Wax Matrix Niacin 



The wax-matrix, extended release formulation of nicotinic acid (WMNA) is produced by Innovite Inc. in Tigard, Oregon since 1976.  Endurance Products Company is the exclusive marketing affiliate of Innovite Inc.  Clinical studies of Innovite’s WMNA have been investigator-initiated and published in peer-reviewed medical journals.  Six studies analyze pharmacokinetic factors such as tablet content, dissolution, bioavailability, and peak plasma levels.  The sixteen remaining studies examine and report on the safety and efficacy of lipid parameters and blood chemistries, with one of these studies reporting clinical outcome responses in ischemic heart disease patients.



Figge et al compared the bioavailability of WMNA to Nicobid® (Roher) by measuring 24 hr urinary recovery and found greater bioavailability for wax-matrix NA.[i]  Meyers et al analyzed free nicotinic acid content of OTC niacin preparations and found variability between preparations, but that WMNA was consistent in free NA content. Of significance, the authors noted that use of OTC sustained-release preparations should be limited to products that have been objectively shown to be safe and effective – of which WMNA was one of only two cited with published clinical data.[ii] In a comparative study funded by Kos, Poon et al compared the dissolution profiles of seven non-prescription NA preparations to Niaspan®, the prescription extended release NA.  They found significant variations in dissolution profiles of the non-prescription preparations, but noted that only one – WMNA, exhibited a comparable dissolution rate to that of Niaspan®. It is notable that WMNA had the lowest standard deviation among trial participants, including Niaspan®.[iii]  An additional comparative dissolution study was conducted by Ito et al, and presented as an abstract at the 2014 National Lipid Association’s Annual Sessions.[iv]  Using a USP Type-1 apparatus, these investigators also found nearly identical dissolution profiles for WMNA and prescription Niaspan®.  A quantitative determination of serum levels has been published by investigators from the Russian Academy of Medical Sciences.  This analysis confirms the intermediate release profile of WMNA, showing a serum peak at about 6 hours[v].  A more recent comparative study of WMNA and innositol hexanicotinate (“No-Flush” niacin) by Keenan[vi], conducted a kinetic sub-analysis for plasma levels of NA and its two major metabolites.  Due to rapid conversion of NA to nicotinamide and nicotinuric acid, the NA peaked within the first hour, followed by nicotinuric acid and then nicotinamide, again confirming an intermediate release.



The remaining studies address clinical efficacy, safety and tolerability.  Alderman et al conducted an uncontrolled trial in 101 patients with CAD and TC/HDL ratios >4.  At 12 months the group achieved a 31% increase in HDL and a 32% decrease in TC/HDL, with only 4% dropout.  Because the investigators used both immediate release (Squibb) and WMNA, the pooled results cannot be attributed to either agent alone.[vii]  Keenan et al examined 201 patients with elevated LDL utilizing four dosages of WMNA compared to placebo and diet treated controls.  The groups given 2000 and 1500 mg demonstrated 26% and 19.3% reductions in LDL, and an 18.4% and 13.3% reduction in TC/HDL ratio.  A linear dose response for LDL-C and triglyceride reductions was observed.  Tolerance was very good with only 3.4% dropping out due to niacin side effects.  The authors conclude “the improved side effect profile and low cost make wax-matrix SRNA an attractive choice when drug therapy is indicated”.[viii]  In a separate post-hoc analysis of the subjects in the previous study, Keenan examined the effects of WMNA in 158 of the hyperlipidemic patients comparing the efficacy and tolerability in younger (age 20 – 49) patients versus older (50-70) patients. Older patients taking 1500-2000mg demonstrated significantly greater improvements than younger patients in TC, HDL, TC/HDL ratio, and triglycerides.  Side effects and toxicity were no greater in older subjects, and intolerance was 3.4%.[ix]  Keenan next studied 98 subjects taking 1500 mg of WMNA and oat bran, each alone and in combination, finding good reductions in LDL and increases in HDL, and determined that very few patients (10%) experienced synergism from the combination.[x]     Aronov et al randomized 89 subjects with elevated cholesterol into groups taking 1500 mg or 2000mg of WMNA. This Russian population crossed over treatment after two months, followed by all subjects taking 2000mg in months five and six.  TC, LDL, HDL, triglycerides, Apolipoproteins, and Lp(a) all improved, and dropout was 4.5%.[xi]  Three additional studies by Russian investigators have been published and presented at major cardiovascular symposiums as abstracts.  In addition to the consistent effect on lipids, these abstracts report analytical findings on lipid transport, CETP activity, and fractional esterification in plasma.[xii][xiii][xiv]  


Combination therapy

Pasternak et al examined 91 patients with coronary heart disease and average lipid levels using a stepped-care combination protocol compared to placebo for 2.5 years. The six step algorithm utilized four drugs: pravastatin, WMNA, cholestyramine , and gemfibrozil, with a goal of achieving TC < 160 mg/dl, and a LDL/HDL ratio of less than 2.0.  WMNA was added to pravastatin in 40 of the 44 patients in the treatment group, and caused additional mean reductions in TC of 6%, LDL 11%, Trig 10% and increased HDL 8%.  The combination produced changes of -26% TC, -39% LDL, -23% Trig, +17% HDL, -35% in TC/HDL, and -46% LDL/HDL.  Most notably, the addition of WMNA to pravastatin enabled an additional 43% to reach their target LDL levels, for a total of 94% of patients who were elevated at baseline.[xv]  This combination protocol was part of the Harvard Atherosclerosis Reversibility Project (HARP). 


No-Flush niacin

In the kinetic analysis mentioned previously, Keenan compared the safety and efficacy of WMNA to inositol hexanicotinate (IHN) and placebo in 120 dyslipidemic patients. All treatments were well tolerated, but IHN was no different than placebo on cholesterol fractions and did not result in measureable changes of nicotinic acid in plasma. [xvi]  WMNA demonstrated significant improvements in TC (-11%), LDL-C (-18%), HDL-C (+12%) and non-HDL-C (-15%).


Russian language

As a result of a physician educational exchange program between cardiologists from Russia and the US, WMNA was brought back to Russiafor clinical use and study in the early 1990s.  The remaining studies are published in Russian.  They are mentioned here owing to unique findings or study groups of interest.  Oganov et al noted in a study of 31 subjects with type IIa and IIb hyperlipoproteinemias that the ratio of lipoproteins was significantly improved. WMNA increased lipoprotein A1 by 16% and decreased lipoprotein A2 by 29%[xvii].  Gorshkova et al examined the effects of WMNA on cholesterol ester transfer protein[xviii] (CETP) noting that there was a reduction in the activity of CETP (personal communication with Irina Gorshkova).  Kukharchuk et al reported on the long-term use of WMNA monotherapy in individuals with ischemic heart disease.[xix]  Subjects received 1500mg daily for two years resulting in improved cholesterol sub-fractions and halted progression of atherosclerosis in 75% of subjects.  Smolenskaia et al reported on the lipid and non-lipid effects of WMNA in patients with arterial hypertension.[xx]  They found that 1500mg/day over six months promoted normalization of serum lipids, improved vascular tonicity and reactivity of cerebral arteries, and produced a mild hypotensive effect in the presence or absence of ischemic heart disease.  A comparative study of WMNA 1500mg/day and besafibrate 600mg/day was reported by Mal.[xxi]  The author concluded that besafibrate should be indicated for isolated hypertriglyceridemia (41.2% reduction in TG) and the WMNA should be indicated for moderate isolated or combined hyperlipidemia (LDL -19.2%, TG -26% and HDL +15.7%). 


Cardiovascular Outcomes

A study by Oganov et al analyzed clinical outcomes benefits in subjects with ischemic disease including post MI in an outpatient rehabilitation setting.[xxii]  The 93 patients were randomized into exercise alone, WMNA alone, or the combination for one year.  Investigators measured physical performance, hemodynamics at rest and exercise, left ventricular systolic function, and clinical course.  WMNA monotherapy had a positive effect on physical performance, arterial pressure and frequency of anginal attacks however, the combination of exercise and NA was superior to either monotherapy.  They conclude that WMNA is recommended in combination with exercise in the secondary prevention of IHD to relieve myocardial ischemia under exercise, raise physical performance, improve lipids and prevent maladaptive vascular left ventricular remodeling.  This paper has been fully translated to English.



In summary, investigators have found that WMNA has consistently delivered clinically significant results on cholesterol sub-fractions, and is a very well tolerated form of niacin, with dropout rates ranging from 3-8% (mean 4.5%), the lowest of any published niacin studies.  In a 2005 review of key articles, guidelines and consensus papers relative to dyslipidemias, authors concluded that WMNA (Endurance Products Co, Tigard, OR), was one of only two non-prescription SR niacin preparations that should be recommended.[xxiii]


Physicians and patients must realize that all NA products are not alike or equivalent and that WMNA is effective at doses lower than those often recommended for other forms of NA.  Pharmacodynamic differences exist with different dosing regimens.  Appropriate liver function monitoring should be done for all niacin products and regimens.

[i] Figge HL, Figge J, Sourney PF, Sacks FM, et al.  Comparison of Excretion of Nicotinuric Acid After Ingestion of Two Controlled Release Nicotinic Acid Preparations inMan.  J of Clinical Pharmacol  1988;28:1136-1140.

[ii] Meyers CD, Carr MC, Park S, Brunzell JD. Varying Cost and Free Nicotinic Acid Content in Over-the-Counter Niacin Preparations for Dyslipidemia.  Annals of Int Med  2003;139:996-1002.

[iii] Poon IO, Chow DS, Liang D.  Dissolution Profiles on Nonprescription Extended Release Niacin…  Am J Health-Syst Pharm.  2006;63:2128-2134.

[iv] Ito MK, et al.  A Comparison in Dissolution Profiles between Extended-Release and Wax-Matrix Niacin.  Journal of Clinical Lipidology 2014;8(3):351-2.

[v] Ivanofskaya EA, Kolomin EY, Karpov RS. Quantitative Determination of Endur-acin in Blood Serum. Khimiko-Farmatsevitcheskii Zhurnal.  1998;32:277-278.

[vi] Keenan JM.  Wax-matrix extended-release niacin vs inositol hexanicotinate: A comparison of wax-matrix, extended-release niacin to inositol hexanicotinate “no-flush” niacin in persons with mild to moderate dyslipidemia.  Journal of Clinical Lipidology 2013;7:14-23.

[vii] Alderman JD, Pasternak RC, Sacks FM, Smith HS, Monrad SM,  Grossman W.  Effect of a Modified, Well-Tolerated Niacin Regimen on Serum Total Cholesterol, High Density Lipoprotein Cholesterol and the Cholesterol to High Density Lipoprotein Ratio.  Am J Cardiol  1989:64:725-729

[viii] Keenan JM, Fontaine PL, Wenz JB, Myers S, Huang Z, Ripsin CM.  Niacin Revisited: a Randomized Controlled Trial of Wax-Matrix Sustained-Release Niacin in Hypercholesterolemia.  Arch Intern Med  1991;151:1424-1432.

[ix] Keenan JM, Bae C, Fontaine PL, Wenz JB, Myers S, Huang Z, Ripsin C.  Treatment of Hypercholesterolemia: Comparison of Younger versus Older Patients Using Wax-Matrix Sustained-Release Niacin.  J Am Geriatric Soc  1992;40:12-18. 

[x] Keenan JM,  Wenz JB, Ripsin CM, Huang Z, McCaffrey DJ.  A Clinical Trial of Oat Bran and Niacin in the Treatment of Hyperlipidemia.  J Fam Pract  1992;34:313-319.

[xi] Aronov DM, Keenan JM, Akhmedzhanov NM, Perova NV, Oganov RY, Kiseleva NY.  Clinical Trial of Wax-Matrix Sustained-Release Niacin in a Russian Population With Hypercholesterolemia.  Arch Fam Med  1996;5:567-575.

[xii] Oganov RG, Perova NV, Kiseleva NG, et al.  Beneficial effects of wax-matrix sustained-release niacin on lipid-transport system in patients with hypercholesterolemia.  Atherosclerosis 1994;109:132-133.

[xiii]  Ozerova I, Kisseleva N, Olferiev A, et al. Effect of wax-matrix sustained-release niacin treatment on cholesterol esterification in plasma.  Atherosclerosis 1997;130S1:S31.

[xiv] Kisseleva N, Olfriev A, Oganov R.  Specific lipid response to Wax-Matrix sustained-release niacin treatment in patients with hypercholesterolemia.  Atherosclerosis 1999;144S1:S23.

[xv] Pasternak RC, Brown LE, Stone PH, Silverman DI, Gibson CM, Sacks FM, for the Harvard Atherosclerosis Reversibility Project (HARP) Study Group.  Effect of Combination Therapy with Lipid-Reducing Drugs in Patients with Coronary Heart Disease and “Normal” Cholesterol Levels.  Annals of Internal Med.  1996;125:529-540

[xvi] Keenan JM.  Wax-matrix extended-release niacin vs inositol hexanicotinate: A comparison of wax-matrix, extended-release niacin to inositol hexanicotinate “no-flush” niacin in persons with mild to moderate dyslipidemia.  Journal of Clinical Lipidology 2013;7:14-23.

[xvii] Oganov RG, Kiseleva NG, Aronov DM, Akhmedzhanov NM, Olfer’ev AM, Kiseleva NS, Perova NV.  The use of Enduracin – a prolonged-action form of nicotinic acid – in correcting atherogenic dyslipidemias.  Kardiologia 1993;33(10):54-9 Russian

[xviii] Gorshkova IN, Kiseleva NG,AkhmedzhanovNM,PerovaNV.  Effect of enduracin on the activity of a cholesterol ester transfer protein in blood plasma of people with hypercholesterolemia.  Biull Eksp Biol Med  1996;121(2):185-7 Russian

[xix] KukharchukVV, Solov’ev Elu, Malyshev PP, Rozhkova TA, Semenova OA, Aronskaia EE.  The effect of long-term Enduracin monotherapy on the clinical and biochemical status of patients with ischemic heart disease.  Ter Arkh 1997;69(9):41-45. Russian

[xx] Smolenskaia OG, Kazakov IaE, Barats SS.  Lipid and non-lipid effects of enduracin in patients with arterial hypertension.  Ter Arkh 1999;7(8):23-27. Russian

[xxi] Mal GS.  Comparative efficacy of prolonged diet and drug therapies for hyperlipidemias in patients with coronary heart disease.  Kliniceskaa medicina  2004:82(5):63-66 Russian

[xxii] Oganov RG, Aronov DM, Krasnitsky VB.  Exercise and nicotinic acid delayed action drug enduracin: Application in outpatient rehabilitation of patients with ischemic heart disease.  Terapevti eskij arhiv Y.  2004;76(4):54-59. Russian

[xxiii] Ito MK, Cheung RJ, Gupta EK, Birtcher KK, Chong PH, Bianco TM, Bleske BE. Key Articles, Guidelines, and Consensus Papers Relative to the Treatment of Dyslipidemias—2005.  Pharmacotherapy 2006;26:939-1010.