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Policosanol

Nutrient Name: Policosanol.

Summary Table
nutrient description

Chemistry and Form

Policosanol contains a natural mixture of eight long-chain aliphatic primary alcohols extracted from the wax of sugarcane ( Saccharum officinarum L.). A similar complex of long-chain aliphatic alcohols can also be derived from rice bran and beeswax, although most of the existing clinical studies have been done with sugarcane-derived material. Octacosanol (18-carbon) is the predominant moiety, constituting approximately 60% of the mixture. Other important constituents include triacontanol (13%) and hexacosanol (6%). Minor components include tetracosanol, heptacocosanol, nonacosanol, dotriacontanol, and tetratriacontanol.

Physiology and Function

Policosanol decreases levels of cholesterol in serum as well as cholesterol content in various tissues, such as liver, heart, and fatty tissue. In numerous clinical trials, policosanol has demonstrated lipid-lowering efficacy comparable to statin drugs and offers the potential to suppress isoprenylation reactions much as statins do, without the attendant hepatotoxicity and other adverse effects typically associated with direct hydroxymethylglutaryl–coenzyme A (HMG-CoA) reductase inhibition. Other trials have produced less positive findings. Policosanol appears to reduce low-density lipoprotein cholesterol (LDL-C) and total cholesterol by inhibiting hepatic cholesterol synthesis before the formation of mevalonate, between the formation of acetate and mevalonate, and downregulating cellular expression of, but not directly inhibiting, HMG-CoA reductase. It also lowers LDL by enhancing the binding, uptake, and degradation of LDL-C in the endoplasmic reticulum.

Nevertheless, scientific knowledge of the exact mechanisms of policosanol's lipid-lowering activity remains incomplete and uncertain. High doses of policosanol can alter prostaglandin synthesis, lower platelet aggregation induced by arachidonic acid (AA), and inhibit proaggregatory thromboxane A2(TXA2) generation induced by collagen; it does not inhibit and may increase levels of the antiaggregatory prostaglandin prostacyclin. Policosanol supports healthy endothelial function by preventing intimal thickening and smooth muscle cell proliferation while also preventing and possibly reversing atherosclerotic lesions and thrombosis. Policosanol may be active as an effective antioxidant in the cardiovascular system, particularly in preventing LDL oxidation, most likely by limiting microsomal lipid peroxidation.

nutrient in clinical practice

Known or Potential Therapeutic Uses

Policosanol has primarily been proposed as part of a comprehensive approach to treating dyslipidemia. Some research suggests that it may be specifically effective in reducing elevated LDL-C and total cholesterol levels, particularly in type II hypercholesterolemia, including the IIa subtype (characterized by elevated total serum cholesterol and LDL-C levels), the IIb subtype (mixed hypercholesterolemia characterized by elevated total serum cholesterol, LDL-C, and triglyceride levels), and diabetes-related hypercholesterolemia. It also appears to increase levels of high-density lipoprotein cholesterol (HDL-C). Efficacy in the treatment of intermittent claudication is consistent with its known effects on platelet aggregation and endothelial function.

Historical/Ethnomedicine Precedent

Policosanol has not been used historically as an isolated nutrient.

Historical Note: Policosanol was largely developed in Cuba during the embargo that prevented access to many Western pharmaceuticals, and the initial laboratory and clinical research was done by Cuban scientists and physicians. Subsequent researchers and commentators, particularly after less successful trials, have suggested that politics may have played a role in earlier published findings of therapeutic efficacy.

Possible Uses

Dyslipidemia, hypercholesterolemia (type II), intermittent claudication, platelet aggregation.

Deficiency Symptoms

Not applicable.

Dietary Sources

Not applicable.

Dosage Forms Available

Capsule, tablet.

Source of Materials for Nutrient Preparations

Isolated constituents from sugarcane (Saccharum officinarum) wax; beeswax, rice bran.

Dosage Range

Adult

Dietary: Not applicable.

Supplemental/Maintenance: Not applicable.

Pharmacological/Therapeutic: 5 to 20 mg per day. A 6-month double-blind clinical trial found that daily dosages greater than 20 mg produce no significant additional cholesterol-lowering efficacy. 1 Many practitioners experienced in nutritional therapeutics advise patients to take their once-daily dose of policosanol in the evening because hepatic synthesis of cholesterol usually occurs primarily during the night.

Toxic: None reported, even at equivalent of approximately 620 times higher than the maximal recommended therapeutic dose (20 mg/day). 2

safety profile

Overview

Clinical trials of policosanol lasting up to 3 years indicate that it is well tolerated and safe for most individuals at usual dosage levels. 3 Policosanol has not been associated with increases in hepatic enzymes or creatine kinase.

Nutrient Adverse Effects

General Adverse Effects

Quantifiable adverse effects include weight loss (1.8% of patients), polyuria (0.7%), and headache (0.6%). Other reported adverse effects include insomnia, somnolence, nervousness, dizziness, excitability, hypotension, hypertension, polyphagia, nausea, epigastric pain, diarrhea, constipation, erythema, pruritus, skin rash, and bleeding from the nose and gums. 4 These symptoms have been recorded in people taking policosanol; causality linking policosanol and these symptoms has not been established.

Research with Swiss mice shows no evidence of policosanol-induced carcinogenicity. 5

Several animal studies, including rat model using doses up to 500 mg/kg, showed no evidence of significant reproductive or mutagenic toxicity. 2,6-9

Adverse Effects Among Specific Populations

No dosage reduction is necessary in individuals with compromised hepatic function. No studies have been conducted involving individuals with compromised renal function. 4

Pregnancy and Nursing

As of this writing, no reported adverse effects have been related to fetal development during pregnancy or to breast-fed infants. However, use during pregnancy is generally contraindicated because cholesterol and associated metabolic products are required for healthy fetal development. Likewise, administration during lactation should be discontinued because little is known about whether the product or some active metabolite is excreted in breast milk.

Infants and Children

Adequate long-term research is lacking, but no adverse effects have been reported in relation to policosanol use by children.

Contraindications

Pregnancy, breastfeeding.

Precautions and Warnings

Although potentially beneficial, concurrent use of policosanol and HMG-CoA reductase inhibitors may be inappropriate given the current lack of knowledge of policosanol's mechanism of action.

interactions review

Strategic Considerations

Data from long-term formal studies of drug interactions, additive toxicity, or integrative therapeutics involving policosanol in humans are generally lacking. Pharmacokinetic research suggests that policosanol does not interact with drug-metabolizing processes involving the cytochrome P450 microsomal system. 2 Consequently, drug-to-drug interactions between policosanol and drugs metabolized through the cytochrome P450 hepatic system are not probable, although adverse pharmacodynamic drug-to-drug interactions cannot be excluded. Furthermore, the consistent lack of toxicity associated with sustained policosanol therapy and its proposed ability to shift lipid parameters positively and inhibit platelet aggregation significantly, without elevating liver enzymes or affecting coagulation parameters, suggest that therapeutic synergy is more likely to characterize potential interactions than is enhanced risk. Adjunctive therapies with a strong safety profile are much in demand given the wide range of uses emerging for statin medications and the widespread use of beta blockers, despite their known toxicities and risks. Thus, policosanol presents significant promise as a therapeutic agent in concert with statins, beta blockers, or other nutritional and botanical agents to treat dyslipidiemia and support lipid homeostasis and healthy cardiovascular function.

Even though largely undertaken by a relatively small number of researchers, mostly by a single research institute in Cuba, the initial positive evidence available on policosanol provides a substantial foundation for further large, well-designed clinical trials into its efficacy and interaction patterns. In contrast to data indicating that policosanol at 5 to 40 mg per day exerts lipoprotein-lowering effects comparable to statins, Berthold et al. 10 (2006) arrived at much less convincing findings. These investigators conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Germany involving 143 patients with “hypercholesterolemia or combined hyperlipidemia having baseline low-density lipoprotein cholesterol (LDL-C) levels of at least 150 mg/dL … and either no or one cardiovascular risk factor other than known coronary heart disease, or baseline LDL-C levels of between 150 and 189 mg/dL … and two or more risk factors.” After a 6-week initial open-label placebo and diet run-in phase, they randomized subjects into five groups receiving sugarcane-derived policosanol (10, 20, 40, or 80 mg daily) or placebo for a double-blind 12-week treatment phase. None of the subjects in the five treatment groups exhibited decreases in LDL-C levels more than 10% from baseline, and “no statistically significant difference between policosanol and placebo was observed.” Furthermore, after this relatively short treatment period, none of the secondary outcome measures—total cholesterol, HDL-C, very-low-density lipoprotein cholesterol (VLDL-C), triglycerides, lipoprotein(a), and ratio of total or LDL-C to HDL-C, exhibited any significant effects of policosanol. 10

In an 8-week, double-blind, randomized controlled trial, Dulin et al. 11 reported that policosanol (20 mg/day) is “ineffective” in the treatment of “mild hypercholesterolemia.”

These conflicting findings indicate that long-term, well-designed studies of adequate size are warranted to determine the therapeutic efficacy of policosanol monotherapy and suggest whether its role as a component of a more comprehensive protocol may be more effective. It should be noted that Berthold's study 10 of 143 patients randomized into five groups is very small (<30 per group), particularly in comparison to statin trials, which typically involve many thousands of patients. Also, the experience with fish oil (omega-3 fatty acids) has shown more dramatic survival benefit than with statins in several trials, despite very modest changes in lipoprotein profiles. Given the earlier research with policosanol suggesting many mechanisms of action, it would seem premature to halt research with this agent after several small, negative clinical trials.

nutrient-drug interactions
Acetylsalicylic Acid (Aspirin) and Other Antiplatelet Medications
Anticoagulant Medications
Beta-1-Adrenoceptor Antagonists (Beta-1-Adrenergic Blocking Agents) and Related Antihypertensive Medications
Oral forms (systemic). Evidence: Propranolol (Inderal). Extrapolated, based on similar properties: Acebutolol (Sectral), atenolol (Tenormin); combination drugs: atenolol and chlortalidone (Co-Tendione, Tenoretic); atenolol and nifedipine (Beta-Adalat, Tenif); betaxolol (Kerlone), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL); combination drug: metoprolol and hydrochlorothiazide (Lopressor HCT); nadolol (Corgard), nebivolol (Nebilet), oxprenolol (Trasicor), penbutolol (Levatol), pindolol (Visken), propranolol (Betachron, Inderal LA, Innopran XL, Inderal); combination drug: propranolol and bendrofluazide (Inderex); sotalol (Betapace, Betapace AF, Sorine), timolol (Blocadren).
Minimal to Mild Adverse Interaction—Vigilance Necessary
Bimodal or Variable Interaction, with Professional Management
Beneficial or Supportive Interaction, with Professional Management

Probability: 4. Plausible
Evidence Base: Preliminary

Effect and Mechanism of Action

Preliminary research, involving animals but also consistent with known mechanisms of action of policosanol and its constituents, suggests that the effects of policosanol on blood pressure may create additive hypotensive effects when combined with antihypertension medications such as beta blockers.

Research

Molina Cuevas et al. 20 investigated the effect of policosanol on arterial blood pressure in rats and its pharmacological interaction with propranolol and nifedipine (a calcium channel blocker). First, they observed that single doses of policosanol, at various potencies, orally administered to spontaneously hypertensive rats did not significantly change arterial pressure. After administering high doses of policosanol (200 mg/kg) to the rats followed by both antihypertensive agents, they found that such pretreatment with policosanol significantly increased propranolol-induced hypotensive effects without modifying cardiac frequency. No alterations were observed in the effects of nifedipine.

In a 3-year randomized trial, Castano et al. 21 investigated the concomitant use of policosanol and beta blockers in 205 “older hypercholesterolemic patients taking beta-blockers.” After a 5-week diet-only baseline period, subjects were randomized to policosanol (5 mg/day) or placebo. After 1 year, subjects receiving policosanol exhibited significantly reduced LDL-C (20.9%), total cholesterol (TC) (19.3%), and triglycerides (TG) (25.7%), along with increased HDL-C levels (4.1%); these beneficial “effects did not wear off” during the 3-year follow-up. After the 3-year trial period, the authors reported that policosanol lowered LDL-C (34.3%), TC (23.2%), and TG (21.2%) and elevated HDL-C (12.3%), and that “reductions in systolic and diastolic blood pressure were observed in policosanol patients compared with those in the placebo group.” Notably, of the 31 patients (15.1%) who discontinued the study, 20 (16 in placebo group and 4 in policosanol group) withdrew because of adverse effects. “The frequency of serious adverse events (SAE), mostly vascular,” in policosanol patients (3.1%) was lower than in the placebo group (14.0%), with the frequency of policosanol patients reporting mild or moderate adverse effects (18.4%) also lower than in the placebo group (28.0%). The investigators concluded that “policosanol was well tolerated in elderly patients taking beta-blockers,” and that additional “reduction of blood pressure and a lower frequency of SAE were observed in policosanol patients compared with those taking placebo.” They added that “cholesterol-lowering efficacy of policosanol” was as “expected” and recommended the coadministration of policosanol in “hypercholesterolemic elderly individuals taking beta-blockers could provide additional benefits in lowering blood pressure.” 21

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The apparent synergistic interaction observed between policosanol and beta blockers could produce unintended and potentially adverse effects or may be therapeutically efficacious, depending on therapeutic strategy, monitoring, respective dosage titration, and the particular needs and characteristics of the individual patient. Further research involving well-designed clinical trials is warranted to elucidate the potential risks and benefits of this pattern of interaction and enable development of safe and effective guidelines for clinical management. Pending such conclusive research, any concomitant use of policosanol and beta blockers should be approached cautiously, and collaboration between health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics would be judicious and most likely to enhance outcomes.

HMG-CoA Reductase Inhibitors (Statins)
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Ezetimibe
Salicylates
Citations and Reference Literature
  • 1.Castano G, Mas R, Fernandez L et al. Effects of policosanol 20 versus 40 mg/day in the treatment of patients with type II hypercholesterolemia: a 6-month double-blind study. Int J Clin Pharmacol Res 2001;21:43-57.View Abstract
  • 2.Mesa AR, Mas R, Noa M et al. Toxicity of policosanol in beagle dogs: one-year study. Toxicol Lett 1994;73:81-90.View Abstract
  • 3.Fernandez L, Mas R, Illnait J et al. Policosanol: results of a postmarketing surveillance of 27,879 patients. Curr Ther Res 1998;59:717-722.
  • 4.Gouni-Berthold I, Berthold HK. Policosanol: clinical pharmacology and therapeutic significance of a new lipid-lowering agent. Am Heart J 2002;143:356-365.View Abstract
  • 5.Aleman CL, Puig MN, Elias EC et al. Carcinogenicity of policosanol in mice: an 18-month study. Food Chem Toxicol 1995;33:573-578.View Abstract
  • 6.Aleman CL, Mas R, Hernandez C et al. A 12-month study of policosanol oral toxicity in Sprague Dawley rats. Toxicol Lett 1994;70:77-87.View Abstract
  • 7.Rodriguez MD, Garcia H. Teratogenic and reproductive studies of policosanol in the rat and rabbit. Teratog Carcinog Mutagen 1994;14:107-113.View Abstract
  • 8.Rodriguez MD, Sanchez M, Garcia H. Multigeneration reproduction study of policosanol in rats. Toxicol Lett 1997;90:97-106.View Abstract
  • 9.Rodriguez MD, Garcia H. Evaluation of peri- and post-natal toxicity of policosanol in rats. Teratog Carcinog Mutagen 1998;18:1-7.View Abstract
  • 10.Berthold HK, Unverdorben S, Degenhardt R et al. Effect of policosanol on lipid levels among patients with hypercholesterolemia or combined hyperlipidemia: a randomized controlled trial. JAMA 2006;295:2262-2269.
  • 11.Dulin MF, Hatcher LF, Sasser HC, Barringer TA. Policosanol is ineffective in the treatment of hypercholesterolemia: a randomized controlled trial. Am J Clin Nutr 2006;84:1543-1548.View Abstract
  • 12.Arruzazabala ML, Valdes S, Mas R et al. Effect of policosanol successive dose increases on platelet aggregation in healthy volunteers. Pharmacol Res 1996;34:181-185.View Abstract
  • 13.Valdes S, Arruzazabala ML, Fernandez L et al. Effect of policosanol on platelet aggregation in healthy volunteers. Int J Clin Pharmacol Res 1996;16:67-72.View Abstract
  • 14.Carbajal D, Arruzazabala ML, Valdes S, Mas R. Effect of policosanol on platelet aggregation and serum levels of arachidonic acid metabolites in healthy volunteers. Prostaglandins Leukot Essent Fatty Acids 1998;58:61-64.View Abstract
  • 15.Arruzazabala ML, Valdes S, Mas R et al. Comparative study of policosanol, aspirin and the combination therapy policosanol-aspirin on platelet aggregation in healthy volunteers. Pharmacol Res 1997;36:293-297.View Abstract
  • 16.Castano G, Mas Ferreiro R, Fernandez L et al. A long-term study of policosanol in the treatment of intermittent claudication. Angiology 2001;52:115-125.View Abstract
  • 17.Arruzazabala ML, Molina V, Mas R et al. Antiplatelet effects of policosanol (20 and 40 mg/day) in healthy volunteers and dyslipidaemic patients. Clin Exp Pharmacol Physiol 2002;29:891-897.View Abstract
  • 18.Noa M, Herrera M, Magraner J, Mas R. Effect of policosanol on isoprenaline-induced myocardial necrosis in rats. J Pharm Pharmacol 1994;46:282-285.View Abstract
  • 19.Carbajal D, Arruzazabala ML, Valdes S, Mas R. Interaction policosanol-warfarin on bleeding time and thrombosis in rats. Pharmacol Res 1998;38:89-91.View Abstract
  • 20.Molina Cuevas V, Arruzazabala ML, Carbajal Quintana D et al. Effect of policosanol on arterial blood pressure in rats. Study of the pharmacological interaction with nifedipine and propranolol. Arch Med Res 1998;29:21-24. Erratum in: Arch Med Res 1998;29:361.View Abstract
  • 21.Castano G, Mas R, Gamez R et al. Concomitant use of policosanol and beta-blockers in older patients. Int J Clin Pharmacol Res 2004;24:65-77.View Abstract
  • 22.Cubeddu LX, Cubeddu RJ, Heimowitz T et al. Comparative lipid-lowering effects of policosanol and atorvastatin: a randomized, parallel, double-blind, placebo-controlled trial. Am Heart J 2006;152:982 e981-985.View Abstract
  • 23.McCarty MF. An ezetimibe-policosanol combination has the potential to be an OTC agent that could dramatically lower LDL cholesterol without side effects. Med Hypotheses 2005;64:636-645.
  • .[No authors listed.] A close look at coenzyme Q10 and policosanol: do these supplements live up to their claims for improving heart health? Harv Heart Lett 2002;13(4):6.
  • .[No authors listed.] Cholesterol-lowering action of policosanol compares well to that of pravastatin and lovastatin. Cardiovasc J S Afr 2003;14(3):161.
  • .[No authors listed.] Complementary care: how statin alternatives stack up: some help control cholesterol; others are potentially harmful. Heart Advis 2005;8(1):4-5.
  • .[No authors listed.] Monograph. policosanol. Altern Med Rev 2004;9(3):312-317. (Review)
  • .[No authors listed.] New policosanol product combines natural cholesterol lowering with omega-3 fatty acids to lower CV risk. Cardiovasc J S Afr 2006;17(2):92.
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  • .Aleman CL, Mas Ferreiro R, Noa Puig M, et al. Carcinogenicity of policosanol in Sprague Dawley rats: a 24 month study. Teratog Carcinog Mutagen 1994;14(5):239-249.
  • .American Herbal Products Association. Use of marker compounds in manufacturing and labeling botanically derived dietary supplements. Silver Spring, MD: American Herbal Products Association; 2001.
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  • .Ansell BJ, Navab M, Hama S, et al. Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation 2003;108:2751-2756.
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  • .Arruzazabala ML, Mas R, Molina V, et al. Effect of policosanol on platelet aggregation in type II hypercholesterolemic patients. Int J Tissue React 1998;20(4):119-124.
  • .Arruzazabala ML, Molina V, Carbajal D, et al. Effect of policosanol on cerebral ischemia in Mongolian gerbils: role of prostacyclin and thromboxane A2. Prostaglandins Leukot Essent Fatty Acids 1993;49(3):695-697.
  • .Arruzazabala ML, Noa M, Menendez R, et al. Protective effect of policosanol on atherosclerotic lesions in rabbits with exogenous hypercholesterolemia. Braz J Med Biol Res 2000;33(7):835-840.
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  • .Brown BG, Zhao X-Q, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345(22):1583-1592.
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  • .Carbajal D, Arruzazabala ML, Mas R, et al. Effect of policosanol on experimental thrombosis models. Prostaglandins Leukot Essent Fatty Acids 1994;50(5):249-251.
  • .Castano G, Fernandez L, Mas R, et al. Comparison of the efficacy, safety and tolerability of original policosanol versus other mixtures of higher aliphatic primary alcohols in patients with type II hypercholesterolemia. Int J Clin Pharmacol Res 2002;22(2):55-66.
  • .Castano G, Fernandez L, Mas R, et al. Effects of addition of policosanol to omega-3 fatty acid therapy on the lipid profile of patients with type II hypercholesterolaemia. Drugs R D 2005;6(4):207-219.
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  • .Castano G, Mas R, Arruzazabala ML, et al. Effects of policosanol and pravastatin on lipid profile, platelet aggregation and endothelemia in older hypercholesterolemic patients. Int J Clin Pharmacol Res 1999;19(4):105-116.
  • .Castano G, Mas R, Fernandez L, et al. A comparison of the effects of D-003 and policosanol (5 and 10 mg/day) in patients with type II hypercholesterolemia: a randomized, double-blinded study. Drugs Exp Clin Res 2005;31(Suppl):31-44.
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  • .Cubeddu LX, Cubeddu RJ, Heimowitz T, et al. Comparative lipid-lowering effects of policosanol and atorvastatin: a randomized, parallel, double-blind, placebo-controlled trial. Am Heart J 2006;152(5):982.e1-e5.
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