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Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy: a randomized double-blind crossover trial. Effects of dual blockade of renin-angiotensin system in type 2 diabetes mellitus patients with diabetic nephropathy. Beneficial impact of spironolactone in diabetic nephropathy. Antiproteinuric effects of combined antihypertensive therapies in patients with overt type 2 diabetic nephropathy. Combination of half doses of angiotensin type 1 receptor antagonist and angiotensin-converting enzyme inhibitor in diabetic nephropathy. Renoprotective Effect of the Addition of Losartan to Ongoing Treatment with an Angiotensin Converting Enzyme Inhibitor in Type-2 Diabetic Patients with Nephropathy Blockade of the renin-angiotensin system increases graft survival in patients with chronic allograft nephropathy. 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Impact of Empagliflozin on Blood Pressure in Patients With Type 2 Diabetes Mellitus and Hypertension by Background Antihypertensive Medication Genome-wide response to antihypertensive medication using home blood pressure measurements: a pilot study nested within the HOMED-BP study. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Int Differential effects of beta-blockers on albuminuria in patients with type 2 diabetes. Vitamin D receptor activation with calcitriol for reducing urinary angiotensinogen in patients with type 2 diabetic chronic kidney disease Baseline characteristics of participants in the Appropriate Blood Pressure Control in Diabetes trial. Choices, persistence and adherence to antihypertensive agents: evidence from RAMQ data. 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Effects of the angiotensin II type 1 receptor antagonist candesartan, compared with angiotensin-converting enzyme inhibitors, on the urinary excretion of albumin and type IV collagen in patients with diabetic nephropathy Angiotensin II Type 1 Receptor Blockers Reduce Urinary Oxidative Stress Markers in Hypertensive Diabetic Nephropathy Effects of dual blockade of the renin–angiotensin system on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy and hypertension in the ORIENT: a post-hoc analysis (ORIENT–Hypertension) Effects of antihypertensive agents, alpha receptor blockers, beta blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and calcium channel blockers, on oxidative stress Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/beta-blocker-based treatment regimen: a subanalysis of the Captopril Prevention Project. 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Renin status does not predict the anti-hypertensive response to angiotensin-converting enzyme inhibition in African–Americans Dual blockade of the renin-angiotensin-aldosterone system is safe and effective in reducing albuminuria in Asian type 2 diabetic patients with nephropathy. Arterial Stiffness and Pharmacological Interventions – The TRanscend Arterial stiffNess Substudy (TRANS study)
BACKGROUND Dual renin-angiotensin system ( RAS ) blockade , mostly by combining an angiotensin converting enzyme ( ACE ) inhibitor with an angiotensin receptor blocker ( ARB ) , is increasingly used in patients with hypertension and diabetes and /or proteinuria and in those with resistant heart failure . However , in the zest of achieving greater nephroprotection and cardioprotection , even patients with uncomplicated essential hypertension are not uncommonly treated with dual RAS blockade . EVIDENCE In 2003 the COOPERATE trial , seemed to confirm that dual RAS blockade was beneficial and that proteinuria reduction was synonymous with nephroprotection . This study had to be withdrawn recently attesting to the suspicion that the data looked to good to be true . Moreover , the large prospect i ve ONTARGET data argue against a nephroprotective effect of dual RAS blockade and together with renal findings from ACCOMPLISH , cast doubt on albuminuria/proteinuria being a reliable surrogate endpoint for renal outcome . Although in heart failure , dual RAS blockade had some benefit without reducing mortality , there remains a distinct safety issue with regard to hyperkalemia and elevated creatinine . Neither in ischaemic heart disease nor in left ventricular hypertrophy had dual RAS blockade any benefits when compared with single RAS blockade . Of note , the combination of an ACE inhibitor with an ARB was recently shown to reduce the risk of dementia . All dual RAS blockade may be created equal and the combination of valsartan with aliskiren , a direct renin inhibitor will be evaluated in diabetic patients in the prospect i ve , r and omized ALTITUDE study . CONCLUSIONS For the time being , given the adverse effects and lack of consistent survival benefits , the use of dual RAS blockade should be avoided unless ironclad data emerge to the contrary Background : Ultrasonographic evidence of increased carotid intima-media thickness ( IMT ) is known to be associated with generalized atherosclerosis . Therapeutic blockade of the renin-angiotensin system ( RAS ) with angiotensin-converting enzyme ( ACE ) inhibitors reportedly reduces carotid IMT in humans . However , there has been no head-to-head comparison of the effects of ACE inhibitor and angiotensin receptor blocker ( ARB ) , a newer type of RAS inhibitor , on carotid IMT . Methods : 57 hypertensive patients were r and omly assigned to treatment with one of two antihypertensive drugs : ACE inhibitor ( quinapril ; n = 25 , group Q ) or ARB ( losartan ; n = 18 , group L ) . Results : After 1 year of treatment , a similar decrease in mean blood pressure was observed in all groups . Carotid IMT was decreased significantly in group Q ( 10 % decrease , p < 0.05 ) but did not change in group L. There were no significant changes in other atherosclerotic factors between these two groups . Conclusion : Our findings suggest that the antiatherosclerotic effect of quinapril is more potent than that of losartan in hypertensive patients . This effect appears unrelated to the drug ’s antihypertensive action or to traditional atherosclerotic factors The renin-angiotensin-aldosterone system ( RAAS ) is an established mediator of progressive renal and cardiovascular disease . Angiotensin II plays a key role in the progression of cardiovascular and renal disease , and drugs that interfere with angiotensin II actions such as angiotensin-converting enzyme inhibitors ( ACEIs ) and angiotensin receptor blockers ( ARBs ) can offer cardiovascular and renal protection beyond their effects on blood pressure . 1–6 Recently , a number of experimental and clinical investigations have implicated aldosterone , independent of angiotensin II , in the pathogenesis of progressive  cardiovascular and renal disease . 7–9 These studies have generated intense interest in aldosterone receptor antagonism , either alone or in combination with an ACEI or an ARB , in the treatment of a wide range of cardiovascular diseases as well as progressive renal injury . Blockade of the renin-angiotensin system ( RAS ) with either an ACEI or an ARB is important in patients with hypertension , heart failure , myocardial infa rct ion , stroke , and various forms of nephropathy , the most common of which is due to diabetes mellitus . Support for RAS blockade derives from large r and omized , controlled , clinical trials demonstrating that these agents attenuate progression of renal disease . 1–6 Lowering blood BACKGROUND Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients . We tested whether dual blockade of the renin-angiotensin system ( RAS ) with both an angiotensin-converting enzyme ( ACE ) inhibitor and an angiotensin II receptor blocker ( ARB ) is superior to maximal recommended dose of ACE inhibitor in type 1 diabetic patients with diabetic nephropathy ( DN ) . METHODS We performed a r and omized , double-blind , crossover trial with 8 weeks treatment with placebo and irbesartan 300 mg ( once daily ) , added on top of enalapril 40 mg ( once daily ) . We included 24 type 1 patients with DN . At the end of each treatment period , albuminuria , 24-hour blood pressure , and glomerular filtration rate ( GFR ) were measured . RESULTS Values on ACE inhibitors + placebo were : albuminuria [ mean ( 95 % CI ) ] , 519 ( 342 to 789 ) mg/24 hours ; blood pressure [ mean ( SEM ) ] , 131 (3)/74 ( 1 ) mm Hg , and GFR [ mean ( SEM ) ] , 65 ( 5 ) mL/min/1.73 m2 . Dual blockade of the RAS induced a reduction in albuminuria [ mean ( 95 % CI ) ] of 25 % ( 15 , 34 ) ( P < 0.001 ) , a reduction in systolic blood pressure of 8 mm Hg ( 4 , 12 ) ( P = 0.002 ) , and a reduction of 4 mm Hg ( 2 , 7 ) ( P = 0.003 ) in diastolic blood pressure . GFR and plasma potassium remained unchanged during both treatment regimes . Dual blockade was safe and well tolerated . CONCLUSION Dual blockade of the RAS is superior to maximal recommended dose of ACE inhibitors with regard to lowering of albuminuria and blood pressure in type 1 patients with DN . Long-term trials are needed to further establish the role of dual blockade of the RAS in renal and cardiovascular protection Microalbuminuria is a strong , consistent and independent risk factor for cardiovascular and renal disease in patients with diabetes and /or hypertension and in the general population . Several r and omized trials have shown the efficacy of inhibiting the renin-angiotensin system ( RAS ) with angiotensin-converting enzyme inhibitors ( ACEIs ) and angiotensin II receptor blockers ( ARBs ) to prevent cardiovascular events and the progression of kidney disease . These 2 classes of drugs are equally effective for renal outcomes in patients with diabetic nephropathy , but only ACEIs have been found to significantly impact the risk of all-cause mortality , predominantly cardiovascular , in patients with diabetic nephropathy . Studies on the cardiorenal efficacy of combined therapy with ACEIs and ARBs in individuals with microalbuminuria or macroalbuminuria and other cardiovascular risk factors have been inconclusive . The Long-term Impact of RAS Inhibition on Cardiorenal Outcomes ( LIRICO ) study aims to address existing questions in this setting . This is a phase III , r and omized , comparative , pragmatic trial with prospect i ve r and omized open blinded endpoint ( PROBE ) design . It will evaluate the comparative efficacy of combined therapy with ACEIs and ARBs versus monotherapy with either ACEIs or ARBs in improving cardiovascular and renal outcomes in microalbuminuric or macroalbuminuric individuals at cardiorenal risk . The study will enroll 2,100 patients , selected in a network of internal medicine , diabetology or nephrology outpatient clinics . Patients will be r and omly allocated to ACEIs , ARBs or their combination . The study has been approved and funded by the Agenzia Italiana del Farmaco ( A.I.F.A. ) within the 2005 funding plan for independent research on drugs Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients . This study tested whether dual blockade of the renin-angiotensin system ( RAS ) with both an angiotensin-converting enzyme ( ACE ) inhibitor ( ACE-I ) and an Angiotensin-II receptor blocker ( ARB ) is superior to either drug alone in type I diabetic patients with diabetic nephropathy ( DN ) . A r and omized double-blind crossover trial was performed with 8-wk treatment with placebo , 20 mg of benazepril once daily , 80 mg of valsartan once daily , and the combination of 20 mg of benazepril and 80 mg of valsartan .  Twenty type I diabetic patients with DN were included . At the end of each treatment period , albuminuria , 24-h BP , and GFR were measured . Eighteen patients completed the study .  Placebo values were : albuminuria [ mean ( 95 % CI ) ] , 701 ( 490 to 1002 ) mg/24 h ; BP [ mean ( SEM ) ] , 144 (4)/79 ( 2 ) mmHg , and GFR [ mean ( SEM ) ] , 82 ( 7 ) ml/min per 1.73 m(2 ) . Treatment with benazepril , valsartan , or dual blockade significantly reduced albuminuria and BP compared with placebo . Benazepril and valsartan were equally effective . Dual blockade induced an additional reduction in albuminuria of 43 % ( 29 to 54 % ) compared with any type of monotherapy , and a reduction in systolic BP of 6 ( 0 to 13 ) mmHg and 7 ( 1 to 14 ) mmHg ( versus benazepril and valsartan , respectively ) and a reduction of 7 ( 4 to 10 ) mmHg diastolic compared with both monotherapies . GFR was reversibly reduced on dual blockade compared with monotherapy and placebo . All treatments were safe and well tolerated . In conclusion , dual blockade of the RAS may offer additional renal and cardiovascular protection in type I diabetic patients with DN OUTCOMES Extensive data from r and omised controlled trials have shown the benefit of treating hypertension . The target blood pressure ( BP ) for antihypertensive management is systolic < 140 mmHg and diastolic < 90 mmHg with minimal or no drug side-effects ; however , stricter BP control is required for patients with end-organ damage , co-existing risk factors and co-morbidity , e.g. diabetes mellitus . The reduction of BP in the elderly and in those with severe hypertension should be achieved gradually over 1 month . Co-existent risk factors should also be controlled . BENEFITS Benefits of management include reduced risks of stroke , cardiac failure , chronic kidney disease and coronary heart disease . RECOMMENDATIONS The correct BP measurement procedure is described , and evaluation of cardiovascular risk factors and recommendations for antihypertensive therapy are stipulated . The total cardiovascular disease risk profile should be determined for all patients to inform management strategies . Lifestyle modification and patient education are cornerstones in the management of every patient . Major indications , pre caution s and contra-indications to each recommended antihypertensive drug are listed . Combination therapy should be considered ab initio if the BP is ≥ 20/10 mmHg . First-line drug therapy for uncomplicated hypertension includes low-dose thiazide-like diuretics , calcium channel blockers ( CCBs ) or angiotensin-converting enzyme inhibitors ( ACE-Is ) ( or ARBs - angiotensin II receptor blockers ) . If the target BP is not obtained , a second antihypertensive should be added from the aforementioned list . If the target BP is still not met , the third remaining antihypertensive agent should be used . In black patients  either thiazide-like diuretics or CCBs can be used initially , because response rates are better than with ACE-Is or β-blockers . In treating resistant hypertension , a central ly acting drug , vasodilator , α-blocker , spironolactone or β-locker should be added . This guideline includes management of specific situations , i.e. hypertensive emergency and urgency , severe hypertension with target organ damage , hypertension in diabetes mellitus , resistant hypertension , fixed drug combinations , new trials in hypertension , and interactions of antihypertensive agents with other drugs . VALIDITY The guideline was developed by the Southern African Hypertension Society Background The benefits of treating hypertension in elderly diabetic patients , in terms of achieving reductions in cardiovascular morbidity and mortality , have been documented in several recent prospect i ve trials . There has , however , been some controversy regarding the effect of different antihypertensive drugs on the frequency of myocardial infa rct ion in this group of patients . Design STOP Hypertension-2 was a prospect i ve , r and omized , open trial with blinded endpoint evaluation . Methods We studied 6614 elderly patients aged 70–84 years ; 719 of them had diabetes mellitus at the start of the study ( mean age 75.8 years ) . Patients were r and omly assigned to one of three treatment strategies : conventional antihypertensive drugs ( diuretics or β-blockers ) , calcium antagonists , or angiotensin converting enzyme ( ACE ) inhibitors . Results Reduction in blood pressure was similar in the three treatment groups of diabetics . The prevention of cardiovascular mortality was also similar ; the frequency of this primary endpoint did not differ significantly between the three groups . There were , however , significantly fewer ( P = 0.025 ) myocardial infa rct ions during ACE inhibitor treatment ( n = 17 ) than during calcium antagonist treatment ( n = 32 ; relative risk 0.51 , 95 % confidence interval 0.28–0.92 ) ; but a ( non-significant ) tendency to more strokes during ACE inhibitor treatment ( n = 34 compared with n = 29 ; relative risk 1.16 , 95 % confidence interval 0.71–1.91 ) . Conclusion Treatment of hypertensive diabetic patients with conventional antihypertensive drugs ( diuretics , β-blockers , or both ) seemed to be as effective as treatment with newer drugs such as calcium antagonists or ACE inhibitors Introduction Antihypertensive treatment of patients with clinical manifestations of diabetic nephropathy , and especially , renin-angiotensin system ( RAS ) inhibition , slows , but may not fully arrest progression towards end-stage renal disease . Studies using ` hard ' endpoints such as doubling of serum creatinine , dialysis , or death that are initiated before emergence of any renal functional abnormalities in diabetes , would be of impractical length and size . We therefore undertook a primary prevention study ( The Renin-Angiotensin System Study or RASS ) to determine if inhibition of the RAS could slow the development of a key diabetic glomerulopathy structural endpoint , increase in mesangial fractional volume ( Vv[Mes/glom ] ) . Methods This is a parallel group , double-blind , placebo-controlled trial with 285 patients with Type 1 diabetes mellitus ( 95 per group ) r and omised to receive the angiotensin-converting enzyme inhibitor , enalapril , the angiotensin II receptor blocker , losartan , or placebo .  All patients are normotensive , normoalbuminuric and have normal or increased glomerular filtration rates at study entry . The study is based on primary endpoint of change in Vv(Mes/glom ) from baseline to the five-year renal biopsy , with baseline and interval measures of albumin excretion rate , glomerular filtration rate , blood pressure , and glycaemia . Baseline , mid-point , and five-year retinal fundus photography are also performed . Results One thous and and sixty-five patients were interviewed , 707 refused participation and 73 were excluded . The target of 285 subjects were r and omised and their clinical and demographic characteristics are described . Biopsy complications occurred in 17 ( 6 % ) , only one of which required hospitalisation . There were no permanent biopsy-related sequelae . Conclusions Renal structural variables are reasonable surrogate endpoints for studies of progression of early diabetic nephropathy . Although requiring substantial recruitment effort , diabetic nephropathy primary prevention trials based on change in renal structure are feasible Background : The renin – angiotensin system ( RAS ) is thought to have a role in carcinogenesis , and RAS inhibition may prevent tumour growth . Methods : We retrospectively investigated the impact of angiotensin I-converting enzyme inhibitors ( ACEIs ) and angiotensin II type-1 receptor blockers ( ARBs ) in 155 patients with pancreatic cancer receiving gemcitabine monotherapy .  Patients were divided into three groups : the ACEI/ARB group ( 27 patients receiving an ACEI or ARB for hypertension ( HT ) ) , the non-ACEI/ARB with HT group ( 25 patients receiving antihypertensive drugs other than ACEIs or ARBs ) , and the non-HT group ( 103 patients receiving no antihypertensive drugs ) . Results : Patient characteristics were not different , except for age and HT medications . Progression-free survival ( PFS ) was 8.7 months in the ACEI/ARB group , 4.5 months in the non-ACEI/ARB with HT group , and 3.6 months in the non-HT group . Overall survival ( OS ) was 15.1 months in the ACEI/ARB group , 8.9 months in the non-ACEI/ARB with HT group , and 9.5 months in the non-HT group . The use of ACEIs/ARBs was a significant prognostic factor for both PFS ( P=0.032 ) and OS ( P=0.014 ) in the multivariate analysis . Conclusions : The ACEIs/ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer . Prospect i ve trials are needed to test this hypothesis Persistence on treatment affects the efficacy of antihypertensive treatment . We prospect ively investigated the persistence on therapy and the extent of  blood pressure ( BP ) control  in 347 hypertensive patients ( age 59.4 ± 6 years ) r and omly allocated to a first-line treatment with : angiotensin-converting enzyme ( ACE ) inhibitors , calcium-channel blockers ( CCBs ) , ß-blockers , angiotensin-II receptor blockers ( ARBs ) , or diuretics and followed-up for 24-months . Persistence on treatment was higher in patients treated with ARBs ( 68.5 % ) and ACE inhibitors ( 64.5 % ) vs CCBs ( 51.6 % ; p < 0.05 ) , β-blockers ( 44.8 % , p < 0.05 ) , and diuretics ( 34.4 % , p < 0.01 ) . No ARB , ACE inhibitor , β-blocker , or diuretic was associated with a higher persistence in therapy compared with the other molecules used in each therapeutic class . The rate of persistence was significantly higher in patients treated with lercanidipine vs others CCBs ( 59.3 % vs 46.6 % , p < 0.05 ) . Systolic and diastolic BP was decreased more successfully in patients treated with ARBs ( −11.2/−5.8 mmHg ) , ACE inhibitors ( −10.5/−5.1 mmHg ) , and CCBs ( −8.5/−4.6 mmHg ) compared with ß-blockers ( −4.0/−2.3 mmHg p < 0.05 ) and diuretics ( −2.3/−2.1 mmHg , p < 0.05 ) . No ARB , ACE inhibitor , β-blocker , or diuretic was associated with a higher BP control compared with the other molecules used in each therapeutic class . A trend toward a better BP control was observed in response to lercanidipine vs other CCBs ( p = 0.059 ) . The present results confirm the importance of persistence on treatment for the management of hypertension in clinical practice OBJECTIVES Despite a broad and efficient pharmacological antihypertensive armamentarium , blood pressure ( BP ) control is suboptimal and heterogeneous throughout Europe . Recent representative data from Switzerl and are limited . The goal of the present survey was therefore to assess the actual control rate of high BP in Switzerl and in accordance with current guidelines . The influence of risk factors , target organ damage and medication on BP levels and control was also evaluated . METHODS A cross-sectional visit-based survey of ambulatory hypertensive patients was performed in 2009 in Switzerl and . 281 r and omly selected physicians provided data on 5 consecutive hypertensive patients attending their practice s for BP follow-up . Data were anonymously collected on demographics , comorbidities and current medication , and BP was recorded . Subsequent modification of pharmacological antihypertensive therapy was assessed . RESULTS Data from 1376 patients were available . Mean age was 65 ± 12 years , 53.9 % were male subjects . 26.4 % had complicated hypertension . Overall , BP control ( < 140/90 mm Hg for uncomplicated and < 130/80 mm Hg for complicated hypertension ) was achieved in 48.9 % . Compared to patients with complicated hypertension , BP control was better in patients with uncomplicated hypertension ( 59.4 % vs. 19.2 % , p < 0.001 ) . As a monotherapy the most prescribed drug class were angiotensin receptor blockers ( ARB , 41 % ) , followed by angiotensin converting enzyme ( ACE ) inhibitors ( 21.5 % ) , betablockers ( 20.8 % ) and calcium channel blockers ( CCB , 10.8 % ) . The most prescribed drug combinations were ARB + diuretic ( 30.1 % ) and ACE inhibitors + diuretic ( 15.3 % ) . 46 % were receiving a fixed drug combination . In only 32.7 % of patients with uncontrolled hypertension was a change in drug therapy made . CONCLUSION This representative survey on treated adult hypertensive patients shows that , compared to earlier reports , the control rate of hypertension has improved in Switzerl and for uncomplicated but not for complicated , particularly diabetes-associated hypertension . ARBs and ACE inhibitors are the most prescribed antihypertensive drugs for monotherapy , whereas diuretics and ARBs were the most used for combination therapy Left ventricular hypertrophy ( LVH ) is frequently found at the initiation of dialysis therapy of diabetic and hypertensive patients , and is highly predictive of future cardiac morbidity and mortality . In patients with hypertension and LVH , both an angiotensin converting enzyme ( ACE ) inhibitor and an angiotensin type 1 receptor ( AT1 ) antagonist regress LVH . However , it remains controversial whether dual blockade of the renin-angiotensin system will regress LVH in these patients using a combination of ACE inhibitor and AT1 antagonist . Thirty-three type II diabetic patients with end-stage renal disease who had just entered into hemodialysis therapy and were diagnosed as having LVH evaluated by echocardiography were selected from three dialysis units staffed by the faculty of Saitama Medical School , Saitama , Japan between 1999 and 2001 . The study was carried out for 1 year . All patients were assigned r and omly to three groups with equal number : group I , an ACE inhibitor , enalapril 10 mg daily ; group II , an AT1 antagonist , losartan 100 mg daily ; group III , combination of enalapril 10 mg and losartan 100 mg daily . All antihypertensive drugs were given 30 min after the cessation of dialysis therapy .  LVH was evaluated by echocardiography before the start of administration of drugs , at 6 months and 12 months after the start of drug therapy . Systolic blood pressure levels less than 140 mmHg were the target for the three groups . Using repeated measures analysis of variance , applied to those with four echocardiograms , there were progressive decreases over time in left ventricular mass index , posterior wall thickness and interventricular septum thickness . There were no significant differences in regression of LVH as well as blood pressure control between enalapril and losartan groups ; however , dual blockade induced an additional 28 % reduction in left ventricular mass index compared with any type of monotherapy . Both ACE inhibitors and AT1 antagonists benefit the regression of LVH in diabetic patients who start dialysis therapy . Moreover , combination therapy with ACE inhibitors and AT1 antagonists would provide more beneficial effects on LVH in these patients than monotherapy While the safety of renin-angiotensin system (RAS)-blocking drugs such as angiotensin-converting enzyme ( ACE ) inhibitors and angiotensin receptor blockers is well known , less is known about the new direct renin inhibitor aliskiren . The authors pooled data from 12 r and omized controlled trials of aliskiren in patients with hypertension and analyzed the incidence and types of adverse events ( AEs ) and laboratory abnormalities . Studies were characterized as short-term ( ≤2 months ) placebo-controlled or long-term ( > 2 months ) active-controlled . Relative risks for AEs of particular interest for RAS blockers were calculated . In short-term studies , AEs occurred in similar proportions of aliskiren 150 mg and 300 mg ( 33.6 % and 31.6 % , respectively ) and placebo treatment groups ( 36.8 % ) . In long-term studies , a lower proportion of patients treated with aliskiren 150 mg and 300 mg had AEs ( 33.7 % and 43.2 % , respectively ) than those treated with ACE inhibitors ( 60.1 % ) , angiotensin receptor blockers ( 53.9 % ) , and thiazide diuretics ( 48.9 % ) . Events of special interest , including angioedema , hyperkalemia , and diarrhea occurred in similar proportions of patients taking aliskiren , placebo , and comparator agents . In studies of up to 36 weeks , patients treated with aliskiren were significantly less likely to develop cough than those treated with ACE inhibitors . At the registered doses of 150 mg and 300 mg daily , aliskiren  has safety and tolerability profiles  similar to placebo , other RAS blockers , and diuretics . Cough rates are lower with aliskiren compared with ACE inhibitors OBJECTIVE We evaluated the renoprotective effects as reflected by short-term changes in albuminuria of dual blockade of the renin-angiotensin system ( RAS ) by adding an angiotensin II receptor blocker ( ARB ) to treatment with maximal recommended doses of an ACE inhibitor ( ACEI ) in patients with type 2 diabetes and nephropathy . RESEARCH DESIGN AND METHODS A total of 20 patients ( 17 men and 3 women ) with type 2 diabetes along with hypertension and nephropathy were enrolled in this double-blind , r and omized , two-period , crossover trial of 8 weeks of treatment with the ARB c and esartan 16 mg daily and placebo added in r and om order to existing treatment with lisinopril/enalapril 40 mg daily or captopril 150 mg daily . At the end of each treatment period , we evaluated albuminuria in three 24-h urinary collection s by turbidimetry , 24-h ambulatory blood pressure ( ABP ) using the Takeda-TM2420 , and glomerular filtration rate ( GFR ) by the (51)Cr-EDTA plasma-clearance technique . RESULTS During monoblockade of the RAS by ACEI treatment , albuminuria was 706 ( 349 - 1,219 ) mg/24 h [ geometric mean ( IQR ) ] ; 24-h ABP was 138 + /- 3/72 + /- 2 mmHg ( mean + /- SE ) ; and GFR was 77 + /- 6 ml x min(-1 ) x 1.73 m(-2 ) ( mean + /- SE ) . During dual blockade of the RAS by addition of c and esartan 16 mg daily , there was a mean ( 95 % CI ) reduction in albuminuria of 28 ( 17 - 38 ) compared with ACEI alone ( P < 0.001 ) . There was a modest reduction in systolic/diastolic 24-h ABP of 3/2 mmHg ( -2 to 8 systolic , -2 to 5 diastolic ; NS ) . Changes in albuminuria did not correlate to changes in ABP . Addition of c and esartan 16 mg daily induced a small , insignificant decrease in GFR of 4 ( -1 to 9 ) ml x min(-1 ) x 1.73 m(-2 ) . CONCLUSIONS Dual blockade of the RAS provides superior short-term renoprotection independent of systemic blood pressure changes in comparison with maximally recommended doses of ACEI in patients with type 2 diabetes as well as nephropathy BACKGROUND Angiotensin-converting enzyme ( ACE ) inhibitors or angiotensin II receptor blockers ( ARB ) have been shown to delay the progression to proteinuria and kidney failure in hypertensive type 2 diabetic patients with diabetic nephropathy . Further synergistic effect may be obtained by combined therapy with both ARB and ACE inhibitors . OBJECTIVE To evaluate the effect of dual blockage of the renin-angiotensin system by adding maximal recommended dose of ARB with maximal recommended dose of ACE inhibitors in type 2 diabetic patients with diabetic nephropathy . MATERIAL AND METHOD Type 2 diabetic patients with urine protein/creatinine ( UPCr ) > 0.5 gm/gm and hypertension who received maximal recommended dose of ACE inhibitors ( Enalapril 40 mg/day ) over three months were r and omized to two groups .  ARB group received adding maximal recommended dose of ARB ( Telmisartan 80 mg/day ) and control group received previous ACE inhibitors only for 24 weeks . RESULTS Eighty patients were enrolled . ARB group led to significantly reduced UPCr from baseline at week 8 , 12 , and 24 ( 2.65 + /- 1.81 , 2.24 + /- 1.85 , 2.24 + /- 1.88 and 1.98 + /- 1.73 gm/gm respectively , p < 0.05 ) but UPCr in the control group was unchanged ( 1.97 + /- 1.56 , 1.85 + /- 1.27 , 1.97 + /- 1.11 and 1.96 + /- 1.42 gm/gm respectively , p > 0.05 ) . ARB group induced an additional reduction in proteinuria of 29.25 % ( 95 % CI 9.68 - 48.82 ) compared with control group . By the end of the present study , glomerular filtration rate had fallen from 41.76 + /- 12.16 to 37.84 + /- 13.59 ml/min/1.73 m2 in ARB group and 50.89 + /- 29.43 to 49.41 + /- 29.85 ml/min/1.73 m2 in control group ( p > 0.05 ) . Serum potassium had changed from 4.51 + /- 0.48 to 4.58 + /- 0.13 mEq/L in ARB group and 4.60 + /- 0.58 to 4.40 + /- 0.13 mEq/L in the control group ( p > 0.05 ) . No other serious adverse effects were reported during treatment . CONCLUSION Adding maximal recommended dose of ARB with maximal recommended dose of ACE inhibitors in type 2 diabetic patients can reduce proteinuria more than ACE inhibitors alone . This treatment is safe and well tolerated BACKGROUND Aldosterone has been suggested to play a role in the initiation and progression of diabetic nephropathy . Currently recommended treatment with angiotensin-converting enzyme ( ACE ) inhibitors or angiotensin II receptor blockers [ renin-angiotensin system ( RAS ) blockade ] does not suppress circulating aldosterone sufficiently . We therefore aim ed to evaluate the short-term effect of aldosterone antagonism with spironolactone on albuminuria and blood pressure in diabetic nephropathy . METHODS Twenty Caucasian type 1 diabetic patients with persistent macroalbuminuria despite antihypertensive treatment , including RAS blockade , completed this double-masked , r and omized cross-over trial . Patients were treated in r and om order with spironolactone 25 mg once daily and matched placebo for two months , respectively , on top of usual antihypertensive treatment . After each treatment period albuminuria , 24-hour blood pressure , and glomerular filtration rate ( GFR ) were determined . RESULTS Spironolactone on top of usual antihypertensive treatment induced a 30 % ( 95 % CI 17 to 41 ) reduction in albuminuria from [ geometric mean ( 95 % CI ) ] 831 ( 624 to 1106 ) mg/24-hour on placebo treatment ( P < 0.001 ) , and a reduction in fractional albumin clearance of 35 % ( 20 to 46 , P < 0.001 ) . Twenty-four-hour blood pressure showed an insignificant reduction of [ mean reduction ( 95 % CI ) ] 8 ( -1 to 17)/3 ( -0.2 to 7 ) mm Hg ( P < 0.10 ) . There was an insignificant reversible reduction in GFR during treatment with spironolactone . On spironolactone treatment , one patient was excluded due to  hyperkalemia  ( plasma potassium 5.7 mmol/L ) and one due to orthostatic dizziness . Otherwise treatment was well tolerated . CONCLUSION Our results suggest that spironolactone treatment on top of recommended antihypertensive treatment reduces blood pressure and may offer additional renoprotection in type 1 diabetic patients with diabetic nephropathy Combined antihypertensive therapy plays a crucial role in achieving targeted blood pressure reductions and renoprotection . We therefore compared the antihypertensive and antiproteinuric effects of combined therapy with either a calcium channel blocker ( CCB ) plus an angiotensin II receptor blocker ( ARB ) or an angiotensin converting enzyme inhibitor ( ACE-I ) plus an ARB in patients with type 2 diabetes mellitus complicated by overt nephropathy and mild to moderate hypertension . After a 12-week dietary control period , diabetic patients with mildly to moderately impaired renal function were r and omly assigned to either a CCB ( amlodipine 5 mg once daily ) or an ACE-I ( temocapril 2 mg once daily ) for 12 weeks ( monotherapy period ) . Both groups then received add-on therapy with an ARB ( c and esartan 4 mg once daily ) for an additional 12 weeks . During the monotherapy period , blood pressure was decreased equally well in both groups . Daily urinary protein excretion remained unchanged in the CCB-treated group ( control period , 4.0 + /- 1.8 g/day vs. CCB period , 4.1 + /- 1.9 g/day ; ns ; n = 8) , but decreased in the ACE-I-treated group ( control period , 4.3 + /- 1.8 g/day vs. ACE-I period , 3.5 + /- 1.7 g/day ; p < 0.05 ; n = 9 ) . After the combined therapy period , blood pressure was decreased to the same degree in both groups . Although ARB plus CCB significantly reduced urinary protein excretion ( to 3.5 + /- 1.5 g/day ; p < 0.05 vs. control period ; n = 8) , a more profound reduction was achieved with ARB plus ACE-I ( to 2.6 + /- 1.3 g/day ; p < 0.01 vs. control period ; n = 9 ) . Monotherapy with the ACE-I increased the serum potassium concentration , and this elevation was sustained after addition of the ARB . In contrast , the serum potassium concentration was not influenced by monotherapy with the CCB , but was significantly increased after addition of the ARB . A decreased hematocrit was observed in the ARB plus ACE-I group . The present study suggests that combined antihypertensive therapy with either a CCB plus an ARB or an ACE-I plus an ARB exerts an antiproteinuric effect in patients with type 2 diabetic nephropathy with mildly impaired renal function . Although the latter combination had a more profound effect , it was associated with an increased serum potassium concentration and worsening of renal anemia . Thus , the combination of a CCB and an ARB should be the first line antihypertensive therapy in those with overt diabetic nephropathy . The long-term efficacy of these combined antihypertensive therapies will need to be further addressed in a future study BACKGROUND To investigate the renoprotective effect of combination therapy with an angiotensin I converting enzyme inhibitor and an angiotensin type I receptor blocker ( ARB ) on diabetic kidney disease , half doses of each monotherapy were given to type 2 diabetic patients with albuminuria . METHODS Urinary albumin index ( UAI ) and blood pressure ( BP ) were measured in a total of 27 out patients with type 2 diabetes mellitus receiving 10 mg imidapril or 8 mg c and esartan per day . Either agent was then substituted with a combination of 5 mg imidapril and 4 mg c and esartan . After 3 months of combination therapy , UAI and BP were measured . Changes in the parameters were assessed by paired t test . RESULTS Although BP was not significantly different prior to and at the end of combination therapy , log-transformed UAI was significantly reduced ( P = 0.003 ) from an initial UAI ( mean log-transformed UAI + /- SD ) of 79.4 (27.4 - 231)mg/g Cre to 52.5 (17.1 - 161)mg/g Cre at the end of combination therapy . The reduction was not associated with the initial UAI , initial BP , decrease in BP , pretreatment medication or other concomitant antihypertensive agents . CONCLUSIONS In patients with type 2 diabetes and nephropathy , dual blockade of the renin system with an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker significantly reduces albuminuria and , thus , may be renoprotective even when the doses of the agents are reduced by one half Angiotensin converting enzyme inhibitors ( ACE-Is ) and angiotensin II receptor blockers ( ARBs ) are frequently used for the treatment for glomerulonephritis and diabetic nephropathy because of their albuminuria- or proteinuria-reducing effects . To many patients who are nonresponsive to monotherapy with these agents , combination therapy appears to be a good treatment option . In the present study , we examined the effects of the addition of an ARB ( losartan ) followed by titration upon addition and at 3 and 6 months ( n=14 ) and the addition of an ACE-I followed by titration upon addition and at 3 and 6 months ( n=20 ) to the drug regimen treatment protocol in type 2 diabetic patients with nephropathy for whom more than 3-month administration of an ACE-I or the combination of an ACE-I plus a conventional antihypertensive was ineffective to achieve a blood pressure ( BP ) of 130/80 mmHg and to reduce urinary albumin to < 30 mg/day . During the 12-month treatment , addition of losartan or addition of an ACE-I to the treatment protocol reduced systolic blood pressure ( SBP ) by 10 % and 12 % , diastolic blood pressure ( DBP ) by 7 % and 4 % , and urinary albumin excretion by 38 % and 20 % of the baseline value , respectively . However , the effects on both BP and urinary albumin were not significantly different between the two therapies . In conclusion , addition of losartan or an ACE-I to an ongoing treatment with an ACE-I , or addition of an ACE-I to ongoing treatment with a conventional antihypertensive were equally effective at reducing the urinary albumin excretion and BP , and provided renal protection in patients with type-2 diabetic nephropathy BACKGROUND Chronic allograft nephropathy ( CAN ) is the leading cause of late allograft failure , with only limited treatment options . Blockade of the renin-angiotensin system ( RAS ) decreases progression in diabetic and non-diabetic renal disease , but the effect on CAN is as yet unclear . Therefore , we have studied retrospectively the effect of RAS blockade on renal survival in patients with biopsy-proven CAN . METHODS The medical records of 72 patients with biopsy-proven CAN were evaluated with regard to time course of graft function , proteinuria , blood pressure , and antihypertensive and immunosuppressive treatment . Cox 's proportional hazards model was used for analysing renal graft survival after the index biopsy . RESULTS On univariate analysis , histological determinants influencing renal survival were the chronic interstitial and chronic tubular score , and clinical parameters were the serum creatinine level at the time of the biopsy , the relative change in serum creatinine level between 12 months post-transplantation and at the time of the biopsy , mean systolic and diastolic blood pressure after the biopsy , and RAS blockade by angiotensin-converting enzyme inhibitor or angiotensin receptor blocker . On multivariate analysis , graft outcome was influenced by the relative change in serum creatinine level between 12 months post-transplantation and the time of the index biopsy , the urinary protein excretion , the mean diastolic blood pressure after the index biopsy , and RAS blockade . Renal graft survival after treatment with RAS blockade was 6.3 ( 0.9 - 10.9 ) years as opposed to 1.8 ( 0.1 - 6.7 ) years in untreated patients ( P = 0.003 ) . CONCLUSION RAS blockade increases graft survival in CAN . In view of the limited treatment options for CAN , this finding is of importance and needs confirmation by a prospect i ve r and omized trial Angiotensin-converting enzyme ( ACE ) inhibitors have favourable effects on hypertension and diabetic nephropathy , but persistent use may result in incomplete blockade of the renin-angiotensin system . Long-term effects of dual blockade using the ACE inhibitor lisinopril and the long-acting angiotensin II receptor blocker ( ARB ) telmisartan on blood pressure and albumin excretion rate ( AER ) were evaluated . Patients with type 2 diabetes mellitus , hypertension ( systolic blood pressure [ SBP ] > or=140 mmHg or diastolic blood pressure [ DBP ] > or=90 mmHg ) and microalbuminuria ( AER 30 - 300 mg/24h ) received 20 mg of lisinopril or 80 mg of telmisartan once a day for 24 weeks . Patients were then r and omised to continuing treatment with the respective monotherapy or with lisinopril plus telmisartan for a further 28 weeks . Significant ( P<0.001 ) declines in SBP ( 11.1 mmHg versus 10.0 mmHg ) , DBP ( 5.6 mmHg versus 5.3 mmHg ) and AER ( 98 mg/24 h versus 80 mg/24 h ) were achieved with lisinopril ( n=95 ) or telmisartan ( n=97 ) , respectively , after 24 weeks . Subsequent treatment with lisinopril plus telmisartan for 28 weeks result ed in further significant reductions ( P<0.001 ) in SBP , DBP and AER compared with either monotherapy . All treatments were well tolerated . Lisinopril plus telmisartan thus provides superior blood pressure and AER control than either monotherapy . We conclude that use of dual blockade may provide a new approach to prevention of diabetic nephropathy in patients with type 2 diabetes , hypertension and microalbuminuria Background Therapies that can slow the progression of liver fibrosis in chronic liver disease are needed . Evidence suggests that the renin-angiotensin system ( RAS ) contributes to inflammation and fibrosis in chronic liver disease . Both animal and limited human studies have shown that RAS inhibition with angiotensin-converting enzyme inhibitors ( ACEi ) and angiotensin receptor-1 [ AT-1 ] blockers ( ARBs ) has antifibrogenic properties . Aims In this study , we evaluated the effects of continuous ACEi/ARB use for 3.5 years on histological liver fibrosis progression in the HALT-C Trial cohort . Methods In the HALT-C Trial , subjects with chronic hepatitis C and advanced hepatic fibrosis ( Ishak stage ≥3 ) underwent serial liver biopsies at baseline , 1.5 years , and 3.5 years after r and omization . The primary outcome was a ≥2-point increase in Ishak fibrosis score in at least one of the two serial biopsies . Sixty-six subjects were continuously taking ACEi/ARBs over the observation period , 126 were taking other antihypertensive medications , and 343 subjects took no antihypertensive medications . Results The three groups were similar in baseline fibrosis scores , and the two groups being treated with antihypertensives were taking a similar number of antihypertensive medications . Fibrosis progression occurred in 33.3 % of the ACEi/ARB group , 32.5 % of the other antihypertensive medications group , and in 25.7 % of subjects taking no antihypertensive medications . No significant associations between ≥2-point increases in fibrosis scores and continuous ACEi/ARB use were apparent at either 1.5 or 3.5 years in diabetes-adjusted and unadjusted odds ratios . Conclusions ACEi/ARB therapy did not retard the progression of hepatic fibrosis Background The aim of his study was to compare the efficacy of pioglitazone with metformin on the reduction of albuminuria in type 2 diabetic patients with hypertension and microalbuminuria treated with renin – angiotensin system inhibitors ( RAS-Is ) . Methods The open-label , r and omized trial was performed in type 2 diabetic patients with hypertension and microalbuminuria . On the basis of the treatment with RAS-Is , 68 patients with microalbuminuria received either pioglitazone ( 15–30 mg/day ; n = 32 ) or metformin ( 500–750 mg/day ; n = 31 ) for 52 weeks . Urinary albumin-to-creatinine ratio ( UACR ) was measured every 12 weeks . Results After 52 weeks of treatment , the changes in the log-UACR from baseline were −8.3 % in the pioglitazone group and + 4.2 % in the metformin group ( p = 0.01 ) , with similar glycemic and blood pressure changes . Conclusion The combination of pioglitazone and RAS-Is showed therapeutic benefit in the reduction of urinary albumin excretion for type 2 diabetic patients with hypertension and microalbuminuria Summary The ABCD ( Appropriate Blood Pressure Control in Diabetes ) Trial is a large , prospect i ve , r and omized clinical trial of 950 patients with non-insulin-dependent diabetes mellitus ( NIDDM ) design ed to compare the effects of intensive blood pressure control with moderate control on the prevention and progression of diabetic nephropathy , retinopathy , cardiovascular disease , and neuropathy in NIDDM . The secondary objective is to determine equivalency of the effects of a calcium channel blocker ( nisoldipine ) and an angiotensin-converting-enzyme inhibitor ( enalapril ) as a first-line antihypertensive agent in the prevention and /or progression of these diabetic vascular complications . The study consists of two study population s aged 40–74 years , 470 hypertensive patients ( diastolic blood pressure of ≥ 90.0 mmHg at time of r and omization ) and 480 normotensive patients ( diastolic blood pressure of 80.0 mmHg at time of r and omization ) . The study duration is 5 years and is scheduled to end in May of 1998 . Patients are r and omized to receive either intensive antihypertensive drug therapy or moderate antihypertensive drug therapy . Patients are also r and omized to nisoldipine or enalapril , with open-label medications added if further blood pressure control is necessary . The primary outcome measure is glomerular filtration rate as assessed by 24-h creatinine clearance . Secondary outcome measures are urinary albumin excretion , left ventricular hypertrophy , retinopathy , and neuropathy . Cardiovascular morbidity and mortality will also be evaluated . Given the data showing the impact of hypertension on complications in NIDDM , the ABCD Trial is design ed to determine if intensive antihypertensive therapy will be more efficacious than moderate antihypertensive therapy on the outcome of diabetic complications in NIDDM . [ Diabetologia ( 1996 ) 39 : 1646–1654 Patients with type 2 diabetes are prone to hypertension and persistent protein leakage from the kidney ( microalbuminuria or macroalbuminuria ) . A progressive decline in renal function can lead to overt diabetic nephropathy and ESRD . The likelihood of cardiovascular disease also is increased . Control of hypertension is paramount to prevent these life-threatening complications . Agents that target the renin-angiotensin system -- angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers -- have been shown to be renoprotective . The groundbreaking Diabetics Exposed to Telmisartan And enalaprIL ( DETAIL ) trial was design ed to address the absence of comparative data on the long-term effects of an angiotensin II receptor blocker versus an angiotensin-converting enzyme inhibitor on renoprotection and survival in 250 patients with hypertension and early type 2 diabetic nephropathy . The primary purpose of the 5-yr double-blind , double-dummy , r and omized study was to establish whether 40 to 80 mg of telmisartan conferred similar ( i.e. , noninferior ) renoprotection to 10 to 20 mg of enalapril as determined by the change from baseline in GFR , measured by the plasma clearance of iohexol . Secondary end points included the emergence of ESRD and all-cause mortality .  Telmisartan was not inferior to enalapril in reducing the decline in GFR : Mean annual declines in GFR were 3.7 and 3.3 ml/min per 1.73 m(2 ) with telmisartan and enalapril , respectively . During the 5-yr study period , no patient developed a serum creatinine > 200 micromol/L , and none required dialysis . There were only six deaths in each treatment group during the study , with half being due to cardiovascular events BACKGROUND Renin-angiotensin system inhibitors have renoprotective effects in patients with chronic kidney disease , but most patients treated with these drugs have residual urinary albumin excretion . Some small clinical studies show that mineralocorticoid receptor blockade reduces albuminuria . Our study aim ed to examine the beneficial effects of addition of a selective aldosterone antagonist , eplerenone , to renin-angiotensin system inhibitors in hypertensive patients with non-diabetic chronic kidney disease . METHODS In this double-blind , r and omised , placebo-controlled trial , we enrolled hypertensive patients , aged 20–79 years , with albuminuria ( urinary albumin-to-creatinine ratio [ UACR ] in the first morning void urine of 30–599 mg/g ) , an estimated glomerular filtration rate of 50 mL/min per 1·73 m2 or more , and who had received an angiotensin-converting enzyme inhibitor , an angiotensin receptor blocker , or both , for at least 8 weeks . Participants were from 59 clinics and hospitals in Japan . Eligible patients were r and omly assigned ( 1:1 ) , stratified by baseline characteristics , to either low-dose eplerenone ( 50 mg/day ) or placebo , with continuation of st and ard antihypertensive treatment to attain therapeutic goals ( < 130/80 mm Hg ) for 52 weeks . We assessed efficacy in all patients who received allocated treatment , provided a baseline and post-treatment urine sample , and remained in follow-up . We assessed safety in all patients who received allocated treatment . The primary efficacy measure was percent change in UACR in the first morning void urine at week 52 from baseline . The trial is registered at the clinical trials registry of University Hospital Medical Information Network ( UMIN ) , trial identification number UMIN000001803 . FINDINGS Between April 1 , 2009 , and March 31 , 2012 , we r and omly allocated 170 patients to the eplerenone group and 166 patients to the  placebo group . In the primary efficacy analysis , mean percent change in UACR from baseline was −17·3 % ( 95 % CI −33·65 to −0·94 ) for 158 patients in the eplerenone group compared with 10·3 % ( −6·75 to 22·3 ) for 146 patients in the placebo group ( absolute difference −27·6 % [ –51·15 to −3·96 ] ; p=0·0222 ) . In the safety analyses , 53 ( 31 % ) of 169 patients in the eplerenone  group had adverse events ( five serious ) , as did 49 ( 30 % ) of 163 in the placebo group ( seven serious ) . Although mean serum potassium concentration was higher in the eplerenone group than the placebo group , severe hyperkalaemia ( > 5·5 mmol/L ) was not recorded in either group . INTERPRETATION Addition of low-dose eplerenone to renin-angiotensin system inhibitors might have renoprotective effects through reduction of albuminuria in hypertensive patients with non-diabetic chronic kidney disease , without serious safety concerns . FUNDING Pfizer BACKGROUND The effects of different antihypertensive medication classes on C-reactive protein ( CRP ) levels are still not well characterized , and might be of relevance to treatment choices . METHODS We studied the association between antihypertensive medication class and CRP levels among participants with treated hypertension in the Multi-Ethnic Study of Atherosclerosis . We performed a cross-sectional study of hypertensive participants free of clinical cardiovascular disease who were taking one or more of the following medication classes : beta-blockers , calcium channel blockers , diuretics , and angiotensin-converting enzyme ( ACE ) inhibitors , or angiotensin II type I receptor blockers ( ARB ) .  RESULTS Among 2340 participants taking one or more antihypertensive medications , the mean serum CRP level was lower among participants taking a beta-blocker than among those not taking a beta-blocker ( 2.13 v 2.54 mg/L , P = .002 ) . This difference persisted after multivariate adjustment ( P = .021 ) . There were no other statistically significant differences in multivariate models . Among 1314 participants receiving monotherapy , the multivariate adjusted mean CRP level among participants taking a beta-blocker was lower ( 1.97 mg/L ) than those taking a diuretic ( 2.72 mg/L , P < .001 ) . In this monotherapy group , participants taking an ACE inhibitor or ARB also had a lower adjusted mean CRP ( 2.25 mg/L ) than those taking a diuretic ( P = .046 ) . African-American race/ethnicity did not modify any of those relationships . CONCLUSIONS The beta-blocker use was associated with lower CRP levels overall and among participants on monotherapy , whereas ACE inhibitor and ARB use was associated with lower CRP levels among participants on monotherapy . These findings warrant further evaluation in r and omized trials Both angiotensin-converting enzyme inhibitors ( ACEIs ) and angiotensin receptor blockers ( ARBs ) can slow the progression of diabetic nephropathy . Even with ACEI or ARB treatment , the proportion of patients who progress to end-stage renal disease ( ESRD ) remains high . Interventions that achieve more complete blockade of the renin-angiotensin system , such as combination ACEI and ARB , might be beneficial . This approach may decrease progression of nondiabetic kidney disease . In diabetic nephropathy , combination therapy decreases proteinuria , but its effect in slowing progression is unknown . In addition , the potential for hyperkalemia may limit the utility of combined therapy in this population . VA NEPHRON-D is a r and omized , double-blind , multicenter clinical trial to assess the effect of combination losartan and lisinopril , compared with losartan alone , on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria . The primary endpoints are time to ( 1 ) reduction in estimated GFR ( eGFR ) of > 50 % ( if baseline < 60 ml/min/1.73 m(2 ) ) ; ( 2 ) reduction in eGFR of 30 ml/min/1.73 m(2 ) ( if baseline > or = 60 ml/min/1.73 m(2 ) ) ; ( 3 ) progression to ESRD ( need for dialysis , renal transplant , or eGFR < 15 ml/min/1.73 m(2 ) ) ; or ( 4 ) death . The secondary endpoint is time to change in eGFR or ESRD . Tertiary endpoints are cardiovascular events , slope of change in eGFR , and change in albuminuria at 1 yr . Specific safety endpoints are serious hyperkalemia ( potassium > 6 mEq/L , requiring admission , emergency room visit , or dialysis ) , all-cause mortality , and other serious adverse events . This paper discusses the design and key method ological issues that arose during the planning of the study BACKGROUND Previous reports have demonstrated the antihypertensive efficacy of high doses of spironolactone in subjects with primary aldosteronism and , to a lesser degree , subjects with resistant hypertension . METHODS In current analysis , we examined the antihypertensive benefit of adding low-dose spironolactone to multidrug regimens that included a diuretic and an angiotensin-converting enzyme ( ACE ) inhibitor or angiotensin receptor blocker ( ARB ) in subjects with resistant hypertension with and without primary aldosteronism . Subjects referred for resistant hypertension were evaluated with an early morning plasma renin activity , 24-h urinary aldosterone and sodium during a high dietary salt ingestion . The diagnosis of primary aldosteronism was confirmed with a renin activity < 1.0 ng/mL/h , urinary aldosterone > 12 mug/24 h and urinary sodium > 200 mEq/24 h. After biochemical evaluation , spironolactone ( 12.5 to 25 mg/d ) was added to each subject 's antihypertensive regimen . If blood pressure ( BP ) remained uncontrolled , the dose of spironolactone was titrated up to 50 mg/d . Follow-up BP was determined at 6 weeks , 3 months , and 6 months . RESULTS A total number of 76 subjects were included in the analysis , 34 of whom had biochemical primary aldosteronism . Low-dose spironolactone was associated with an additional mean decrease in BP of 21 + /- 21/10 + /- 14 mm Hg at 6 weeks and 25 + /- 20/12 + /- 12 mm Hg at 6-month follow-up . The BP reduction was similar in subjects with and without primary aldosteronism and was additive to the use of ACE inhibitors , ARBs , and diuretics . CONCLUSIONS We conclude that low-dose spironolactone provides significant additive BP reduction in African American and white subjects with resistant hypertension with and without primary aldosteronism OBJECTIVE Many patients with diabetic nephropathy ( DN ) have levels of albuminuria > 1 g/day and blood pressure > 135/85 mmHg , despite antihypertensive combination therapy , including recommended doses of ACE inhibitors , e.g. , lisinopril/enalapril at 20 mg daily . We tested the concept that such patients might benefit from dual blockade of the renin-angiotensin system ( RAS ) . RESEARCH DESIGN AND METHODS We performed a r and omized double-blind crossover study of 2 months treatment with c and esartan cilexetil 8 mg once daily and placebo in addition to previous antihypertensive treatment . We included 18 type 2 diabetic patients with DN fulfilling the above-mentioned criteria . All received recommended doses of ACE inhibitor and , in addition , 15 patients received diuretics , 11 received a calcium channel antagonist , and 3 received a beta-blocker . At the end of each treatment period , we measured the glomerular filtration rate ( GFR ) , 24-h blood pressure , albuminuria , and IgGuria . RESULTS The addition of c and esartan to usual antihypertensive therapy induced a mean ( 95 % CI ) reduction in albuminuria of 25 % ( 2 - 58 ) , P = 0.036 ( geometric mean [ 95 % CI ] from 1,764 mg/24 h [ 1,225 - 2,540 ] to 1,334 mg/24 h [ 890 - 1,998 ] ) . It also produced a mean reduction of 35 % ( 9 - 53 ) in the fractional clearance of albumin ( P = 0.016 ) , a reduction of 32 % ( 1 - 54 ) in fractional clearance of IgG ( P = 0.046 ) , a reduction in 24-h systolic blood pressure of 10 mmHg ( 2 - 18 ) ( P = 0.019 ) ( mean + /- + /- SE ) from 148 + /- 3 to 138 + /- 5 mmHg , and a mean reduction in GFR of 5 ml . min(-1 ) . 1.73 m(-2 ) ( 0.1 - 9 ) ( P = 0.045 ) . CONCLUSIONS Dual blockade of the RAS reduces albuminuria and blood pressure in type 2 diabetic patients with DN responding insufficiently to previous antihypertensive therapy , including ACE inhibitors in recommended doses When observed in elderly hypertensive patients , increased pulse pressure ( PP ) and arterial stiffness are known to be independent risk factors for cardiovascular diseases . Increased systolic blood pressure ( SBP ) leads to left ventricular hypertrophy , while decreased diastolic blood pressure ( DBP ) results in decreased coronary circulation . It is known that increased arterial stiffness is the major cause of increased PP . Thus basic morbid states of cardiac failure or ischemic heart diseases are more likely to develop in elderly hypertensive patients with increased PP and arterial stiffness , and there is need of antihypertensive drugs that decrease these effects in elderly hypertensives . In this study , we compared the effects of an angiotensin-receptor blocker ( ARB : valsartan ) , an angiotensin-converting enzyme inhibitor ( ACE-I : temocapril ) , and long-acting Ca antagonists ( L- and N-type Ca channel blocker : cilnidipine ; and L-type Ca channel blocker : nifedipine CR ) on PP and arterial stiffness measured by pulse wave velocity in elderly hypertensive patients for 3 months . The ARB yielded the largest reductions in PP and brachial-ankle pulse wave velocity ( baPWV ) , followed by the ACE-I and L- and N-type Ca channel blocker , while the L-type Ca channel blocker yielded no improvement . The effects on arterial stiffness and PP thus varied among the drug characteristics . Although ARB achieved the largest reduction in baPWV , this decrease was not associated with any reductions in PP , SBP , DBP , or mean blood pressure , as were the baPWV-decreases achieved by the other drugs , suggesting that ARB may further reduce the risk of arteriosclerosis in elderly hypertensive patients by decreasing arterial stiffness in addition to its antihypertensive effect BACKGROUND Treatment of hypertension with diuretics , beta-blockers , or both leads to improved outcomes . It has been postulated that agents that inhibit the renin-angiotensin system confer benefit beyond the reduction of blood pressure alone . We compared the outcomes in older subjects with hypertension who were treated with angiotensin-converting-enzyme ( ACE ) inhibitors with the outcomes in those treated with diuretic agents . METHODS We conducted a prospect i ve , r and omized , open-label study with blinded assessment of end points in 6083 subjects with hypertension who were 65 to 84 years of age and received health care at 1594 family practice s. Subjects were followed for a median of 4.1 years , and the total numbers of cardiovascular events in the two treatment groups were compared with the use of multivariate proportional-hazards models . RESULTS At base line , the treatment groups were well matched in terms of age , sex , and blood pressure . By the end of the study , blood pressure had decreased to a similar extent in both groups ( a decrease of 26/12 mm Hg ) . There were 695 cardiovascular events or deaths from any cause in the ACE-inhibitor group ( 56.1 per 1000 patient-years ) and 736 cardiovascular events or deaths from any cause in the diuretic group ( 59.8 per 1000 patient-years ; the hazard ratio for a cardiovascular event or death with ACE-inhibitor treatment was 0.89 [ 95 percent confidence interval , 0.79 to 1.00 ] ; P=0.05 ) . Among male subjects , the hazard ratio was 0.83 ( 95 percent confidence interval , 0.71 to 0.97 ; P=0.02 ) ; among female subjects , the hazard ratio was 1.00 ( 95 percent confidence interval , 0.83 to 1.21 ; P=0.98 ) ; the P value for the interaction between sex and treatment-group assignment was 0.15 . The rates of nonfatal cardiovascular events and myocardial infa rct ions decreased with ACE-inhibitor treatment , whereas a similar number of strokes occurred in each group ( although there were more fatal strokes in the ACE-inhibitor group ) . CONCLUSIONS Initiation of antihypertensive treatment involving ACE inhibitors in older subjects , particularly men , appears to lead to better outcomes than treatment with diuretic agents , despite similar reductions of blood pressure OBJECTIVE To provide up date d , evidence -based recommendations for the therapy of hypertension in adults . OPTIONS For patients with hypertension , a number of antihypertensive agents may control blood pressure . R and omized trials evaluating first-line therapy with thiazides , beta-adrenergic antagonists , angiotensin-converting enzyme inhibitors , calcium channel blockers , alpha-blockers , central ly acting agents or angiotensin II receptor antagonists were review ed . OUTCOMES The health outcomes that were considered were changes in blood pressure , cardiovascular morbidity , and cardiovascular and /or all-cause mortality rates . Economic outcomes were not considered due to insufficient evidence . EVIDENCE MEDLINE was search ed for the period March 1999 to October 2001 to identify studies not included in the 2000 revision of the Canadian Recommendations for the Management of Hypertension . Reference lists were scanned , experts were polled , and the personal files of the subgroup members and authors were used to identify other published studies . All relevant articles were review ed and appraised , using prespecified levels of evidence , by content experts and method ological experts . VALUES A high value was placed on the avoidance of cardiovascular morbidity and mortality . BENEFITS , HARMS AND COSTS Various antihypertensive agents reduce the blood pressure of patients with sustained hypertension . In certain setting s , and for specific classes of drugs , blood-pressure lowering has been associated with reduced cardiovascular morbidity and /or mortality . RECOMMENDATIONS The present document contains detailed recommendations pertaining to treatment thresholds , target blood pressures , and choice of agents in various setting s in patients with hypertension . The main changes from the 2000 Recommendations are the addition of a section on the treatment of hypertension in patients with diabetes mellitus , the amalgamation of the previous sections on treatment of hypertension in the young and old into one section , increased emphasis on the role of combination therapies over repeated trials of single agents and expansion of the section on the treatment of hypertension after stroke . Implicit in the recommendations for therapy is the principle that treatment for an individual patient should take into consideration global cardiovascular risk , the presence and /or absence of target organ damage , and comorbidities . VALIDATION All recommendations were grade d according to strength of the evidence and voted on by the Canadian Hypertension Recommendations Working Group . Individuals with potential conflicts of interest relative to any specific recommendation were excluded from voting on that recommendation . Only those recommendations achieving high levels of consensus are reported here . These guidelines will continue to be up date d annually BACKGROUND Blockade of the renin-angiotensin system ( RAS ) with angiotensin converting enzyme ( ACE ) inhibitors or with angiotensin II type 1 ( AT1 ) receptor blockers has been shown to reduce proteinuria and to slow down the progression of renal disease in diabetic and non-diabetic primary proteinuric nephropathies . Additionally , this beneficial effect is not dependent on blood pressure control . METHODS To assess and compare the effects of lisinopril ( up to 40 mg/day ) , c and esartan ( up to 32 mg/day ) and combination therapy ( lisinopril up to 20 mg/day plus c and esartan up to 16 mg/day ) on urinary protein excretion , 45 patients with primary proteinuric nephropathies ( urinary protein/creatinine ratio 3.8+/-2.4 g/g ) and normal or slightly reduced renal function ( CCr 95+/-33 mL/min ) were enrolled in a six month multicenter , prospect i ve , open , r and omized , active-controlled and parallel-group trial with 1:1:1 allocation . Blood pressure goal was set at or below 125/75 mm Hg for all patients , with additional antihypertensive medication prescribed if required . RESULTS Renal function , estimated by creatinine clearance , remained stable throughout the study . Hyperkalemia ( K>5.5 mmol/L ) was detected in 3.1 % of all measurements in follow-up , and was more frequent in patients treated with lisinopril alone or lisinopril plus c and esartan ( P<0.001 ) than in those on c and esartan alone . No other relevant adverse event was recorded . The blood pressure goal ( < 125/75 mm Hg ) was achieved by week 4 in all treatment groups ( P<0.005 when compared to baseline ) , and afterwards the mean systolic and diastolic blood pressure remained below these values until the end of the trial with no statistically significant differences between groups . Urinary protein/creatinine ratio ( percentage reduction 95 % confidence intervals CI ) decreased in patients treated with lisinopril alone to -33 % ( CI -12 - 56 ) to -31 % ( CI 0 - 68 ) and to -50 % ( CI -9 - 90 ) , in patients treated with c and esartan to -28 % ( CI -12 - 45 ) , to -41 % ( CI -30 - 52 ) and to -48 % ( CI -32 - 63 ) , in patients treated with the combination of both to -60 % ( CI -44 - 77 ) to -54 % ( CI -38 - 69 ) and to -70 % ( CI -57 - 83 ) at two , three , and six months , respectively . All comparisons with baseline achieved statistical significance and treatment with combination therapy was statistically more effective in proteinuria reduction than treatment with c and esartan alone at two and six months ( P=0.004 and P=0.023 , respectively ) and than treatment with lisinopril only at two months ( P=0.03 ) . CONCLUSION Dual blockade of the renin-angiotensin system with ACE inhibitors and AT1 receptor blockers produces a beneficial antiproteinuric effect that could not be explained only by the systemic blood pressure reduction . All treatments were well tolerated Chronic kidney disease ( CKD ) in heart failure ( HF ) increases the risk of hyperkalaemia ( HK ) , limiting angiotensin‐converting enzyme inhibitor ( ACE‐I ) or angiotensin receptor blocker ( ARB ) use . Patiromer is a sodium‐free , non‐absorbed potassium binder approved for HK treatment . We retrospectively evaluated patiromer 's long‐term safety and efficacy in HF patients from AMETHYST‐DN BACKGROUND Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in patients with diabetes . Approximately 30 % of type 1 patients with diabetic nephropathy ( DN ) have albuminuria > 1 g/day , and blood pressure > 135 and /or > 85 mmHg despite antihypertensive therapy with recommended doses of ACE inhibitor ( ACEI ) and diuretics . We tested the effect of dual blockade of the renin-angiotensin system ( RAS ) in these patients . METHODS We performed a r and omised double blind crossover trial with 2 months treatment with Irbesartan 300 mg o.d . and placebo added on top of previous antihypertensive treatment . We included 21 type 1 patients with DN responding insufficiently to ACEI and diuretics , as defined above . At the end of each treatment period , albuminuria , 24-h blood pressure and glomerular filtration rate ( GFR ) were measured . RESULTS Addition of 300 mg Irbesartan to the patients ' usual antihypertensive therapy induced a mean reduction in albuminuria of 37 % ( 95 % CI 20 - 49 , P<0.001 ) ; from 1574 mg/24 h ( 95 % CI 1162 - 2132 ) to 996 mg/24 h ( 95 % CI 699 - 1419 ) , a reduction in 24-h blood pressure of 8 mmHg systolic ( 95 % CI -2 to 18 ) and 5 mmHg diastolic ( 95 % CI 1 - 9 ) ( P=0.11 and 0.01 , respectively ) ( from placebo , mean ( SE ) 146 (4)/80 ( 2 ) mmHg ) . GFR remained unchanged . Serum potassium increased ( mean 4.3 to 4.6 mmol/l , P=0.02 ) . Intervention to reduce serum potassium was needed in two patients with GFR < 35 ml/min/1.73 m(2 ) . Otherwise the dual blockade with Irbesartan was safe and well tolerated . CONCLUSIONS Dual blockade of the RAS may offer additional renal and cardiovascular protection in type 1 patients with DN responding insufficiently to conventional antihypertensive therapy , including recommended doses of ACEI and diuretics In this paper , we present the results of a re analysis of the data of two large r and omized , double-blind , parallel group studies with a similar design , comparing the efficacy of an angiotensin-receptor blocker ( olmesartan medoxomil ) with that of an angiotensin-converting enzyme inhibitor ( ramipril ) , by applying two different blood pressure targets recently recommended by hypertension guidelines for all patients , irrespective of the presence of diabetes ( < 140/90 mmHg ) , and for elderly hypertensive patients ( < 150/90 mmHg ) . The efficacy of olmesartan was not negatively affected by age , sex , hypertension type , diabetes status or other concomitant clinical conditions , or cardiovascular risk factors . In most cases , olmesartan provided better blood pressure control than ramipril . Olmesartan was significantly more effective than ramipril in male patients , in younger patients ( aged 65–69 years ) , in those with metabolic syndrome , obesity , dyslipidemia , preserved renal function , diastolic ± systolic hypertension , and , in general , in patients with a high or very high cardiovascular risk . Interestingly , patients previously untreated or treated with two or more antihypertensive drugs showed a significantly larger response with olmesartan than with ramipril . Thus , our results confirm the good efficacy of olmesartan in elderly hypertensives even when new blood pressure targets for antihypertensive treatment are considered . Such results may be relevant for the clinical practice , providing some hint on the possible different response of elderly hypertensive patients to two different drugs acting on the renin – angiotensin system , when patients are targeted according to the blood pressure levels recommended by recent hypertension guidelines Background Several studies have demonstrated that spironolactone has an anti-albuminuric property in diabetic nephropathy . As an adverse event , spironolactone often induces the elevation of creatinine levels with hypotension and hyperkalemia . Therefore , we aim ed to evaluate the efficacy and safety of spironolactone in Japanese patients with type 2 diabetes treated with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers . Methods Fifty-two Japanese patients with diabetic nephropathy and albuminuria ( 100 mg/gCr–2000 mg/gCr ) treated with renin – angiotensin system ( RAS ) blockade were enrolled in a prospect i ve , r and omized , open-label study . The patients were subjected to add-on treatment with spironolactone 25 mg once daily and compared with matched controls for 8 weeks . The primary outcome was a reduction in the rate of albuminuria at 8 weeks compared with the baseline value . This study was registered with UMIN Clinical Trials Registry ( 000008016 ) . Results Albuminuria was reduced by 33 % ( 95 % confidence interval : 22–54 ; P = 0.0002 ) at 8 weeks with spironolactone . In the spironolactone group , blood pressure tended to lower and the estimated glomerular filtration rate ( eGFR ) was significantly decreased compared to those in the control group . When adjusted by systolic blood pressure and eGFR , spironolactone treatment still showed a significant effect on albuminuria reduction in a linear mixed model ( coefficient ± st and ard error ; 514.4 ± 137.6 mg/gCr , P < 0.0005 ) . No patient was excluded from the study because of hyperkalemia . Conclusions Spironolactone reduced albuminuria along with conventional RAS inhibitors in patients with diabetic nephropathy . Our study suggests that spironolactone exerts anti-albuminuric effects independent of systemic hemodynamic alterations Background : Nowadays Vitamin D deficiency is a notable medical condition world-wide and also in Iran . Since , vitamin D can have renoprotective effect by inhibiting the renin-angiotensin system ; it appears that low vitamin D level can worsen the renal injury in diabetic patients . This study demonstrates the effect of vitamin D3 therapy on reducing proteinuria in diabetic patients with concomitant diabetic nephropathy and vitamin D deficiency after controlling hypertension and use of angiotensin converting enzyme inhibitors ( ACEIs ) or angiotensin II type receptor blockers ( ARBs ) . Material s and Methods : In this r and omized double blinded parallel groups clinical trial , 51 diabetic patients with proven nephropathy and vitamin D deficiency/insufficiency and stable hypertension , dyslipidemia , and hyperglycemic treatment were enrolled . The patients were divided r and omly into two groups ( treatment and placebo group ) . Patients received oral vitamin D3 ( pearl 50000 IU ) or placebo one pearl every week for 12 weeks . Patients were assessed at baseline and 12 weeks after intervention from the point of 25(OH ) D level , and urine albumin/creatinine ration ( UACR ) . Results : Mean serum 25(OH ) D concentrations were 14.06 ng/ml and 16.05 ng/ml before treatment . Furthermore , after intervention , its levels were risen to 71.23 and 17.63 in drug and placebo groups , respectively . Whereas , UACR as the main variable did not change significantly after intervention in both groups ( P = 0.919 ) . Conclusion : According to our finding , there was not a decrease in proteinuria in diabetic patients who received vitamin D for a period of 3 months Objective The combination of an angiotensin-converting enzyme ( ACE ) inhibitor and an angiotensin II ( Ang II ) receptor antagonist ( ARB ) could provide a higher degree of blockade of the renin-angiotensin system(RAS ) than either agent alone . The primary aim of this study was to look at the effect of three therapeutic regimens ( titrated ACE inhibitor ( ACE-I ) versus titrated ARB versus the combination of an ACE-I and an ARB ) on the attainment of adequate blood pressure ( BP ) control and antiproteinuric effect . Both ACE-I and ARB were titrated as monotherapy up to the maximal recommended dose . Methods A pilot r and omised , parallel group open-label study was conducted in 36 patients with primary renal disease , proteinuria above 1.5 g/day and BP > 140/90 mmHg while on therapy with an ACE-I.  Patients were r and omly assigned to ( 1 ) benazepril , n=12 ; ( 2 ) valsartan , n=12 ; or ( 3 ) benazepril plus valsartan , n=12 . Other antihypertensive therapies could also be added to attain goal BP ( < 140/90 mmHg ) . The primary endpoint was the change in proteinuria during six months of follow-up . Results In the presence of similar BP decreases and stable creatinine clearance values , mean proteinuria decreases were 0.5±1.7 , 1.2±2.0 and 2.5±1.8 g/day in groups 1 , 2 and 3 , respectively . When compared with baseline values , only the fall induced by the combination of ARB and ACE-I attained statistical significance ( p<0.05 ) . Conclusion The antiproteinuric capacity of monotherapy at recommended doses with either an ACE-I or an ARB is lower than that obtained with the combination of the two drugs As the population ages , the incidence of type 2 diabetes will increase as will the incidence of concomitant vascular complications . Hypertension substantially increases the risk of cardiovascular disease in patients with diabetes . Results from the recent Appropriate Blood Pressure Control in Diabetes ( ABCD ) trial demonstrated an advantage of an angiotensin-converting enzyme ( ACE ) inhibitor ( enalapril ) over a long-acting calcium antagonist ( nisoldipine ) with regard to the incidence of cardiovascular events over a 5-year follow-up period in hypertensive persons with type 2 diabetes . This trial was a prospect i ve , r and omized , blinded study comparing the effects of moderate blood pressure control ( target diastolic pressure 80 - 89 mm Hg ) with those of intensive control ( target diastolic pressure 75 mm Hg ) on the incidence and progression of diabetic vascular complications . The study also compared nisoldipine with enalapril as first-line antihypertensive therapy in terms of prevention and progression of complications of diabetes . In 470 hypertensive patients , the incidence of fatal and nonfatal myocardial infa rct ions was significantly ( p = 0.001 ) higher among those receiving nisoldipine ( n = 25 ) compared with those receiving enalapril ( n = 5 ) . Comparison with previous studies suggests that the difference observed between nisoldipine and enalapril result ed from a beneficial effect of enalapril rather than a deleterious effect from nisoldipine . Since these findings in the ABCD trial are based on a secondary endpoint , they require confirmation . Nevertheless , they suggest that ACE inhibitors should be the initial antihypertensive medication used in patients with type 2 diabetes and hypertension Combination of an angiotensin-converting enzyme inhibitor ( ACEI ) with an angiotensin II receptor blocker is advocated as a treatment option in diabetic patients with nephropathy and residual albuminuria while on antihypertensive therapy . Abrogation of albuminuria is a key treatment goal to prevent disease progression . The assumption is that albuminuria reduction is the result of more complete blockade of the renin angiotensin system ; thus , the ACEI-angiotensin II receptor blocker combination would have a greater albuminuria-lowering effect than the combination of an ACEI with a calcium channel blocker such as amlodipine , which causes similar reductions in BP but does not affect the renin angiotensin system . Twenty-eight patients who had type 1 diabetes and known diabetic renal disease and had a persistently elevated albumin creatinine ratio ( ACR ) > 10 mg/mmol despite office BP recordings < or = 140/80 mmHg on maximal recommended dose of the ACEI lisinopril were studied . Patients were allocated to receive either c and esartan ( 16 mg/d ) or amlodipine ( 10 mg/d ) in addition to preexisting ACEI inhibition and followed for 24 wk in a r and omized , double-blind , parallel-group trial . By week 24 , ACR fell by 56 % with c and esartan and 54 % with amlodipine ( P < 0.01 versus baseline for both ) with no significant difference between groups . Mean arterial BP fell between 3 and 6 mmHg similarly in both groups . In neither group was a significant correlation found between the change in ACR and the change in BP . C and esartan and amlodipine  lowered ACR and BP by a similar degree . The fall in ACR was disproportionate to the fall of systemic BP and independent of it . The mechanism of the reduction in albuminuria seen with these agents in combination with an ACEI remains to be eluci date In the EMPA-REG BP trial , empagliflozin 10 mg and 25 mg once daily reduced glycohemoglobin , blood pressure ( BP ) , and weight versus placebo in patients with type 2 diabetes mellitus and hypertension . Patients  received placebo ( n=271 ) , empagliflozin  10 mg ( n=276 ) , or empagliflozin 25 mg ( n=276 ) for 12 weeks ( n = full analysis set ) . This present analysis investigated changes from baseline to week 12 in mean 24-hour systolic BP ( SBP ) and diastolic BP ( DBP ) in patients receiving 0 , 1 , or ≥2 antihypertensive medications and patients receiving/not receiving diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers . Compared with placebo , empagliflozin 10 mg and 25 mg reduced mean 24-hour SBP/DBP in patients receiving 0 ( 10 mg : −3.89/−2.58 mm Hg ; 25 mg : −3.77/−2.45 mm Hg ) , 1 ( 10 mg : −4.74/−1.97 mm Hg ; 25 mg : −4.27/−1.81 mm Hg ) , or ≥2 ( 10 mg : −2.36/−0.68 mm Hg ; 25 mg : −4.17/−1.54 mm Hg ) antihypertensives . The effect of empagliflozin was not significantly different between subgroups by number of antihypertensives for changes in SBP ( interaction P value 0.448 ) or DBP ( interaction P value 0.498 ) . Empagliflozin  reduced 24-hour mean SBP/DBP irrespective of diuretic or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use , with no significant difference between subgroups by use/no use of diuretics ( interaction P values 0.380 [ systolic ] ; 0.240 [ diastolic ] ) or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers ( interaction P values 0.900 [ systolic ] ; 0.359 [ diastolic ] ) . In conclusion , in patients with type 2 diabetes mellitus and hypertension  , empagliflozin for 12 weeks reduced SBP and DBP  versus placebo , irrespective of the number of antihypertensives and use of diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers . Clinical Trial Registration —URL : https:// clinical trials.gov . Unique identifier : NCT01370005 BACKGROUND Patients with mild-to-moderate essential hypertension in the HOMED-BP trial were r and omly allocated to first-line treatment with a calcium channel blocker ( CCB ) , angiotensin-converting enzyme inhibitor ( ACEI ) or angiotensin II receptor blocker ( ARB ) . METHODS We recruited 265 ( 93 for CCB , 71 for ACEI and 101 for ARB ) patients who completed the genomic study .  Home blood pressure was measured for 5 days off-treatment before r and omization and for 5 days after 2 - 4 weeks of r and omized drug treatment . Genotyping was performed by 500 K DNA microarray chips . The blood pressure responses to the three drugs were analyzed separately as a quantitative trait . For replication of SNPs with p < 10(-4 ) , we used the multicenter GEANE study , in which patients were r and omized to valsartan or amlodipine . RESULTS SNPs in PICALM , TANC2 , NUMA1 and APCDD1 were found to be associated with CCB responses and those in ABCC9 and YIPF1 were found to be associated with ARB response with replication . CONCLUSION Our approach , the first based on high-fidelity phenotyping by home blood pressure measurement , might be a step in moving towards the personalized treatment of hypertension BACKGROUND Angiotensin-converting enzyme ( ACE ) inhibitors reduce mortality , myocardial infa rct ion , stroke , heart failure , need for revascularization , nephropathy , and diabetes and its complications . Although angiotensin-II receptor blockers ( ARBs ) have been less extensively evaluated , theoretically they may have " protective " effects similar to those of ACE inhibitors , but with better tolerability . Currently , there is uncertainty about the role of ARBs when used alone or in combination with an ACE inhibitor in high-risk population s with controlled hypertension . OBJECTIVES Primary objectives of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial ( ONTARGET ) are to determine if the combination of the ARB telmisartan and the ACE inhibitor ramipril is more effective than ramipril alone , and if telmisartan is at least as effective as ramipril . The Telmisartan R and omized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease ( TRANSCEND ) will determine if telmisartan is superior to placebo in patients who are intolerant of ACE inhibitors . The primary outcome for both trials is the composite of cardiovascular death , myocardial infa rct ion , stroke , or hospitalization for heart failure . METHOD High-risk patients with coronary , peripheral , or cerebrovascular disease or diabetes with end-organ damage are being recruited and followed for 3.5 to 5.5 years in 2 parallel , r and omized , double-blind clinical trials . PROGRESS Recruitment from 730 centers in 40 countries for ONTARGET ( n = 25,620 ) was completed in July 2003 . For TRANSCEND , 5776 patients ( out of a projected total of 6000 ) have been recruited ( by May 10 , 2004 ) . Baseline patient characteristics are comparable to the Heart Outcomes Prevention Evaluation ( HOPE ) trial , the basis of the design of the current study , confirming that patients are at high-risk Increases in the cardiovascular risk marker microalbuminuria are attenuated by blood pressure reduction using blockers of the renin-angiotensin system . Such changes in microalbuminuria have not been observed when beta-blockers are used . A prespecified secondary end point of the Glycemic Effects in Diabetes Mellitus Carvedilol-Metoprolol Comparison in Hypertensives ( GEMINI ) trial was to examine the effects of different beta-blockers on changes in albuminuria in the presence of renin-angiotensin system blockade . Participants with hypertension and type 2 diabetes were r and omized to either metoprolol tartrate ( n=737 ) or carvedilol ( n=498 ) in blinded fashion after a washout period of all antihypertensive agents except for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers . Blinded medication was titrated to achieve target blood pressure , with a-5 month follow-up period . The current analysis examined microalbuminuria , using spot urine albumin : creatinine , in participants who had values at screening and trial end . A greater reduction in microalbuminuria was observed for those r and omized to carvedilol ( -16.2%Delta ; 95 % confidence interval , -25.3 , -5.9 ; P=0.003 ) . Of those with normoalbuminuria at baseline , fewer progressed to microalbuminuria on carvedilol versus metoprolol ( 20 of 302 [ 6.6 % ] versus 48 of 431 [ 11.1 % ] , respectively ; P=0.03 ) . Microalbuminuria development was not related to differences in blood pressure or achievement of blood pressure goal ( 68 % carvedilol versus 67 % , metoprolol ) . Presence of metabolic syndrome at baseline was the only independent predictor of worsening albuminuria throughout the study ( P=0.004 ) . Beta-blockers have differential effects on microalbuminuria in the presence of renin-angiotensin system blockade . These differences can not be explained by effects on blood pressure or alpha1-antagonism but may relate to antioxidant properties of carvedilol Abstract Background Recently , it has been reported that urinary angiotensinogen levels is a specific index of the intrarenal renin-angiotensin-aldosterone system ( RAAS ) status and it is significantly correlated with urinary albumin : creatinine ( Cr ) ratio in hypertensive patients . The aim of the present study was to assess the effect of activation of the Vitamin D receptor with calcitriol on albuminuria and urinary angiotensinogen as a novel biomarker of the intra-renal RAAS status in patients with diabetic nephropathy ( DN ) . Methods Ninety-eight patients with type 2 diabetes and albuminuria who were treated with RAAS inhibitors ( angiotensin-converting enzyme inhibitor ( ACE-i ) or angiotensin receptor blocker ( ARB ) ) have participated in this study . Patients were r and omized to receive either placebo ( n = 50 ) or 0.25 μg/day calcitriol ( n = 48 ) . We have examined urinary albumin : Cr ratio and urinary angiotensinogen : Cr ratio before and 24 weeks later after treatment in both group . Results The mean urinary albumin : Cr ratio and urinary angiotensinogen : Cr ratio were significantly higher in patients with DN than in normal controls ( p < 0.001 ) . Urinary angiotensinogen : Cr ratio was significantly , positively correlated with urinary albumin : Cr ratio in both groups ( in the placebo group ; p = 0.01 , r = 0.4236 , in calcitriol group ; p = 0.01 , r = 0.4564 ) . Conclusion These data indicated that administration of Vitamin D receptor activator in combination with RAAS inhibitors had an additional benefit in lowering albuminuria in patients with DN . More pronounced reduction of urinary albumin : Cr ratio that was positively correlated with angiotensinogen : Cr ratio in calcitriol group suggested that Vitamin D receptor activation might blunt albuminuria by reducing urinary angiotensinogen levels reflecting intra-renal RAAS status The ABCD ( Appropriate Blood Pressure Control in Diabetes ) trial is a large , prospect i ve , r and omized clinical trial design ed to compare the effects of intensive with moderate blood pressure control on the prevention and progression of diabetic nephropathy , retinopathy , cardiovascular disease , and neuropathy in non-insulin-dependent diabetes ( NIDDM ) . The secondary objective is to determine equivalency of the effects of a calcium channel blocker ( nisoldipine ) and of an angiotensin-converting enzyme inhibitor ( enalapril ) as a first-line antihypertensive agent in the prevention and /or progression of these diabetic vascular complications . The study consists of two study population s : a hypertensive one ( diastolic blood pressure of > or = 90.0 mm Hg at the time of r and omization ) and a normotensive one ( diastolic blood pressure of 80.0 - 89.0 mm Hg at the time of r and omization ) . A total of 950 men and women aged 40 - 74 years were r and omized and are being followed for 5 years at a single center . There were 470 r and omized participants in the hypertensive population and 480 r and omized participants in the normotensive population . This report summarizes the demographic , biochemical , and clinical characteristics of the r and omized patients at the time of entry into the trial and evaluates the balance between the treatment groups within each population BACKGROUND Most treatment recommendations for hypertension are based on criteria that consider efficacy , safety and cost . Given the need for long-term use of antihypertensive agents , treatment compliance should also be taken into consideration in the selection process . OBJECTIVE The purpose of the present study was to estimate persistence and adherence to  antihypertensive agents in a real-life setting . METHODS Persistence and adherence to treatment were estimated using data from the Regie de l'assurance maladie du Quebec . RESULTS Data from a r and om sample of 4561 subjects with a diagnosis of hypertension covered by the Regie de l'assurance maladie du Quebec drug plan and using one of the antihypertensive agents reimbursed by the drug plan for the first time between January 2000 and December 2001 were analyzed . The persistence rate observed after a two-year period with diuretics was significantly lower ( 52.8 % ) than with any other classes of antihypertensive agent ( P<0.01 ) . Persistence rates for beta-blockers , calcium channel blockers , angiotensin-II receptor blockers and angiotensin-I converting enzyme inhibitors were 69.3 % , 64.3 % , 60.9 % and 58.9 % , respectively . After two years , the proportion of patients who were 80 % adherent to their treatment was 64.9 % for angiotensin-I converting enzyme inhibitors , 65.0 % for angiotensin-II receptor blockers , 64.2 % for calcium channel blockers , 60.3 % for beta-blockers and 50.9 % for diuretics . The proportion of patients who were 80 % adherent to their treatment was significantly lower for diuretics than with any other antihypertensive agents ( P<0.01 ) . CONCLUSION Persistence and adherence to treatment are essential to treatment success . Results of the present study indicate that , in a real-life setting , patients are significantly less compliant to diuretics than to any other antihypertensive agents OBJECTIVE To provide up date d , evidence -based recommendations for the prevention and management of hypertension in adults . OPTIONS AND OUTCOMES For lifestyle and pharmacological interventions , evidence was review ed from r and omized controlled trials and systematic review s of trials . Changes in cardiovascular morbidity and mortality were the primary outcomes of interest . However , for lifestyle interventions , blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field . For treatment of patients with kidney disease , the progression of kidney dysfunction was also accepted as a clinical ly relevant primary outcome . EVIDENCE A Cochrane collaboration librarian conducted an independent MEDLINE search from 2005 to August 2006 to up date the 2006 Canadian Hypertension Education Program recommendations . In addition , reference lists were scanned and experts were contacted to identify additional published studies . All relevant articles were review ed and appraised independently by both content and method ological experts using prespecified levels of evidence . RECOMMENDATIONS Dietary lifestyle modifications for prevention of hypertension , in addition to a well-balanced diet , include a dietary sodium intake of less than 100 mmol/day . In hypertensive patients , the dietary sodium intake should be limited to 65 mmol/day to 100 mmol/day . Other lifestyle modifications for both normotensive and hypertensive patients include : performing 30 min to 60 min of aerobic exercise four to seven days per week ; maintaining a healthy body weight ( body mass index of 18.5 kg/m2 to 24.9 kg/m2 ) and waist circumference ( less than 102 cm in men and less than 88 cm in women ) ; limiting alcohol consumption to no more than 14 units per week in men or nine units per week in women ; following a diet reduced in saturated fat and cholesterol , and one that emphasizes fruits , vegetables and low-fat dairy products , dietary and soluble fibre , whole grains and protein from plant sources ; and considering stress management in selected individuals with hypertension . For the pharmacological management of hypertension , treatment thresholds and targets should take into account each individual 's global atherosclerotic risk , target organ damage and any comorbid conditions : blood pressure should be lowered to lower than 140/90 mmHg in all patients and lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease . Most patients require more than one agent to achieve these blood pressure targets . In adults without compelling indications for other agents , initial therapy should include thiazide diuretics ; other agents appropriate for first-line therapy for diastolic and /or systolic hypertension include angiotensin-converting enzyme ( ACE ) inhibitors ( except in black patients ) , long-acting calcium channel blockers ( CCBs ) , angiotensin receptor blockers ( ARBs ) or beta-blockers ( in those younger than 60 years of age ) . First-line therapy for isolated systolic hypertension includes long-acting dihydropyridine CCBs or ARBs . Certain comorbid conditions provide compelling indications for first-line use of other agents : in patients with angina , recent myocardial infa rct ion , or heart failure , beta-blockers and ACE inhibitors are recommended as first-line therapy ; in patients with cerebrovascular disease , an ACE inhibitor plus diuretic combination is preferred ; in patients with nondiabetic chronic kidney disease , ACE inhibitors are recommended ; and in patients with diabetes mellitus , ACE inhibitors or ARBs ( or , in patients without albuminuria , thiazides or dihydropyridine CCBs ) are appropriate first-line therapies . All hypertensive patients with dyslipidemia should be treated using the thresholds , targets and agents outlined in the Canadian Cardiovascular Society position statement ( recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease ) . Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy . Once blood pressure is controlled , acetylsalicylic acid therapy should be considered . VALIDATION All recommendations were grade d according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence -Based Recommendations Task Force . All recommendations reported here achieved at least 95 % consensus . These guidelines will continue to be up date d annually Antihypertensive agents may , even within the same class , exert variable effects on arterial stiffness variables .  Nebivolol could have a better impact than atenolol on arterial stiffness , by increasing the bioavailability of endothelium-derived nitric oxide . Angiotensin-converting enzyme inhibitors ( ACEIs ) and angiotensin receptor blockers ( ARBs ) increase plasma renin activity ( enhancing the production of angiotensin II via non-ACE-related pathways ) whereas aliskiren does not , potentially affecting central hemodynamics differently . We compared the effects of two renin-angiotensin-aldosterone system ( RAAS ) inhibitors ( quinapril and aliskiren ) and 2 beta-blockers ( atenolol and nebivolol ) on arterial stiffness variables . Treatment-naïve patients ( n = 72 ; 68.1 % males ; age , 47.6 ± 10.6 years ) with uncomplicated stage I-II essential hypertension were r and omly assigned to quinapril , aliskiren , atenolol , or nebivolol for 10 weeks . Central systolic and diastolic blood pressure ( BP ) , central pulse pressure ( PP ) , augmentation index ( AIx ) , and pulse wave velocity ( PWV ) were measured at baseline , 2 , and 10 weeks . The same measurements were performed in 20 normotensive subjects ( 65.0 % males ; age , 40.0 ± 8.9 years ) . Peripheral and central systolic and diastolic BP , peripheral PP , and PWV were significantly and similarly reduced by all agents . However , PWV continued to decline between the second and last visit in patients on quinapril and aliskiren but did not change in those on nebivolol or atenolol  . Central PP and AIx decreased in patients on quinapril , aliskiren , and nebivolol but did not change in those taking atenolol . The decrease in central PP and AIx did not differ between patients on quinapril , aliskiren , and nebivolol . Despite similar reductions in peripheral BP , atenolol is less effective than nebivolol and RAAS inhibitors in improving central pulsatile hemodynamics . Aliskiren exerts similar effects on markers of arterial stiffness  as quinapril . The clinical relevance of these differences remains to be established Structural alterations of subcutaneous small resistance arteries are associated with a worse clinical prognosis in hypertension and noninsulin-dependent diabetes mellitus ( NIDDM ) . However , no data are presently available about the effects of antihypertensive therapy on vascular structure in hypertensive patients with NIDDM . Therefore , we have investigated the effect of an angiotensin-converting enzyme inhibitor , enalapril , and a highly selective angiotensin receptor blocker , c and esartan cilexetil , on indices of subcutaneous small resistance artery structure in 15 patients with mild hypertension and NIDDM . Eight patients were treated with c and esartan ( 8 to 16 mg per day ) and 7 with enalapril ( 10 to 20 mg per day ) for 1 year . Each patient underwent a biopsy of the subcutaneous fat from the gluteal region at baseline and after 1 year of treatment . Small arteries were dissected and mounted on a micromyograph and the media-to-internal lumen ratio was evaluated ; moreover , endothelium-dependent vasodilation to acetylcholine was assessed . A similar blood pressure-lowering effect and a similar reduction of the media-to-lumen ratio of small arteries was observed with the 2 drugs . Vascular collagen content was reduced and metalloproteinase-9 was increased by c and esartan , but not by enalapril . Changes of circulating indices of collagen turnover and circulating matrix metalloproteinase paralleled those of vascular collagen . The 2 drugs equally improved endothelial function . In conclusion , antihypertensive treatment with drugs that inhibit the renin-angiotensin-aldosterone system activity is able to correct , at least in part , alterations in small resistance artery structure in hypertensive patients with NIDDM .  C and esartan may be more effective than enalapril in reducing collagen content in the vasculature Background : We have previously demonstrated in the R and omized Olmesartan and Diabetes Microalbuminuria Prevention study that the angiotensin receptor blocker ( ARB ) olmesartan delays the onset of microalbuminuria in patients with type 2 diabetes . Now , we investigated the effect in the sub population with hypertension . Methods : Overall , 4020 patients with type 2 diabetes and hypertension at baseline ( defined by a SBP/DBP ≥130/80 mmHg or use of antihypertensive medication ) received either 40 mg olmesartan once daily or placebo for a median of 3.2 years in a r and omized , double-blind , multicenter , controlled trial . Additional antihypertensive drugs ( except angiotensin-converting enzyme inhibitors or ARBs ) were used as needed to lower blood pressure ( BP ) to less than 130/80 mmHg . Results : The average BP was 126.3/74.7 and 129.5/76.6 mmHg , respectively ( P < 0.001 ) . Olmesartan delayed the time to onset of microalbuminuria by 25 % ( hazard ratio = 0.75 ; 95 % confidence interval = 0.61–0.92 , P = 0.007 ) . Patients with a baseline SBP above the median of 136.7 mmHg and a SBP reduction above the median of 17.45 mmHg had a lower incidence of microalbuminuria than patients with a SBP reduction of less than 17.45 ( 8.1 vs. 11.2 % , P < 0.0001 ) . Independent from the baseline BP and the degree of BP reduction a 15–39 % increase in the time to onset of microalbuminuria was detectable by olmesartan treatment . Cardiovascular events were comparable and occurred in 93 ( 4.6 % ) patients taking olmesartan and 86 ( 4.4 % ) taking placebo . Conclusion : Patients with a better BP reduction are less likely to develop microalbuminuria . Treatment with olmesartan delayed the onset of microalbuminuria independent of the baseline BP and the degree of BP reduction Abstract To compare the efficacy of spironolactone and trichlormethiazide , as add‐on therapy to renin – angiotensin system ( RAS ) blockade , for reduction of albuminuria in diabetic patients with chronic kidney disease ( CKD ) , we conducted this r and omized , open‐labeled , parallel‐group , active‐controlled , per‐ protocol ‐ design study . Type 2 diabetic patients receiving an angiotensin‐converting enzyme inhibitor or angiotensin II receptor blocker , with persistent albuminuria ( ≥100 mg/g creatinine ) were r and omly assigned to either spironolactone ( 25 mg/day ) or trichlormethiazide ( 2 mg/day ) . The primary outcome was the change in albuminuria at 24 weeks of treatment . In patients who completed 24 weeks of treatment with spironolactone ( n = 18 ) and trichlormethiazide ( n = 15 ) , albuminuria decreased significantly by −57.6 ± 21.3 % ( SD ) ( P < 0.001 ) and −48.4 ± 27.1 % ( P < 0.001 ) , respectively . There was no significant difference in the change in albuminuria between groups ( P = 0.270 ) . This pilot study suggests add‐on therapy with spironolactone or trichlormethiazide to RAS blockade may be comparably beneficial to reducing albuminuria in type 2 diabetic patients . This trial was registered with UMIN‐CTR ( no. UMIN000008914 ) Introduction : Blockade of the renin-angiotensin system ( RAS ) is a critical approach to the management of hypertension , especially in proteinuric patients . It is well proven that the direct renin inhibitor aliskiren shows comparable clinical efficacy to the angiotensin II receptor blocker valsartan on blood pressure control and albuminuria . However , there is only limited data on the h and -to-h and effectiveness of these two RAS blockers in improving arterial stiffness . We tested whether aliskiren or valsartan would improve arterial stiffness in hypertensive patients with albuminuria who are already on antihypertensive therapy . Material and methods : Thirty-four patients with hypertension and albuminuria < 1 g , after a wash-out period of three weeks , were r and omized to aliskiren or valsartan in a 24-week r and omized parallel-group study . Results : A nonsignificant difference in blood pressure was seen between the two treatment groups . Albuminuria was significantly reduced in both groups ( 56 % for the aliskiren group , p < 0.05 , and 38 % for the valsartan group , p < 0.05 ) . Only valsartan but not aliskiren significantly reduced carotid-femoral pulse wave velocity ( –1.1 ± 0.8 m/s ( p = 0.02 ) for valsartan and + 0.1 ± 0.7 m/s ( ns ) for aliskiren ) . Conclusion : The results of our study showed that valsartan  improves arterial stiffness to a significantly greater extent than aliskiren , despite a similar antihypertensive and antiproteinuric effect BACKGROUND Addition of spironolactone ( SPR ) to angiotensin-converting enzyme ( ACE ) inhibitors or angiotensin II receptor blockers ( ARBs ) might provide antiproteinuric effects beyond what is gained by either medication alone . This study was design ed to assess the long-term efficacy of SPR/ARB combination in comparison with the st and ard ACE/ARB regimen in diabetic nephropathy . METHODS In an open-label , parallel-group , single-center , r and omized clinical trial ( NCT01667614 ) , 136 patients with diabetes and proteinuria , already treated with enalapril and losartan , were included . In 74 patients , ACE inhibitors  were discontinued . After a wash-out period of 2 weeks , 25 mg SPR daily was initiated . The remainder of the patients ( n = 62 ) received ACE inhibitors and ARBs as before . Patients were followed every 3 months for 18 months . During each visit , systolic and diastolic blood pressure ( BP ) , urinary albumin excretion ( UAE ) , serum creatinine , estimated glomerular filtration rate ( eGFR ) and serum potassium concentrations were determined . RESULTS After 18 months , three patients in the SPR/ARB group developed asymptomatic hyperkalemia .  SPR/ARB significantly reduced both systolic and diastolic BP ( P < 0.001 and 0.001 , respectively ) . SPR/ARB  decreased UAE by 46 , 72 and 59 % after 3 , 12 and 18 months , respectively . Compared with the continuation regimen , SPR/ARB was superior in UAE reduction ( P = 0.017 after 18 months ) , independent of BP change . In both groups , eGFR declined significantly over the trial course and the decline rate did not differ significantly between the two groups . CONCLUSIONS Addition of SPR to ARB provides added benefits with respect to BP control and proteinuria diminution . These antiproteinuric effects are not accompanied by prevention of eGFR loss compared with conventional therapy with ACE/ARB Although inhibitors of the renin – angiotensin system are effective as first-line antihypertensive drugs in hypertensive patients with chronic kidney disease , they can not completely prevent the progression of renal injury . Many animal studies , including our own , and a few human studies suggest that mineralocorticoid receptor blockade could inhibit the ongoing renal damage in chronic kidney disease . Thus , we design ed this double-blinded , r and omized , placebo-controlled trial to evaluate the antialbuminuric effect of a low dose ( 50 mg day−1 ) of the mineralocorticoid receptor antagonist eplerenone . The study subjects will include 340 hypertensive patients ( blood pressure : 130–180/80–100 mm Hg ) with albuminuria ( urinary albumin/creatinine ratio : 30–600 mg g−1 in the first morning void urine ) , who are treated with an inhibitor of the renin – angiotensin system . Other classes of antihypertensive drugs may be added as needed to achieve the target blood pressure ( < 130/80 mm Hg ) . The primary study end point is the change in the urinary albumin/creatinine ratio after a 1-year study period . This trial is expected to show whether a low dose of mineralocorticoid receptor antagonists can exert an antialbuminuric effect in patients with chronic kidney disease Objective The Captopril Prevention Project ( CAPPP ) was design ed as a prospect i ve intervention trial comparing the effect of a treatment based on the angiotensin-converting enzyme ( ACE ) inhibitor captopril with that of a conventional diuretic and /or β-blocker-based therapy , in 10 985 hypertensive patients . There was no difference in the primary cardiovascular morbidity and mortality endpoint . A lower incidence of diabetes mellitus during captopril treatment was observed in the whole CAPPP cohort that was non-diabetic at baseline ( n = 10 413 ) as well as in such CAPPP patients that were previously untreated ( n = 5033 ) . Methods and results A multivariate analysis of variables associated with the risk of developing diabetes in CAPPP demonstrated that glucose , body mass index ( BMI ) , haemoglobin ( Hb ) , age , ‘ SBP × Untreated ’ ( the interaction between systolic blood pressure at baseline and newly diagnosed hypertension ) , cholesterol and prior antihypertensive treatment came out as risk factors . Based on these factors , a risk score for development of diabetes was calculated for all non-diabetic patients , who were divided into tertiles . For each tertile of risk , captopril therapy was associated with a reduced risk of diabetes development compared with conventional diuretic and /or β-blocker therapy . When the non-diabetic cohort was divided into two subcohorts ; previously treated and previously untreated patients , it turned out that the risk factors for developing diabetes differed between these two subcohorts . Only glucose , BMI and Hb came out as risk factors in all analysed cohorts . Conclusion A captopril-based antihypertensive treatment regimen is associated with a lower risk of diabetes development , compared with conventional therapy based on diuretics and /or β-blockers The presence of edema in different phases and stages of essential hypertension may be due to antihypertensive treatment . Some drugs may cause edema by inducing vasodilatation , increasing the capillary exchange surface and capillary filtration .  Pycnogenol has an important anti-edema effect in diabetic microangiopathy and chronic venous insufficiency . This 8-week study evaluated capillary filtration in 2 comparable treatment groups with hypertension treated with a calcium antagonist ( nifedipine ) or angiotensin-converting enzyme inhibitor to define its efficacy in preventing edema caused by antihypertensives . A significant decrease in filtration was observed in the Pycnogenol groups . Pycnogenol controls this type of edema , it helps to prevent and limit long-term damage in the microcirculation in hypertensive patients , and allows the dose of anti-hypertensive drugs to be reduced in most patients Notwithst and ing the availability of antihypertensive drugs and practice guidelines , blood pressure control remains suboptimal . The complexity of current treatment guidelines may contribute to this problem . To determine whether a simplified treatment algorithm is more effective than guideline -based management , we studied 45 family practice s in southwestern Ontario , Canada , using a cluster r and omization trial comparing the simplified treatment algorithm with the Canadian Hypertension Education Program guidelines . The simplified treatment algorithm consisted of the following : ( 1 ) initial therapy with a low-dose angiotensin-converting enzyme inhibitor/diuretic or angiotensin receptor blocker/diuretic combination ; ( 2 ) up-titration of combination therapy to the highest dose ; ( 3 ) addition of a calcium channel blocker and up-titration ; and ( 4 ) addition of a non — first-line antihypertensive agent . The proportion of patients treated to target blood pressure ( systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg for patients without diabetes mellitus or systolic blood pressure < 130 mm Hg and diastolic blood pressure < 80 mm Hg for diabetic patients ) at 6 months was analyzed at the practice level . The proportion of patients achieving target was significantly higher in the intervention group ( 64.7 % versus 52.7 % ; absolute difference : 12.0 % ; 95 % CI : 1.5 % to 22.4 % ; P=0.026 ) . Multivariate analysis of patient-level data showed that assignment to the intervention arm increased the chance of reaching the target by 20 % ( P=0.028 ) , when adjusted for other covariates . In conclusion , the Simplified Treatment Intervention to Control Hypertension Study indicates that a simplified antihypertensive algorithm using initial low-dose fixed-dose combination therapy is superior to guideline -based practice for the management of hypertension Reduction of nephrotic range albuminuria is associated with markedly improved renal and cardiovascular outcome in patients with diabetic nephropathy . Aldosterone has been suggested to play a role in the progression of diabetic nephropathy . We therefore aim ed to evaluate the short-term effect of aldosterone antagonism with spironolactone on nephrotic range albuminuria and blood pressure in diabetic nephropathy . Twenty Caucasian patients with diabetic nephropathy and nephrotic range albuminuria ( > 2500 mg/24 h ) despite recommended antihypertensive treatment completed this double-masked , r and omized crossover trial . Patients were treated in r and om order with spironolactone 25 mg once daily and matched placebo for 2 months , on top of ongoing antihypertensive treatment , including an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker in maximally recommended doses . Median ( range ) number of antihypertensive drugs was 3 ( 2 - 5 ) . After each treatment period , albuminuria , 24-h ambulatory blood pressure , and glomerular filtration rate ( GFR ) were determined . Spironolactone on top of recommended renoprotective treatment induced a 32 % ( 95 % confidence interval ( CI ) : 21 - 42 % ) reduction in albuminuria from ( geometric mean ( 95 % CI ) ) 3718 ( 2910 - 4749 ) mg/24 h on placebo treatment ( P<0.001 ) . There was a significant reduction in 24-h blood pressure of 6 (2 - 10)/4 ( 2 - 6 ) mm Hg and day blood pressure of 7 (3 - 12)/5 ( 3 - 7 ) mm Hg ( P<0.01 ) , whereas night blood pressure remained unchanged . Spironolactone induced an insignificant reversible reduction in GFR of 3 ml/min/1.73 m2 from 64 ( 27 ) ml/min/1.73 m2 . No patients were excluded due to adverse events . Our results suggest that spironolactone treatment on top of recommended renoprotective treatment including maximal renin-angiotensin system blockade may offer additional renoprotection in patients with diabetic nephropathy and nephrotic range albuminuria Abstract Background . We previously reported that the angiotensin II type 1 receptor antagonist c and esartan was effective in reducing blood pressure and microalbuminuria in hypertensive patients with diabetic nephropathy after angiotensin-converting enzyme ( ACE ) inhibitors were replaced due to side effects . In the present study , the clinical effects of c and esartan were investigated and compared with ACE inhibitors in patients with stage 2 or 3A diabetic nephropathy , mainly with respect to the effects on the urinary excretion of albumin and type IV collagen . Methods . Forty-nine patients ( 26 males/23 females ) with diabetic nephropathy ( stage 2 or 3A ) , including normotensive patients , were the study subjects . The patients were treated with either an ACE inhibitor ( 23 patients ) or c and esartan ( 26 patients ) for 11 ± 3 months . The urinary excretion of albumin and urinary type IV collagen was measured . Results . Posttreatment blood pressure tended to decrease , but such a decrease did not reach a statistically significant level , nor did it show any intergroup difference . The urinary albumin excretion was positively correlated with pretreatment mean blood pressure and left ventricular mass index , but the urinary type IV collagen excretion did not show such correlations . The urinary albumin excretion decreased significantly after treatment to a similar extent in both groups , whereas the urinary type IV collagen excretion decreased significantly only in the c and esartan group . Conclusion . It was revealed that ACE inhibitors and c and esartan  reduced urinary albumin excretion to a similar extent in patients with diabetic nephropathy . From the results of the present study , it is inferred that the renoprotective effect of c and esartan in diabetic nephropathy may partially differ from that of ACE inhibitors We tested the hypothesis that blockade of angiotensin II type 1 receptors reduces oxidative stress markers in parallel with urinary albumin and type IV collagen excretions . Sixty-six diabetic patients with nephropathy were r and omly assigned to either the angiotensin II receptor blocker ( ARB ; n=33 ) or trichlormethiazide ( n=33 ) group . The majority of patients had been treated with angiotensin-converting enzyme inhibitors or calcium channel blockers for ≥1 year before the present study . Reduction of blood pressure was not different between the 2 groups , and HbA1c levels did not change over the study period ( 8 weeks ) . Treatment with ARB ( c and esartan 8 mg/day , n=11 or valsartan 80 mg/day , n=22 ) for 8 weeks reduced the levels of plasma monocyte chemoattractant protein 1 , interleukin 6 , urinary 8-epi-prostagl and in F2&agr ; , 8-hydroxydeoxyguanosine , albumin , and type IV collagen , whereas the levels of these markers were not altered with trichlormethiazide ( 2 mg/day ) . Significant correlation was observed between the reduction of the urinary 8-epi- prostagl and in F2&agr ; and 8-hydroxydeoxyguanosine and those of the urinary albumin and type IV collagen . Subjects with large oxidative stress had large reduction rates because of ARB administration and showed large urinary albumin suppression . These results suggest that ARBs  reduce oxidative stress and inflammation in diabetic patients independent of their effects on blood pressure . In addition , increases in oxidative stress caused by angiotensin II may play an important role in the progression of diabetic nephropathy . Our results may help to explain the clinical observation that ARB reduces urinary albumin excretion very efficiently in some patients but not in others Combination therapy with angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors ( ACEIs ) requires further evaluation in patients with diabetic nephropathy and hypertension . In a post hoc analysis of the Olmesartan Reducing Incidence of Endstage renal disease in diabetic Nephropathy Trial with hypertension , we examined the effects of olmesartan on renal and cardiovascular outcomes in the presence or absence of an ACEI . Among 563 patients r and omized to receive either olmesartan ( n=280 ) or placebo ( n=283 ) , 73.5 % ( n=414 ) received a concomitant ACEI . Compared with placebo , olmesartan significantly reduced proteinuria in both the ACEI-treated and non-ACEI-treated groups . The respective changes in the urinary protein creatinine ratio in the olmesartan-treated and placebo-treated groups were −32.6 % and + 21.1 % without an ACEI ( P=0.001 ) and −17.0 % and + 2.2 % with an ACEI ( P=0.028 ) . In the olmesartan group , 115 patients developed primary renal outcomes ( 41.1 % ) compared with 129 ( 45.6 % ) in the placebo group ( hazard ratio ( HR ) : 0.97 , P=0.787 ) . The respective HRs in the ACEI-treated and non-ACEI-treated groups were 1.02 ( P=0.891 ) and 0.84 ( P=0.450 ) . 40 olmesartan-treated patients ( 14.3 % ) and 53 placebo-treated patients ( 18.7 % ) developed secondary cardiovascular outcomes ( HR : 0.65 , P=0.042 ) . The respective HRs in the ACEI-treated and non-ACEI-treated groups were 0.69 ( P=0.129 ) and 0.51 ( P=0.129 ) . Olmesartan was well tolerated . Dual blockade treatment caused more hyperkalemia than monotherapy . In patients with diabetic nephropathy and hypertension  , olmesartan significantly reduced proteinuria , independent of ACEI treatment and cardiovascular outcome but failed to show additional renal benefit compared with ACEI treatment alone . The cardiovascular benefit of dual treatment requires further evaluation Background Free oxygen radicals and insufficiency of antioxidant enzymes have been implicated in the pathogenesis of hypertension disease ( HD ) . Trace elements function as a co-factor in antioxidant enzymes . The antioxidant system and trace elements have been investigated in many different studies including HD , but these subjects have not been investigated as a whole in these patients . Objective The aim of the present study was to investigate the antioxidative system and trace elements in hypertensive patients given different antihypertensive therapy .  Methods We examined  malondialdehyde and superoxide dismutase activities together with copper and zinc levels in plasma of 102 patients with HD and in 51 healthy controls . Results It was found that in patients with HD , plasma malondialdehyde was significantly higher than those of controls , while plasma superoxide dismutase activities were significantly lower in patients with HD . Plasma zinc levels were significantly higher than those of controls and plasma copper levels were significantly lower in patients with HD . Plasma lipid levels and oxidative state were analyzed in five different treatment groups given antihypertensive drug therapy before and after a 3-month treatment period . Conclusions In conclusion , our clinical study shows that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have notable effects on oxidative stress , and are an essential step in managing essential hypertension by the way of improvement of endothelial dysfunction . Although it has been shown that calcium channel blockers , beta blockers and alpha receptor blockers have antioxidant effects in in vitro conditions , we did not demonstrate these effects in our clinical study OBJECTIVE The Captopril Prevention Project ( CAPPP ) evaluated the effects of an ACE inhibitor-based therapeutic regimen on  cardiovascular mortality and morbidity in hypertension .  One planned sub analysis of the CAPPP was to evaluate the outcome in the diabetic patient group . RESEARCH DESIGN AND METHODS In the CAPPP , 572 ( 4.9 % of 10,985 hypertensive patients ) had diabetes at baseline and were studied according to a prospect i ve , r and omized , open , blinded , end point trial design . Patients aged 25 - 66 years with diastolic blood pressure > or = 100 mmHg were included and r and omized to receive either captopril or conventional antihypertensive treatment ( diuretics and /or beta-blockers ) . RESULTS The primary end point , fatal and nonfatal myocardial infa rct ion and stroke as well as other cardiovascular deaths , was markedly lower in the captopril than in the conventional therapy group ( relative risk [ RR ] = 0.59 ; P = 0.018 ) . Specifically , cardiovascular mortality , defined as fatal stroke and myocardial infa rct ion , sudden death , and other cardiovascular death , tended to be lower in the captopril group ( RR = 0.48 ; P = 0.084 ) , and no difference was observed between the study groups for stroke ( RR = 1.02 ; P = 0.96 ) . Myocardial infa rct ions were less frequent in the captopril group than in the conventional therapy group ( RR = 0.34 ; P = 0.002 ) . Furthermore , total mortality was lower in the captopril as compared with the conventional therapy group ( RR = 0.54 ; P = 0.034 ) . Patients with impaired metabolic control seemed to benefit the most from ACE inhibitor-based therapy . CONCLUSIONS Captopril is superior to a diuretic/beta-blocker antihypertensive treatment regimen in preventing cardiovascular events in hypertensive diabetic patients , especially in those with metabolic decompensation Participants : 263 patients ( mean age about 45 years ; 54 % non-diabetic biopsy-proven renal disease , impaired rena ( creatinine clearance rate , 20–70 mL/min ) , persistent prot > 0.3 g/24 h , and hypertension . Patients with proteinuria > Trial : Nakao N , Yoshimura A , Morita H , et al. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor  in non-diabetic renal disease ( COOPERATE ) : a r and omized controlled trial . Lancet 2003 ; 361 : 117 - 124 OBJECTIVE Angiotensin II has been shown to increase hepatic glucose production and decrease insulin sensitivity . Patients who utilize either an ACE inhibitor ( ACEI ) or angiotensin receptor blocker ( ARB )  may experience a decreased incidence of new-onset type 2 diabetes . RESEARCH DESIGN AND METHODS Three review ers conducted a systematic literature search of Medline , EMBASE , CINAHL , and the Cochrane Library ( 1966 to present ) to extract a consensus of trial data involving an ACEI or ARB with an end point of new-onset type 2 diabetes . Studies were included if they were r and omized controlled trials verses placebo/routine therapy . A r and om-effects model was utilized . Subgroup and sensitivity analyses were conducted . RESULTS Eleven trials were identified , including 66,608 patients . An ACEI or ARB prevented new-onset type 2 diabetes ( odds ratio 0.78 [ 95 % CI 0.73 - 0.83 ] ) . The influence of either an ACEI ( six trials ) or an ARB ( five trials ) alone on new-onset type 2 diabetes was similar ( 0.79 [ 0.71 - 0.89 ] and 0.76 [ 0.70 - 0.82 ] , respectively ) . Regardless of indication for use , hypertension ( seven trials ) , coronary artery disease ( two trials ) , or heart failure ( two trials ) , reductions in new-onset type 2 diabetes were maintained ( 0.79 [ 0.72 - 0.85 ] , 0.76 [ 0.60 - 0.95 ] , and 0.70 [ 0.50 - 0.96 ] , respectively ) . No statistical heterogeneity was observed for any evaluation ( P > 0.1 for all comparisons ) . ACEIs and ARBs did not reduce the odds of mortality , cardiovascular , or cerebrovascular events versus control therapy among all of these studies combined or the hypertension trials . ACEIs and ARBs did reduce the odds of these outcomes among the coronary artery disease studies versus control therapy . CONCLUSIONS ACEIs or ARBs may decrease patients ' odds of developing new-onset type 2 diabetes but does not reduce the odds of mortality , cardiovascular , or cerebrovascular outcomes over the study follow-up periods among patients with hypertension BACKGROUND Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers has been shown to lessen the rate of decrease in glomerular filtration rate in patients with diabetic nephropathy . STUDY DESIGN A multicenter open-label r and omized controlled trial to compare the efficacy of combining the angiotensin-converting enzyme inhibitor lisinopril and the angiotensin II receptor blocker irbesartan with that of each drug in monotherapy ( at both high and equipotent doses ) in slowing the progression of type 2 diabetic nephropathy . SETTING & POPULATION 133 patients with type 2 diabetic nephropathy ( age , 66 ± 8 years ; 76 % men ) from 17 centers in Spain . INTERVENTION Patients were r and omly assigned ( 1:1:2 ) to lisinopril ( n = 35 ) , irbesartan ( n = 28 ) , or the combination of both ( n = 70 ) . OUTCOMES The primary composite outcome was a > 50 % increase in baseline serum creatinine level , end-stage renal disease , or death . RESULTS Baseline values for mean estimated glomerular filtration rate and blood pressure were 49 ± 21 mL/min/1.73 m(2 ) and 153 ± 19/81 ± 11 mm Hg . Mean geometric baseline proteinuria was protein excretion of 1.32 ( 95 % CI , 1.10 - 1.62 ) g/g creatinine . After a median follow-up of 32 months , 21 ( 30 % ) patients in the combination group , 10 ( 29 % ) in the lisinopril group , and 8 ( 29 % ) in the irbesartan group reached the primary outcome . HRs were 0.96 ( 95 % CI , 0.44 - 2.05 ; P = 0.9 ) and 0.90 ( 95 % CI , 0.39 - 2.02 ; P = 0.8 ) for the combination versus the lisinopril and irbesartan groups , respectively . There were no significant differences in proteinuria reduction or blood pressure control between groups . The number of adverse events , including hyperkalemia , was similar in all 3 groups . LIMITATIONS The study was not double blind . The sample size studied was small . CONCLUSIONS We were unable to show a benefit of the combination of lisinopril and irbesartan compared to either agent alone at optimal high doses on the risk of progression of type 2 diabetic nephropathy Hypertension is the most common condition seen in primary care and leads to myocardial infa rct ion , stroke , renal failure , and death if not detected early and treated appropriately . Patients want to be assured that blood pressure ( BP ) treatment will reduce their disease burden , while clinicians want guidance on hypertension management using the best scientific evidence . This report takes a rigorous , evidence -based approach to recommend treatment thresholds , goals , and medications in the management of hypertension in adults . Evidence was drawn from r and omized controlled trials , which represent the gold st and ard for determining efficacy and effectiveness . Evidence quality and recommendations were grade d based on their effect on important outcomes . There is strong evidence to support treating hypertensive persons aged 60 years or older to a  BP goal  of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg ; however , there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal , or in those younger than 30 years for a diastolic goal , so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion . The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease ( CKD ) as for the general hypertensive population younger than 60 years . There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor , angiotensin receptor blocker , calcium channel blocker , or thiazide-type diuretic in the nonblack hypertensive population , including those with diabetes . In the black hypertensive population , including those with diabetes , a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy . There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes . Although this guideline provides evidence -based recommendations for the management of high BP and should meet the clinical needs of most patients , these recommendations are not a substitute for clinical judgment , and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient BACKGROUND Microalbuminuria is an early marker of diabetic nephropathy , and its prevention can be considered to be the primary prevention of diabetic nephropathy . Angiotensin converting enzyme inhibitors and non-dihydropyridinic calcium antagonists have specific renoprotective properties in diabetes , and preliminary evidence is available that their combination can delay the onset and limit the progression of nephropathy in experimental diabetes more effectively than either of the two agents alone . DESIGN OF CLINICAL TRIAL The Bergamo Nephrologic Diabetes Complication Trial is a prospect i ve , r and omized , double-blind , parallel-group study aim ed at evaluating the possibility of preventing the onset of nephropathy in 2400 hypertensive non-insulin-dependent diabetes mellitus patients who have a normal albumin excretion rate . During phase A of the study , patients will be r and omized to one of the following treatments for 3 years : a non-dihydropyridinic calcium antagonist ( slow-release verapamil 240 mg/day ) , an angiotensin converting enzyme inhibitor ( tr and olapril 2 mg/day ) , the combination of these drugs ( verapamil 180 mg/day plus tr and olapril 2 mg/day ) and placebo . Other antihypertensive agents will be allowed in order to achieve and maintain systolic and diastolic blood pressures consistently below 140 and 90 mmHg , respectively , in all patients . The primary efficacy variable of phase A will be progression to microalbuminuria . In phase B progression to macro-albuminuria will be evaluated in patients who became microalbuminuric in phase A. These patients will be r and omized to 2 years of treatment with tr and olapril ( 2 mg/day ) alone or combined with verapamil ( 180 mg/day ) OBJECTIVE Evidence suggests that the effectiveness of angiotensin-converting enzyme ( ACE ) inhibition diminishes with time , result ing in increasing angiotensin II levels , the action of which can be inhibited by the addition of an angiotensin receptor blocker ( ARB ) . In the present study , the renal protective effects of ACE inhibitors and ARBs were compared over a five-year period in a prospect i ve , r and omized , open-blind study in 68 nondiabetic Japanese patients with elevated serum creatinine levels . PATIENTS AND METHODS Japanese patients with renal insufficiency were r and omly assigned to receive either an  ACE inhibitor ( benazepril 1.25 to 5 mg daily or tr and olapril 0.5 to 4 mg daily ) or ARB ( c and esartan 2 to 8 mg daily or losartan 25 to 100 mg daily )  at the Kidney Disease Center at Saitama Medical School Hospital . The primary study endpoint was a change in glomerular filtration rate ( GFR ) between the baseline value and the last available value obtained during the five-year treatment period , as estimated by the Cockcraft-Gault equation . Secondary endpoints included the annual changes in GFR , serum creatinine level , urinary protein excretion , and blood pressure , as well as the rate of development of endstage renal disease . RESULTS There were no significant differences in the primary endpoint between the two groups . However , after 4 years , the decline in GFR in patients treated with ARBs was significantly greater than that seen in patients treated with an ACE inhibitor ( p<0.05 ) . Furthermore , the rate of introduction of dialysis therapy was also significantly greater in the ARB-treated patients ( 52.7 % in ACE inhibitor and 81.2 % in ARB group at year 5 . p<0.01 ) . CONCLUSION While our data suggested that ARB , like ACE , treatment might slow the progression of renal dysfunction , it also pointed to the necessity to be alerted to the progression to endstage renal disease with longterm medication Objective : The renin-angiotensin system is thought to be involved in the progression of chronic renal diseases of both diabetic and non-diabetic origin . It has been confirmed that angiotensin-converting enzyme inhibitors ( ACEIs ) and angiotensin II receptor blockers ( ARBs ) reduce urinary protein excretion and attenuate the development of renal injury . Clinical data comparing the renal effects of ACEIs and ARBs , either singly or in combination , are scarce and usually concern the use of st and ard or high doses . Material and Methods : This was a prospect i ve , r and omized , 9-month study of the effects of low doses of losartan ( 25 mg ; n=18 ) versus enalapril ( 10 mg ; n=18 ) versus the combination of losartan ( 25 mg ) and enalapril ( 10 mg ) ( n=16 ) on proteinuria , kidney function and metabolic profile in 54 patients with biopsy-proven chronic glomerulonephritis , hypertension and normal or slightly impaired kidney function . The clinical evaluation and laboratory tests were performed before treatment ( baseline ) and after 3 and 9 months of therapy . Results : After 3 months , significant decreases in proteinuria were observed in all groups : losartan , 22.6 % ( p=0.02 ) ; enalapril , 43 % ( p=0.012 ) ; and combined therapy , 63 % ( p=0.001 ) . This anti-proteinuric effect was even greater after 9 months of therapy : losartan , 44.2 % ( p=0.02 ) ; enalapril , 49.6 % ( p=0.02 ) ; and combined therapy , 51 % ( p=0.003 ) . There was no significant difference between losartan and enalapril with respect to their impact on proteinuria level . Proteinuria reduction was significantly greater in patients receiving combined therapy in comparison with losartan treatment after 3 months of therapy ( p=0.02 ) . Creatinine clearance and serum creatinine were stable during the entire study period in all patients . No significant changes in lipids , serum uric acid or protein levels were observed . Conclusions : These results indicate that proteinuria is reduced by low doses of losartan or enalapril . The combination of these drugs seems to be beneficial and may offer an additional renoprotective effect . This needs to be confirmed in a study with a larger sample size ABCD : Appropriate Blood pressure Control in Diabetes ABI : ankle – brachial index ABPM : ambulatory blood pressure monitoring ACCESS : Acute C and esartan Cilexetil Therapy in Stroke Survival ACCOMPLISH : Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension ACCORD : Action to Control Cardiovascular Risk in Diabetes ACE : angiotensin-converting enzyme ACTIVE I : Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events ADVANCE : Action in Diabetes and Vascular Disease : Preterax and Diamicron-MR Controlled Evaluation AHEAD : Action for HEAlth in Diabetes ALLHAT : Antihypertensive and Lipid-Lowering Treatment to Prevent Heart ATtack ALTITUDE : ALiskiren Trial In Type 2 Diabetes Using Cardio-renal Endpoints ANTIPAF : ANgioTensin II Antagonist In Paroxysmal Atrial Fibrillation APOLLO : A R and omized Controlled Trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly People ARB : angiotensin receptor blocker ARIC : Atherosclerosis Risk In Communities ARR : aldosterone renin ratio ASCOT : Anglo-Sc and inavian Cardiac Outcomes Trial ASCOT-LLA : Anglo-Sc and inavian Cardiac Outcomes Trial — Lipid Lowering Arm ASTRAL : Angioplasty and STenting for Renal Artery Lesions A-V : atrioventricular BB : beta-blocker BMI : body mass index BP : blood pressure BSA : body surface area CA : calcium antagonist CABG : coronary artery bypass graft CAPPP : CAPtopril Prevention Project CAPRAF : C And esartan in the Prevention of Relapsing Atrial Fibrillation CHD : coronary heart disease CHHIPS : Controlling Hypertension and Hypertension Immediately Post-Stroke CKD : chronic kidney disease CKD-EPI : Chronic Kidney Disease — EPIdemiology collaboration CONVINCE : Controlled ONset Verapamil INvestigation of CV Endpoints CT : computed tomography CV : cardiovascular CVD : cardiovascular disease D : diuretic DASH : Dietary Approaches to Stop Hypertension DBP : diastolic blood pressure DCCT : Diabetes Control and Complications Study DIRECT : DIabetic REtinopathy C and esartan Trials DM : diabetes mellitus DPP-4 : dipeptidyl peptidase 4 EAS : European Atherosclerosis Society EASD : European Association for the Study of Diabetes ECG : electrocardiogram EF : ejection fraction eGFR : estimated glomerular filtration rate ELSA : European Lacidipine Study on Atherosclerosis ESC : European Society of Cardiology ESH : European Society of Hypertension ESRD : end-stage renal disease  EXPLOR : Amlodipine – Valsartan Combination Decreases Central Systolic Blood Pressure more Effectively than the Amlodipine – Atenolol Combination FDA : U.S. Food and Drug Administration FEVER : Felodipine EVent Reduction study GISSI-AF : Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Atrial Fibrillation HbA1c : glycated haemoglobin HBPM : home blood pressure monitoring HOPE : Heart Outcomes Prevention Evaluation HOT : Hypertension Optimal Treatment HRT : hormone replacement therapy HT : hypertension HYVET : HYpertension in the Very Elderly Trial IMT : intima-media thickness I-PRESERVE : Irbesartan in Heart Failure with Preserved Systolic Function INTERHEART : Effect of Potentially Modifiable Risk Factors associated with Myocardial Infa rct ion in 52 Countries INVEST : INternational VErapamil SR/T Tr and olapril ISH : Isolated systolic hypertension JNC : Joint National Committee JUPITER : Justification for the Use of Statins in Primary Prevention : an Intervention Trial Evaluating Rosuvastatin LAVi : left atrial volume index LIFE : Losartan Intervention For Endpoint Reduction in Hypertensives LV : left ventricle/left ventricular LVH : left ventricular hypertrophy LVM : left ventricular mass MDRD : Modification of Diet in Renal Disease MRFIT : Multiple Risk Factor Intervention Trial MRI : magnetic resonance imaging NORDIL : The Nordic Diltiazem Intervention study OC : oral contraceptive OD : organ damage ONTARGET : ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial PAD : peripheral artery disease PATHS : Prevention And Treatment of Hypertension Study PCI : percutaneous coronary intervention PPAR : peroxisome proliferator-activated receptor PREVEND : Prevention of REnal and Vascular ENdstage Disease PROFESS : Prevention Regimen for Effectively Avoiding Secondary Strokes PROGRESS : Perindopril Protection Against Recurrent Stroke Study PWV : pulse wave velocity QALY : Quality adjusted life years RAA : renin-angiotensin-aldosterone RAS : renin-angiotensin system RCT : r and omized controlled trials RF : risk factor ROADMAP : R and omized Olmesartan And Diabetes MicroAlbuminuria Prevention SBP : systolic blood pressure SCAST : Angiotensin-Receptor Blocker C and esartan for Treatment of Acute STroke SCOPE : Study on COgnition and Prognosis in the Elderly SCORE : Systematic COronary Risk Evaluation SHEP : Systolic Hypertension in the Elderly Program STOP : Swedish Trials in Old Patients with Hypertension STOP-2 : The second Swedish Trial in Old Patients with Hypertension SYSTCHINA : SYSTolic Hypertension in the Elderly : Chinese trial SYSTEUR : SYSTolic Hypertension in Europe TIA : transient ischaemic attack TOHP : Trials Of Hypertension Prevention TRANSCEND : Telmisartan R and omised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease UKPDS : United Kingdom Prospect i ve Diabetes Study VADT : Veterans ' Affairs Diabetes Trial VALUE : Valsartan Antihypertensive Long-term Use Evaluation WHO : World Health Organization # # # 1.1 Principles The 2013 guidelines on hypertension of the European Society of Hypertension ( ESH ) and the European Society of Cardiology BACKGROUND Few studies have directly compared the renoprotective effects of angiotensin II-receptor blockers and angiotensin-converting-enzyme ( ACE ) inhibitors in persons with type 2 diabetes . METHODS In this prospect i ve , multicenter , double-blind , five-year study , we r and omly assigned 250 subjects with type 2 diabetes and early nephropathy to receive either the angiotensin II-receptor blocker telmisartan ( 80 mg daily , in 120 subjects ) or the ACE inhibitor enalapril ( 20 mg daily , in 130 subjects ) . The primary end point was the change in the glomerular filtration rate ( determined by measuring the plasma clearance of iohexol ) between the baseline value and the last available value during the five-year treatment period . Secondary end points included the annual changes in the glomerular filtration rate , serum creatinine level , urinary albumin excretion , and blood pressure ; the rates of end-stage renal disease and cardiovascular events ; and the rate of death from all causes . RESULTS After five years , the change in the glomerular filtration rate was -17.5 ml per minute per 1.73 m2 ( where the minus sign denotes a decrement ) in the telmisartan-treated subjects , as compared with -15.0 ml per minute per 1.73 m2 in the enalapril-treated subjects ; the treatment difference was thus -2.6 ml per minute per 1.73 m2 ( 95 percent confidence interval , -7.1 to 2.0 ml per minute per 1.73 m2)[corrected ] The lower boundary of the confidence interval , in favor of enalapril , was greater than the predefined margin of -10.0 ml per minute per 1.73 m2 , indicating that telmisartan was not inferior to enalapril . The effects of the two agents on the secondary end points were not significantly different after five years . CONCLUSIONS Telmisartan is not inferior to enalapril in providing long-term renoprotection in persons with type 2 diabetes . These findings do not necessarily apply to persons with more advanced nephropathy , but they support the clinical equivalence of angiotensin II-receptor blockers and ACE inhibitors in persons with conditions that place them at high risk for cardiovascular events OBJECTIVES The purpose of this study was to determine if statins ( hydroxymethylglutaryl CoA reductase inhibitors [ HMG-CoA ] ) , angiotensin-converting enzyme ( ACE ) inhibitors , and angiotensin receptor blockers ( ARBs ) reduce cardiovascular ( CV ) events and pulmonary morbidity in chronic obstructive pulmonary disease ( COPD ) patients . BACKGROUND Few current COPD therapies alter prognosis . Although statins , ACE inhibitors , and ARBs improve outcomes in CV population s , their benefits in COPD patients both with and without concomitant heart disease has not previously been studied . METHODS A time-matched nested case-control study of two population -based retrospective cohorts was undertaken : 1 ) COPD patients having undergone coronary revascularization ( high CV risk cohort ) ; and 2 ) COPD patients without previous myocardial infa rct ion ( MI ) and newly treated with nonsteroidal anti-inflammatory drugs ( low CV risk cohort ) . Prespecified outcomes were COPD hospitalization , MI , and total mortality . RESULTS These drugs reduced both CV and pulmonary outcomes , with the largest benefits occurring with the combination of statins and either ACE inhibitors or ARBs . This combination was associated with a reduction in COPD hospitalization ( risk ratio [ RR ] 0.66 , 95 % confidence interval [ CI ] 0.51 to 0.85 ) and total mortality ( RR 0.42 , 95 % CI 0.33 to 0.52 ) not only in the high CV risk cohort but also in the low CV risk cohort ( RR 0.77 , 95 % CI 0.67 to 0.87 , and RR 0.36 , 95 % CI 0.28 to 0.45 , respectively ) . The combination also reduced MI in the high CV risk cohort ( RR 0.39 , 95 % CI 0.31 to 0.49 ) . Benefits were similar when steroid users were included . CONCLUSIONS These agents may have dual cardiopulmonary protective properties , thereby substantially altering prognosis of patients with COPD . These findings need confirmation in r and omized clinical trials The study was design ed to assess the antihypertensive effect of combined angiotensin-converting enzyme ( ACE ) inhibition and angiotensin II type 1 receptor ( AT1 ) antagonism in patients with essential hypertension . Twenty patients with uncontrolled ambulatory diastolic blood pressure ( BP ) after 6 weeks of ACE inhibitor monotherapy ( benazepril , 20 mg , o.d . ) were r and omized to receive double-blind valsartan , 80 mg , o.d . ( AT1 antagonist ) or matching placebo for 5 weeks while continuing to receive background benazepril . Then patients crossed over to the alternative regimen for a second 5-week period . The 24-h ambulatory BP was monitored on the final day of the benazepril monotherapy period and on the final day of each double-blind treatment period . Valsartan added to benazepril produced a significant antihypertensive effect with a benefit over placebo of 6.5 + /- 12.6/4.5 + /- 8.0 mm Hg ( systolic/diastolic ) for average awake ambulatory BP ( p < 0.05 ) , 7.1 + /- 9.4/5.6 + /- 6.5 mm Hg for asleep BP ( p < 0.01 ) , and 6.8 + /- 9.7/4.9 + /- 6.8 mm Hg for average 24-h ambulatory BP ( p < 0.01 ) . Pulse rate was unaffected . Plasma active renin was higher on the benazepril-valsartan combination compared with benazepril-placebo ( p < 0.05 ) . There was no change in routine biochemical variables when valsartan was added to benazepril . Six patients reported mild dizziness or fatigue ( three also with placebo ) . These data suggest that in hypertensive patients uncontrolled with an ACE inhibitor , the addition of an AT1 antagonist provides a powerful and safe antihypertensive drug combination The angiotensin-converting enzyme ( ACE ) inhibitor tr and olapril , a non-sulfhydryl prodrug which is hydrolysed into tr and olaprilat , was studied in 322 hypertensives of African – American descent using a double-blind , r and omised , placebo-controlled , parallel study design . Following 6 weeks of double-blind treatment with placebo or 0.25 to 16 mg/day tr and olapril , an analysis of drug effect on trough blood pressure ( BP ) stratified by age , gender , weight , pre-treatment plasma renin activity , and tr and olaprilat concentration was performed . Two mg was the lowest effective tr and olapril dose , whereas doses above 4 mg did not significantly reduce trough BP . Reduction in BP did not correlate with trough plasma tr and olaprilat concentration . Pre-treatment plasma renin activity was not a reliable indicator of antihypertensive response , as similar reductions in BP occurred even in patients with the lowest renin levels . There were no observable differences based on age , gender or measurements of the renin-angiotensin- aldosterone axis . In conclusion , neither age , gender or plasma renin activity influenced anti-hypertensive response to angiotensin-converting enzyme inhibition in African – INTRODUCTION Blockade of the renin-angiotensin-aldosterone system ( RAAS ) by either the angiotensin converting enzyme inhibitor ( ACE-I ) or the angiotensin II receptor blocker ( ARB ) has been shown to reduce albuminuria and delay the progression of diabetic nephropathy . This study evaluated the effect of dual blockade of the RAAS by adding an ACEI or an ARB to the administration of either drug alone on albuminuria in Asian type 2 diabetic patients with nephropathy . METHODS 34 patients were r and omly assigned to receive either enalapril 20 mg or losartan 100 mg once daily for eight weeks . Following this , all patients received a combination of enalapril 10 mg and losartan 50 mg daily for eight weeks , followed by enalapril 20 mg and losartan 100 mg daily for another eight weeks . The blood pressure and 24-hour urinary albumin excretion ( UAE ) were monitored . RESULTS Following monotherapy with enalapril , there was a mean and st and ard error ( SE ) reduction in the UAE and mean arterial pressure ( MAP ) of 9.8 ( SE 6.8 ) percent ( p-value is 0.061 ) and 5.3 ( SE 2.2 ) mmHg ( p-value is 0.026 ) , respectively ; the reduction in UAE and MAP following monotherapy with losartan was by 10.9 ( SE 14.1 ) percent ( p-value is 0.053 ) and 4.5 ( SE 1.9 ) mmHg ( p-value is 0.034 ) , respectively . Combination therapy with enalapril and losartan further reduced the UAE ( 11.2 [ SE 8.7 ] percent , p-value is 0.009 ] despite there being no significant change in the MAP ( -1.2 [ SE 1.47 ] mmHg , p-value is 0.42 ) . The adverse effects included dry cough ( seven [ 19.4 percent ] patients , result ing in the withdrawal of medication in two patients ) , and transient hyperkalaemia ( two [ six percent ] patients ) . CONCLUSION Dual blockade of the RAAS is safe and effective in reducing albuminuria in Asian type 2 diabetic patients with nephropathy The degree of arterial stiffness is correlated with the risk of cardiovascular diseases and it is a powerful predictor for morbidity and mortality . Studies have shown that arterial stiffness reduction is associated with an improvement in survival . Reduction of arterial stiffness by pharmacological drugs varies according to the drugs and doses used and duration of treatment . This effect on the arteries differs among the various classes of drugs and among individual drugs in the same class . Quantification of the stiffness and other properties of the arterial wall can be used to monitor the responses to therapy in individuals with hypertension and other cardiovascular diseases . These measures can then be used as surrogate markers for the risk of clinical events . Inhibition of the renin-angiotensin system ( RAS ) is associated with an important decrease in cardiovascular risk . Findings from clinical trials support the hypothesis that the protective effects of RAS inhibition are partly independent from blood pressure reduction and related to several mechanisms including vascular protective effects . The aim of the TRanscend Arterial stiffNess Sub study ( TRANS ) is to assess the effect of an angiotensin II receptor blocker ( ARB ) , telmisartan , on the arterial stiffness in a subgroup of patients from the Telmisartan R and omized Assessment Study in aCE iNtolerant subjects with cardiovascular Disease ( TRANSCEND ) trial . The TRANSCEND trial is an international , multicenter , r and omized double blind placebo controlled trial of telmisartan that enrolled patients at high risk for cardiovascular events . Some clinical baseline data of the TRANS sub study are reported . When completed , the results of the TRANS sub study will show whether the beneficial effects of treatment with telmisartan on cardiovascular outcome may be related to an improvement in arterial stiffness
We found predominantly moderate quality evidence that all-cause mortality is similar when first-line RAS inhibitors are compared to other first-line antihypertensive agents .
First-line thiazides caused less HF and stroke than first-line RAS inhibitors .
Compared with first-line CCBs , first-line RAS inhibitors reduced HF but increased stroke .
The magnitude of the reduction in HF exceeded the increase in stroke .
The small differences in effect on blood pressure between the different classes of drugs did not correlate with the differences in the primary outcomes
BACKGROUND Renin-angiotensin system ( RAS ) inhibitors are widely prescribed for treatment of hypertension , especially for diabetic patients on the basis of postulated advantages for the reduction of diabetic nephropathy and cardiovascular morbidity and mortality .
Despite widespread use of angiotensin converting enzyme ( ACE ) inhibitors and angiotensin receptor blockers ( ARBs ) for hypertension in both diabetic and non-diabetic patients , the efficacy and safety of RAS inhibitors compared to other antihypertensive drug classes remains unclear .
OBJECTIVES To evaluate the benefits and harms of first-line RAS inhibitors compared to other first-line antihypertensive drugs in patients with hypertension .