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Effect of a lifestyle intervention program with energy-restricted Mediterranean diet and exercise on the serum polyamine metabolome in individuals at high cardiovascular disease risk: a randomized clinical trial.
Fernández-García, JC, Martínez-Sánchez, MA, Bernal-López, MR, Muñoz-Garach, A, Martínez-González, MA, Fitó, M, Salas-Salvadó, J, Tinahones, FJ, Ramos-Molina, B
The American journal of clinical nutrition. 2020;(5):975-982
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Abstract
BACKGROUND Many food items included in the Mediterranean diet (MedDiet) are rich in polyamines, small aliphatic amines with potential cardioprotective effects. The consumption of a MedDiet could increase polyamine concentrations. Based on experimental models, polyamine concentrations may be also influenced by physical activity (PA). OBJECTIVES We aimed to evaluate whether an intervention based on an energy-restricted MedDiet (er-MedDiet) and PA promotion, in comparison with an energy-unrestricted MedDiet and traditional health care, influences the serum pattern of polyamines and related metabolites in subjects at high risk of cardiovascular disease (CVD). METHODS This was a substudy from the PREDIMED-Plus trial, an ongoing randomized clinical trial including 6874 participants allocated either to an intensive weight-loss lifestyle intervention based on er-MedDiet, PA promotion, and behavioral support (er-MedDiet + PA group), or to an energy-unrestricted MedDiet and traditional health care group (MedDiet group). A total of 75 patients (n = 38, er-MedDiet + PA group; n = 37, MedDiet group) were included in this study. Serum concentrations of arginine, ornithine, polyamines, and acetyl polyamines at baseline and 26 wk of intervention were measured by an ultra-high-performance LC-tandem MS platform. RESULTS At week 26, study groups had similar adherence to the MedDiet but patients randomly assigned to the er-MedDiet + PA group showed significantly lower mean energy intake (-340.3 kcal/d; 95% CI: -567.3, -113.4 kcal/d; P = 0.004), higher mean PA (1290.6; 95% CI: 39.9, 2541.3 metabolic equivalent tasks · min/d; P = 0.043), and higher mean decrease in BMI (in kg/m2) (-1.3; 95% CI: -1.8, -0.6; P < 0.001) than the MedDiet group. However, no significant differences in serum polyamines or related metabolites were found between study groups after 26 wk of intervention and no significant between-group differences were found in glycated hemoglobin, HDL-cholesterol, or triglyceride concentrations. CONCLUSIONS In individuals at high CVD risk, an er-MedDiet with increased PA did not result in significant changes of serum concentrations of polyamines or related metabolites in comparison with an energy-unrestricted MedDiet and no increase in PA. This trial was registered at isrctn.com as ISRCTN89898870.
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Bixalomer in Hyperphosphatemic Patients With Chronic Kidney Disease Not on Dialysis: Phase 3 Randomized Trial.
Akizawa, T, Origasa, H, Kameoka, C, Tsukada, J, Kuroishi, K, Yamaguchi, Y
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2016;(6):588-597
Abstract
Currently, calcium- or metal-containing phosphate binders are available to treat hyperphosphatemia in predialysis patients with chronic kidney disease. Bixalomer, a non-calcium, metal-free phosphate binder, has not been studied in these patients. We evaluated the efficacy and safety of bixalomer versus placebo for treatment of hyperphosphatemia in Japanese predialysis patients with chronic kidney disease. This multicenter, randomized, double-blind, phase 3 trial, randomized eligible patients 1:1 to receive bixalomer or placebo for 12 weeks. Bixalomer was started at 1500 mg/day and adjusted up to 7500 mg/day depending on serum phosphorus concentrations. The primary endpoint was change in serum phosphorus concentration from baseline to end of treatment. After a 4-week pre-investigational period, 163 patients (bixalomer: N = 81; placebo: N = 82) were randomized. The adjusted mean change (95% confidence interval) from baseline to end of treatment in serum phosphorus was significantly greater with bixalomer (-0.78 [-0.98, -0.57] mg/dL) versus placebo (0.20 [-0.00, 0.41] mg/dL); mean difference: -0.98 (-1.27, -0.69), P < 0.001. At end of treatment, 57.5% of bixalomer-treated patients achieved target serum phosphorus concentrations, mean serum intact parathyroid hormone and fibroblast growth factor-23 decreased, and there were no significant changes in corrected serum calcium. The safety and tolerability of bixalomer was similar to placebo. The most common drug-related adverse events were gastrointestinal (>24% patients per group). There was a significant increase in bicarbonate concentrations with bixalomer versus placebo (P = 0.003). Bixalomer was superior to placebo for hyperphosphatemia in Japanese predialysis patients with chronic kidney disease and may constitute a new treatment option.
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A randomized trial of JTT-751 versus sevelamer hydrochloride in patients on hemodialysis.
Yokoyama, K, Akiba, T, Fukagawa, M, Nakayama, M, Sawada, K, Kumagai, Y, Chertow, GM, Hirakata, H
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2014;(5):1053-60
Abstract
BACKGROUND JTT-751 is a novel phosphate binder containing ferric citrate as the active ingredient. METHODS In this Phase 3, multicenter, randomized, open-label, parallel-group study, we compared the efficacy and safety of JTT-751 and sevelamer hydrochloride in patients undergoing hemodialysis. A total of 230 patients with a serum phosphate ≥1.97 and <3.23 mmol/L were randomized to JTT-751 (dose adjusted between 1.5 and 6.0 g/day) or sevelamer hydrochloride (dose adjusted between 3.0 and 9.0 g/day) for 12 weeks. The primary outcome was change in serum phosphate from baseline to end of treatment. Secondary outcomes included the changes in corrected serum calcium and intact parathyroid hormone (PTH). The changes in ferritin, transferrin saturation and erythropoiesis-stimulating agent dose were additional outcomes. RESULTS Changes in serum phosphate at the end of treatment were -0.82 mmol/L in the JTT-751 group and -0.78 mmol/L in the sevelamer group, establishing non-inferiority of JTT-751 compared with sevelamer (least squares mean, -0.03 mmol/L; 95% confidence interval, -0.13 to 0.07 mmol/L). Corrected serum calcium increased and PTH decreased from baseline within both groups; changes between groups were similar. Gastrointestinal disorders were the most common adverse events in both groups; the incidence of diarrhea was higher in the JTT-751 group, while constipation occurred frequently in the sevelamer group. Treatment with JTT-751 resulted in significant relative increases in serum ferritin and transferrin saturation. CONCLUSIONS Efficacy and safety of JTT-751 was comparable to sevelamer in patients on hemodialysis with hyperphosphatemia. Differential adverse effects were observed; biochemical markers of iron status increased in patients treated with JTT-751. TRIAL REGISTRATION NUMBER CTI-111433 (The Japan Pharmaceutical Information Center at: http//www.clinicaltrials.jp). Date of registration: 7 March 2011.
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The effects of colestilan versus placebo and sevelamer in patients with CKD 5D and hyperphosphataemia: a 1-year prospective randomized study.
Locatelli, F, Spasovski, G, Dimkovic, N, Wanner, C, Dellanna, F, Pontoriero, G
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2014;(5):1061-73
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BACKGROUND This study compared the effects of short-term titrated colestilan (a novel non-absorbable, non-calcium, phosphate binder) with placebo, and evaluated the safety and efficacy of colestilan over 1 year compared with sevelamer, in patients with chronic kidney disease (CKD) 5D. METHODS This prospective multicentre study comprised a 4-week phosphate binder washout period, a 16-week short-term, flexible-dose, treatment period (including a 4-week placebo-controlled withdrawal period) and a 40-week extension treatment phase. RESULTS At Week 16 (the end of the 4-week placebo-controlled withdrawal period), serum phosphorus level was 0.43 mmol/L (1.32 mg/dL) lower with colestilan than placebo (P < 0.001; primary end point). Serum LDL-C level was also lower with colestilan than with placebo (P < 0.001). Both colestilan and sevelamer produced significant reductions from baseline in serum phosphorus levels (P < 0.001), maintained for 1 year, and the proportion of patients achieving target levels of ≤1.78 mmol/L (5.5 mg/dL) or ≤1.95 mmol/L (6.0 mg/dL) at study end were similar (65.3 and 73.3%, respectively, for colestilan, and 66.9 and 77.4%, respectively, for sevelamer). Serum calcium level remained stable in the colestilan group but tended to increase slightly in the sevelamer group (end-of-study increase of 0.035 mmol/L over baseline). Both binders produced similar reductions from baseline in LDL-C level (P < 0.001), and responder rates after 1 year, using a target of <1.83 mmol/L (70 mg/dL) or <2.59 mmol/L (100 mg/dL) were similar in both groups (50.7 and 85.3% for colestilan and 54.0 and 80.6% for sevelamer). Colestilan was generally well tolerated. CONCLUSIONS Colestilan is effective and safe for the treatment of hyperphosphataemia in patients with CKD 5D, and affords similar long-term phosphorus and cholesterol reductions/responder rates to sevelamer.
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The real-world dose-relativity of sevelamer hydrochloride and lanthanum carbonate monotherapy in patients with end-stage renal disease.
Wilson, RJ, Keith, MS, Preston, P, Copley, JB
Advances in therapy. 2013;(12):1100-10
Abstract
INTRODUCTION Sevelamer hydrochloride (SH) and lanthanum carbonate (LC) are calcium-free phosphate binders used for the management of hyperphosphatemia in patients with end-stage renal disease (ESRD). The objective of this analysis was to evaluate the real-world dose-relativity between SH and LC monotherapy in US patients with ESRD. METHODS This was a post hoc analysis of a 16-week, real-world study (Vemuri et al. in BMC Nephrol 12:49, 2011) of the efficacy of conversion to LC monotherapy from other phosphate binders. The SH:LC dose-relativity ratio, based on the mean daily dose, was calculated in the subset of patients from the Vemuri study who converted from SH to LC monotherapy and had available SH and LC dose data. RESULTS A total of 950 patients converted from SH to LC monotherapy and had recorded dose data. The post hoc analysis population comprised 691 patients with available dose data for both SH at baseline and LC at week 16. The mean (SD) serum phosphate level at baseline was 5.91 (1.66) mg/dL. After conversion to LC monotherapy for 16 weeks, the mean (SD) serum phosphate level was 5.93 (1.85) mg/dL. The mean (SD) daily baseline SH dose was 7,703 (3,642) mg and the mean (SD) daily LC dose at week 16 was 2,800 (939) mg (9.6 versus 2.8 tablets, respectively; P < 0.0001), resulting in a SH:LC dose-relativity ratio of 2.8. The median individual patient SH:LC dose-relativity ratio was 2.6 (95% CI 2.6-2.8). Across baseline SH dose subgroups (2,400-4,800, >4,800-7,200, >7,200-9,600, and >9,600 mg/day), the mean daily SH dose was 4,051, 7,047, 9,253, and 13,150 mg, respectively. In comparison, the mean daily LC dose was 2,445-3,156 mg. Thus, patients requiring baseline SH doses >7,200 mg/day (41% of the analysis population) had higher SH:LC dose-relativity ratios of 3.1-4.2 (median individual patient ratios 3.1-4.0). CONCLUSION In this post hoc analysis of real-world dose-relativity, the overall SH:LC dose-relativity ratio was 2.8 (median individual patient ratio 2.6 (95% CI 2.6-2.8). These findings are consistent with the World Health Organization-defined daily dose and previous studies of the relative phosphate binding capacity of the two drugs. Patients requiring SH doses >7,200 mg/day had higher SH:LC dose-relativities of 3.1-4.2 (median individual patient ratios 3.1-4.0). These findings have implications for the tablet burden and cost-effectiveness of SH and LC in the treatment of hyperphosphatemia.
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Sevelamer versus calcium carbonate in incident hemodialysis patients: results of an open-label 24-month randomized clinical trial.
Di Iorio, B, Molony, D, Bell, C, Cucciniello, E, Bellizzi, V, Russo, D, Bellasi, A, ,
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2013;(4):771-8
Abstract
BACKGROUND Whether the use of sevelamer rather than a calcium-containing phosphate binder improves cardiovascular (CV) survival in patients receiving dialysis remains to be elucidated. STUDY DESIGN Open-label randomized controlled trial with parallel groups. SETTINGS & PARTICIPANTS 466 incident hemodialysis patients recruited from 18 centers in Italy. INTERVENTION Study participants were randomly assigned in a 1:1 fashion to receive either sevelamer or a calcium-containing phosphate binder (although not required by the protocol, all patients in this group received calcium carbonate) for 24 months. OUTCOMES All individuals were followed up until completion of 36 months of follow-up or censoring. CV death due to cardiac arrhythmias was regarded as the primary end point. MEASUREMENTS Blind event adjudication. RESULTS At baseline, patients allocated to sevelamer had higher serum phosphorus (mean, 5.6 ± 1.7 [SD] vs 4.8 ± 1.4 mg/dL) and C-reactive protein levels (mean, 8.8 ± 13.4 vs 5.9 ± 6.8 mg/dL) and lower coronary artery calcification scores (median, 19 [IQR, 0-30] vs 30 [IQR, 7-180]). At study completion, serum phosphate levels were lower in the sevelamer arm (median dosages, 4,800 and 2,000 mg/d for sevelamer and calcium carbonate, respectively). After a mean follow-up of 28 ± 10 months, 128 deaths were recorded (29 and 88 due to cardiac arrhythmias and all-cause CV death). Sevelamer-treated patients experienced lower CV mortality due to cardiac arrhythmias compared with patients treated with calcium carbonate (HR, 0.06; 95% CI, 0.01-0.25; P < 0.001). Similar results were noted for all-cause CV mortality and all-cause mortality, but not for non-CV mortality. Adjustments for potential confounders did not affect results. LIMITATIONS Open-label design, higher baseline coronary artery calcification burden in calcium carbonate-treated patients, different mineral metabolism control in sevelamer-treated patients, overall lower than expected mortality. CONCLUSIONS These results show that sevelamer compared to a calcium-containing phosphate binder improves survival in a cohort of incident hemodialysis patients. However, the better outcomes in the sevelamer group may be due to better phosphate control rather than reduction in calcium load.
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Calcium carbonate, but not sevelamer, is associated with better outcomes in hemodialysis patients: results from the French ARNOS study.
Jean, G, Lataillade, D, Genet, L, Legrand, E, Kuentz, F, Moreau-Gaudry, X, Fouque, D, ,
Hemodialysis international. International Symposium on Home Hemodialysis. 2011;(4):485-92
Abstract
A favorable survival effect of phosphate binders (PBs) on incident hemodialysis (HD) patients was recently reported, but no definitive advantages of calcium-based or noncalcium-based PBs have been demonstrated. The aim of this study was to assess the impact of the prescription of PBs using calcium carbonate (CaCO(3) ) or sevelamer HCl (SV) on survival. Baseline PB prescription was recorded using a cross-sectional analysis of prevalent HD patients from the regional Association Régionale des Néphrologues OStéodystrophie French cohort. A prospective 42-month survival analysis study was performed. In July 2005, 1347 HD patients were included. CaCO(3) , SV, and mixed PBs were prescribed in 55%, 42%, and 24% of cases, respectively, and 26% were not prescribed PBs. Using a Cox proportional model adjusted for several parameters, CaCO(3) use was found to be associated with less mortality (HR, 0.64 [0.4-0.78]), but not in the case of SV use (HR, 1.13 [0.92-1.3]). SV prescription was associated with higher mortality than CaCO(3) (HR, 1.46 [1.1-1.9]). CaCO3, but not sevelamer prescription, is associated with a favorable effect on survival in a French HD population. This novel result can be partly accounted for by the differences in mineral metabolism disorder management that exist between randomized controlled trials and "real life" conditions.
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Evaluation of calcium acetate/magnesium carbonate as a phosphate binder compared with sevelamer hydrochloride in haemodialysis patients: a controlled randomized study (CALMAG study) assessing efficacy and tolerability.
de Francisco, AL, Leidig, M, Covic, AC, Ketteler, M, Benedyk-Lorens, E, Mircescu, GM, Scholz, C, Ponce, P, Passlick-Deetjen, J
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2010;(11):3707-17
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BACKGROUND Phosphate binders are required to control serum phosphorus in dialysis patients. A phosphate binder combining calcium and magnesium offers an interesting therapeutic option. METHODS This controlled randomized, investigator-masked, multicentre trial investigated the effect of calcium acetate/magnesium carbonate (CaMg) on serum phosphorus levels compared with sevelamer hydrochloride (HCl). The study aim was to show non-inferiority of CaMg in lowering serum phosphorus levels into Kidney Disease Outcome Quality Initiative (K/DOQI) target level range after 24 weeks. Three hundred and twenty-six patients from five European countries were included. After a phosphate binder washout period, 255 patients were randomized in a 1:1 fashion. Two hundred and four patients completed the study per protocol (CaMg, N = 105; dropouts N = 18; sevelamer-HCl, N = 99; dropouts N = 34). Patient baseline characteristics were similar in both groups. RESULTS Serum phosphorus levels had decreased significantly with both drugs at week 25, and the study hypothesis of CaMg not being inferior to sevelamer-HCl was confirmed. The area under the curve for serum phosphorus (P = 0.0042) and the number of visits above K/DOQI (≤1.78 mmol/L, P = 0.0198) and Kidney disease: Improving global outcomes (KDIGO) targets (≤1.45 mmol/L, P = 0.0067) were significantly lower with CaMg. Ionized serum calcium did not differ between groups; total serum calcium increased in the CaMg group (treatment difference 0.0477 mmol/L; P = 0.0032) but was not associated with a higher risk of hypercalcaemia. An asymptomatic increase in serum magnesium occurred in CaMg-treated patients (treatment difference 0.2597 mmol/L, P < 0.0001). There was no difference in the number of patients with adverse events. CONCLUSION CaMg was non-inferior to the comparator at controlling serum phosphorus levels at Week 25. There was no change in ionized calcium; there was minimal increase in total serum calcium and a small increase in serum magnesium. It had a good tolerability profile and thus may represent an effective treatment of hyperphosphataemia.
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A randomized, crossover design study of sevelamer carbonate powder and sevelamer hydrochloride tablets in chronic kidney disease patients on haemodialysis.
Fan, S, Ross, C, Mitra, S, Kalra, P, Heaton, J, Hunter, J, Plone, M, Pritchard, N
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2009;(12):3794-9
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BACKGROUND Sevelamer carbonate is an improved, buffered form of sevelamer hydrochloride developed for the treatment of hyperphosphataemia in CKD patients. Sevelamer carbonate formulated as a powder for oral suspension presents a novel, patient-friendly alternative to tablet phosphate binders. This study compared the safety and efficacy of sevelamer carbonate powder with sevelamer hydrochloride tablets in CKD patients on haemodialysis. METHODS This was a multi-centre, open-label, randomized, crossover design study. Thirty-one haemodialysis patients were randomly assigned to either sevelamer carbonate powder or sevelamer hydrochloride tablets for 4 weeks followed by a crossover to the other regimen for an additional 4 weeks. RESULTS The mean serum phosphorus was 1.6 +/- 0.5 mmol/L (5.0 +/- 1.5 mg/dL) during sevelamer carbonate powder treatment and 1.7 +/- 0.4 mmol/L (5.2 +/- 1.1 mg/dL) during sevelamer hydrochloride tablet treatment. Sevelamer carbonate powder and sevelamer hydrochloride tablets are equivalent in controlling serum phosphorus; the geometric least square mean ratio was 0.95 (90% CI 0.87-1.03). No statistically significant or clinically meaningful differences were observed in calcium x phosphorus product and lipid levels between sevelamer carbonate powder and sevelamer hydrochloride tablets. Serum bicarbonate levels increased 2.7 +/- 3.7 mmol/L (2.7 +/- 3.7 mEq/L) during sevelamer carbonate treatment. No statistically significant change in bicarbonate was observed during sevelamer hydrochloride treatment. Sevelamer carbonate powder and sevelamer hydrochloride were well tolerated during this study. CONCLUSIONS Sevelamer carbonate powder and sevelamer hydrochloride tablets are equivalent in controlling serum phosphorus and well tolerated in CKD patients on haemodialysis. Bicarbonate levels improved only during sevelamer carbonate treatment. Sevelamer carbonate powder should provide a welcomed new option for the treatment of hyperphosphataemia for CKD patients on dialysis.
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Linking Centers for Medicare & Medicaid Services data with prospective DCOR trial data: methods and data comparison results.
St Peter, WL, Liu, J, Weinhandl, ED, Fan, Q
Hemodialysis international. International Symposium on Home Hemodialysis. 2008;(4):480-91
Abstract
The Dialysis Clinical Outcomes Revisited (DCOR) trial was a large randomized, multicenter 3-year trial comparing the effects of sevelamer with calcium-based binders on mortality, hospitalization, morbidity, and medical costs in hemodialysis subjects. Dialysis Clinical Outcomes Revisited was prospectively designed to link subjects to the Centers for Medicare & Medicaid Services End-Stage Renal Disease (CMS ESRD) database to collect additional baseline characteristic data and to enhance outcome evaluation. Subjects were linked to the CMS ESRD database by means of an algorithm using several patient identifiers. Some baseline characteristic data were collected exclusively from the CMS ESRD database. Mortality and hospitalization end points were obtained from the CMS ESRD database and compared with similar data collected prospectively into a case-report form (CRF) database. Of the 2103 patients who participated in the DCOR study, 2101 were successfully linked to the CMS ESRD database. Patient baseline data showed that treatment groups were well-balanced, except that a higher proportion of subjects in the calcium-based binder group had atherosclerotic heart disease. Calculated mortality rates were similar between databases, but more deaths were identified in the CMS than in the CRF database. These additional deaths were verified through several sources. More hospitalizations were also detected in the CMS than in the CRF database. The CMS database was a good source of death end points and hospitalization occurrence. Linking patients to the data-rich CMS ESRD database allowed assessment of additional important secondary end points at a relatively low cost compared with prospective data collection.