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Effects of the Dual Endothelin Receptor Antagonist Aprocitentan on Body Weight and Fluid Homeostasis in Healthy Subjects on a High Sodium Diet.
Gueneau de Mussy, P, Sidharta, PN, Wuerzner, G, Maillard, MP, Guérard, N, Iglarz, M, Flamion, B, Dingemanse, J, Burnier, M
Clinical pharmacology and therapeutics. 2021;(3):746-753
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Abstract
Aprocitentan is a novel, oral, dual endothelin receptor antagonist (ERA) in development in difficult-to-control hypertension. As fluid retention and edema are concerns with ERAs, we investigated whether aprocitentan causes weight gain in healthy subjects on a high sodium diet and explored potential mechanisms if occurring. This double-blind, randomized, placebo-controlled, crossover study enrolled 28 subjects. Three doses of aprocitentan (10, 25, or 50 mg/day for 9 days) were compared with placebo. Increases in body weight were observed with aprocitentan (placebo-corrected mean weight gains [90% confidence interval]) of 0.43 [0.05-0.80], 0.77 [0.03-1.51], and 0.83 [0.33-1.32] kg at 10 mg, 25 mg, and 50 mg, respectively. Decreases in hemoglobin and uric acid were observed. Plasma volume increased at most by 5.5% without dose-response relationship. Urinary sodium excretion decreased at 10 mg and 25 mg but not at 50 mg. Therefore, aprocitentan produced moderate weight increases in healthy subjects on high sodium diet, without obvious sodium retention.
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A pilot study on efficacy and safety of a new salt substitute with very low sodium among hypertension patients on regular treatment.
Mu, L, Li, C, Liu, T, Xie, W, Li, G, Wang, M, Wang, R, Rao, H, He, Q, Wang, W, et al
Medicine. 2020;(8):e19263
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Abstract
OBJECTIVES To understand the possible effect of a novel salt substitute with very low sodium in reducing blood pressure, salt intake and use of anti-hypertensive medications among patients on regular medications, to inform the future randomized trials. DESIGN Single-arm pilot trial. SETTING A community health service center in Chongqing, China. PARTICIPANTS A total of 43 patients with hypertension taking anti-hypertensive medications regularly. INTERVENTION Patients received the salt substitute with 18% sodium chloride for 8 weeks. MAIN OUTCOME MEASURES Patients were followed up weekly for the use of antihypertensive medications and measurements of blood pressure. We collected 24-h urine before and after the trial to measure sodium and potassium intake. RESULTS Among 39 patients who completed the 8 weeks' intervention, 30.8% patients stopped or reduced anti-hypertensive medications during the trial. For patients that stopped or reduced medication, the mean SBP and DBP before intervention were 122.1 ± 9.6 and 68.9 ± 9.4 mm Hg and both did not increase after intervention (SBP change: 2.8 mm Hg (-5.1, 10.8), P = .48; DBP change: 1.8 mm Hg (-2.2, 5.7), P = .38). For the rest patients, the mean SBP and DBP before intervention were 141.6 ± 16.9 and 74.6 ± 6.6 mm Hg but reduced significantly after the intervention (SBP change: -16.0 mm Hg (-21.3, -10.6), P < .001; DBP change: -5.5 mm Hg (-8.1, -2.9), P < .001). The 24-h urine sodium decreased (P < .001) and potassium increased (P < .001) among all patients. No severe adverse events were reported. CONCLUSIONS The novel salt substitute showed potential in reducing blood pressure and use of antihypertensive medications. Further randomized double-blind controlled trial is warranted to validate these findings.Clinical Trial Registration-URL:http://www.clinicaltrials.gov. Unique identifier: NCT03226327.
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The intake assessment of diverse dietary patterns on childhood hypertension: alleviating the blood pressure and lipidemic factors with low-sodium seafood rich in omega-3 fatty acids.
Izadi, A, Khedmat, L, Tavakolizadeh, R, Mojtahedi, SY
Lipids in health and disease. 2020;(1):65
Abstract
BACKGROUND Childhood hypertension (CH) is related to the dietary intake and diversity of children. The study aimed to assess the critical role of dietary diversity, and seafood long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) in reducing CH among the Iranian community. METHODS A cross-sectional two-phase study with 7-12-year-old Iranian students was designed. In the initial phase, the socio-demographic characteristics, and blood pressure status (normal, pre-hypertension, and hypertension) based on systolic (SBP) and diastolic (DBP) blood pressure data were assessed. The 24-h dietary recall questionnaire was used to generate the dietary diversity score (DDS, count of consumed food groups) and dietary variety score (DVS, the cumulative number of daily consumed food items). In the second phase, the association between CH reduction and changes in serum 25-hydroxyvitamin D (25OHD), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TG) levels of schoolchildren intervened by a seafood diet rich in omega-3 fatty acids were assessed using the regression analyses. RESULTS The pre-hypertension and hypertension prevalence rates were 7.8 and 9.15%, respectively. CH was significantly associated with age, gender, and DDS. A significant inverse association was found between the high intake of seafood and CH (P = 0.032). The gas-chromatography analysis showed the high presence of α-linolenic (ALA, 6.72%), eicosapentaenoic (EPA, 7.62%), docosapentaenoic (DPA, 5.88%), and docosahexaenoic (DHA, 18.52%) acids in the seafood-based diet (p < 0.05). The low blood pressure levels with regular consumption of this healthy-functional diet were significantly associated with a reduction in BMI, LDL, TC, and TG, and a remarkable increase in 25OHD and HDL levels. The multiple linear regression showed that the SBP was highly associated with the TC (p < 0.001; β = 0.464). CONCLUSIONS The age and DDS were efficient predictors for the different CH status. A regular seafood-rich dietary pattern due to the high LC n-3 PUFAs contents could significantly reduce the obesity-related cardiovascular risk factors.
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Renal effects of a sodium-glucose cotransporter 2 inhibitor, tofogliflozin, in relation to sodium intake and glycaemic status.
Nunoi, K, Sato, Y, Kaku, K, Yoshida, A, Suganami, H
Diabetes, obesity & metabolism. 2019;(7):1715-1724
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Abstract
AIMS: Little is known about whether sodium intake is associated with the clinical effects of SGLT2 inhibitors (SGLT2is); however, SGLT2is may increase urinary sodium excretion. Thus, we investigated the impact of daily sodium intake on the estimated glomerular filtration rate (eGFR) via an SGLT2i, tofogliflozin (TOFO), in patients with type 2 diabetes (T2D). METHODS Individual-level data on 775 T2D patients in TOFO Phase 3 trials were analysed. Adjusted changes in variables during 52 weeks of TOFO therapy were compared according to basal daily salt intake (DSI), which was measured based on estimated daily urinary sodium excretion using the Tanaka formula. Multivariable analysis was used to investigate the impact of basal DSI on changes in eGFR at Weeks 4 and 52. RESULTS Sixty-six percent of participants were men; mean age, HbA1c, body mass index, eGFRMDRD and median DSI were 58.5 years, 8.0%, 25.6 kg/m2 , 83.9 mL/min/1.73 m2 and 9.3 g/d, respectively. In all participants, eGFRMDRD sharply dipped during Week 4, and gradually increased by Week 52, showing a significant increase overall from baseline to Week 52. Multivariable analysis showed that basal DSI and HbA1c levels were independently correlated with eGFRMDRD changes at Weeks 4 and 52. Additionally, lower baseline HbA1c and DSI levels were significantly correlated with a greater increase in eGFRMDRD at Week 52. CONCLUSIONS Dietary salt intake, in addition to glycaemic control, correlates with changed eGFRMDRD via TOFO. Thus, an appropriate dietary approach to therapy should be considered before treatment of T2D patients with an SGLT2i.
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Study of low salt diet in hypertensive patients with chronic kidney disease.
Koh, KH, Wei-Soon, LH, Jun, L, Lui-Sian, LN, Hui-Hong, CT
The Medical journal of Malaysia. 2018;(6):376-381
Abstract
INTRODUCTION The efficacy of blood pressure (BP) reduction with salt restriction in CKD subjects and its sustainability is not well established. METHODS We enrolled 75 hypertensive patients with CKD into one-month salt restricting diet. 24-hour urinary sodium and potassium was measured to verify their salt intake followed by 1½ year follow-up. RESULTS Their creatinine clearance was 43 ± standard deviation 33ml/min/1.73m2. Urinary Na excretion (24HUNa) was 173±129mmol/day, reducing to 148±81 by 31±6 day. Mean, systolic and diastolic BP (MBP, SBP, DBP) were reduced from 102±9 to 97±11 (p<0.001), 148±10 to 139±16 (p<0.001), 78±12 to 75±12 mmHg (p=0.012) respectively. Moderate correlations were shown between reductions in 24-hour urinary Na and MBP, SBP, DBP: r=0.366, 0.260, 0.365; p=0.001, 0.025, 0.001; whereas 24-hour urinary Na-K ratio showed mild correlation. Subjects have some tendency to drift back to previous Na intake profile in follow-up and thus repetitive education is necessary. In subanalysis, 34 subjects with baseline 24HUNa >150 mmol/day, benefited significantly with MBP, SBP, DBP reduction from 102±9 to 95±9 (p=0.001), 146±10 to 135±14 mmHg (p=0.001), 80±11 to 75±11 mmHg (p=0.002) in line with 24HUNa reduction from 253±154 to 163±87mmol/day (p=0.004) and urinary protein-creation ratio reduction from geometric mean of 95 to 65 g/mol. Thirty five subjects with 24HUNa reduction of >20mmol/day have significant reduction in MBP, SBP, DBP: -8 vs -2, -15 vs -4, -5 vs -2 mmHg (p=0.027, 0.006, 0.218) and urinary protein-creatinine ratio: -82 vs 2g/mol (p=0.030) compared to the other forty subjects. CONCLUSION Quantification of 24-hour urinary Na helps in predicting potential antihypertensive effect with dietary salt reduction of CKD subjects. Salt restriction reduces BP especially in patients with estimated daily sodium intake of >150mmol/day. Reduction in sodium intake beyond 20mmol/day reduced both BP and proteinuria.
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Effect of Food Intake on the Pharmacodynamics of Tenapanor: A Phase 1 Study.
Johansson, SA, Knutsson, M, Leonsson-Zachrisson, M, Rosenbaum, DP
Clinical pharmacology in drug development. 2017;(5):457-465
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Abstract
Tenapanor (RDX5791/AZD1722) is a minimally systemic small-molecule inhibitor of the sodium/hydrogen exchanger NHE3. Tenapanor acts in the gut to reduce absorption of sodium and phosphate. This phase 1 open-label, 3-way crossover study (NCT02226783) evaluated the effect of food on the pharmacodynamics of tenapanor. Eighteen volunteers completed a randomized sequence of three 4-day treatments with tenapanor hydrochloride 15 mg twice daily: before food, after food, and while fasting. Participants received a diet standardized for sodium content. Stool sodium was significantly higher with tenapanor administration before versus after food (difference, +8.8 mmol/day, P = .006) or while fasting (+11.8 mmol/day, P = .0004). Differences in urinary sodium were not significant. Stool phosphorus was not significantly different with tenapanor before versus after food and significantly higher before food versus while fasting (+4.9 mmol/day, P = .006). Urinary phosphorus was significantly lower when tenapanor was administered before (-3.9 mmol/day, P = .0005) or after food (-3.7 mmol/day, P = .0009) versus while fasting. No serious adverse events were reported. These data suggest the effect of tenapanor on sodium absorption is most pronounced when administered before meals, whereas the effect on phosphate is similar whether administered before or after meals. This may support different timings of tenapanor administration with respect to food for sodium- and phosphate-related indications.
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Sodium Intake and All-Cause Mortality Over 20 Years in the Trials of Hypertension Prevention.
Cook, NR, Appel, LJ, Whelton, PK
Journal of the American College of Cardiology. 2016;(15):1609-1617
Abstract
BACKGROUND The relationship between lower sodium intake and total mortality remains controversial. OBJECTIVES This study examined the relationship between well-characterized measures of sodium intake estimated from urinary sodium excretion and long-term mortality. METHODS Two trials, phase I (1987 to 1990), over 18 months, and phase II (1990 to 1995), over 36 months, were undertaken in TOHP (Trials of Hypertension Prevention), which implemented sodium reduction interventions. The studies included multiple 24-h urine samples collected from pre-hypertensive adults 30 to 54 years of age during the trials. Post-trial deaths were ascertained over a median 24 years, using the National Death Index. The associations between mortality and the randomized interventions as well as with average sodium intake were examined. RESULTS Among 744 phase I and 2,382 phase II participants randomized to sodium reduction or control, 251 deaths occurred, representing a nonsignificant 15% lower risk in the active intervention (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.66 to 1.09; p = 0.19). Among 2,974 participants not assigned to an active sodium intervention, 272 deaths occurred. There was a direct linear association between average sodium intake and mortality, with an HR of 0.75, 0.95, and 1.00 (references) and 1.07 (p trend = 0.30) for <2,300, 2,300 to <3,600, 3,600 to <4,800, and ≥4,800 mg/24 h, respectively; and with an HR of 1.12 per 1,000 mg/24 h (95% CI: 1.00 to 1.26; p = 0.05). There was no evidence of a J-shaped or nonlinear relationship. The HR per unit increase in sodium/potassium ratio was 1.13 (95% CI: 1.01 to 1.27; p = 0.04). CONCLUSIONS We found an increased risk of mortality for high-sodium intake and a direct relationship with total mortality, even at the lowest levels of sodium intake. These results are consistent with a benefit of reduced sodium and sodium/potassium intake on total mortality over a 20-year period.
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Comparing Sodium Intake Strategies in Heart Failure: Rationale and Design of the Prevent Adverse Outcomes in Heart Failure by Limiting Sodium (PROHIBIT) Study.
Butler, J, Papadimitriou, L, Georgiopoulou, V, Skopicki, H, Dunbar, S, Kalogeropoulos, A
Circulation. Heart failure. 2015;(3):636-45
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Hydration Status and Sodium Balance of Endurance Runners Consuming Postexercise Supplements of Varying Nutrient Content.
Pryor, JL, Johnson, EC, Del Favero, J, Monteleone, A, Armstrong, LE, Rodriguez, NR
International journal of sport nutrition and exercise metabolism. 2015;(5):471-9
Abstract
Postexercise protein and sodium supplementation may aid recovery and rehydration. Preserved beef provides protein and contains high quantities of sodium that may alter performance related variables in runners. The purpose of this study was to determine the effects of consuming a commercial beef product postexercise on sodium and water balance. A secondary objective was to characterize effects of the supplementation protocols on hydration, blood pressure, body mass, and running economy. Eight trained males (age = 22 ± 3 y, VO2max = 66.4 ± 4.2 ml·kg-1·min-1) completed three identical weeks of run training (6 run·wk-1, 45 ± 6 min·run-1, 74 ± 5% HRR). After exercise, subjects consumed either, a beef nutritional supplement (beef jerky; [B]), a standard recovery drink (SRD), or SRD+B in a randomized counterbalanced design. Hydration status was assessed via urinary biomarkers and body mass. No main effects of treatment were observed for 24 hr urine volume (SRD, 1.7 ± 0.5; B, 1.8 ± 0.6; SRD+B, 1.4 ± 0.4 L·d-1), urine specific gravity (1.016 ± 0.005, 1.018 ± 0.006, 1.017 ± 0.006) or body mass (68.4 ± 8.2, 68.3 ± 7.7, 68.2 ± 8.1 kg). No main effect of treatment existed for sodium intake-loss (-713 ± 1486; -973 ± 1123; -980 ± 1220 mg·d-1). Mean arterial pressure (81.0 ± 4.6, 81.1 ± 7.3, 83.8 ± 5.4 mm Hg) and average exercise running economy (VO2: SRD, 47.9 ± 3.2; B, 47.2 ± 2.6; SRD+B, 46.2 ± 3.4 ml·kg-1·min-1) was not affected. Urinary sodium excretion accounted for the daily sodium intake due to the beef nutritional supplement. Findings suggest the commercial beef snack is a viable recovery supplement following endurance exercise without concern for hydration status, performance decrements, or cardiovascular consequences.
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Lower levels of sodium intake and reduced cardiovascular risk.
Cook, NR, Appel, LJ, Whelton, PK
Circulation. 2014;(9):981-9
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BACKGROUND Recent studies have raised the possibility of adverse effects of low sodium, particularly <2300 mg/d, on cardiovascular disease; however, these paradoxical findings might have resulted from suboptimal measurement of sodium and potential biases related to indication or reverse causation. METHODS AND RESULTS Phases 1 and 2 of the Trials of Hypertension Prevention (TOHP) collected multiple 24-hour urine specimens among prehypertensive individuals. During extended post-trial surveillance, 193 cardiovascular events or cardiovascular disease deaths occurred among 2275 participants not in a sodium reduction intervention with 10 (TOHP II) or 15 (TOHP I) years of post-trial follow-up. Median sodium excretion was 3630 mg/d, with 1.4% of the participants having intake <1500 mg/d and 10% <2300 mg/d, consistent with national levels. Compared with those with sodium excretion of 3600 to <4800 mg/d, risk for those with sodium <2300 mg/d was 32% lower after multivariable adjustment (hazard ratio, 0.68; 95% confidence interval, 0.34-1.37; P for trend=0.13). There was a linear 17% increase in risk per 1000 mg/d increase in sodium (P=0.05). Spline curves supported a linear association of sodium with cardiovascular events, which continued to decrease from 3600 to 2300 and 1500 mg/d, although the data were sparse at the lowest levels. Controlling for creatinine levels had little effect on these results. CONCLUSIONS Results from the TOHP studies, which overcome the major methodological challenges of prior studies, are consistent with overall health benefits of reducing sodium intake to the 1500 to 2300 mg/d range in the majority of the population, in agreement with current dietary guidelines.