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Type 2 diabetes mellitus complicated by hypertension in Japanese patients: switching treatment from high-dose angiotensin II receptor blockers to losartan plus hydrochlorothiazide.
Yamamoto, S, Okada, Y, Mori, H, Nishida, K, Uriu, K, Tanaka, Y
Internal medicine (Tokyo, Japan). 2014;(12):1283-9
Abstract
OBJECTIVE The aim of the present study was to assess changes in blood pressure and metabolism after switching treatment from maximum-dose angiotensin II receptor blocker (ARB) therapy to a mixture of conventional-dose ARBs and low-dose diuretics. METHODS This study was conducted among 43 Japanese patients with type 2 diabetes complicated with hypertension in whom continuous treatment with high doses of ARBs did not reduce their blood pressure to the target level (a systolic blood pressure of 130 mmHg or lower and a diastolic blood pressure of 80 mmHg or lower). The antihypertensive and metabolic effects of switching from high-dose ARBs to a combination of losartan (50 mg/day) plus hydrochlorothiazide (12.5 mg/day) were examined. The primary endpoint was a decrease in blood pressure at 24 weeks. RESULTS The combination treatment significantly decreased both systolic (baseline: 147±11; 24 weeks: 133±13 mmHg) and diastolic (baseline: 79±8; 24 weeks: 72±10 mmHg) blood pressure. This treatment was also associated with a significant increase in the HbA1c level (baseline: 7.0±0.8%; 24 weeks: 7.2±0.9%) and a significant decrease in the urinary albumin-creatinine ratio (baseline: 280±590; 24 weeks: 110±253 mg/g creatinine). However, the combination treatment had no effect on lipid metabolism or the serum uric acid or potassium levels. CONCLUSION In patients with diabetes, sodium reabsorption in the renal tubules is enhanced, which leads to the development of salt-sensitive hypertension. Therefore, the concurrent use of a diuretic that promotes sodium excretion can increase the antihypertensive effects of other drugs. This study demonstrated that switching from high-dose ARB treatment to losartan/hydrochlorothiazide combination therapy results in significant control of blood pressure.
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Characteristics of children and young adults with Marfan syndrome and aortic root dilation in a randomized trial comparing atenolol and losartan therapy.
Lacro, RV, Guey, LT, Dietz, HC, Pearson, GD, Yetman, AT, Gelb, BD, Loeys, BL, Benson, DW, Bradley, TJ, De Backer, J, et al
American heart journal. 2013;(5):828-835.e3
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BACKGROUND The Pediatric Heart Network designed a clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in children and young adults with Marfan syndrome randomized to receive atenolol or losartan. We report here the characteristics of the screened population and enrolled subjects. METHODS AND RESULTS Between 2007 and 2011, 21 clinical sites randomized 608 subjects, aged 6 months to 25 years who met the original Ghent criteria and had a body surface area-adjusted aortic root diameter z-score >3.0. The mean age at study entry was 11.2 years, 60% were male, and 25% were older teenagers and young adults. The median aortic root diameter z-score was 4.0. Aortic root diameter z-score did not vary with age. Mitral valve prolapse and mitral regurgitation were more common in females. Among those with a positive family history, 56% had a family member with aortic surgery, and 32% had a family member with a history of aortic dissection. CONCLUSIONS Baseline demographic, clinical, and anthropometric characteristics of the randomized cohort are representative of patients in this population with moderate to severe aortic root dilation. The high percentage of young subjects with relatives who have had aortic dissection or surgery illustrates the need for more definitive therapy; we expect that the results of the study and the wealth of systematic data collected will make an important contribution to the management of individuals with Marfan syndrome.
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Efficacy and safety of the losartan-hydrochlorothiazide combination tablet in patients with hypertension uncontrolled by angiotensin II receptor antagonist therapy: the Aichi Research on Combination therapy for Hypertension (ARCH) Study.
Maeda, K, Adachi, M, Kinoshita, A, Koh, N, Miura, Y, Murohara, T
Internal medicine (Tokyo, Japan). 2012;(10):1167-75
Abstract
BACKGROUND The guidelines recommend combination therapy for patients who are unable to achieve target BP with monotherapy; some fixed dose therapies including an angiotensin II receptor blocker (ARB) and diuretics are available in Japan. However, to date there have been few reports on this long-term treatment and the patient profiles suited for this combination remain ambiguous. METHOD The Aichi Research on Combination therapy for Hypertension Study was a multicenter, open-label, prospective observational study that investigated the efficacy and safety of 1-year treatment with the losartan-hydrochlorothiazide (HCTZ) combination tablet in patients with hypertension uncontrolled by either ARB monotherapy or combination therapy with a calcium channel blocker (CCB). An ARB was switched to a losartan-HCTZ tablet after a pre-observation period. RESULTS A total of 614 of 648 patients were evaluable (mean age, 66.3 years; 52.8% men; mean baseline blood pressure, BP, 157.7/87.9 mmHg). The BP had decreased significantly to 138.0/78.2 mmHg by month 3 (p<0.001, t-test), and 36.2% of the patients had achieved their target BP. The hypotensive effect lasted for 1 year and was found equally in the losartan-HCTZ arm and the losartan-HCTZ plus CCB arm. A stratified analysis showed significant hypotensive effects in patients with higher baseline BP, women, and patients who did not drink alcohol (p<0.001, unpaired t-test). CONCLUSION The losartan-HCTZ combination tablet was found to have an early hypotensive effect, good tolerability, and stable long-term benefits in patients with hypertension uncontrolled by ARB monotherapy or combination therapy with a CCB.
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A randomized trial comparing the effect of ramipril and losartan in survivors of ST-elevation myocardial infarction.
Marinsek, M, Sinkovic, A
The Journal of international medical research. 2009;(5):1577-87
Abstract
This study investigated the effect of 8 weeks of treatment with ramipril or losartan on N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels, plasminogen activator inhibitor-1 (PAI-1) activity, echocardiographic parameters and lipid profiles in patients after acute myocardial infarction (MI). Patients were randomly assigned to receive up to 10 mg/day ramipril (n = 27) or up to 100 mg/day losartan (n = 26). No significant differences in any of the tested variables were observed between the two treatment groups, either before or after treatment. Within the losartan-treated group a significant decrease in levels of NT-proBNP (211.1 +/- 211.5 versus 94.7 +/- 150.1 pg/ml), total cholesterol (5.7 +/- 1.0 versus 4.6 +/- 1.1 mmol/l), and low-density lipoprotein-cholesterol (3.5 +/- 0.9 versus 2.7 +/- 1.0 mmol/l) was observed after treatment compared with baseline. Thus, after an acute MI, losartan seems equal to ramipril in terms of the NT-proBNP levels, echocardiographic parameters, PAI-1 activity and lipid profiles that were achieved.
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Combination angiotensin receptor blocker/hydrochlorothiazide as initial therapy in the treatment of patients with severe hypertension.
Salerno, CM, Demopoulos, L, Mukherjee, R, Gradman, AH
Journal of clinical hypertension (Greenwich, Conn.). 2004;(11):614-20
Abstract
Patients with severe hypertension are at high risk for cardiovascular events. The authors hypothesized that initial treatment with a combination angiotensin receptor blocker/diuretic agent would be safe and more effective than initial treatment with a single agent for these patients. In this 6-week, double-blind trial, 585 patients were randomized to losartan/hydrochlorothiazide or losartan as monotherapy and titrated as needed at 2-week intervals to reach goal blood pressure (<90 mm Hg). Almost twice as many patients achieved goal at the primary end point of 4 weeks on 50 mg losartan/12.5 mg hydrochlorothiazide vs. the losartan regimen (50-100 mg; p=0.002). Additionally, almost three times as many patients achieved goal blood pressures at 6 weeks (p<0.001). Adverse experiences on losartan/hydrochlorothiazide (43%) were significantly less than with the angiotensin receptor blocker alone (52.6%). This study confirmed the efficacy and tolerability of initial use of a fixed combination of losartan/hydrochlorothiazide vs. losartan without a thiazide.
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Renoprotective effect of losartan in comparison to amlodipine in patients with chronic kidney disease and hypertension--a report of the Japanese Losartan Therapy Intended for the Global Renal Protection in Hypertensive Patients (JLIGHT) study.
Iino, Y, Hayashi, M, Kawamura, T, Shiigai, T, Tomino, Y, Yamada, K, Kitajima, T, Ideura, T, Koyama, A, Sugisaki, T, et al
Hypertension research : official journal of the Japanese Society of Hypertension. 2004;(1):21-30
Abstract
A 12-month, multicenter (57 clinical institutions), randomized, open-labeled trial was undertaken to compare the efficacy of the angiotensin II receptor antagonist losartan and the calcium channel blocker amlodipine in patients with proteinuric chronic kidney disease (CKD) and hypertension. A total of 117 patients (79, chronic glomerulonephritis; 14, diabetic nephropathy; 24, other CKD) were randomly allocated into two treatment groups. Losartan and amlodipine exerted the same efficacy for blood pressure (BP) control; however, losartan significantly reduced the 24-h urinary protein excretion at months 3, 6, and 12, with the reduction of 20.7%, 35.2%, 35.8%, whereas amlodipine did not change the amount of proteinuria over the 12-month study period. When patients were stratified into groups according to the level of BP control at 3 months, the reduction in urinary protein excretion by losartan was evident in the group for which a BP of <140/90 mmHg was achieved, as well as in the group for which the goal BP (<130/85 mmHg) for treatment of CKD was not achieved. When patients were stratified according to baseline urinary protein excretion, those with > or = 2 g/day showed a reduction in proteinuria by losartan of 23.3%, 39.4%, and 47.9% at months 3, 6, and 12, and those with <2 g/day showed a reduction of 18.5% and 31.2% at months 3 and 6, respectively. No fatal adverse events were experienced in either drug group. We conclude that losartan reduced proteinuria in patients with CKD and hypertension. This positive effect may contribute to the renal protective benefit of losartan, and is beyond the magnitude of BP control.
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Tonic levels of angiotensin II reduce tonic levels of vascular nitric oxide even in salt-replete man.
Sim, JS, Farquharson, C, Struthers, AD
Journal of the renin-angiotensin-aldosterone system : JRAAS. 2004;(2):84-8
Abstract
INTRODUCTION Losartan improves stimulated endothelial function in patients with cardiovascular disease, but there are no data to establish whether losartan has this effect in normal man. Furthermore, whether losartan improves basal nitric oxide (NO) activity is controversial. We therefore examined whether treatment with losartan improved basal NO activity in normal, salt-replete man. If so, this would imply that tonic levels of angiotensin II (Ang II) reduce tonic basal levels of NO, even in salt-replete normal man. METHODS We performed a randomised, placebo-controlled, double-blind crossover study in 24 healthy volunteers, comparing losartan 50 mg daily for one month versus placebo. Brachial artery endothelial function was assessed by bilateral venous occlusion plethysmography, measuring the response to intra-arterial infusions of the endothelial-dependent and endothelial-independent vasodilators, acetylcholine and sodium nitroprusside respectively and the endothelial-dependent vasoconstrictor NG-monomethyl-L-arginine. Results were analysed by multiple analysis of variance and statistical significance was taken as a p value of RESULTS Losartan significantly increased the vasoconstriction in response to NG-monomethyl-L-arginine (-37+2% vs. -32+2%, losartan vs. placebo; p=0.05). Losartan improved the vasodilatation response to acetylcholine; however, this result did not reach significance (214+20% vs. 174+20%, losartan vs. placebo; p=0.15). Losartan did not affect the response to nitroprusside (172+15% vs. 176+16%, losartan vs. placebo; p=0.84). There was no significant difference in blood pressure between the two study days. CONCLUSIONS Losartan improves basal NO bioactivity in healthy salt-replete volunteers. Even in salt-replete man, basal Ang II levels exert a tonic effect, which reduces basal NO.
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The JNC 7 approach compared to conventional treatment in diabetic patients with hypertension: a double-blind trial of initial monotherapy vs. combination therapy.
Fox, JC, Leight, K, Sutradhar, SC, Demopoulos, LA, Gleim, GW, Lewin, AJ, Bakris, GL
Journal of clinical hypertension (Greenwich, Conn.). 2004;(8):437-42; quiz 443-4
Abstract
The JNC 7 states that persons with blood pressure (BP) more than 20/10 mm Hg above goal should be started on combination drug therapy. This criterion includes patients with BP >160/100 mm Hg and diabetics with hypertension. The goal BP for persons with diabetes mellitus is <130/80 mm Hg. A randomized, double-blind trial force titrated initial combination therapy utilizing an angiotensin receptor blocker (ARB) combination (losartan/hydrochlorothiazide [LOS/HCTZ]) compared with an angiotensin-converting enzyme (ACE) inhibitor (ramipril), for 8 weeks, and tested the hypothesis that combination therapy is more likely to achieve goal BP vs. monotherapy. At 4 weeks, 30.5% of LOS/HCTZ and 14.4% of ramipril recipients achieved goal diastolic BP (p<0.001). More participants achieved goal systolic BP in the ARB/HCTZ group at 4 weeks (29.8% vs. 14.4%; p<0.001). At 4 weeks, mean diastolic BP had decreased 10.2+/-7.4 mm Hg in the LOS/HCTZ group compared with 6.4+/-6.8 mm Hg in the ramipril group (p<0.001), and systolic BP had fallen 15.4+/-13.1 mm Hg in the ARB/HCTZ compared with 9.2+/-10.2 mm Hg in the ACE-inhibitor group (p<0.001). Significant differences favoring the combination were also noted at 8 weeks. Drug-related adverse experiences were 10.3% for the combination compared with 12.7% for the monotherapy group. Initial combination therapy with an ARB/HCTZ was more effective than ACE-inhibitor monotherapy in achieving BP goals in participants with diabetes with no significant differences in the incidence of adverse experiences. These observations confirm other studies of combination therapies, such as b blocker/diuretic, ACE inhibitor/diuretic, or ACE inhibitor/calcium channel blocker. The use of two medications will achieve goal BP in more patients than monotherapy. This observation is important in treatment of high-risk patients with diabetes.
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Effects of losartan on diabetic maculopathy in type 2 diabetic patients: a randomized, double-masked study.
Knudsen, ST, Bek, T, Poulsen, PL, Hove, MN, Rehling, M, Mogensen, CE
Journal of internal medicine. 2003;(2):147-58
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OBJECTIVE Diabetic maculopathy (DMa) is a leading cause of visual loss in the western world. Preliminary studies have suggested that angiotensin converting enzyme inhibitors might be effective in preventing the progression of diabetic retinopathy, but no studies have quantitatively assessed the effect of this treatment on macular oedema in patients with DMa. We evaluated the effect of treatment with the angiotensin II receptor antagonist losartan on macular oedema and hard exudates in patients with an advanced stage of DMa. DESIGN Randomized, placebo-controlled, double-masked and parallel-group trial. SETTING Academic medical centre. SUBJECTS Twenty-four type 2 diabetic patients with DMa. INTERVENTION Subjects were randomly assigned to a 4-month treatment with either losartan (50 mg o.d.) or placebo. MAIN OUTCOME MEASURES (i) Degree of macular oedema as estimated by optical coherence tomography scanning of the retina; (ii) fundus photography and flourescein angiography; (iii) 24-h ambulatory blood pressure (BP); (iv) urinary albumin excretion (UAE); and (v) transcapillary escape rate of albumin (TERalb). RESULTS Central retinal thickness increased from 244 +/- 16 to 256 +/- 31 microm in the losartan group, whilst there was no change in the placebo group (245 +/- 36 microm vs. 242 +/- 30 microm), P = 0.017. Day BP were lowered in the losartan group (from 144/83 +/- 17/10 to 138/78 +/- 20/11 mmHg) compared with the placebo group (140/81 +/- 14/5 to 139/82 +/- 13/9 mmHg), P = 0.27 for systolic and P = 0.009 for diastolic BP. Importantly, there were no changes in night BP in any of the groups. We found no changes in the number of hard exudates, semiquantitative retinopathy grade, visual acuity, UAE, or TERalb in any of the groups. CONCLUSIONS Type 2 diabetic patients with maculopathy do not seem to benefit from short-term treatment with losartan (50 mg once daily) as far as retinal thickness is concerned, as this dose may increase retinal thickness in the central macular area. Long-term studies are required to assess the clinical implications of these findings.
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Efficacy of losartan in patients with primary focal segmental glomerulosclerosis resistant to immunosuppressive treatment.
Usta, M, Ersoy, A, Dilek, K, Ozdemir, B, Yavuz, M, Güllülü, M, Yurtkuran, M
Journal of internal medicine. 2003;(3):329-34
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OBJECTIVES Angiotensin II may play an important role in the progression of renal disease. Currently, angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists are commonly used for renoprotection. To our knowledge, there is no study investigating this effect of angiotensin II receptor antagonists in patients with primary focal segmental glomerulosclerosis (FSGS) in the literature. The aim of this study was to evaluate the effects of losartan on proteinuria and renal function in patients with FSGS refractory to immunosuppressive treatment. DESIGN Twenty-three normotensive patients with FSGS proven through renal biopsy were included in the study. Thirteen of them, five men and eight women, were given losartan in a dose of 50 mg day(-1) during 12 months, and 10, four men and six women, were in the control group. Mean arterial blood pressure (MAP), 24-h urine protein excretion, serum total protein and albumin levels were determined just before the start of treatment as well as after 1, 6 and 12 months of the study. In addition, serum creatinine, creatinine clearance (CrCl), cholesterol and triglyceride levels were determined at the beginning and end of the study. RESULTS Age, gender and baseline levels of proteinuria, serum albumin, total protein, creatinine, CrCl and MAPs were similar in the two groups. Nephrotic range of proteinuria was present in five of 13 patients (38.4%) in the losartan group and in four of 10 patients (40%) in the control group. In the losartan group, 24-h proteinuria had decreased from 3.6 +/- 0.5 g to 2.3 +/- 0.5 g after 1 month, to 2.4 +/- 0.7 g after 6 months and to 1.9 +/- 0.7 g after 12 months. In the control group, a significant increase in proteinuria compared with the baseline value was noticed after 12 months. Proteinuria levels were significantly higher in the control group than in the losartan group after 6 and 12 months. Whilst total protein and albumin levels increased in the losartan group, they did not change significantly in the control group. The total protein levels after 6 and 12 months, and albumin levels after 6 months were significantly higher in the losartan group than in the control group. No significant change was observed between the baseline and the 12-month creatinine and CrCl levels of the groups when intra- and inter-group comparisons were made. Furthermore, serum cholesterol levels of the losartan group were reduced significantly. The changes in MAP values did not reach significant levels in either of the groups. There was no correlation between the percentage changes in MAP and in proteinuria of the losartan group after 12 months. CONCLUSIONS Angiotensin II receptor antagonists may be an alternative therapy in FSGS patients who are resistant to immunosuppressive therapy.