Niacin and analogs for phosphate control in dialysis—perspective from a developing country

Abstract

Hyperphosphatemia is an important modifiable risk factor in the dialysis population because it is linked to increased mortality. Existing phosphate-reducing agents either increase the risk of vascular calcification or are costly with high pill burden. Niacin shows promise as a cheap drug with low pill burden and a novel mode of action. Niacin and its metabolite nicotinamide inhibit the small intestinal sodium-phosphate cotransporter. Approximately 50% of intestinal phosphate absorption occurs through this route under physiological conditions. Studies performed on the dialysis population with niacin and nicotinamide have shown significant phosphate reduction with lowering of the calcium-phosphorus product. The well documented increase in serum HDL levels may also offer survival benefits. Side-effects include flushing, which is controlled with aspirin, diarrhea, and thrombocytopenia, which may be treatment-limiting. Niacin is cheap and phosphate reduction can be achieved by administration of one or two tablets per day. These factors will boost compliance in developing countries. Further basic research and large-scale clinical trials are needed in this field.

Extended-release niacin/laropiprant lowers serum phosphorus concentrations in patients with type 2 diabetes

“…Various independent clinical reports that niacin preparations reduce phosphorus concentrations in humans [25][26][27][28]41,42 across the spectrum of phosphatemia, and renal function, are consistent with these mechanistic 36-40 data.…”

“…36,37 Basolateral Na-K ATPase provides the requisite energy required for this active phosphate transport. 25 By using a rat model of ESRD, Eto et al 39 showed that nicotinamide inhibits Na-Pi2b expression, reducing phosphate absorption and preventing the inexorable increase in serum phosphorus concentrations ordinarily associated with renal failure. In previous studies in healthy rats researchers had shown, independently, that nicotinamide inhibited sodium-dependent intestinal phosphate co-transport 37 whereas niceritrol increased fecal (but not urinary) phosphate excretion.…”

“…One communication 31 included the description of a pilot intervention study that used each of these binders as a prelude to an outcome intervention; the other 32 provided a formal sample size and power calculation for a placebo-controlled phosphate binder study-dependent upon as yet undetermined entry concentrations of the phosphatonin fibroblast growth factor 23 and assuming a 20% reduction in mortality with active treatment. Neither trial rationalization blueprint, 31,32 however, referenced any of the published literature [25][26][27][28]41,42 on the phosphorus-lowering efficacy of niacin compounds.…”

“…Uncontrolled studies 25 and two small, limited duration placebo-controlled trials 26,27 indicate that niacin compoundsincluding once-daily extended-release formulations 25 -lower serum phosphorus concentrations in patients with ESRD (ie, stage 5 CKD, an eGFR , 15 mL/min/m 2 ). We sought to expand upon these observations, and our own recently published findings 28 from a 24-week study that included 258 patients with type 2 diabetes (of a total of 1549 patients) by evaluating the impact of extended-release niacin (ERN), given in fixed-dose combination with laropiprant (L), a specific inhibitor of prostaglandin-mediated, niacin-induced flushing, versus placebo, on serum phosphorus concentrations measured serially during a 36-week randomized, placebo-controlled trial of w800 dyslipidemic patients, all of whom had type 2 diabetes.…”

Hypophosphatemic Effect of Niacin in Patients without Renal Failure

“…Approximately 50% of net phosphorus absorption occurs in the duodenum and jejunum via an active transport pathway through the epithelial Na-Pi co-transporters contained in abundantly expressed, "ready to use" vesicles located within the small intestinal brush border (30,35). The energy required for this active phosphorus transport is provided by basolateral Na-K-ATPase (35).…”