Dr. Ron’s Research Review – January 15, 2020

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This week’s research review focuses on studies showing that niacinamide increases HDL and lowers LDL.

Phosphorus in Hemodialysis

Hemodialysis patients with phosphorus levels > or =5.0 mg/dl were randomly assigned to 8 wk of niacinamide or placebo, titrated from 500 to 1500 mg/d. After a 2-wk washout period, patients switched to 8 wk of the alternative therapy.
Thirty-three patients successfully completed the trial. Serum phosphorus fell significantly from 6.26 to 5.47 mg/dl with niacinamide but not with placebo (5.85 to 5.98 mg/dl).
A concurrent fall in calcium-phosphorus product was seen with niacinamide, whereas serum calcium, intact parathyroid hormone, uric acid, platelet, triglyceride, LDL, and total cholesterol levels remained stable in both arms. Serum HDL levels rose with niacinamide (50 to 61 mg/dl but not with placebo. Adverse effects were similar between both groups. Among patients who were > or =80% compliant, results were similar, although the decrease in serum phosphorus with niacinamide was more pronounced (6.45 to 5.28 mg/dl) and the increase in HDL approached significance (49 to 58 mg/dl).
In hemodialysis patients, niacinamide effectively reduces serum phosphorus when co-administered with binders and results in a potentially advantageous increase in HDL cholesterol. (Cheng et al., 2008)

Phosphorus in Hemodialysis

A study examined whether nicotinamide reduces serum levels of phosphorus and intact parathyroid hormone (iPTH) in patients undergoing hemodialysis.
Sixty-five hemodialysis patients with a serum phosphorus level of more than 6.0 mg/dL after a 2-week washout of calcium carbonate were enrolled in this study. Nicotinamide was administered for 12 weeks. The starting dose was 500 mg/day, and the dose was increased by 250 mg/day every 2 weeks until serum phosphorus levels were well controlled at less than 6.0 mg/dL. A 2-week post-treatment washout period followed the cessation of nicotinamide. Blood samples were collected every week for measurement of serum calcium, phosphorus, lipids, iPTH, and blood nicotinamide adenine dinucleotide (NAD).
The mean dose of nicotinamide was 1080 mg/day. The mean blood NAD concentration increased from 9.3 +/- 1.9 nmol/105 erythrocytes before treatment to 13.2 +/- 5.3 nmol/105 erythrocytes after treatment (P < 0.01). The serum phosphorus concentration increased from 5.4 +/- 1.5 mg/dL to 6.9 +/- 1.5 mg/dL with the pretreatment washout, then decreased to 5.4 +/- 1.3 mg/dL after the 12-week nicotinamide treatment (P < 0.0001), and rose again to 6.7 +/- 1.6 mg/dL after the post-treatment washout. Serum calcium levels decreased during the pretreatment washout from 9.1 +/- 0.8 mg/dL to 8.7 +/- 0.7 mg/dL with the cessation of calcium carbonate. No significant changes in serum calcium levels were observed during nicotinamide treatment. Median serum iPTH levels increased with pretreatment washout from 130.0 (32.8 to 394.0) pg/mL to 200.0 (92.5 to 535.0) pg/mL and then decreased from the maximum 230.0 (90.8 to 582.0) pg/mL to 150.0 (57.6 to 518.0) pg/mL after the 12-week nicotinamide treatment (P < 0.05). With nicotinamide, serum high-density lipoprotein (HDL) cholesterol concentrations increased from 47.4 +/- 14.9 mg/dL to 67.2 +/- 22.3 mg/dL (P < 0.0001) and serum low-density lipoprotein (LDL) cholesterol concentrations decreased from 78.9 +/- 18.8 mg/dL to 70.1 +/- 25.3 mg/dL (P < 0.01); serum triglyceride levels did not change significantly.
Nicotinamide may provide an alternative for controlling hyperphosphatemia and hyperparathyroidism without inducing hypercalcemia in hemodialysis patients. (Takahashi et al., 2004)

Niacinamide Dose

Acute administration of nicotinamide-like nicotinic acid caused a decrease of serum cholesterol, triglycerides and free-fatty acids in the fasted rat. However, the dose of nicotinamide required for these effects was much larger than that of nicotinic acid.
The serum half-life of nicotinamide was found to be three times greater than nicotinic acid. The duration of hypolipidemic activity of nicotinamide was longer than that of nicotinic acid. Nicotinic acid was found to accumulate in the serum in amounts proportional to the injected dose of nicotinamide. The concentration of nicotinic acid in the serum after nicotinamide treatment was larger than minimal serum concentrations necessary to produce free-fatty acid lowering.
It was concluded that the lipopenic action of nicotinamide was indirect and was dependent upon deamidation to nicotinic acid. It seems from these observations that nicotinamide might offer some therapeutic advantage over nicotinic acid as a hypolipidemic agent. Clinically, 3-6 g/day of nicotinic acid are used. At these doses, it appears to lower all serum lipid constituents.
Hypolipidemic data in vivo showed an effective dose ratio for nicotinamide to nicotinic acid of about three. Extrapolation of this ratio to man would necessitate a dose of 9-18 g/day. It is of interest to note that the dosage of either nicotinic acid and nicotinamide recommended by Hoffe is 3-18 g/day for treatment of schizophrenia. Such a large dose, if tolerated, would have the advantage of less frequent administration because of the longer half-life of nicotinamide. Nicotinamide administration may also eliminate many of the distressing side effects observed after nicotinic acid therapy. (Dalton et al., 1970)

Niaspan

A multicenter trial evaluated the safety and efficacy of escalating doses of Niaspan (niacin extended-release tablets) and placebo (administered once-a-day at bedtime) in patients with primary hyperlipidemia on the percent change from baseline in levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B. (Goldberg et al., 2000)
Extended-release niacin was initiated at a dose of 375 mg/day, raised to 500 mg/day, and further increased in 500-mg increments at 4-week intervals to a maximum of 3,000 mg/day. A total of 131 patients (n = 87, extended-release niacin; n = 44, placebo) were treated for 25 weeks with study medication after a 6-week diet lead-in/drug washout phase and 2-week baseline LDL cholesterol stability phase.
Decreases in LDL cholesterol were 3% at 500 mg, 9% at 1,000 mg, 14% at 1,500 mg, 17% at 2,000 mg, 22% at 2,500 mg, and 21% at 3,000 mg.
For HDL cholesterol increases were 10% at 500 mg, 15% at 1,000 mg, 22% at 1,500 mg, 26% at 2,000 mg, 30.0% at 2,500 mg, and 29.5% at 3,000 mg.
Decreases in apolipoprotein B were 2% at 500 mg, 7% at 1,000 mg, 14% at 1,500 mg, 16% at 2,000 mg, 22% at 2,500 mg, and 20% at 3,000 mg (p 􏰀0.05 vs placebo for all doses except 500 mg).
Reductions in triglycerides were 5% at 500 mg, 11% at 1,000 mg, 28% at 1,500 mg, 35% at 2,000 mg, 39% at 2,500 mg, and 44% at 3,000 mg.
The most common adverse events were flushing and gastrointestinal disturbance. Transaminase increases were relatively small, and the proportion of patients who developed liver function abnormalities on extended-release niacin was not significantly different from placebo.
Thus, extended-release niacin was generally well tolerated and demonstrated a dose-related ability to alter favorably most elements of the lipid profile. (Goldberg et al., 2000)

 

Dr. Ron

 


Articles

 

A randomized, double-blind, placebo-controlled trial of niacinamide for reduction of phosphorus in hemodialysis patients.
            (Cheng et al., 2008) Download
BACKGROUND AND OBJECTIVES:  Niacinamide inhibits intestinal sodium/phosphorus transporters and reduces serum phosphorus in open-label studies. A prospective, randomized, double-blind, placebo-controlled crossover trial was performed for assessment of the safety and efficacy of niacinamide. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:  Hemodialysis patients with phosphorus levels > or =5.0 mg/dl were randomly assigned to 8 wk of niacinamide or placebo, titrated from 500 to 1500 mg/d. After a 2-wk washout period, patients switched to 8 wk of the alternative therapy. Vitamin D analogs and calcimimetics were held constant; phosphorus binders were not changed unless safety criteria were met. RESULTS:  Thirty-three patients successfully completed the trial. Serum phosphorus fell significantly from 6.26 to 5.47 mg/dl with niacinamide but not with placebo (5.85 to 5.98 mg/dl). A concurrent fall in calcium-phosphorus product was seen with niacinamide, whereas serum calcium, intact parathyroid hormone, uric acid, platelet, triglyceride, LDL, and total cholesterol levels remained stable in both arms. Serum HDL levels rose with niacinamide (50 to 61 mg/dl but not with placebo. Adverse effects were similar between both groups. Among patients who were > or =80% compliant, results were similar, although the decrease in serum phosphorus with niacinamide was more pronounced (6.45 to 5.28 mg/dl) and the increase in HDL approached significance (49 to 58 mg/dl). CONCLUSIONS:  In hemodialysis patients, niacinamide effectively reduces serum phosphorus when co-administered with binders and results in a potentially advantageous increase in HDL cholesterol. Further study in larger randomized trials and other chronic kidney disease populations is indicated.

Antilipaemic effect of nicotinamide.
            (Dalton, 1967) Download
The antilipaemic effect of nicotinic acid is well known1 and the clinical value of this compound as an agent for lowering the content of cholesterol has been demonstrated. Although many explanations have been offered, the mechanism by which nicotinic acid exerts its antilipaemic effect is not known. It is generally agreed, however, that the effect of decreasing cholesterol is unrelated to this compound's known vitamin role as a precursor of pyridine nucleotides, because nicotinamide, which is more readily incorporated into pyridine nucleotides, has little effect on serum cholesterol concentrations in man.


Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia.
            (Goldberg et al., 2000) Download
This multicenter trial evaluated the safety and efficacy of escalating doses of Niaspan (niacin extended-release tablets) and placebo (administered once-a-day at bedtime) in patients with primary hyperlipidemia on the percent change from baseline in levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B. Extended-release niacin was initiated at a dose of 375 mg/day, raised to 500 mg/day, and further increased in 500-mg increments at 4-week intervals to a maximum of 3,000 mg/day. A total of 131 patients (n = 87, extended-release niacin; n = 44, placebo) were treated for 25 weeks with study medication after a 6-week diet lead-in/drug washout phase and 2-week baseline LDL cholesterol stability phase. Significant decreases from baseline in levels of LDL cholesterol and apolipoprotein B became apparent with the 500-mg/day dose and were consistent at all subsequent doses (p < or =0. 05), reaching 21% and 20%, respectively, at the 3,000-mg/day dose. Significant increases from baseline in levels of high-density lipoprotein cholesterol became apparent with the 500-mg/day dose and were consistent at all subsequent doses (p < or = 0.05), reaching 30% at the 3,000-mg dose. Significant decreases from baseline in triglycerides and lipoprotein(a) occurred at the 1,000-mg dose and were apparent at all subsequent doses (p < or =0.05), reaching 44% and 26%, respectively, at the 3,000-mg dose. The most common adverse events were flushing and gastrointestinal disturbance. Transaminase increases were relatively small, and the proportion of patients who developed liver function abnormalities on extended-release niacin was not significantly different from placebo. Thus, extended-release niacin was generally well tolerated and demonstrated a dose-related ability to alter favorably most elements of the lipid profile.

Nicotinamide suppresses hyperphosphatemia in hemodialysis patients.
            (Takahashi et al., 2004) Download
BACKGROUND:  The use of calcium- or aluminum-based phosphate binders against hyperphosphatemia is limited by the adverse effects of hypercalcemia or aluminum toxicity in long-term hemodialysis. Because nicotinamide is an inhibitor of sodium-dependent phosphate cotransport in rat renal tubule and small intestine, we examined whether nicotinamide reduces serum levels of phosphorus and intact parathyroid hormone (iPTH) in patients undergoing hemodialysis. METHODS:  Sixty-five hemodialysis patients with a serum phosphorus level of more than 6.0 mg/dL after a 2-week washout of calcium carbonate were enrolled in this study. Nicotinamide was administered for 12 weeks. The starting dose was 500 mg/day, and the dose was increased by 250 mg/day every 2 weeks until serum phosphorus levels were well controlled at less than 6.0 mg/dL. A 2-week posttreatment washout period followed the cessation of nicotinamide. Blood samples were collected every week for measurement of serum calcium, phosphorus, lipids, iPTH, and blood nicotinamide adenine dinucleotide (NAD). RESULTS:  The mean dose of nicotinamide was 1080 mg/day. The mean blood NAD concentration increased from 9.3 +/- 1.9 nmol/105 erythrocytes before treatment to 13.2 +/- 5.3 nmol/105 erythrocytes after treatment (P < 0.01). The serum phosphorus concentration increased from 5.4 +/- 1.5 mg/dL to 6.9 +/- 1.5 mg/dL with the pretreatment washout, then decreased to 5.4 +/- 1.3 mg/dL after the 12-week nicotinamide treatment (P < 0.0001), and rose again to 6.7 +/- 1.6 mg/dL after the posttreatment washout. Serum calcium levels decreased during the pretreatment washout from 9.1 +/- 0.8 mg/dL to 8.7 +/- 0.7 mg/dL with the cessation of calcium carbonate. No significant changes in serum calcium levels were observed during nicotinamide treatment. Median serum iPTH levels increased with pretreatment washout from 130.0 (32.8 to 394.0) pg/mL to 200.0 (92.5 to 535.0) pg/mL and then decreased from the maximum 230.0 (90.8 to 582.0) pg/mL to 150.0 (57.6 to 518.0) pg/mL after the 12-week nicotinamide treatment (P < 0.05). With nicotinamide, serum high-density lipoprotein (HDL) cholesterol concentrations increased from 47.4 +/- 14.9 mg/dL to 67.2 +/- 22.3 mg/dL (P < 0.0001) and serum low-density lipoprotein (LDL) cholesterol concentrations decreased from 78.9 +/- 18.8 mg/dL to 70.1 +/- 25.3 mg/dL (P < 0.01); serum triglyceride levels did not change significantly. CONCLUSION:  Nicotinamide may provide an alternative for controlling hyperphosphatemia and hyperparathyroidism without inducing hypercalcemia in hemodialysis patients.

 

References

Cheng, SC, et al. (2008), ‘A randomized, double-blind, placebo-controlled trial of niacinamide for reduction of phosphorus in hemodialysis patients.’, Clin J Am Soc Nephrol, 3 (4), 1131-38. PubMed: 18385391
Dalton, C, TC VanTrabert, and JX Dwyer (1970), ‘Relationship of nicotinamide and nicotinic acid to hypolipidemia.’, Biochem Pharmacol, 19 (9), 2609-19. PubMed: 4249087
Goldberg, A, et al. (2000), ‘Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia.’, Am J Cardiol, 85 (9), 1100-5. PubMed: 10781759
Takahashi, Y, et al. (2004), ‘Nicotinamide suppresses hyperphosphatemia in hemodialysis patients.’, Kidney Int, 65 (3), 1099-104. PubMed: 14871431