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. Low blood pressure and the risk of dementia in very old individuals Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial Effect of antihypertensive therapy on progression of carotid intima-media thickness in patients with type 2 diabetes mellitus. Effects of individual risk factors on the incidence of cardiovascular events in the treated hypertensive patients of the Hypertension Optimal Treatment Study. HOT Study Group. UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Ambulatory blood pressure monitoring and endothelium-dependent vasodilation in the elderly athletes. Blood Pressure and Pulse Pressure Effects on Renal Outcomes in the Veterans Affairs Diabetes Trial (VADT) The Bedtime Administration of Doxazosin Controls Morning Hypertension and Albuminuria in Patients with Type-2 Diabetes: Evaluation Using Home-Based Blood Pressure Measurements Microalbuminuria Reduction With Valsartan in Patients With Type 2 Diabetes Mellitus: A Blood Pressure–Independent Effect Predictors of Cognitive Decline in Older Adult Type 2 Diabetes from the Veterans Affairs Diabetes Trial Time course of the antiproteinuric and antihypertensive effects of direct renin inhibition in type 2 diabetes. The effects of alcohol on ambulatory blood pressure and other cardiovascular risk factors in type 2 diabetes: a randomized intervention Oral calcium supplementation ambulatory blood pressure and relation to changes in intracellular ions and sodium-hydrogen exchange. Blood Pressure, Internal Carotid Artery Flow Parameters, and Age-Related White Matter Hyperintensities The influence of prehypertension, hypertension, and glycated hemoglobin on the development of type 2 diabetes mellitus in prediabetes: the Korean Genome and Epidemiology Study (KoGES) Effects of intensive blood pressure control in the management of patients with type 2 diabetes mellitus in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Long-term effectiveness of a community-based model of care in Māori and Pacific patients with type 2 diabetes and chronic kidney disease: a 4-year follow up of the DElay Future End Stage Nephropathy due to Diabetes (DEFEND) study. Prognostic value of blood pressure in patients with high vascular risk in the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial study Impact of Visit-to-Visit Glycemic Variability on the Risks of Macrovascular and Microvascular Events and All-Cause Mortality in Type 2 Diabetes: The ADVANCE Trial Reducing Consumption of Sugar-Sweetened Beverages Is Associated With Reduced Blood Pressure: A Prospective Study Among United States Adults The KEEPS-Cognitive and Affective Study: baseline associations between vascular risk factors and cognition. Differential effects of angiotensin converting enzyme inhibition and diuretic therapy on reductions in ambulatory blood pressure, left ventricular mass, and vascular hypertrophy. Total homocysteine is associated with nephropathy in non-insulin-dependent diabetes mellitus. Risks of cardiovascular events and effects of routine blood pressure lowering among patients with type 2 diabetes and atrial fibrillation: results of the ADVANCE study.
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 Background : The role of blood pressure ( BP ) as a risk factor for dementia is complex and may be age dependent . In very old individuals , low BP might increase risk for dementia , perhaps by reducing cerebral perfusion pressure . Methods : The association between BP and dementia was examined in the Bronx Aging Study , a prospect i ve study of 488 community-dwelling elderly individuals over age 75 , dementia-free at baseline ( 1980 to 1983 ) and followed at 12- to 18-month intervals . Subjects with baseline BP and with at least one follow-up visit were included ( n = 406 ) .  Incident dementia was diagnosed using the criteria of the Diagnostic and Statistical Manual of Mental Disorders ( 3rd rev . ed . ) . Results : Over 21 years ( median 6.7 years ) , 122 subjects developed dementia ( 65 Alzheimer ’s disease [ AD ] , 28 vascular dementia , 29 other dementias ) . Relative risk of dementia increased for each 10-mm Hg decrement in diastolic ( hazard ratio [ HR ] 1.20 , 95 % CI 1.03 to 1.40 ) and mean arterial ( HR 1.16 , 95 % CI 1.02 to 1.32 ) pressure , adjusted for age , sex , and education . Low diastolic BP significantly influenced risk of developing AD but not vascular dementia . Upon examination of groups defined by BP , mildly to moderately raised systolic BP ( 140 to 179 mm Hg ) was associated with reduced risk for AD ( HR vs normal systolic BP group 0.55 , 95 % CI 0.32 to 0.96 ) , whereas low diastolic BP ( ≤70 mm Hg ) was associated with increased risk of AD ( HR vs normal diastolic BP group 1.91 , 95 % CI 1.05 to 3.48 ) . Subjects with persistent low BP over 2 years had higher risk of developing dementia ( HR 2.19 , 95 % CI 1.27 to 3.77 ) . Conclusions : Low diastolic pressure is associated with higher risk of dementia  in elderly individuals over age 75 .  Dementia risk was higher in subjects with persistently low BP BACKGROUND Blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes , and guidelines recommend intensive lowering of blood pressure for diabetic patients with hypertension . We assessed the effects of the routine administration of an angiotensin converting enzyme ( ACE ) inhibitor-diuretic combination on serious vascular events in patients with diabetes , irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs . METHODS The trial was done by 215 collaborating centres in 20 countries . After a 6-week active run-in period , 11 140 patients with type 2 diabetes were r and omised to treatment with a fixed combination of perindopril and indapamide or matching placebo , in addition to current therapy . The primary endpoints were composites of major macrovascular and microvascular events , defined as death from cardiovascular disease , non-fatal stroke or non-fatal myocardial infa rct ion , and new or worsening renal or diabetic eye disease , and analysis was by intention-to-treat . The macrovascular and microvascular composites were analysed jointly and separately . This trial is registered with Clinical Trials.gov , number NCT00145925 . FINDINGS After a mean of 4.3 years of follow-up , 73 % of those assigned active treatment and 74 % of those assigned control remained on r and omised treatment . Compared with patients assigned placebo , those assigned active therapy had a mean reduction in systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg . The relative risk of a major macrovascular or microvascular event was reduced by 9 % ( 861 [ 15.5 % ] active vs 938 [ 16.8 % ] placebo ; hazard ratio 0.91 , 95 % CI 0.83 - 1.00 , p=0.04 ) . The separate reductions in macrovascular and microvascular events were similar but were not independently significant ( macrovascular 0.92 ; 0.81 - 1.04 , p=0.16 ; microvascular 0.91 ; 0.80 - 1.04 , p=0.16 ) . The relative risk of death from cardiovascular disease was reduced by 18 % ( 211 [ 3.8 % ] active vs 257 [ 4.6 % ] placebo ; 0.82 , 0.68 - 0.98 , p=0.03 ) and death from any cause was reduced by 14 % ( 408 [ 7.3 % ] active vs 471 [ 8.5 % ] placebo ; 0.86 , 0.75 - 0.98 , p=0.03 ) . There was no evidence that the effects of the study treatment differed by initial blood pressure level or concomitant use of other treatments at baseline . INTERPRETATION Routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events , including death . Although the confidence limits were wide , the results suggest that over 5 years , one death due to any cause would be averted among every 79 patients assigned active therapy Antihypertensive therapy reduces the incidence of cardiovascular events in people with diabetes mellitus ( DM ) . However , the effects of treatment on sub clinical atherosclerosis are less well studied . Results of a post hoc cohort analysis of the association between antihypertensive treatment and carotid artery intima-media thickness ( CIMT ) in the Troglitazone Atherosclerosis Regression Trial ( TART ) , a r and omized trial design ed to evaluate the impact of troglitazone treatment on CIMT progression in adults with insulin-requiring type 2 DM , are reported . CIMT , blood pressure ( BP ) , and use of antihypertensive agents  were measured throughout the 2-year treatment period . In multivariable mixed-effects models , the annual rate of change in CIMT in relation to BP and duration of antihypertensive agent use , adjusting for covariates , was evaluated . Higher systolic BP was associated with a higher CIMT progression rate ( p=0.03 ) . This association was reduced by antihypertensive treatment in a duration -dependent manner ( p for interaction=0.035 ) . Adjustment for age , treatment assignment , and change in fasting glucose during the trial did not attenuate these associations . In conclusion , regular use of antihypertensive agents reduces the harmful impact of increased BP on atherosclerosis progression in patients with DM . The antiatherogenic effect of antihypertensive agents , including BP normalization and possible direct vascular wall protection , can be detected by CIMT progression using B-mode ultrasound in patients with DM BACKGROUND The Hypertension Optimal Treatment ( HOT ) Study has provided information about cardiovascular events in 18790 hypertensives , subjected to pronounced blood pressure ( BP ) lowering for a mean of 3.8 years . The HOT study data have subsequently been analysed after stratification of the patients according to global cardiovascular risk , and it has been found that , despite intensive blood pressure lowering in all risk strata , morbid event rates increased with increasing risk stratum . OBJECTIVES Previously analysed global risk strata were based on combinations of risk factors . The analyses presented here were intended to provide information on the relative role that the presence of each individual factor may have in increasing cardiovascular risk , despite good BP control . METHODS Risk ratios ( RR ) for patients with and those without a risk factor were calculated with 95 % confidence intervals ( CI ) using a Cox proportional hazard model , and adjusted for all variables except the one under examination . RESULTS For all risk factors considered and for all types of event , RR were always greater than 1 , indicating a greater risk in the presence , compared with that in the absence of each factor . The male gender was a statistically significant risk for cardiovascular ( CV ) events , CV and total mortality and particularly for myocardial infa rct ion ( MI ) ; age > or = 65 years for CV events , stroke , CV and particularly total mortality ; smoking for all events analysed , but particularly for total mortality ( twice higher in smokers than in non-smokers ) ; high serum cholesterol ( > 6.8 mmol/l ) for CV events , MI and CV mortality ; high serum creatinine ( > 155 micromol/l ) for CV events , stroke , CV and total mortality ; diabetes for CV events , stroke , total mortality and particularly CV mortality ; and ischaemic heart disease for all events analysed . Adjusted RR were often close to or greater than 2 . CONCLUSIONS Each of the risk factors considered was found to be an important cause of residual risk , despite good BP control . These findings emphasize the importance of addressing other correctable risk factors , e.g. smoking , hypercholesterolaemia and diabetes , as well as rigorous control of blood pressure , and of initiating antihypertensive therapy before cardiovascular and renal damage becomes manifest OBJECTIVE To determine the role of hyperglycemia in prospect i ve analyses of peripheral vascular disease ( PVD ) in type 2 diabetes , taking into account other potential risk factors . RESEARCH DESIGN AND METHODS Potential risk factors for the development of PVD were examined in 3,834 of 5,102 individuals enrolled in the U.K. Prospect i ve Diabetes Study ( UKPDS ) without PVD at diagnosis of diabetes , followed for 6 years , and for whom relevant data were available . PVD was defined as two of the following : ankle-arm blood pressure index < 0.8 , absence of both dorsalis pedis and posterior tibial pulses to palpation in one or both legs , and intermittent claudication . Logistic regression was used to estimate the association between potential risk factors measured 3 - 4 months after diagnosis of diabetes and incident PVD . The prevalence of PVD at 3-year intervals to 18 years was determined . RESULTS Hyperglycemia , assessed as HbA(1c ) , was associated with an increased risk for incident PVD , independent of other risk factors including age , increased systolic blood pressure , reduced HDL cholesterol , smoking , prior cardiovascular disease , peripheral sensory neuropathy , and retinopathy . Each 1 % increase in HbA(1c ) was associated with a 28 % increased risk of PVD ( 95 % CI 12 - 46 ) , and each 10-mmHg increase in systolic blood pressure with a 25 % increase in risk ( 95 % CI 10 - 43 ) . CONCLUSIONS Hyperglycemia , as well as smoking , dyslipidemia , and blood pressure are potentially modifiable risk factors for the development of PVD AIM Regular exercise is a key component of cardiovascular risk prevention strategies , because it is associated with a variety of beneficial metabolic and vascular effects that reduce mortality and the incidence of cardiovascular adverse events . Endothelium plays an important role in the local regulation of vascular tone and structure , mainly by nitric oxide ( NO ) synthesis and action . Aim of the present study was to evaluate in elderly athletes the effect of regular aerobic exercise on arterial blood pressure ( BP ) and on endothelium-dependent flow-mediated dilation ( FMD ) of the brachial artery . METHODS The study population included 30 male subjects ( mean age 65.6+/-5.6 years ) , who had practice d endurance running at a competitive level for at least 40 years , and 28 age- and sex-matched subjects ( mean age 64.5+/-4.5 years ) with sedentary lifestyle and free of cardiovascular disease . Athletes and control subjects underwent  st and ard 12-lead ECG , clinic BP , 24-h ambulatory BP monitoring and endothelium-dependent FMD and endothelium-independent response to glyceryl trinitrate ( GTN ) , 400 microg , in the brachial artery by high-resolution ultrasonography . RESULTS Systolic clinic and ambulatory 24-h BP were significantly lower in the athletes , than in the controls ( P<0.001 , respectively ) . Systolic and diastolic 24-h BP variability , when assessed either by the st and ard deviation ( S.D. ) , or by the coefficient of variation ( CV ) , were also significantly lower in the athletes ( P<0.01 ) . The athletes also had a lower 24-h , day-time and night-time heart rate ( HR ) ( P<0.01 ) , as well as a lower HR variability ( P<0.01 ) . As regards circadian BP change , the % Delta was statistically significant greater in athletes ( P<0.05 ) . Elderly athletes showed higher FMD than elderly sedentary subjects ( P<0.001 ) , whereas no differences were shown in the response to GTN . CONCLUSIONS Our results , suggest that long-term physical activity can counteract the age-related endothelial dysfunction that characterizes sedentary aging , preserving the capacity of the endothelium-dependent vasodilation and reduces BP values improving arterial pressure control OBJECTIVE Blood pressure ( BP ) control for renal protection is essential for patients with type 2 diabetes . Our objective in this analysis of Veterans Affairs Diabetes Trial ( VADT ) data was to learn whether on- study systolic BP ( SBP ) , diastolic BP ( DBP ) , and pulse pressure ( PP ) affected renal outcomes measured as albumin-to-creatinine ratio ( ACR ) and estimated glomerular filtration rate ( eGFR ) . RESEARCH DESIGN AND METHODS The VADT was a prospect i ve , r and omized study of 1,791 veterans with type 2 diabetes to determine whether intensive glucose control prevented major cardiovascular events . In this post hoc study , time-varying covariate survival analyses and hazard ratios ( HR ) were used to determine worsening of renal outcomes . RESULTS Compared with SBP 105–129 mmHg , the risk of ACR worsening increased significantly for SBP 130–139 mmHg ( HR 1.88 [ 95 % CI 1.28–2.77 ] ; P = 0.001 ) and for SBP ≥140 mmHg ( 2.51 [ 1.66–3.78 ] ; P < 0.0001 ) . Compared with a PP range of 40–49 mmHg , PP < 40 was associated with significantly lowered risk of worsening ACR ( 0.36 [ 0.15–0.87 ] ; P = 0.022 ) and PP ≥60 with significantly increased risk ( 2.38 [ 1.58–3.59 ] ; P < 0.0001 ) . Analyses of BP ranges associated with eGFR worsening showed significantly increased risk with rising baseline SBP and an interaction effect between SBP ≥140 mmHg and on- study A1C . These patients were 15 % more likely than those with SBP < 140 mmHg to experience eGFR worsening ( 1.15 [ 1.00–1.32 ] ; P = 0.045 ) for each 1 % ( 10.9 mmol/mol ) A1C increase . CONCLUSIONS SBP ≥130 mmHg and PP > 60 mmHg were associated with worsening ACR . The results suggest that treatment of SBP to < 130 mmHg may lessen ACR worsening . The interaction between SBP ≥140 mmHg and A1C suggests that the effect of glycemic control on reducing progression of renal disease may be greater in hypertensive patients The control of high blood pressure ( BP ) after awakening in the morning ( morning hypertension ) as determined by home BP ( HBP ) , as well as BP control throughout the day , may prevent diabetic vascular complications . We examined the effect of an α-adrenergic blocker ( doxazosin ) on BP measurements taken by HBP after awakening and during clinic visits ( CBP ) in 50 patients with type-2 diabetes and morning hypertension . We evaluated the urinary albumin excretion rate as an indicator of nephropathy . Doxazosin was taken orally once at bedtime for 1 to 3 months . The mean ( ± SD ) dose was 2.9 ± 2.1 mg/day ( 1 to 8 mg/day ) . The BP was measured monthly at the clinic during the day and at home after awakening in the morning . In this short-term trial ( 2.8 ± 0.4 months ) , the systolic HBP decreased significantly from 164 ± 17 mmHg before treatment to 146 ± 19 mmHg after treatment , and the diastolic HBP decreased significantly from 85 ± 14 mmHg before treatment to 80 ± 9 mmHg after treatment . The systolic , but not the diastolic CBP , decreased significantly after treatment . There was no significant difference in the systolic or diastolic values between the HBP and the CBP after treatment . The percentage change in the systolic HBP after treatment was three times greater than for the systolic CBP . The median ( interquartile ) urinary albumin excretion rate decreased significantly ( P < 0.001 ) from 62 ( 25–203 ) mg/g creatinine before treatment to 19 ( 9–76 ) mg/g creatinine after treatment . On multiple regression analysis , the decrease in the systolic HBP with treatment positively correlated with the reduction in urinary excretion of albumin . The control of morning hypertension reduced the albuminuria found in both untreated and treated hypertensive patients with type-2 diabetes . Bedtime administration of doxazosin appears to be safe and effective in reducing morning hypertension as measured by HBP . This finding also demonstrates that HBP taken in the morning has a stronger predictive power for the albuminuria level than does CBP Background —Elevated urine albumin excretion ( UAER ) is a modifiable risk factor for renal and cardiovascular disease in type 2 diabetes . Blockade of the renin-angiotensin system lowers UAER , but whether this effect is independent of blood pressure ( BP ) reduction remains controversial . The MicroAlbuminuria Reduction With VALsartan ( MARVAL ) study was design ed to evaluate the BP-independent effect of valsartan on UAER in type 2 diabetic patients with microalbuminuria . Methods and Results —Three hundred thirty-two patients with type 2 diabetes and microalbuminuria , with or without hypertension , were r and omly assigned to 80 mg/d valsartan or 5 mg/d amlodipine for 24 weeks . A target BP of 135/85 mm Hg was aim ed for by dose-doubling followed by addition of bendrofluazide and doxazosin whenever needed . The primary end point was the percent change in UAER from baseline to 24 weeks . The UAER at 24 weeks was 56 % ( 95 % CI , 49.6 to 63.0 ) of baseline with valsartan and 92 % ( 95 % CI , 81.7 to 103.7 ) of baseline with amlodipine , a highly significant between-group effect ( P < 0.001 ) . Valsartan lowered UAER similarly in both the hypertensive and normotensive subgroups . More patients reversed to normoalbuminuria with valsartan ( 29.9 % versus 14.5%;P = 0.001 ) . Over the study period , BP reductions were similar between the two treatments ( systolic/diastolic 11.2/6.6 mm Hg for valsartan , 11.6/6.5 mm Hg for amlodipine ) and at no time point was there a between-group significant difference in BP values in either the hypertensive or the normotensive subgroup . Conclusions —For the same level of attained BP and the same degree of BP reduction , valsartan lowered UAER more effectively than amlodipine in patients with type 2 diabetes and microalbuminuria , including the subgroup with baseline normotension . This indicates a BP-independent antiproteinuric effect of valsartan Aims Cognitive decline disproportionately affects older adult type 2 diabetes . We tested whether r and omized intensive ( INT ) glucose-lowering reduces the rate(s ) of cognitive decline in adults with advanced type 2 diabetes ( mean : age , 60 years ; diabetes duration , 11 years ) from the Veterans Affairs Diabetes Trial . Methods A battery of neuropsychological tests [ digit span , digit symbol substitution ( DSym ) , and  Trails-making Test-Part B ( TMT-B ) ] was administered at baseline in ~1700 participants and repeated at year 5 . Thirty-seven risk factors were evaluated as predictors of cognitive decline in multivariable regression analyses . Results The mean age-adjusted DSym or TMT-B declined significantly in all study participants ( P < 0.001 ) . R and omized INT glucose-lowering did not significantly alter the rate of cognitive decline . The final model of risk factors associated with 5-year decline in age-adjusted TMT-B included as significant predictors : longer baseline diabetes duration ( beta = −0.028 ; P = 0.0057 ) , lower baseline diastolic blood pressure ( BP ; beta = 0.028 ; P = 0.002 ) , and baseline calcium channel blocker medication use ( beta = −0.639 ; P < 0.001 ) . Higher baseline pulse pressure was significantly associated with decline in age-adjusted TMT-B suggesting a role for both higher systolic and lower diastolic BPs . Baseline thiazide diuretic use ( beta = −0.549 ; P = 0.015 ) was an additional significant predictor of 5-year decline in age-adjusted digit symbol score . Post-baseline systolic BP-lowering was significantly associated ( P < 0.001 ) with decline in TMT-B performance . There was a significant inverse association between post-baseline plasma triglyceride-lowering ( P = 0.045 ) and decline in digit symbol substitution task performance . Conclusion A 5-year period of r and omized INT glucose-lowering did not significantly reduce the rate of cognitive decline  in older-aged adults with type 2 diabetes .  Systolic and diastolic BPs as well as plasma triglycerides appeared as modifiable risk factors of the rate of cognitive decline in older adult type 2 diabetes Inhibition of renin with an active site inhibitor , aliskiren , lowers blood pressure ( BP ) in diabetic patients . Here , we studied the time course of the antihypertensive and antiproteinuric effect of renin inhibition in 15 patients with type 2 diabetes and elevated urinary albumin/creatinine ratios ( UACRs ) to check whether aliskiren can decrease proteinuria . After a 4-week washout of previous medications , patients received aliskiren and furosemide daily for 28 days followed by a 4-week withdrawal period . Twenty-four-hour BPs were measured at baseline throughout treatment and withdrawal periods . The UACR was significantly reduced after 2 - 4 days of treatment with another significant reduction after 28 days . Systolic blood pressure ( SBP ) was significantly lower after 7 days with no further reduction after 28 days . The BP returned toward baseline 3 days after withdrawal , whereas the UACR was still significantly reduced compared with baseline 12 days after withdrawal . Our study shows that aliskiren reduced 24 h SBP , and this was associated with a reduction in albuminuria in type 2 diabetic patients Objective : Although prospect i ve studies suggest light-to-moderate chronic alcohol intake protects against coronary artery disease in type 2 diabetic patients , the balance of effects on individual cardiovascular risk factors needs further assessment . We examined the effects of alcohol consumption on 24-h ambulatory blood pressure ( BP ) and heart rate ( HR ) , high-density lipoprotein cholesterol , fibrinogen , C-reactive protein , homocysteine , and glycaemic control in well controlled type 2 diabetes . Methods : Twenty-four participants aged 49–66 year were r and omized to a three-period crossover study with women drinking red wine 230 ml/day ( ∼24 g alcohol/day ) and men drinking red wine 300 ml/day ( ∼31 g alcohol/day ) , or equivalent volumes of dealcoholized red wine ( DRW ) or water , each for 4 weeks . Ambulatory BP and HR were monitored every 30 min for 24 h at the end of each period . Home blood glucose monitoring was carried out twice weekly throughout . Results : Red wine increased awake SBP and DBP relative to water by 2.5 ± 1.2 /1.9 ± 0.7 mmHg ( P = 0.033 , P = 0.008 , respectively ) , with a similar nonsignificant trend relative to DRW . Asleep DBP fell with red wine relative to DRW ( 2.0 ± 0.8 mmHg , P = 0.016 ) with a similar nonsignificant trend relative to water . Red wine increased 24-h , awake and asleep HR relative to water and DRW . Relative to DRW , red wine did not affect glycaemic control or any other cardiovascular risk factor . Conclusion : In well controlled type 2 diabetic individuals 24–31 g alcohol/day ( ∼2–3 st and ard drinks ) raises awake BP and 24-h HR and lowers asleep BP but does not otherwise favourably or adversely modify cardiovascular risk factors BACKGROUND Calcium ( Ca2 + ) supplementation has been shown paradoxically to reduce intracellular Ca2 + and induce vascular relaxation . The aim of the study was to assess 24-h blood pressure ( BP ) change after Ca2 + supplementation and to investigate its relation to changes in intracellular ions and the activity of the first isoform of sodium-hydrogen exchange ( NHE-1 ) in subjects with hypertension and type 2 diabetes . METHODS This parallel , r and omized controlled , single-blinded trial , consisted of 31 patients with type 2 diabetes , and hypertension who were allocated to receive 1,500 mg of Ca2 + per day ( n = 15 ) or no treatment ( n = 16 ) for 8 weeks . RESULTS In the Ca2 + group a decrease of 1.7 + /- 2.7 mm Hg ( mean + /- SE ) P = 0.52 for mean 24-h systolic BP ( SBP ) and 2.1 + /- 1.5 mm Hg , P = 0.19 for mean 24-h diastolic BP ( DBP ) was recorded . Whereas in the control group an increase of 1.4 + /- 2.7 mm Hg , P = 0.59 for mean 24-h SBP and 1.2 + /- 2.8 mm Hg , P = 0.83 for mean 24-h DBP was observed . Intraplatelet Ca2 + decreased whereas intraplatelet magnesium ( Mg2 + ) and erythrocyte K+ increased in the intervention group . Change in mean 24-h SBP in the pooled group correlated with both change in intraplatelet Ca2 + ( r = 0.49 , P < 0.05 ) and NHE-1 activity ( r = 0.6 , P < 0.001 ) . The contribution of intraplatelet Ca2 + was attenuated when both parameters were entered in a multivariate regression model . CONCLUSIONS The present study shows a weak , statistically nonsignificant trend towards association of  Ca2 + supplementation on 24-h BP in hypertensive subjects with type 2 diabetes . However , our results indicated an interrelation of [Ca2+]i levels and NHE-1 activity on BP in patients with hypertension and type 2 diabetes White matter hyperintensities ( WMH ) are associated with hypertension . We examined interactions among blood pressure ( BP ) , internal carotid artery ( ICA ) flow velocity parameters , and WMH . We obtained BP measurements from 694 community-dwelling subjects at mean ages 69.6 ( ±0.8 ) years and again at 72.6 ( ±0.7 ) years , plus brain MRI and ICA ultrasound at age 73±1 years . Diastolic and mean BP decreased and pulse pressure increased , but systolic BP did not change between 70 and 73 years . Multiple linear regression , corrected for vascular disease and risk factors , showed that WMH at the age of 73 years were associated with history of hypertension ( & bgr;=0.13 ; P<0.001 ) and with BP at the age of 70 years ( systolic & bgr;=0.08 , mean & bgr;=0.09 , diastolic & bgr;=0.08 ; all P<0.05 ) ; similar but attenuated associations were seen for BP at the age of 73 years . Lower diastolic BP and higher pulse pressure were associated with higher ICA pulsatility index at the age 73 years ( diastolic BP age 70 years : st and ardized & bgr;=−0.24 , P<0.001 ; pulse pressure age 70 years : & bgr;=0.19 , P<0.001 ) . WMH were associated with higher ICA pulsatility index ( & bgr;=0.13 ; P=0.002 ) after adjusting for BP and correction for multiple testing . Therefore , falling diastolic BP and increased pulse pressure are associated with increased ICA pulsatility index , which in turn is associated with WMH . This suggests that hypertension and WMH may either associate indirectly because hypertension increases arterial stiffness that leads to WMH over time , or coassociate through advancing age and stiffer vessels , or both . Reducing vascular stiffness may reduce WMH progression and should be tested in r and omized trials , in addition to testing antihypertensive therapy Background It has been reported that elevated blood pressure ( BP ) was significantly associated with the increased risk for type 2 diabetes mellitus ( T2DM ) . However , there is still limited information about the influence of BP on the risk for T2DM across the level of glycated hemoglobin ( HbA1c ) . Method In a cohort of the Korean Genome and Epidemiology Study ( KoGES ) , 2830 non-diabetic Korean adults with prediabetes defined by HbA1c level of 5.7–6.4 % were followed-up for 10 years . Multivariate cox proportional hazards assumption was used to assess the risk for T2DM according to the baseline BP categories ( normal , prehypertension and hypertension ) and HbA1c level ( low : 5.7–5.9 % and high : 6.0–6.4 % ) . Results The risk for T2DM significantly increased proportionally to BP categories ( adjusted HR ; reference in normal BP , 1.32 [ 1.10–1.59 ] in prehypertension and 1.61 [ 1.35–1.92 ] in hypertension ) . Subgroup analysis indicated that individuals with high HbA1c had the higher risk for T2DM than individuals with low HbA1c regardless of BP . Additionally , combined presence of hypertension and high HbA1c had the highest risk for T2DM ( adjusted HR : 3.82 [ 3.00–4.87 ] ) . In each systolic and diastolic BP level , the risk for T2DM significantly increased from systolic BP ≥ 130 mmHg ( adjusted HRs : 1.39 ( [ 1.15–1.71 ] ) and diastolic BP ≥ 80 mmHg ( adjusted HRs : 1.30 ( [ 1.07–1.58 ] ) . Conclusion BP and HbA1c may be useful tools in identifying individuals with prediabetes more potentially predisposed to T2DM . Prospect i ve studies should be considered to examine whether controlling BP actually lowers the risk for T2DM To appreciate the importance of the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial,1 one needs to remember that the systolic blood pressure ( BP ) target currently recommended by major guidelines for diabetic patients , that is , 130 mm Hg , except in the Appropriate Blood Pressure Control in Diabetes Study ( ABCD ) normotensive trial,7 which consisted of only a few hundred patients and had changes in creatinine clearance as the primary end point . Thus , ACCORD represents the only large-scale r and omized trial that provides information on what happens to the cardiovascular risk of diabetic patients  when SBP is reduced to 130 mm Hg as a result of r and omization to the usual ( rather than the tight ) BP control treatment strategy . Thus , the message from ACCORD to guidelines and clinical practice is that in diabetic patients it is not necessary to adopt BACKGROUND / AIM The Delay Future End Stage Nephropathy due to Diabetes study was a r and omised controlled trial of Māori and Pacific patients with advanced diabetic nephropathy , comparing a community-based model of care with usual care . The intervention group achieved lower blood pressure ( BP ) , proteinuria and less end-organ damage . After the intervention ended , all patients reverted to usual care , and were followed to review the sustainability of the intervention . METHODS A retrospective observation of 65 patients ( aged 47 - 75 years ) with type 2 diabetes , hypertension , chronic kidney disease 3/4 and proteinuria ( > 0.5 g/day ) previously r and omised to intervention/community care or usual care for 11 - 21 months . Follow up thereafter was until death , end-stage renal disease ( ESRD ) ( estimated glomerular filtration rate ( eGFR ) ≤ 10 mL/min/1.73 m(2 ) ) /dialysis or 1 February 2014 . Primary end-points were death and ESRD/dialysis . Secondary outcomes were annualised glomerular filtration rate decline , non-fatal vascular events and hospitalisations . RESULTS Median ( interquartile ranges ( IQR ) ) post-trial follow up was 49 ( 21 - 81 ) months and similar in both groups . The median ( IQR ) eGFR decline was -3.1 ( -5.5 , -2.3 ) and -5.5 ( -7.1 , -3.0 ) mL/min/year in the intervention and usual care groups respectively ( P = 0.11 ) . Similar number of deaths , renal and vascular events were observed in both groups . At the end of follow up , the number of prescribed antihypertensive medications was similar ( 3.4 ± 1.0 vs 3.3 ± 1.4 ; P = 0.78 ) . There were fewer median ( IQR ) hospital days ( 8 ( 3 , 18 ) vs 15.5 ( 6 , 49 ) days , P = 0.03 ) in the intervention group . CONCLUSIONS Short-term intensive BP control followed by usual care did not translate into reduction in long-term mortality or ESRD rates , but was associated with reduced hospitalisations Background Hypertension guidelines advise aggressive blood pressure ( BP ) lowering in patients with diabetes or high cardiovascular risk , but supporting evidence is limited . We analysed the impact of BP on cardiovascular events in well treated high-risk patients enrolled in a large clinical trial ( Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial ) . Methods Twenty-five thous and five hundred and eighty-eight patients with atherosclerotic disease or diabetes with organ damage , tolerant to angiotensin-converting enzyme inhibitors , were r and omized to ramipril , telmisartan or both . We related the primary composite outcome and its components to : baseline SBP ; SBP changes from baseline to event ; and average in-trial SBP . Results The risk of myocardial infa rct ion did not increase with baseline SBP and was unaffected by subsequent SBP change . In contrast , stroke risk progressively increased with baseline SBP ( P for trend < 0.0001 ) and decreased with reduction . In patients with  baseline SBP  less than 130 mmHg , adjusted for several covariates , cardiovascular mortality increased with further SBP reduction ( P < 0.0001 ) . A J-curve ( nadir around 130 mmHg ) occurred in the relationship between in-treatment SBP and all outcomes except stroke . Conclusion In high-risk patients , the benefits from SBP lowering below 130 mmHg are driven mostly by a reduction of stroke ; myocardial infa rct ion is unaffected and cardiovascular mortality is unchanged or increased . Future trials should be design ed to test the value of SBP lowering in high-risk patients with SBP in the range of 130–150 mmHg OBJECTIVE There is no consensus on the importance of visit-to-visit glycemic variability in diabetes . Therefore , we assessed the effects of visit-to-visit variability ( VVV ) in HbA1c and fasting glucose on major outcomes in the ADVANCE ( Action in Diabetes and Vascular Disease : Preterax and Diamicron MR Controlled Evaluation ) trial . RESEARCH DESIGN AND METHODS ADVANCE was a factorial r and omized controlled trial of intensive glucose control and blood pressure lowering in patients with type 2 diabetes . VVV in the intensive glucose treatment group was defined using the SD of five measurements of HbA1c and glucose taken 3–24 months after r and omization . Outcomes were combined macro- and microvascular events and all-cause mortality occurring post 24 months . Sensitivity analyses were performed using other indices of variability and in the st and ard glucose treatment group . RESULTS Among 4,399 patients in the intensive group , an increase in VVV of HbA1c was associated with an increased risk of vascular events ( P = 0.01 ) and with mortality ( P < 0.001 ) : highest versus lowest tenth hazard ratio ( 95 % CI ) 1.64 ( 1.05–2.55 ) and 3.31 ( 1.57–6.98 ) , respectively , after multivariable adjustment . A clear association was also observed between VVV of fasting glucose and increased risk of vascular events ( P < 0.001 ; 2.70 [ 1.65–4.42 ] ) . HbA1c variability was positively associated with the risk of macrovascular events ( P = 0.02 for trend ) , whereas glucose variability was associated with both macro- and microvascular events ( P = 0.005 and P < 0.001 for trend , respectively ) . Sensitivity analyses using other indices , and patients in the st and ard glucose treatment group , were broadly consistent with these results . CONCLUSIONS Consistency of glycemic control is important to reduce the risks of vascular events and death in type 2 diabetes Background — Increased consumption of sugar-sweetened beverages ( SSBs ) has been associated with an elevated risk of obesity , metabolic syndrome , and type II diabetes mellitus . However , the effects of SSB consumption on blood pressure ( BP ) are uncertain . The objective of this study was to determine the relationship between changes in SSB consumption and changes in  BP among adults . Methods and Results — This was a prospect i ve analysis of 810 adults who participated in the PREMIER Study ( an 18-month behavioral intervention trial ) .  BP and dietary intake  ( by two 24-hour recalls ) were measured at baseline and at 6 and 18 months . Mixed-effects models were applied to estimate the changes in BP in responding to changes in SSB consumption . At baseline , mean SSB intake was 0.9±1.0 servings per day ( 10.5±11.9 fl oz/d ) , and mean systolic BP/diastolic BP was 134.9±9.6/84.8±4.2 mm Hg . After potential confounders were controlled for , a reduction in SSB of 1 serving per day was associated with a 1.8-mm Hg ( 95 % confidence interval , 1.2 to 2.4 ) reduction in systolic BP and 1.1-mm Hg ( 95 % confidence interval , 0.7 to 1.4 ) reduction in diastolic BP over 18 months . After additional adjustment for weight change over the same period , a reduction in SSB intake was still significantly associated with reductions in systolic and diastolic BPs  ( P<0.05 ) . Reduced intake of sugars was also significantly associated with reduced BP . No association was found for diet beverage consumption or caffeine intake and BP . These findings suggest that sugars may be the nutrients that contribute to the observed association between SSB and BP . Conclusions — Reduced consumption of SSB and sugars was significantly associated with reduced BP . Reducing SSB and sugar consumption may be an important dietary strategy to lower BP . Clinical Trial Registration — URL : http:// clinical trials.gov . Unique identifier : NCT00000616 Midlife vascular risk factors influence later cognitive decline and Alzheimer 's disease ( AD ) . The decrease in serum estradiol levels during menopause has been associated with cognitive impairment and increased vascular risk , such as high blood pressure ( BP ) , which independently contributes to cognitive dysfunction and AD . We describe the extent to which vascular risk factors relate to cognition in healthy , middle-aged , recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Cognitive and Affective Study ( KEEPS-Cog ) at baseline . KEEPS-Cog is a double-blind , r and omized , placebo-controlled , parallel group , clinical trial , investigating the efficacy of low-dose , transdermal 17β-estradiol and oral conjugated equine estrogen on cognition . All results are cross-sectional and represent baseline data only . Analyses confirm that the KEEPS-Cog cohort ( n = 571 ) was middle aged ( mean 52.7 years , range 42 - 59 years ) , healthy , and free of cognitive dysfunction .  Higher systolic BP was weakly related to poorer performance in auditory working memory and attention ( p = 0.004 ; adjusted for multiple comparisons p = 0.10 ) . This relationship was not associated with endogenous hormone levels , and systolic BP was not related to any other cognitive domain . BP levels may be more sensitive than other vascular risk factors in detecting subtle differences in cognitive task performance in healthy , recently menopausal women . Lower BP early in menopause may affect cognitive domains known to be associated with AD Diuretic-based therapy is less effective in reducing the cardiac complications of hypertension than the risk of stroke and may be less effective in reducing left ventricular ( LV ) mass than is therapy with angiotensin converting enzyme ( ACE ) inhibition . In view of the strong association of LV hypertrophy with cardiovascular risk , this study was design ed to compare the impact of therapy with a diuretic and ACE inhibition on cardiac and vascular structure . Fifty essential hypertensives ( 74 % male , 88 % nonwhite ) participated in a double-blind study for 6 months and were r and omized to either ramipril or hydrochlorothiazide ( HCTZ ) . Echocardiography , carotid ultrasonography  , and  ambulatory blood pressure ( BP ) monitoring were performed at baseline and 3 and 6 months after initiation of therapy . The 22 ramipril patients were comparable to the 28 HCTZ patients at baseline in age , race , and 24-h BP . Although HCTZ result ed in a greater reduction in 24-h BP , only treatment with ramipril result ed in a decrease in LV mass ( 193 to 179 g , P < .005 , v 184 to 182 g , P = NS ) , attributable to a reduction in wall thicknesses but not in chamber diameter . In multivariate analysis , both change in BP and treatment group were independent predictors of change in LV mass . Importantly , although neither drug reduced carotid artery cross-sectional area , relative wall thickness increased due to a tendency for vessel diameter to decrease and wall thickness to increase , particularly in the diuretic group . Ramipril caused a sustained fall in plasma angiotensin II , whereas HCTZ increased angiotensin II levels . Although diuretic therapy was more effective in lowering ambulatory BP in this predominantly nonwhite population , only therapy with ACE inhibition was associated with regression of LV mass . Vascular geometry was altered consistent with the reduction in distending pressure result ing in vascular remodelling Non-insulin-dependent diabetes mellitus ( NIDDM ) and hyperhomocysteinemia are both associated with premature vascular disease . We tested the hypothesis that homocysteine is associated with vascular disease and other diabetic complications in patients with NIDDM . The current investigation is a cross-sectional analysis of baseline variables for participants in the Appropriate Blood Pressure Control in Diabetes ( ABCD ) Trial . Men and women aged 40 to 74 years with NIDDM and a mean diastolic blood pressure ( BP ) of 80 mm Hg or higher were eligible . We measured serum levels of total homocysteine ( tHcy ) , cystathionine , and methylmalonic acid ( MMA )  and correlated these values with clinical and other laboratory measures of the complications of diabetes mellitus in 452 subjects .  tHcy was higher in males than in females and correlated with the duration of hypertension and systolic BP . tHcy was significantly correlated with MMA ( r = .35 , P < .0001 ) and cystathionine ( r = .53 , P < .0001 ) levels and inversely correlated with serum B12 ( r = -.23 , P < .0001 ) and folate ( r = -.18 , P < .0001 ) . It was significantly correlated with serum creatinine ( r = .28 , P < .0001 for males and r = .39 , P < .0001 for females ) and inversely correlated with creatinine clearance ( r = -.19 , P < .005 for males and r = -.30 , P < .0001 for females ) . tHcy was not increased in subjects with cardiovascular disease or retinopathy , but it was increased in those with neuropathy ( 10.3 v 9.3 micromol/L , P < .05 ) and macroalbuminuria ( 11.0 v 9.2 micromol/L , P < .005 ) . Of these subjects , 2.2 % met the criteria for vitamin B12 deficiency and 1 % met the criteria for folate deficiency . We conclude that elevations of tHcy in this population appear to be the result of a combination of vitamin deficiency and decreased renal function and do not appear to be a predictor of cardiovascular disease AIMS The aim of this study was to investigate serious clinical outcomes associated with atrial fibrillation ( AF ) and the effects of routine blood pressure lowering on such outcomes in the presence or absence of AF , among individuals with type 2 diabetes . METHODS AND RESULTS About 11 140 patients with type 2 diabetes ( 7.6 % of whom had AF at baseline ) were r and omized to a fixed combination of perindopril and indapamide or placebo in the Action in Diabetes and Vascular Disease : preterAx and diamicroN-MR Controlled Evaluation ( ADVANCE ) study . We compared total mortality and cardiovascular disease outcomes and effects of r and omized treatment for 4.3 years on such outcomes between patients with and without AF at baseline . After multiple adjustments , AF was associated with a 61 % ( 95 % confidence interval 31 - 96 , P < 0.0001 ) greater risk of all-cause mortality and comparable higher risks of cardiovascular death , stroke , and heart failure ( all P < 0.001 ) . Routine treatment with a fixed combination of perindopril and indapamide produced similar relative , but greater absolute , risk reductions for all-cause and cardiovascular mortalities in patients with AF , compared with those without AF . The number of patients needed to be treated with perindopril-indapamide for 5 years to prevent one cardiovascular death was 42 for patients with AF and 120 for patients without AF at baseline . CONCLUSION Atrial fibrillation is relatively common in type 2 diabetes and is associated with substantially increased risks of death and cardiovascular events in patients with type 2 diabetes . This arrhythmia identifies individuals who are likely to obtain greater absolute benefits from blood pressure-lowering treatment . Atrial fibrillation in diabetic patients should be regarded as a marker of particularly adverse outcome and prompt aggressive management of all risk factors
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 .