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On-treatment HDL cholesterol predicts incident atrial fibrillation in hypertensive patients with left ventricular hypertrophy.
Okin, PM, Hille, DA, Wachtell, K, Kjeldsen, SE, Julius, S, Devereux, RB
Blood pressure. 2020;(5):319-326
Abstract
Purpose: Hypertensive patients are at increased risk of atrial fibrillation (AF). Although low baseline high density lipoprotein (HDL) cholesterol has been associated with a higher risk of AF, this has not been verified in recent population-based studies. Whether changing levels of HDL over time are more strongly related to the risk of new AF in hypertensive patients has not been examined.Material and methods: Incident AF was examined in relation to baseline and on-treatment HDL levels in 8267 hypertensive patients with no history of AF, in sinus rhythm on their baseline electrocardiogram, randomly assigned to losartan- or atenolol-based treatment. HDL levels at baseline and each year of testing were categorised into quartiles according to baseline HDL levels.Results: During 4.7 ± 1.10 years of follow-up, 645 patients (7.8%) developed new AF. In univariate Cox analyses, compared with the highest quartile of HDL levels (>1.78 mmol/l), patients with on-treatment HDL in the lowest quartile (≤ 1.21 mmol/l) had a 53% greater risk of new AF. Patients with on-treatment HDL in the second and third quartiles had intermediate increased risks of AF. Baseline HDL in the lowest quartile was not a significant predictor of new AF (hazard ratio (HR): 1.14, 95% confidence interval (CI): 0.90-1.43). In multivariable Cox analyses adjusting for multiple baseline and time-varying covariates, the lowest quartile of on-treatment HDL remained associated with a nearly 54% increased risk of new AF (HR: 1.54, 95% CI: 1.16-2.05) whereas a baseline HDL≤ ⩽1.21 mmol/l was not predictive of new AF (HR: 1.01, 95% CI: 0.78-1.31).Conclusion: Lower on-treatment HDL is strongly associated with risk of new AF. These findings suggest that serial assessment of HDL can estimate AF risk better than baseline HDL in hypertensive patients with left ventricular hypertrophy. Future studies may investigate whether therapies that increase HDL can lower risk of developing AF.Clinical Trials Registration: http://clinicaltrials.gov/ct/show/NCT00338260?order=1.
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Serum uric acid and progression of diabetic nephropathy in type 1 diabetes.
Pilemann-Lyberg, S, Lindhardt, M, Persson, F, Andersen, S, Rossing, P
Journal of diabetes and its complications. 2018;(5):470-473
Abstract
AIMS: Uric acid (UA) is a risk factor for CKD. We evaluated UA in relation to change in GFR in patients with type 1 diabetes. METHODS Post hoc analysis of a trial of losartan in diabetic nephropathy, mean follow-up 3 years (IQR 1.5-3.5). UA was measured at baseline. Primary end-point was change in measured GFR. UA was tested in a linear regression model adjusted for known progression factors (gender, HbA1c, systolic blood pressure, cholesterol, baseline GFR and baseline urinary albumin excretion rate (UAER)). RESULTS Baseline UA was 0.339 mmol/l (SD ±0.107), GFR 87 ml/min/1.73 m2 (±23), geometric mean UAER 1023 mg/24 h (IQR, 631 - 1995). Mean rate of decline in GFR was 4.6 (3.7) ml/min/year. In the upper quartile of baseline UA the mean decline in GFR from baseline to the end of the study was 6.2 (4.9) ml/min/1.73 m2 and 4.1 (3.1) ml/min/1.73 m2 in the three lower quartiles of UA, (p = 0.088). In a linear model including baseline covariates (UAER, GFR, total cholesterol, HDL cholesterol) UA was associated with decline in GFR (r2 = 0.45, p < 0.001). CONCLUSION Uric acid was weakly associated with decline in GFR in type 1 diabetic patients with overt nephropathy.
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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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Abstract
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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Antihypertensive efficacy of the losartan/hydrochlorothiazide combination and its effect on plasma B-type natriuretic peptide in hypertensive patients uncontrolled by angiotensin II type 1 receptor antagonist-based therapy: a multicentre prospective observational study.
Meno, H, Inou, T, Tanaka, M, Tsuchiya, Y, Shiga, Y, Kobayashi, K, Nakamura, Y, Ota, T, Kubara, I
Clinical drug investigation. 2012;(3):171-8
Abstract
BACKGROUND AND OBJECTIVES Although strict blood pressure (BP) control is effective in the prevention of cardiovascular events, it is often insufficient in many hypertensive patients. B-type natriuretic peptide (BNP) has been shown to be associated with cardiovascular events. We investigated the effects of the losartan/hydrochlorothiazide combination on BP and plasma BNP in hypertensive patients uncontrolled by an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB])-based therapy. METHODS In a multicentre prospective observational study, we enrolled 185 patients aged 36-79 years (mean age 63.8 years) with essential hypertension but without symptoms of heart failure who received an ARB-based therapy for ≥3 months but failed to achieve a target BP recommended by the Japanese Society of Hypertension (JSH). ARBs were switched to losartan (LOS) 50 mg/hydrochlorothiazide (HCTZ) 12.5 mg. The antihypertensive efficacy, safety, and effects of this combination on blood biochemical parameters and plasma BNP were evaluated for 12 months. RESULTS Mean ± SD systolic and diastolic BP decreased from 152 ± 13/87 ± 10 mmHg to 128 ± 14/74 ± 10 mmHg, respectively, after 12 months (p < 0.001). Mean ± SD plasma BNP levels decreased significantly from 46.0 ± 83.0 pg/mL to 40.8 ± 68.0 pg/mL (p < 0.05). The percentage of patients who achieved the JSH 2004 target BP was 51% after 12 months; the percentage was 63% in elderly patients aged ≥65 years without complications, and 43% in patients with concomitant diabetes mellitus or chronic kidney disease. No association was found between a decrease in plasma BNP levels and BP, age, body mass index or estimated glomerular filtration rate. There was a significant increase in serum uric acid and a decrease in serum potassium, but both were within the range of normal values. Adverse events were observed in 8.6% of the patients. CONCLUSION Antihypertensive treatment using two types of drugs (LOS/HCTZ) with different mechanisms yielded potent antihypertensive efficacy with safety and decreased plasma BNP levels.
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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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A renoprotective effect of low dose losartan in patients with type 2 diabetes.
Sawaki, H, Terasaki, J, Fujita, A, Nakagawa, S, Kanatsuna, N, Sadahiro, K, Isotani, H, Imagawa, A, Hanafusa, T
Diabetes research and clinical practice. 2008;(1):86-90
Abstract
It has been reported that angiotensin II receptor blocker (ARB) improves proteinuria in diabetic patients. However, whether this is a direct effect of ARB or through lowering blood pressure is still controversial. The aim of this study is to determine the direct effect of ARB on diabetic nephropathy. Thirty-four type 2 diabetic patients with early kidney damage were divided into two groups: losartan group (n=17) and control group (n=17). In losartan group, low dose (25mg) of losartan was administered once daily for a year. Blood pressure at home, blood pressure at office and urinary albumin/creatinine ratio (UACR) were measured before and during the treatment. After a 1-year observation, the increment of UACR was significantly smaller in losartan group than that in control group [-23.8+/-13.7 mg/gCr vs. 15.9+/-13.2mg/gCr, mean+/-S.E.M., P=0.0114]. Mean blood pressure levels did not change before and during the observation period both in losartan group and control group, though only systolic blood pressure at home decreased slightly but significantly. There were no significant differences in the levels of HbA(1c), fasting plasma glucose, total cholesterol, triglyceride and body mass index between the two groups. The observed decrease in UACR in the losartan-treated group might be attributed to a direct renoprotective action in addition to a subtle decrease in systolic blood pressure at home.
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Short-term administration of an angiotensin-receptor antagonist in patients with impaired fasting glucose improves insulin sensitivity and increases free IGF-I.
Zandbergen, AA, Lamberts, SW, Janssen, JA, Bootsma, AH
European journal of endocrinology. 2006;(2):293-6
Abstract
OBJECTIVE Blocking the renin-angiotensin system (RAS) may reduce the risk of developing type-2 diabetes, but data are inconclusive and the mechanisms involved are unclear. RAS and RAS inhibition also influence the IGF-I system, which is important in glucose homeostasis. We investigated the effects of the angiotensin-receptor antagonist, losartan, on insulin resistance and IGF-I levels DESIGN AND METHODS In this hypothesis-generating study, five individuals with impaired fasting glucose received 100 mg losartan during 8 weeks. Before and after the treatment period, insulin sensitivity was assessed using the homeostasis model assessment of insulin resistance (HOMA), as well as the 2-h continuous infusion of glucose with model assessment (CIGMA). Furthermore, serum levels of free and total IGF-I, IGF-binding protein-3 (IGFBP-3), lipids and HbAlc were measured. RESULTS After the treatment period, the HOMA score for insulin resistance had decreased from 5.3+/-1.1 to 3.7+/-0.9 (P=0.004) and the 2-h CIGMA score from 23.4+/-3.1 to 15.9+/-2.1 (P=0.07). The serum levels of free IGF-I had increased from 57+/-18.8 to 134+/-31.3 pmol/l (P=0.04). In terms of percentage, the decrease of HOMA correlated with the increase in free IGF-I levels (Pearson's correlation coefficient r=-0.8; P=0.07). A trend in the same direction was observed with 2-h CIGMA. No differences were observed in lipids, total IGF-I, IGFBP-3 or HbAlc. CONCLUSIONS Losartan raised serum levels of free IGF-I, which might contribute to the improvement of insulin resistance associated with losartan treatment. These observations, if confirmed in broader studies, will help our understanding of the pathogenesis of type-2 diabetes mellitus, as well as the role of angiotensin-receptor antagonists in its prevention.
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Drug-disease interactions: losartan effect is not downregulated by rheumatoid arthritis.
Daneshtalab, N, Lewanczuk, RZ, Russell, AS, Jamali, F
Journal of clinical pharmacology. 2006;(11):1344-55
Abstract
Inflammatory conditions, such as rheumatoid arthritis, reduce response to calcium channel and beta-adrenergic antagonists but not the angiotensin II type 1 receptor (AT(1)R) antagonist valsartan. Inflammation also reduces clearance of some drugs or active metabolite, thereby reducing response. Active (n = 14) and controlled rheumatoid arthritis (n = 12) and healthy subjects (n = 12) received losartan (100 mg). Blood pressures were measured, and samples were taken for pharmacokinetic and inflammatory mediator concentration determination. Active disease significantly increased arthritic index, nitric oxide, and Creactive protein. Although no between-group difference in plasma losartan concentration-time curves was observed, concentrations of the active metabolite, EXP 3174, were significantly reduced by arthritis. This, however, was not accompanied by reduced clinical response. One subject produced no detectable concentrations of EXP 3174 likely due to insufficient CYP2C9 activity. Despite reduced concentrations of the active metabolite, AT1R antagonists potency does not appear to be reduced by inflammation.