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A pilot double-blind randomized placebo-controlled crossover pharmacodynamic study of the centrally active aminopeptidase A inhibitor, firibastat, in hypertension.
Azizi, M, Courand, PY, Denolle, T, Delsart, P, Zhygalina, V, Amar, L, Lantelme, P, Mounier-Vehier, C, De Mota, N, Balavoine, F, et al
Journal of hypertension. 2019;(8):1722-1728
Abstract
OBJECTIVES We conducted a pilot multicenter double-blind randomized placebo-controlled crossover pharmacodynamic study to evaluate the blood pressure (BP) and the hormonal effects of firibastat, a first-in-class aminopeptidase A inhibitor prodrug, in patients with hypertension. METHODS Thirty-four patients with daytime ambulatory BP of at least 135/85 mmHg and less than 170/105 mmHg, after a 2-week run-in period were randomly assigned to receive either firibastat (250 mg b.i.d. for 1 week uptitrated to 500 mg b.i.d. for 3 weeks) and then placebo for 4 weeks each or vice versa, with a 2-week washout period on placebo. RESULTS At 4 weeks, daytime ambulatory systolic BP (SBP) decreased by 2.7 mmHg (95% confidence interval -6.5 to +1.1 mmHg) with firibastat versus placebo (P = 0.157). Office SBP decreased by 4.7 mmHg (95% confidence interval -11.1 to +1.8 mmHg) with firibastat versus placebo (P = 0.151). However, more the basal daytime ambulatory SBP was elevated, more the firibastat-induced BP decrease was marked. Firibastat did not influence 24h-ambulatory heart rate. Firibastat had no effect on plasma renin, aldosterone, apelin and copeptin concentrations. No major adverse events occurred. There was one episode of reversible skin allergy with facial edema. CONCLUSION In patients with hypertension, a 4-week treatment with firibastat, tended to decrease daytime SBP relative to placebo. Firibastat did not modify the activity of the systemic renin-angiotensin system These results have justified designing a larger, powered trial of longer duration to fully assess its safety and effectiveness. CLINICAL TRIAL REGISTRATION http://www.clinicaltrials.gov. NCT02322450.
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Effect of Patiromer in Hyperkalemic Patients Taking and Not Taking RAAS Inhibitors.
Kloner, RA, Gross, C, Yuan, J, Conrad, A, Pergola, PE
Journal of cardiovascular pharmacology and therapeutics. 2018;(6):524-531
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INTRODUCTION Hyperkalemia (potassium >5.0 mEq/L) affects heart failure patients with renal disease regardless of the use of renin-angiotensin-aldosterone system inhibitors (RAASi). The open-label TOURMALINE study showed that patiromer, a sodium-free, nonabsorbed potassium binder, lowers serum potassium of hyperkalemic patients similarly when given with or without food; unlike prior studies, patients were not required to be taking RAASi. We conducted post hoc analyses to provide the first report of patiromer in patients not taking RAASi. METHODS Hyperkalemic patients received patiromer, 8.4 g/d to start, adjusted to achieve and maintain serum potassium of 3.8 to 5.0 mEq/L. If taking RAASi, stable doses were required. The primary end point was the proportion of patients with serum potassium 3.8 to 5.0 mEq/L at week 3 or 4. This analysis presents data by patients taking or not taking RAASi. RESULTS Demographics and baseline characteristics were similar in patients taking (n = 67) and not taking RAASi (n = 45). Baseline mean (SD) serum potassium was 5.37 (0.37) mEq/L and 5.42 (0.43) mEq/L in patients taking and not taking RAASi, respectively. Mean (SD) daily patiromer doses were similar (10.7 [3.2] and 11.5 [4.0] g, respectively). The primary end point was achieved in 85% (95% confidence interval [CI]: 74-93) of patients taking RAASi and in 84% (95% CI: 71-94) of patients not taking RAASi. From baseline to week 4, the mean (SE) change in serum potassium was -0.67 (0.08) mEq/L in patients taking RAASi and -0.56 (0.10) mEq/L in patients not taking RAASi (both P < .0001 vs baseline, P = nonsignificant between groups). Adverse events were reported in 26 (39%) patients taking RAASi and 25 (54%) not taking RAASi; the most common adverse event was diarrhea (2% and 11%, respectively; no cases were severe). Five patients (2 taking RAASi) reported 6 serious adverse events; none considered related to patiromer. CONCLUSIONS Patiromer was effective and generally well-tolerated for hyperkalemia treatment, whether or not patients were taking RAAS inhibitors.
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Liraglutide Treatment May Affect Renin and Aldosterone Release.
Sedman, T, Heinla, K, Vasar, E, Volke, V
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2017;(1):5-9
Abstract
Nowadays, GLP-1 receptor agonists are widely used as effective and safe antidiabetic medications. In addition to glucose-dependent insulin secretion, their effects reach beyond glucose control. Previously, it has been shown that acute administration of GLP-1 receptor agonists increases circulating glucocorticoid and mineralocorticoid levels in both humans and rodents. So far, no studies have reported the effects of chronic administration of GLP-1 receptor agonists on the hypothalamic-pituitary-adrenal axis in humans. The aim of the current study was to examine the effects of acute and chronic treatment with the GLP-1 receptor agonist liraglutide on adrenal function in humans. Ten healthy volunteers were recruited into a single group open-label clinical trial. Each participant was tested for baseline levels, and after acute and chronic treatment with 0.6 mg liraglutide daily. A graded glucose infusion test was performed 3 times. We found that aldosterone tended to be suppressed (albeit not statistically different) after acute administration of liraglutide, and increased after chronic dosing; the difference was statistically significant when compared between acute and chronic dosing. Changes in aldosterone levels followed the changes in renin concentrations and the aldosterone-to-renin ratio remained stable. No statistically significant differences were observed in ACTH or cortisol levels. In conclusion, we have shown that a low dose of GLP-1 receptor agonist may interfere with renin and aldosterone release. Further studies in a larger patient sample and with higher doses of GLP-1 receptor agonists are warranted to corroborate this finding. The study protocol was registered at clinical.trials.gov (NCT02089256) and EU Clinical Trial Register (2014-000238-43).
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Short- and long-term effects of the use of RAAS blockers immediately after renal transplantation.
Chatzikyrkou, C, Eichler, J, Karch, A, Clajus, C, Scurt, FG, Ramackers, W, Lehner, F, Menne, J, Haller, H, Mertens, PR, et al
Blood pressure. 2017;(1):30-38
Abstract
BACKGROUND The efficacy and safety of renin angiotensin aldosterone system blockers (RAASB's) if introduced immediately after renal transplantation have not been extensively investigated. METHODS The medical charts of 142 kidney transplant recipients who received a RAASB in the early postoperative period and of 114 matched controls were analyzed. The RAASB was given primarily for blood pressure control. RESULTS 117 patients continued to receive and 50 controls remained continuously free of the RAASB in the first year. The RAASB was added on average at postoperative day 8 and the mean duration of follow-up was 5.4 years. Systolic, blood pressure at treatment initiation was increased in the RAASB group (150 ± 17 vs. 141 ± 16, p < 0.001). At discharge from hospital and during follow-up blood pressure was similar in both groups, without differences in GFR, potassium and proteinuria. The endpoints "graft failure" and "graft failure or death from any cause" were significantly better in patients treated with RAASB's (p = 0.03 and p = 0.04, respectively). The treatment effects in the RAASB group persisted even after adjustment for demographic parameters, immunological risk factors, peritransplant risk factors, duration of dialysis prior to transplantation and medical comorbidities. CONCLUSIONS Thus, RAASB's can be used effectively and safely to treat hypertension in the early postoperative period after kidney transplantation and are renoprotective in the long term.
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Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers.
Heerspink, HJ, Johnsson, E, Gause-Nilsson, I, Cain, VA, Sjöström, CD
Diabetes, obesity & metabolism. 2016;(6):590-7
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AIMS: To characterize the effect of dapagliflozin on albuminuria and estimated glomerular filtration rate (eGFR) and to determine whether effects on albuminuria were mediated through changes in glycated haemoblogin (HbA1c), systolic blood pressure (SBP), body weight or eGFR. METHODS We conducted a post hoc analysis of data pooled from two phase III clinical trials in hypertensive patients with type 2 diabetes (T2DM) on stable angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, randomly assigned to dapagliflozin 10 mg/day or matched placebo. This analysis included only patients with microalbuminuria or macroalbuminuria at baseline. RESULTS Patients were randomized to receive dapagliflozin 10 mg (n = 167) or placebo (n = 189). Dapagliflozin resulted in greater 12-week reductions in albuminuria compared with placebo: -33.2% [95% confidence interval (CI) -45.4, -18.2]. The reduction in albuminuria was also present after adjusting for age, sex and changes in HbA1c, SBP, body weight and eGFR: -23.5% (95% CI -37.6, -6.3). There was a decrease in eGFR with dapagliflozin versus placebo that was readily reversed 1 week after last dose. No serious renal-related adverse events were observed in any group. CONCLUSIONS Dapagliflozin was effective in lowering albuminuria in patients with T2DM and hypertension using renin-angiotensin system blockade therapy. Reductions in albuminuria were still present after adjusting for changes in HbA1c, SBP, body weight and eGFR. Dapagliflozin-induced improvements in glycaemic control and reductions in SBP, coupled with other potentially beneficial renal effects, may lead to a reduced long-term renal and cardiovascular risk.
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Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade.
Weber, MA, Mansfield, TA, Alessi, F, Iqbal, N, Parikh, S, Ptaszynska, A
Blood pressure. 2016;(2):93-103
Abstract
Hypertension and type 2 diabetes mellitus (T2DM) are risk factors for cardiovascular disease. Dapagliflozin improves glycemic control and systolic blood pressure (SBP) in T2DM patients. This double-blind phase III study evaluated the effects of dapagliflozin on glycemic control and blood pressure in patients with inadequately controlled T2DM and hypertension, despite ongoing therapy with a renin-angiotensin system blocker. Patients were randomized to receive dapagliflozin 10 mg (n = 302) or placebo (n = 311) once daily for 12 weeks. Endpoints were change from baseline to week 12 in seated SBP and glycosylated hemoglobin (HbA1c); longitudinal repeated-measures analysis was performed. Additional endpoints included other hemodynamic measures, serum uric acid, fasting plasma glucose, body weight, blood lipids and heart rate. After 12 weeks, dapagliflozin-treated versus placebo-treated patients showed significant reductions in HbA1c (-0.6% vs -0.1%, p < 0.0001), mean seated SBP (-10.4 vs -7.3 mmHg, p = 0.0010) and mean 24 h ambulatory SBP (-9.6 vs -6.7 mmHg, p = 0.0043). Dapagliflozin also reduced body weight compared with placebo (-1.0 vs -0.3 kg). Dapagliflozin was well tolerated, with adverse events consistent with previous studies. Dapagliflozin improved glycemic control, and reduced SBP as well as body weight in patients with poorly controlled T2DM and hypertension.
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Treatment with patiromer decreases aldosterone in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors.
Weir, MR, Bakris, GL, Gross, C, Mayo, MR, Garza, D, Stasiv, Y, Yuan, J, Berman, L, Williams, GH
Kidney international. 2016;(3):696-704
Abstract
Elevated serum aldosterone can be vasculotoxic and facilitate cardiorenal damage. Renin-angiotensin system inhibitors reduce serum aldosterone levels and/or block its effects but can cause hyperkalemia. Patiromer, a nonabsorbed potassium binder, decreases serum potassium in patients with chronic kidney disease on renin-angiotensin system inhibitors. Here we examined the effect of patiromer treatment on serum aldosterone, blood pressure, and albuminuria in patients with chronic kidney disease on renin-angiotensin system inhibitors with hyperkalemia (serum potassium 5.1-6.5 mEq/l). We analyzed data from the phase 3 OPAL-HK study (4-week initial treatment phase of 243 patients; 8-week randomized withdrawal phase of 107 patients). In the treatment phase, the (mean ± standard error) serum potassium was decreased concordantly with the serum aldosterone (-1.99 ± 0.51 ng/dl), systolic/diastolic blood pressure (-5.64 ± 1.04 mm Hg/-3.84 ± 0.69 mm Hg), and albumin-to-creatinine ratio (-203.7 ± 54.7 mg/g), all in a statistically significant manner. The change in the plasma renin activity (-0.44 ± 0.63 μg/l/hr) was not significant. In the withdrawal phase, mean aldosterone levels were sustained with patiromer (+0.23 ± 1.07 ng/dl) and significantly increased with placebo (+2.78 ± 1.25 ng/dl). Patients on patiromer had significant reductions in mean systolic/diastolic blood pressure (-6.70 ± 1.59/-2.15 ± 1.06 mm Hg), whereas those on placebo did not (-1.21 ± 1.89 mm Hg/+1.72 ± 1.26 mm Hg). Significant changes in plasma renin activity were found only in the placebo group (-3.90 ± 1.41 μg/l/hr). Thus, patiromer reduced serum potassium and aldosterone levels independent of plasma renin activity in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors.
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Low Response of Renin-Angiotensin System to Sodium Intake Intervention in Chinese Hypertensive Patients.
Feng, W, Cai, Q, Yuan, W, Liu, Y, Bardeesi, ASA, Wang, J, Chen, J, Huang, H
Medicine. 2016;(6):e2602
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The interactions of sodium balance and response of renin-angiotensin-aldosterone system are important for maintaining the hemodynamic stability in physiological conditions. However, the influence of short-term sodium intake intervention in the response of renin-angiotensin system (RAS) on hypertensive patients is still unclear. Thus, we conducted a clinical trial to investigate the effects of short-term sodium intake intervention on the response of RAS in hypertensive patients.One hundred twenty-five primary Chinese hypertensive patients were divided into high, moderate, and low sodium groups by 24-hour urinary sodium excretion (UNa). All the patients received a 10-day dietary sodium intake intervention with standardized sodium (173.91mmol/day) and potassium (61.53mmol/day). Blood pressure, urinary sodium, urinary potassium, plasma sodium, potassium, creatinine, the levels of plasma renin activity, plasma angiotensin II concentrations (AT-II), and plasma aldosterone concentrations were detected before and after the intervention.Before the intervention, no differences were found in blood pressure and RAS among 3 groups. After standardized dietary sodium intake intervention, both UNa excretion and systolic pressure decreased in high-sodium group, while they increased in moderate and low-sodium groups. Intriguingly, there were no changes in the levels of plasma renin activity, AT-II, and plasma aldosterone concentrations among 3 groups during the intervention.The present study demonstrated that the influenced sodium excretion and blood pressure by short-term sodium intake intervention were independent of RAS quick response in Chinese hypertensive patients.
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Effects of Sodium Restriction on Activation of the Renin-Angiotensin-Aldosterone System and Immune Indices During HIV Infection.
Srinivasa, S, Burdo, TH, Williams, KC, Mitten, EK, Wong, K, Fitch, KV, Stanley, T, Adler, GK, Grinspoon, SK
The Journal of infectious diseases. 2016;(9):1336-1340
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BACKGROUND Human immunodeficiency virus (HIV)-infected patients demonstrate increased activation of the renin-angiotensin-aldosterone system (RAAS). We evaluated changes in immune markers with physiological RAAS activation. METHODS Immune activation markers were assessed serially in 18 HIV-infected and 7 non-HIV-infected subjects consuming an ad libitum diet followed by a standardized low-sodium diet. RESULTS Levels of CCL-2 (P = .0004) and soluble CD163 (P = .0001) significantly increased with sodium restriction and RAAS activation, compared with levels in individuals with ad libitum sodium intake, among chronically treated HIV-infected subjects (mean duration of ART [±SEM], 11 ± 1 years), but not among non-HIV-infected subjects of similar age and sex. CONCLUSIONS Dietary sodium restriction, which activates RAAS, uniquely stimulates critical indices of immune activation during HIV infection. CLINICAL TRIALS REGISTRATION NCT01407237.
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Probucol in Albuminuric Type 2 Diabetes Mellitus Patients on Renin-Angiotensin System Blockade: A 16-Week, Randomized, Double-Blind, Placebo-Controlled Trial.
Jin, SM, Han, KA, Yu, JM, Sohn, TS, Choi, SH, Chung, CH, Park, IeB, Rhee, EJ, Baik, SH, Park, TS, et al
Arteriosclerosis, thrombosis, and vascular biology. 2016;(10):2108-14
Abstract
OBJECTIVE To determine the effect of probucol on urine albumin excretion in type 2 diabetes mellitus patients with albuminuria using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. APPROACH AND RESULTS This was a 16-week, phase II, randomized, placebo-controlled, parallel-group study in type 2 diabetes mellitus patients with a urinary albumin/creatinine ratio of ≥300 mg/g using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, conducted in 17 tertiary referral hospitals. Eligible patients were randomized to probucol 250 mg/d (n=44), probucol 500 mg/d (n=41), and placebo (n=41) groups in a ratio of 1:1:1 after block randomization procedures, keeping the treatment assignment blinded to the investigators, patients, and study assistants. The primary end point was change in the geometric mean of urinary albumin/creatinine ratio from baseline to week 16 (ClinicalTrials.gov identifier NCT01726816). The study was started on November 8, 2012, and completed on March 24, 2014. The least squares mean change±SE from baseline in urinary albumin/creatinine ratio at week 16 was -7.2±639.5 mg/g in the probucol 250 mg/d group (n=43; P=0.2077 versus placebo group), 9.3±587.4 mg/g in the probucol 500 mg/d group (n=40; P=0.1975 versus placebo group), and 259.0±969.1 mg/g in the placebo group (n=41). Although the majority of subjects were on statins, probucol treatment significantly lowered total cholesterol and low-density lipoprotein cholesterol levels. QT prolongation occurred in one and two subjects in control and probucol 250 mg/d groups, respectively. CONCLUSIONS Four months of probucol up to 500 mg/d failed to reduce urinary albumin excretion.