Effect of Sevelamer on Dyslipidemia and Chronic Inflammation in Maintenance Hemodialysis Patients

Abstract

Background: Hemodialysis (HD) patients often experience cardiovascular events, that might be related to altered calcium–phosphate metabolism, dyslipidemia, and chronic inflammation in addition to hypertension. Sevelamer, a non-calcium-containing phosphate binder, may improve the lipid profile of HD patients. However, the influence of sevelamer on chronic inflammation has not been clarified. Methods: We enrolled 36 maintenance HD patients with a serum calcium (Ca) or phosphate (P) level constantly greater than 9.5 mg/dL and 5.5 mg/dL, respectively. The dose of sevelamer was titrated to achieve a serum Ca and P in the target ranges. The study period was 24 weeks. Patients underwent the following measurements: bone mineral markers, lipids, and a high-sensitivity C-reactive protein (hs-CRP). Results: In the 28 patients who completed the study, sevelamer significantly reduced the mean non-high-density lipoprotein cholesterol (non-HDL-C) level by 15% and 20% (p < 0.0001) after 12 and 24 weeks, respectively, in addition to reducing the serum P level and Ca × P product. Similarly, there was a significant reduction of the serum hs-CRP level after 12 and 24 weeks [median at baseline: 1.03 mg/dL (interquartile range 0.26–3.98 mg/dL) versus 0.57 (0.17–1.47) and 0.38 (0.16–1.03), respectively, p = 0.0259]. The reduction rate of hs-CRP was significantly correlated with those of non-HDL-C (r = 0.451, p < 0.0401) and P (r = 0.453, p < 0.0008) Conclusion: Hs-CRP levels were reduced by sevelamer administration, as well as non-HDL-C, P, and the Ca × P product. Sevelamer may have an anti-inflammatory effect, in addition to lowering phosphate and lipid levels in HD patients.

• sevelamer
• high-sensitivity C-reactive protein
• hemodialysis
• dyslipidemia
• non-HDL-C
• Ca × P product
• cardiovascular disease

Introduction

HD patients frequently suffer from cardiovascular events and have accelerated atherosclerosis, which may be related to abnormal calcium–phosphate metabolism and dyslipidemia in addition to hypertension. In general, prevention of cardiovascular events involves the treatment of hypertension, dyslipidemia, and diabetes mellitus among other factors.[1] Several studies have shown that sevelamer, a non-calcium-containing phosphate binder, can improve the lipid profile of HD patients.[2-4] HMG-CoA reductase inhibitors, such as pravastatin and atorvastatin, have been shown to reduce cardiovascular events in clinical trials via an anti-inflammatory effect in addition to their lipid-lowering action.[5&6] The aim of the present study was to investigate the effects of sevelamer on the calcium-phosphate balance, lipid profile, and chronic inflammation in maintenance HD patients.

Subjects and Methods

The subjects were selected from among 178 ethnic Japanese patients who had been on maintenance HD (4 h × 3 times weekly with dialysate containing 3.0 mEq/L of calcium) for more than 6 months at three dialysis centers in Miyazaki, Japan. We enrolled patients whose serum Ca or P level was constantly above 9.5 mg/dL or 5.5 mg/dL, respectively. Patients were excluded if they were taking lipid-lowering agents such as HMG-CoA reductase inhibitors or if they suffered from chronic inflammatory diseases such as collagen disease or chronic infection. There were 36 patients who had been receiving calcium carbonate (as a calcium-based phosphate binder) and/or vitamin D analogue therapy for 3 months or more. Written informed consent was obtained from all of the subjects.

Sevelamer was started at a daily dose of 1.5 g (0.5g tds before meals). The dose of the phosphate binder was titrated every 2 weeks to achieve a serum Ca concentration, serum P concentration, and Ca × P product in the target ranges of 8.5–9.5 mg/dL, 3.5–5.5 mg/dL, and less than 55 mg²/dL², respectively. Vitamin D analogue therapy was also titrated to achieve serum Ca, serum P, and Ca × P product values within the above target ranges. The target range for intact parathyroid hormone (intact-PTH) was 85–300 pg/mL.[7&8] The study period was 24 weeks. Patients underwent the following measurements at the beginning of sevelamer administration, as well as after 12 and 24 weeks of therapy: serum Ca, P, intact-PTH, bone alkaline phosphatase (BAP), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and hs-CRP. Non-HDL-C level was calculated by subtracting the HDL-C level from the TC level [(non-HDL-C) = (TC)–(HDL-C)]. Blood samples were taken just before the first HD session of the week. Serum hs-CRP was measured with an N Latex high-sensitivity CRP kit (Dade Behring Holdings, Inc.). The lower limit of the assay was 0.16 mg/L. One investigator collected medical and clinical records. Laboratory data were measured at one institution.

Statistical Analysis

Results are expressed as the mean ± standard deviation (SD). Statistical analysis was performed using the Macintosh Stat View program (version 4.5; Abacus Concepts Inc., Berkeley, USA). Differences between two mean values were evaluated by the Wilcoxon signed rank test, and differences between three mean values were assessed by one-way repeated measures ANOVA or Friedman's test, with p < 0.05 being accepted as indicating statistical significance.

Results

Eight subjects dropped out because of severe constipation caused by sevelamer therapy (n = 5) or incidental illness/injury (n = 3), and 28 patients completed the study. Table 1 lists the baseline characteristics of the subjects. After 12 weeks, the mean dose of sevelamer was 1.69 ± 0.70 g/day (range: 0.75–4.5 g/day) corresponding to a mean dose of 0.032 g/kg, and it was 1.85 ± 0.85 g/day (range: 0.75–5.25 g/day) corresponding to a mean, 0.035 g/kg after 24 weeks. On the other hand, the dose of calcium carbonate was gradually reduced from 3.2 ± 2.4 g/day at baseline to 2.9 ± 2.5 after 12 weeks and 2.7 ± 2.6 g/day after 24 weeks. Five patients (18%) were able to stop taking calcium carbonate by 24 weeks.

Table 1. Baseline patient characteristics

Number	28
Age (yr)	60.6 ± 10.6
Gender (F/M)	(12/16)
Primary renal disease
Glomerulonephritis	15
Hypertension	4
Diabetes mellitus	5
Other	4
Duration of hemodialysis (mo)	109 ± 77
Dry weight (kg)	52.6 ± 10.5
Calcium carbonate (g/day)	3.2 ± 2.4
Number (percentage) of vitamin D analogue user
Oral calcitol	13 (46.4%)
Intravenous maxacalcitol	6 (21.4%)
Vitamin D analogue dose
Oral calcitol (µg/week)	2.36 ± 1.09
Maxacalcitol (µg/week)	13.8 ± 7.3

The values of bone mineral markers and the lipid profile at baseline, after 12 weeks, and after 24 weeks of sevelamer therapy are listed in Table 2. The mean Ca level was unchanged, whereas the mean P level and the Ca × P product showed a significant decrease (p < 0.0003 and < 0.0001, respectively, by one-way repeated measures ANOVA). Finally, 19 patients (68%) achieved the target range of the Ca × P product (less than 55 mg²/dL²) during sevelamer therapy. Intact-PTH was unchanged, but BAP increased significantly from 20.0 ± 8.2 to 28.3 ± 10.8 U/L (p < 0.0001, Wilcoxon signed rank test). The changes of BAP tended to be correlated with those of intact-PTH (r = 0.353, p = 0.051).

Table 2. Changes of bone mineral markers and lipids during the 24-week study period

	Baseline	12 weeks	24 weeks	p value
Ca (mg/dL)	9.6 ± 0.9	9.5 ± 0.8	9.4 ± 0.7	nsa
P (mg/dL)	6.6 ± 1.2	5.5 ± 1.5	5.5 ± 1.4	0.0003^a
Ca × P product (mg^2/dL^2)	63.3 ± 11.9	52.6 ± 14.8	51.6 ± 14.6	< 0.0001^a
Intact-PTH (pg/mL)	229 ± 148	221 ± 152	249 ± 174	ns^a
BAP (U/L)	20.0 ± 8.2	—	28.3 ± 10.8	< 0.0001b
Albumin (g/dL)	3.9 ± 0.2	4.0 ± 0.3	3.9 ± 0.3	ns^a
TC (mg/dL)	154 ± 30	142 ± 32	140 ± 35	< 0.0001^a
HDL-C (mg/dL)	42 ± 11	47 ± 14	50 ± 12	< 0.0001^a

Ca: calcium; P: phosphate; PTH; parathyroid hormone; BAP: bone alkaline phosphatase; TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol.

^aOne-way repeated measures ANOVA.

^bWilcoxon signed rank test.

Concerning the lipid profile, the mean TC decreased significantly, while HDL-C increased. The serum albumin level did not change. Figure 1 shows the changes of non-HDL-C levels. Sevelamer reduced the mean non-HDL-C level by 15% and 20% (p < 0.0001 by one-way repeated measures ANOVA) after 12 weeks and 24 weeks, respectively. At 24 weeks, the reduction rate [(reduction rate %) = (the data of 24 weeks)/(the data of baseline) × 100] of non-HDL-C was significantly correlated with TC (r = 0.689, p < 0.0006) and P (r = 0.506, p < 0.0191) (Table 3).

Table 3. Correlation between reduction rate of non-HDL-C or hs-CRP versus other parameters

	Non-HDL-C (%)		hs-CRP (%)
	r	p value	r	p value
Non-HDL-C (%)	—	—	0.451	0.0401
TC (%)	0.689	0.0006	0.128	ns
HDL-C (%)	0.318	ns	0.113	ns
hs-CRP (%)	0.451	0.0401	—	—
Ca (%)	0.236	ns	0.162	ns
P (%)	0.506	0.0191	0.453	0.0008
Ca × P (%)	0.395	0.0763	0.157	ns
Intact PTH (%)	0.304	ns	0.369	ns
BAP (%)	0.004	ns	0.004	ns
Sevelamer (mg/kg)	− 0.420	0.0578	0.073	ns

Reduction rate (%) = (the data of 24 weeks)/(the data of baseline) × 100. Sevelamer; dose (mg/kg) of sevelamer administration per kilogram of dry weight at 24 weeks.

Figure 1 Changes of non-HDL-C levels during the treatment. Values are mean ± SD. Difference was assessed by one-way repeated measures ANOVA.

The profile of serum hs-CRP (median/interquartile range) at baseline and after 12 and 24 weeks of the therapy is shown in Figure 2. There was a significant reduction of the hs-CRP level (p = 0.0259 by Friedman's test) during sevelamer therapy. The reduction rate of hs-CRP was significantly correlated with non-HDL-C (r = 0.451, p < 0.0401) and P (r = 0.453, p < 0.0008) (Table 3).

Figure 2 Changes of hs-CRP levels during treatment. Values are median/(interquartile range). Difference was assessed by Friedman's test.

Discussion

This prospective study revealed that even low doses of sevelamer can reduce both serum P and non-HDL-C levels, as well as the hs-CRP level. Although about 10% of the treated patients suffered from constipation as a side effect, low-dose sevelamer combined with calcium carbonate showed an anti-inflammatory effect and also improved the Ca × P product and lipid profile.

Cardiovascular events occur frequently in HD patients, and their cardiovascular mortality rate is extremely high compared with that of a matched general population.[1] Progressive vascular calcification probably due to the altered calcium–phosphate metabolism may contribute to the exceptionally high rate of cardiovascular disease among HD patients, in addition to the high prevalence of traditional risk factors such as hypertension, dyslipidemia, and diabetes mellitus. Coronary artery calcification in HD patients is associated with a history of cardiovascular events, and the prevalence and extent of vascular calcification are strong predictors of cardiovascular mortality.[9&10] To prevent ectopic calcification of the coronary arteries and aorta, we should control hyperphosphatemia, while avoiding hypercalcemia and elevation of the Ca × P product.[11] Sevelamer is a nonabsorbed calcium-free phosphate binder that lowers serum P levels without increasing Ca levels and thus prevents ectopic calcification.[12] This study revealed that the addition of a low dose of sevelamer to calcium carbonate therapy induced a significant reduction of the serum P level and Ca × P product in association with the decreased dose of calcium carbonate. Most patients were able to achieve the treatment target (a Ca × P product of less than 55 mg²/dL²) within 12 weeks and maintained the improvement at 24 weeks. We also found a significant increase of BAP after treatment with sevelamer.

Several studies have shown that sevelamer may demonstrate a beneficial effect on the lipid profile, because it also acts as a bile acid sequestrant.[2-4] Clinical trials performed in the general population or non-renal disease subjects have shown that elevation of TC or LDL-C, or a decrease of HDL-C, are risk factors for cardiovascular events, and that lipid-lowering agents such as HMG-CoA reductase inhibitors (statins) reduce the incidence of cardiovascular disease and death.[5&6] In HD patients, however, marked elevation of LDL-C or TC is unusual, and non-HDL-C level is considered to be a predictor of atherosclerosis and cardiovascular mortality.[13] Our study also showed that sevelamer could induce a reduction of the non-HDL-C level over time, and the dose sevelamer was correlated with the change in non-HDL-C. However, it remains unknown whether sevelamer can effectively reduce the incidence of cardiovascular events in HD patients, as shown by studies on statins.[14]

Since Ross reported that inflammation plays a major role in determining atherosclerotic plaque vulnerability, the process of chronic, low-grade inflammation is believed to the etiological event in the onset and progression of atherosclerosis.[15] In long-term HD patients, an increase of serum CRP is an independent determinant of cardiovascular events.[16&17] Measurement of hs-CRP has been confirmed to be a useful tool for evaluating low-grade systemic inflammation.[18] Recently, some studies have provided evidence that statins reduce the hs-CRP level in addition to having a beneficial effect on the lipid profile.[19&20] In the present study, in which none of the subjects received statins, sevelamer significantly reduced the hs-CRP level over time. This anti-inflammatory action of sevelamer may be related to prevention of ectopic calcification or suppression of low-grade, local inflammation in the vascular wall secondary to a lipid-lowering effect, because the change of hs-CRP induced by sevelamer was correlated with the changes of P and non-HDL-C. Further investigations are needed to clarify whether sevelamer has a reduction of cardiovascular incidence and death.

In conclusion, administration of sevelamer reduced the hs-CRP level in HD patients as well as the Ca × P product and the non-HDL-C level. These findings suggest that sevelamer may have anti-inflammatory as well as phosphate-binding and lipid-lowering properties. Considering that cardiovascular events in HD patients are related to vascular calcification, dyslipidemia, and chronic vessel wall inflammation, sevelamer may have a beneficial effect on cardiovascular disease in such patients.