Sustained Hypophosphatemic Effect of Once-Daily Niacin/Laropiprant in Dyslipidemic CKD Stage 3 Patients

Ix, Joachim H.; Ganjoo, Prerna; Tipping, Diane; Tershakovec, Andrew M.; Bostom, Andrew G.

doi:10.1053/j.ajkd.2011.03.010

Cited by 18 publications

(18 citation statements)

References 10 publications

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“…82 Experimental studies have shown that exposure to phosphate-depleted diets or phosphate binders upregulates NPT2b expression, and leads to enhanced dietary phosphate absorption when dietary phosphate loading is reinstated. 39,62,70 This is consistent with the observations from human studies that demonstrate spikes in serum phosphate with dietary phosphate loading only after a period of dietary phosphate depletion, 29,31,32 which is presumably due to a compensatory increase in active intestinal phosphate transport in the setting of low luminal dietary phosphate. These data suggest that attempts to reduce dietary phosphate absorption using phosphate binders alone may be limited by NPT2b upregulation and resultant increases in dietary phosphate absorption at times when phosphate binders are not present in the intestinal lumen.…”

Section: Phosphate Binderssupporting

confidence: 86%

“…Insights from elegant experimental studies described below suggest that the potency of phosphate binders may, in part, be offset by the contribution of active transport to total intestinal phosphate absorption. 62 32 The same intervention also resulted in an approximately 11% decline in FGF23 levels in the niacin-treated group compared with placebo. 60 The efficacy of blocking dietary phosphate absorption on biochemical and even cardiovascular endpoints in CKD is also supported by results from recent experimental studies.…”

Section: Phosphate Bindersmentioning

confidence: 97%

“…This observation suggests that, in addition to blocking active phosphate transport in the gut, niceritrol and other nicotinic acid derivatives may induce a renal phosphate leak, perhaps by reducing the levels of renal sodium phosphate co-transporters (NPT2a and NPT2c). 82 These dual actions may explain the sustained hypophosphatemic effects of niacin in patients with CKD stage 3 32 and were also recently implicated as the causal mechanisms for hepatectomy-related hypophosphatemia, in which renal and intestinal sodium phosphate transport were decreased due to increased levels of nicotinic acid derivatives. 82 Experimental studies have shown that exposure to phosphate-depleted diets or phosphate binders upregulates NPT2b expression, and leads to enhanced dietary phosphate absorption when dietary phosphate loading is reinstated.…”

Section: Phosphate Bindersmentioning

confidence: 98%

“…Only a large randomized controlled clinical outcomes trial can generate such convincing evidence. Although several phosphate-and FGF23-lowering approaches have been tested in small short-term studies, [29][30][31][32] additional pilot studies are needed to address major knowledge gaps and to inform the design of the full-scale trial (Figure 1). First, we need to evaluate the phosphate and FGF23 response to interventions aimed at lowering dietary phosphate absorption in long-term interventional studies of patients with CKD.…”

Section: Testing Strategies To Reduce Phosphate and Fgf23 Levels In Ckdmentioning

confidence: 99%

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Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD

Isakova

Sprague

et al. 2015

Journal of the American Society of Nephrology

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120

127

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Patients with CKD often progress to ESRD and develop cardiovascular disease (CVD), yet available therapies only modestly improve clinical outcomes. Observational studies report independent associations between elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels and risks of ESRD, CVD, and death. Phosphate excess induces arterial calcification, and although elevated FGF23 helps maintain serum phosphate levels in the normal range in CKD, it may contribute mechanistically to left ventricular hypertrophy (LVH). Consistent epidemiologic and experimental findings suggest the need to test therapeutic approaches that lower phosphate and FGF23 in CKD. Dietary phosphate absorption is one modifiable determinant of serum phosphate and FGF23 levels. Limited data from pilot studies in patients with CKD stages 3-4 suggest that phosphate binders, low phosphate diets, or vitamin B3 derivatives, such as niacin or nicotinamide, may reduce dietary phosphate absorption and serum phosphate and FGF23 levels. This review summarizes current knowledge regarding the deleterious systemic effects of phosphate and FGF23 excess, identifies questions that must be addressed before advancing to a full-scale clinical outcomes trial, and presents a novel therapeutic approach to lower serum phosphate and FGF23 levels that will be tested in the COMBINE Study: The CKD Optimal Management With BInders and NicotinamidE study.

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Section: Phosphate Binderssupporting

confidence: 86%

Section: Phosphate Bindersmentioning

confidence: 97%

Section: Phosphate Bindersmentioning

confidence: 98%

Section: Testing Strategies To Reduce Phosphate and Fgf23 Levels In Ckdmentioning

confidence: 99%

See 2 more Smart Citations

Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD

Isakova

Sprague

et al. 2015

Journal of the American Society of Nephrology

Self Cite

120

127

View full text Add to dashboard Cite

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“…Clinical trials of niacin and niacin derivatives, which are known to inhibit the expression of intestinal NPT2b and kidney NPT2a, have shown significant reductions in serum phosphorus in patients with mild to moderate CKD. 21 FGF23 seems to be a sensitive marker of impaired kidney function, with elevations preceding detectable increases in serum creatinine. 22 Circulating FGF23 concentrations are strongly associated with progression to ESRD and mortality, and higher concentrations of FGF23 have recently been shown to cause left ventricular hypertrophy in rats.…”

Section: Discussionmentioning

confidence: 99%

Effects of Phosphate Binders in Moderate CKD

Block

Wheeler

Persky

et al. 2012

Journal of the American Society of Nephrology

475

383

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Some propose using phosphate binders in the CKD population given the association between higher levels of phosphorus and mortality, but their safety and efficacy in this population are not well understood. Here, we aimed to determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with moderate to advanced CKD. We randomly assigned 148 patients with estimated GFR=20-45 ml/min per 1.73 m 2 to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline to the average of months 3, 6, and 9. Serum phosphorus decreased from a baseline mean of 4.2 mg/dl in both active and placebo arms to 3.9 mg/dl with active therapy and 4.1 mg/dl with placebo (P=0.03). Phosphate binders, but not placebo, decreased mean 24-hour urine phosphorus by 22%. Median serum intact parathyroid hormone remained stable with active therapy and increased with placebo (P=0.002). Active therapy did not significantly affect plasma C-terminal fibroblast growth factor 23 levels. Active therapy did, however, significantly increase calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1% versus 0.6%, P=0.05; abdominal aorta: median increases of 15.4% versus 3.4%, P=0.03). In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. The safety and efficacy of phosphate binders in CKD remain uncertain. CKD is a significant public health concern; roughly 13% of the US population has an estimated GFR (eGFR) below 60 ml/min per 1.73 m 2 or albuminuria. 1 The risks of death and cardiovascular disease in CKD are not fully explained by associated diabetes, hypertension, and other conventional risk factors. 2 With declining kidney function, serum phosphorus concentration increases but generally remains within the normal range until late in stage 4 or 5 CKD. A normal or near-normal serum phosphorus concentration is maintained at the expense of elevated levels of the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). 3,4 Serum concentrations of phosphorus and hormones responsible for its regulation have been implicated as putative cardiovascular risk factors. [5][6][7][8][9]

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Drugs for Treatment of Dyslipidemia Available in the USA

Streja

2019

Endocrine Disorders in Kidney Disease

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Sustained Hypophosphatemic Effect of Once-Daily Niacin/Laropiprant in Dyslipidemic CKD Stage 3 Patients

Cited by 18 publications

References 10 publications

Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD

Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD

Effects of Phosphate Binders in Moderate CKD

Drugs for Treatment of Dyslipidemia Available in the USA

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