareness of renal and cardiovascular risk in Diabetes study evaluating the global prevalence and determinants of microalbuminuria ( MA ) . A cross-sectional study evaluating 32,208 type II diabetic patients without known albuminuria from 33 countries was performed . Overall , 8057 patients were excluded , either because of prior known proteinuria or non-diabetic nephropathy ( 3670 ) , or because of invalid urine collection s ( 4387 ) . One single r and om urinary albumin/creatinine ratio was obtained in 24,151 patients ( 75 % ) . The overall global prevalence of normo- , micro- , and macroalbuminuria was 51 , 39 , and 10 % , respectively . The Asian and Hispanic patients had the highest prevalence of a raised urinary albumin/creatinine ratio ( 55 % ) and Caucasians the lowest ( 40.6 ) , P<0.0001 . HbA1c , systolic blood pressure ( BP ) , ethnicity , retinopathy , duration of diabetes , kidney function , body height , and smoking were all independent risk factors of MA , P<0.0001 . Estimated glomerular filtration rate was below 60 ml/min/1.73 m(2 ) in 22 % of the 11,573 patients with available data . Systolic BP below 130 mmHg was found in 33 and 43 % had an HbA1c below 7 % . The frequency of patients receiving aspirin  was 32 % , statins 29 % , and BP-lowering therapy 63 % . A high prevalence globally of MA and reduced kidney function , both conditions associated with enhanced renal and cardiovascular risk , was detected in type II diabetic patients without prior known nephropathy . Early detection , monitoring of vascular complications , and more aggressive multifactorial treatment aim ing at renal and vascular protection are urgently needed Background Managing cardiovascular risk factors is important for reducing vascular complications in type 2 diabetes , even in individuals who have achieved glycemic control . Nut consumption is associated with reduced cardiovascular risk ; however , there is mixed evidence about the effect of nuts on blood pressure ( BP ) , and limited research on the underlying hemodynamics . This study assessed the effect of pistachio consumption on BP , systemic hemodynamics , and heart rate variability in adults with well‐controlled type 2 diabetes . Methods and Results We enrolled 30 adults ( 40 to 74 years ) with type 2 diabetes in a r and omized , crossover , controlled feeding study . After a 2‐week run‐in period , participants consumed a low‐fat control diet ( 27 % fat ) containing low‐fat/high‐carbohydrate snacks and a moderate‐fat diet ( 33 % fat ) containing pistachios ( 20 % of total energy ) for 4 weeks each , separated by a 2‐week washout . Following each diet period , we assessed BP , systemic hemodynamics , and heart rate variability at rest and during acute mental stress , and , in a subset of participants ( n=21 ) , 24‐hour ambulatory BP . BP at rest and during stress did not differ between treatments . The pistachio diet significantly reduced total peripheral resistance ( −3.7±2.9 % , P=0.004 ) , increased cardiac output ( 3.1±2.3 % , P=0.002 ) , and improved some measures of heart rate variability ( all P<0.05 ) . Systolic ambulatory BP was significantly reduced by 3.5±2.2 mm Hg ( P=0.046 ) following the pistachio diet , with the greatest reduction observed during sleep ( −5.7±2.6 mm Hg , P=0.052 ) . Conclusions A moderate‐fat diet containing pistachios modestly improves some cardiovascular risk factors  in adults with well‐controlled type 2 diabetes . Clinical Trial Registration URL : www . clinical trials.gov . Unique identifier : NCT00956735 The publication of the U.K. Prospect i ve Diabetes Study ( UKPDS ) in 1998 helped to shape the management of type 2 diabetes in recent years ( 1 ) . The study demonstrated several points . First , sulfonylureas are as safe as insulin in controlling blood glucose . Second , metformin reduced cardiovascular disease in an overweight subgroup . Third , the same benefit of glycemic control in reducing microvascular disease ( previously noted in type 1 diabetes ) is applied equally to patients with type 2 diabetes . A separation in A1C of ∼1 % in the UKPDS reduced the risk of microvascular disease ( largely diabetic retinopathy ) by ∼25 % . This reflected the data from the Diabetes Control and Complications Trial , where a separation in A1C of 2 % in intensive and st and ard groups led to a reduction in microvascular disease of ∼50 % ( 2 ) . A fourth demonstration was that there was no significant reduction in macrovascular disease but a trend toward fewer myocardial infa rct ions with more intensive glucose control . Fifth , using the current treatment of the time ( first-generation sulfonylureas , human ultratard insulin , or metformin ) , it proved impossible to maintain glucose control , which tended to deteriorate throughout the study . It is now generally believed that the progressive fall in endogenous insulin production as β-cell numbers decline makes it difficult , if not impossible , to maintain tight control using st and ard treatment . Sixth , the UKPDS also showed that in those patients with hypertension , lowering blood pressure ( BP ) to moderate levels with either captopril or atenolol could reduce microvascular disease ( 3 ) . In a subsequent study , the UKPDS investigators presented the rates of both micro- and macrovascular disease according to the achieved levels of A1C during the study ( 4 ) . They showed a linear relationship between A1C and both groups of complications . The implication of the article was that if glycemic control could be tightened below the levels achieved in the UKPDS , then it might be possible to reduce rates , not only of microvascular complications , but also cardiovascular disease as well . The aim of the glucose arm of the Action in Diabetes and Vascular Disease : Preterax and Diamicron MR Controlled Evaluation ( ADVANCE ) trial ( 5 ) was to build on the information gained by the UKPDS and to answer the question as to whether intensifying glucose control to achieve an A1C of < 6.5 % would provide additional benefit in reducing the risk of both micro- and macrovascular disease . ADVANCE also asked questions about BP lowering in patients with type 2 diabetes . The aims of the BP arm were to establish whether routine provision of  BP-lowering therapy  produced additional benefits in terms of macro- and microvascular disease , irrespective of baseline BP , and added to the benefits produced by other cardiovascular preventive therapies , including ACE inhibitors 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 UNLABELLED Patients with type 2 diabetes mellitus have markedly increased risks of developing vascular diseases . These risks are reduced by lowering blood pressure in hypertensive individuals . However , the association between blood pressure and vascular risk appears continuous , with no clearly defined blood pressure level below which the risks fail to further decline . Intensive glucose lowering in these patients has also been shown to reduce microvascular disease , but effects on macrovascular disease remain uncertain . OBJECTIVES ADVANCE ( Action in Diabetes and Vascular disease ; preterAx and diamicroN-MR Controlled Evaluation ) will examine the hypotheses that intensive blood pressure lowering ( with an angiotensin-converting enzyme [ ACE ] inhibitor-diuretic combination ) and glucose control in high-risk hypertensive or non-hypertensive individuals with type 2 diabetes reduce the incidence of vascular diseases . The study will also provide an opportunity to examine the effects of blood pressure lowering against a background of ACE inhibition among such patients . DESIGN This 2 x 2 factorial r and omised controlled trial will recruit 10 000 adults with type 2 diabetes at elevated risk of vascular disease , from approximately 200 clinical centres in 20 countries worldwide . Eligible patients are r and omised to , first , the fixed combination of perindopril 2mg/indapamide 0.625 mg then perindopril 4 mg/indapamide 1.25 mg or matching placebo , and , second , to an intensive sulphonylurea-based glucose control regimen ( target glycosylated haemoglobin [ HbA(1c ) ] < /= 6.5 % ) , or usual guidelines -based therapy . Any participant in whom ACE inhibition is thought to be indicated is provided with background perindopril therapy . The scheduled period of treatment and follow-up is 4.5 years . Primary outcomes are a composite of macrovascular and a composite of microvascular events . CURRENT STATUS By mid-September 2002 , more than 8000 patients had been recruited from 17 countries , with registration s expected to be completed by December 2002 . Approximately half the participants recruited will be from Asia or from Eastern Europe . Final results are expected early in 2007 . ( Author 's note : registration closed on January 24 , 2003 , with sufficient participants to exceed the target of 10 000 r and omised subjects . OBJECTIVE To determine the cost-effectiveness of routine administration , irrespective of blood pressure ( BP ) , of a fixed-dose combination of perindopril and indapamide to patients with type 2 diabetes mellitus . DESIGN , SETTING AND PARTICIPANTS Prospect i ve cost-effectiveness analysis within the Action in Diabetes and Vascular Disease : Preterax and Diamicron-MR Controlled Evaluation ( ADVANCE ) trial , an international , multicentre , r and omised controlled trial of 11,140 participants with type 2 diabetes r and omly allocated to receive perindopril plus indapamide ( 4 mg-1.25 mg/day ) or placebo . MAIN OUTCOME MEASURES Health-related quality -of-life measured by the EuroQol-5D , re source utilisation , and cost-effectiveness ( cost per death averted at 4.3 years ' average follow-up , and estimated cost per life-year gained , by extrapolation ) . RESULTS The mean health-related quality -of-life score of survivors was 0.80 ( on a 0 - 1 scale [ death to full health ] ) , with no difference between treatment groups . Active treatment reduced hospital admissions for coronary heart disease and coronary revascularisation by 5 % . For the Australian participants , perindopril-indapamide cost A$ 1368 per patient during the trial period , but reduced total hospitalisation costs by A$ 410 and other medication costs ( mainly other BP-lowering drugs ) by A$ 332 . The absolute reduction in all-cause mortality for the active treatment group was 1.1 % , giving a cost per life saved of A$ 49,200 . Lifetime extrapolation gave an estimated cost per life-year saved of A$ 10,040 ( discounted at 5 % per year ) . CONCLUSION The combination of perindopril and indapamide in patients with type 2 diabetes appears to be cost-effective . TRIAL REGISTRATION United States National Library of Medicine NCT00145925 Aims To determine the effects of empagliflozin on blood pressure ( BP ) and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes mellitus ( T2DM ) . Methods We conducted a post hoc analysis of data from a phase III trial in patients with T2DM and hypertension receiving 12 weeks ' empagliflozin and four phase III trials in patients with T2DM receiving 24 weeks ' empagliflozin ( cohort 1 , n = 823 ; cohort 2 , n = 2477 ) . BP was measured using 24‐h BP monitoring ( cohort 1 ) or seated office measurements ( cohort 2 ) . Results Empagliflozin  reduced systolic BP ( SBP ) and diastolic BP in both cohorts ( p < 0.001 vs placebo ) , without increasing heart rate  . Empagliflozin  reduced pulse pressure ( PP ; adjusted mean difference vs placebo cohort 1 : −2.3 mmHg ; cohort 2 : −2.3 mmHg ) , mean arterial pressure ( MAP ; cohort 1 , −2.3 mmHg ; cohort 2 , −2.1 mmHg ) and double product ( cohort 1 , −385 mmHg × bpm ; cohort 2 , −369 mmHg × bpm ) all p < 0.001 vs placebo . There was a trend towards a reduction in the ambulatory arterial stiffness index ( AASI )  with empagliflozin in cohort 1 ( p = 0.059 vs placebo ) . AASI was not measured in cohort 2 . Subgroup analyses showed that there were greater reductions in PP with increasing baseline SBP in cohort 1 ( p = 0.092 ) . In cohort 2 , greater reductions in MAP were achieved in patients with higher baseline SBP ( p = 0.027 ) and greater reductions in PP were observed in older patients ( p = 0.011 ) . Conclusions Empagliflozin  reduced BP and had favourable effects on markers of arterial stiffness and vascular resistance Objectives : Arginine is converted in the endothelial cells to nitric oxide ( NO ) and citrulline . NO is a potent vasodilator in humans , but diabetics may have a reduced generation of NO which results in endothelial dysfunction . The aim of this study was to evaluate the effects of oral arginine on nitric oxide production , counter-regulatory hormones and blood pressure in mildly hypertensive type 2 diabetic patients . Methods : A prospect i ve , crossover clinical trial was performed over a three-day stay in the General Clinical Research Center . Six patients with type 2 diabetes mellitus and mild hypertension consented and were given orally three grams of arginine per hour for 10 hours on either day 2 or day 3 . On both days 2 and 3 , blood pressure was monitored between 5 AM and 4 PM and mean pressure determined . Results : Oral arginine  increased plasma citrulline from 31.3 ± 6.0 to 41.5 ± 6.0 μmol/L ( mean ± SEM ; p < 0.05 ) which may reflect an increased conversion of arginine into NO and citrulline . Arginine  reduced systolic BP from 135 ± 7 to 123 ± 8 mmHg ; p < 0.05 . Diastolic BP fell from 86.9 ± 1.7 to 80.7 ± 2.4 mmHg ; p < 0.05 ) . The reduction in BP was noted to occur two hours after starting oral arginine , and BP returned to normal within one hour of stopping the arginine . The oral arginine had no effect on C-peptide , insulin or other hormone concentrations . Conclusions : These data suggest that oral arginine may increase endothelial nitric oxide synthase ( NOS ) to increase vascular NO and temporally reduce blood pressure in mildly hypertensive type 2 diabetic patients Background — The effect of intensive blood pressure ( BP ) lowering on kidney function among individuals with established cerebrovascular disease and preserved estimated glomerular filtration rate ( eGFR ) is not established . Methods and Results — Among 2610 participants r and omized to a lower ( < 130 mm Hg ) versus higher ( 130–149 mm Hg ) systolic BP target with repeated measures of serum creatinine , we evaluated differences by study arm in annualized eGFR decline and rapid decline ( eGFR decline > 30 % ) using linear mixed models and logistic regression , respectively . We assessed associations of both treatment and kidney function decline with stroke , major vascular events , and the composite of stroke , death , major vascular events , or myocardial infa rct ion using multivariable Cox regression , separately and jointly including a test for interaction . Analyses were conducted by treatment arm . Mean age was 63±11 years ; 949 participants ( 36 % ) were diabetic ; and mean eGFR was 80±19 mL·min−1·1.73 m−2 . At 9 months , achieved systolic BP was 137±15 versus 127±14 mm Hg in the higher versus lower BP group , and differences were maintained throughout follow-up ( mean , 3.2 years ) . Compared with the higher target , the lower BP target had a −0.50–mL·min−1·1.73 m−2 per year ( 95 % confidence interval [ CI ] , −0.79 to −0.21 ) faster eGFR decline . Differences were most pronounced during the first year ( −2.1 mL·min−1·1.73 m−2 ; 95 % CI , −0.97 to −3.2 ) , whereas rates of eGFR decline did not differ after year 1 ( −0.095 ; 95 % CI , −0.47 to 0.23 ) . A total of 313 patients ( 24 % ) in the lower BP group had rapid kidney function decline compared with 247 ( 19 % ) in the higher BP group ( odds ratio , 1.4 ; 95 % CI , 1.1–1.6 ) . Differences in rapid decline by treatment arm were apparent in the first year ( odds ratio , 1.4 ; 95 % CI , 1.1–1.8 ) but were not significant after year 1 ( odds ratio , 1.0 ; 95 % CI , 0.73–1.4 ) . Rapid decline was associated with higher risk for stroke , major vascular events , and composite after full adjustment among individuals r and omized to the higher BP target ( stroke hazard ratio , 1.93 ; 95 % CI , 1.15–3.21 ) but not the lower BP arm ( stroke hazard ratio , 0.93 ; 95 % CI , 0.50–1.75 ; all P for interaction < 0.06 ) . Conclusions — In patients with prior lacunar stroke and relatively preserved kidney function , intensive BP lowering was associated with a greater likelihood of rapid kidney function decline . Differences were observed primarily during the first year of antihypertensive treatment . Rapid kidney function decline was not associated with increased risk for clinical events among those undergoing intensive BP lowering . Clinical Trial Registration — URL : http://www . clinical Trials.gov . Unique identifier : NCT00059306 Diets rich in green , leafy vegetables have been shown to lower blood pressure ( BP ) and reduce the risk of cardiovascular disease .  Green , leafy vegetables and beetroot are particularly rich in inorganic nitrate . Dietary nitrate supplementation , via sequential reduction to nitrite and NO , has previously been shown to lower BP and improve endothelial function in healthy humans . We sought to determine if supplementing dietary nitrate with beetroot juice , a rich source of nitrate , will lower BP and improve endothelial function and insulin sensitivity in individuals with type 2 diabetes ( T2DM ) . Twenty-seven patients , age 67.2±4.9 years ( 18 male ) , were recruited for a double-blind , r and omized , placebo-controlled crossover trial . Participants were r and omized to begin , in either order , a 2-week period of supplementation with 250ml beetroot juice daily ( active ) or 250ml nitrate-depleted beetroot juice ( placebo ) . At the conclusion of each intervention period 24-h ambulatory blood pressure monitoring , tests of macro- and microvascular endothelial function , and a hyperinsulinemic isoglycemic clamp were performed . After 2 weeks administration of beetroot juice mean ambulatory systolic BP was unchanged : 134.6±8.4mmHg versus 135.1±7.8mmHg ( mean±SD ) , placebo vs active-mean difference of -0.5mmHg ( placebo-active ) , p=0.737 ( 95 % CI -3.9 to 2.8 ) . There were no changes in macrovascular or microvascular endothelial function or insulin sensitivity . Supplementation of the diet with 7.5mmol of nitrate per day for 2 weeks caused an increase in plasma nitrite and nitrate concentration , but did not lower BP , improve endothelial function , or improve insulin sensitivity in individuals with T2DM BACKGROUND In healthy participants , short-term flavan-3-ol and isoflavone intakes improve vascular function ; however , the potential combined benefit of these compounds on atherosclerosis progression remains unclear for those at elevated risk of cardiovascular disease . OBJECTIVE The objective was to examine whether combined isoflavone and flavan-3-ol intake alters vascular function in postmenopausal women with type 2 diabetes mellitus ( T2DM ) . DESIGN A double-blind , parallel- design , placebo-controlled 1-y trial was conducted in postmenopausal T2DM patients r and omly assigned to a split dose of 27 g flavonoid-enriched chocolate/d [ 850 mg flavan-3-ols ( 90 mg epicatechin ) + 100 mg isoflavones ( aglycone equivalents)/d ] or matched placebo .  Intima-media thickness of the common carotid artery ( CCA-IMT ) , pulse wave velocity ( PWV ) , augmentation index , blood pressure ( BP ) , and vascular biomarkers were assessed . RESULTS A total of 93 patients completed the trial . Overall , the flavonoid intervention did not significantly change CCA-IMT , augmentation index , or BP , but pulse pressure variability improved ( flavonoid : -0.11 ± 0.07 mm Hg/min ; placebo : 0.10 ± 0.11 mm Hg/min ; P = 0.04 ) . In a subgroup with PWV data , net improvements were observed [ flavonoid ( n = 18 ) : -0.07 ± 0.38 m/s ; placebo ( n = 17 ) : 0.68 ± 0.25 m/s ; P = 0.01 ] , which equated to a 10 % CV risk reduction . Equol producers ( n = 17 ) had larger reductions in diastolic BP , mean arterial pressure , and PWV ( -2.24 ± 1.31 mm Hg , -1.24 ± 1.30 mm Hg , and -0.68 ± 0.40 m/s , respectively ; P < 0.01 ) compared with non-equol producers ( n = 30 ) . CONCLUSIONS Although the 1-y intervention did not change CCA-IMT or BP , clinical ly relevant improvements in arterial stiffness were observed ; equol producers were particularly responsive . Flavonoids may augment existing therapeutic strategies to reduce cardiovascular disease risk in postmenopausal T2DM patients , and longer studies are needed to examine the effects on atherosclerosis progression . This trial was registered at clinical trials.gov as NCT00677599 Background —  High blood pressure  (  BP ) is a risk factor for cerebrovascular disease , including stroke . Little is known about the importance of BP on the progression of microvascular disease of the brain , which has been associated with functional decline in mobility and cognition in older people . Methods and Results — This was a prospect i ve cohort of subjects 75 to 89 years of age to determine relations among vascular risk factors , white matter hyperintensity volume , and functional status . Ninety-nine subjects were enrolled through the use of a balanced 3 × 3 matrix stratified by age and mobility performance , and 72 subjects completed all sets of baseline and follow-up studies at 2 years . Subjects were excluded if there were medications or systemic or neurological diseases that could compromise mobility .  Ambulatory and clinic BP monitoring , magnetic resonance imaging , gait studies , and neuropsychological testing  were performed at baseline and after 24 months . Brain classification into normal white matter and T2-hyperintense white matter hyperintensity volume was performed with semiautomated segmentation . Quantitative measures of mobility and cognitive function were obtained longitudinally . Increased ambulatory systolic BP , but not clinic systolic BP , from baseline to 24 month follow-up was associated with increased white matter hyperintensity volume over that same period , as well as measures of executive function/processing speed . Similar associations were observed for 24-hour BP , awake BP , and sleep BP but not for the surge between the sleep and awake time at the 24-month time point . Conclusions — These data demonstrate for the first time the importance of 24-hour systolic BP in the progression of brain white matter hyperintensity volume burden associated with impairment of cognitive function in older people . The 24-hour systolic BP may be a potential target for intervention in the elderly to reduce vascular disease of the brain and impairment of function BACKGROUND AND AIMS Patients with established coronary artery disease ( CAD ) are likely to receive a combination of aspirin , a statin , and blood pressure (BP)-lowering agents . Combining these pharmacologic agents into a cardiovascular combination pill , such as a polypill , could be considered to reduce prescription gaps and nonadherence in high-risk patients . We aim ed to evaluate the effect of the concomitant use of aspirin , a statin , and BP-lowering agent(s ) in patients with CAD on vascular morbidity and mortality  in current clinical practice in an observational study to provide insights in the combination pill concept related to feasibility and applicability . METHODS In total , 2,706 patients with CAD enrolled in the Second Manifestations of ARTerial disease study were followed for the occurrence of a subsequent vascular event ( ie , myocardial infa rct ion , ischemic cerebrovascular accident , vascular death ) and all-cause mortality . The relationship between combination therapy and cardiovascular events and all-cause mortality was assessed using Cox proportional hazards regression models to calculate hazards ratios ( HRs ) with a 95 % CI . Both covariate and propensity score adjusting methods were used to reduce confounding by indication . RESULTS A combination of aspirin , a statin , and ≥1 BP-lowering agent(s ) was used by 67 % of the patients . During a median of 5.0 years ( interquartile range 2.4 - 10.2 years ) , 347 vascular events occurred and 162 patients died . Combination therapy with aspirin , statin , and ≥1 BP-lowering agent was associated with a lower risk of myocardial infa rct ion ( HR 0.68 , 95 % CI 0.49 - 0.96 ) , ischemic cerebrovascular accident ( HR 0.37 , 95 % CI 0.16 - 0.84 ) , composite vascular end point ( HR 0.66 , 95 % CI 0.49 - 0.88 ) , vascular mortality ( HR 0.53 , 95 % CI 0.33 - 0.85 ) , and all-cause mortality ( HR 0.69 , 95 % CI 0.49 - 0.96 ) compared with the absence of combination therapy , after adjusting for confounding covariates in a propensity score . The use of 1 or only 2 components of combination therapy was associated with a higher risk for cardiovascular events compared with the combined use of aspirin , a statin , and ≥1 BP-lowering agent(s ) . CONCLUSION Two-thirds of the patients with CAD use a combination of aspirin , a statin , and ≥1 BP-lowering agent(s ) , components of a cardiovascular fixed-dose combination pill . Combination therapy with these agents is associated with a lower risk of vascular events and total mortality . Although treatment effect in observational studies should be interpreted with caution , the results of this study support supposed benefits from combination therapy . However , the effect of fixed-dose combination pill on clinical outcome needs to be demonstrated in r and omized clinical trials OBJECTIVES We sought to determine predictors for adverse outcomes in hypertensive patients with coronary artery disease ( CAD ) . BACKGROUND Factors leading to adverse outcomes in hypertensive patients with CAD are poorly understood . The INternational VErapamil-tr and olapril STudy ( INVEST ) compared outcomes in hypertensive patients with CAD that were assigned r and omly to either a verapamil sustained-release (SR)- or an atenolol-based strategy for blood pressure ( BP ) control . Tr and olapril and hydrochlorothiazide were used as added agents . During follow-up ( 61,835 patient-years ) , BP control and the primary outcome ( death , nonfatal myocardial infa rct ion , and nonfatal stroke ) were not different between strategies . METHODS We investigated risk for adverse outcome associated with baseline factors , follow-up BP , and drug treatments using Cox modeling . RESULTS Previous heart failure ( adjusted hazard ratio [ HR ] 1.96 ) , as well as diabetes ( HR 1.77 ) , increased age ( HR 1.63 ) , U.S. residency ( HR 1.61 ) , renal impairment ( HR 1.50 ) , stroke/transient ischemic attack ( HR 1.43 ) , smoking ( HR 1.41 ) , myocardial infa rct ion ( HR 1.34 ) , peripheral vascular disease ( HR 1.27 ) , and revascularization ( HR 1.15 ) predicted increased risk . Follow-up systolic BP < 140 mm Hg or diastolic BP < 90 mm Hg ( HRs 0.82 or 0.70 , respectively ) and tr and olapril with verapamil SR ( HRs 0.78 and 0.79 ) were associated with reduced risk . CONCLUSIONS In hypertensive patients with CAD , increased risk for adverse outcomes was associated with conditions related to the severity of CAD and diminished left ventricular function . Lower follow-up BP and addition of tr and olapril to verapamil SR each were associated with reduced risk The role of salt restriction in patients with impaired glucose tolerance and diabetes mellitus is controversial , with a lack of well controlled , longer term , modest salt reduction trials in this group of patients , in spite of the marked increase in cardiovascular risk . We carried out a 12-week r and omized double-blind , crossover trial of salt restriction with salt or placebo tablets , each for 6 weeks , in 46 individuals with diet-controlled type 2 diabetes mellitus or impaired glucose tolerance and untreated normal or high normal blood pressure ( BP ) . From salt to placebo , 24-hour urinary sodium was reduced by 49±9 mmol ( 2.9 g salt ) . This reduction in salt intake led to fall in clinic BP from 136/81±2/1 mm Hg to 131/80±2/1 mm Hg , ( systolic BP ; P<0.01 ) . Mean ambulatory 24-hour BP was reduced by 3/2±1/1 mm Hg ( systolic BP , P<0.01 and diastolic BP , P<0.05 ) , and albumin/creatinine ratio was reduced from 0.73 mg/mmol ( 0.5–1.5 ) to 0.64 mg/mmol ( 0.3–1.1 ; P<0.05 ) . There was no significant change in fasting glucose , hemoglobin A1c , or insulin sensitivity . These results demonstrate that a modest reduction in salt intake , to approximately the amount recommended in public health guidelines , leads to significant and clinical ly relevant falls in BP in individuals who are early on in the progression of diabetes mellitus with normal or mildly raised BP . The reduction in urinary albumin excretion may carry additional benefits in reducing cardiovascular disease above the effects on BP ABBREVIATIONS A1C = hemoglobin A1C ; AACE = American Association of Clinical Endocrinologists ; ACCORD = Action to Control Cardiovascular Risk in Diabetes ; ACCORD BP = Action to Control Cardiovascular Risk in Diabetes Blood Pressure ; ACEI = angiotensin-converting enzyme inhibitor ; ADVANCE = Action in Diabetes and Vascular Disease : Preterax and Diamicron MR Controlled Evaluation ; AGI = alpha-glucosidase inhibitor ; apo B = apolipoprotein B ; ASCVD = atherosclerotic cardiovascular disease ; BAS = bile acid sequestrant ; BCR-QR = bromocriptine quick release ; BMI = body mass index ; BP = blood pressure ; CCB = calcium channel blocker ; CHD = coronary heart disease ; CKD = chronic kidney disease ; CVD = cardiovascular disease ; DASH = Dietary Approaches to Stop Hypertension ; DPP4 = dipeptidyl peptidase 4 ; eGFR = estimated glomerular filtration rate ; ER = extended release ; FDA = Food and Drug Administration ; GLP1 = glucagon-like peptide 1 ;  HDL-C = high-density lipoprotein cholesterol ; IMPROVE-IT = Improved Reduction of Outcomes : Vytorin Efficacy International Trial ; LDL-C = low-density lipoprotein cholesterol ; LDL-P = low-density lipoprotein particle ; Look AHEAD = Look Action for Health in Diabetes ; NPH = neutral protamine Hagedorn ; OSA = obstructive sleep apnea ; RCT = r and omized controlled trial ; SU = sulfonylurea ; SGLT2 = sodium glucose cotransporter-2 ; SMBG = self-monitoring of blood glucose ; T2D = type 2 diabetes ; TZD = thiazolidinedione ; VADT = Veterans Affairs Diabetes Trial
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
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 .