Policosanol

By Steven Bratman, MD

Policosanol is a product extracted from sugar cane that contains eight higher aliphatic alcohols, predominantly octacosanol (60%), followed by triacontanol and hexacosanol.1,2 Minor constituents include tetracosanol, heptacosanol, nonacosanol, dotriacontanol, and tetratriacontanol. Although it is widely used as a hypolipidemic agent in Cuba, policosanol is not widely available in this country. A sizeable body of published studies indicates that policosanol possesses significant hypolipidemic actions. However, virtually all of this research has been performed by members of one Cuban research group, led by Rosa Mas, PhD.

Placebo-Controlled Trials

A search of the literature and a query directed to the Cuban researchers identified 15 randomized, double-blind, placebo-controlled trials of policosanol (5-20 mg/d) for the treatment of hyperlipidemia.2-16 All but one study were performed in Cuba by research groups connected with Dr. Mas. More than 1,000 individuals were enrolled in these trials, which ranged in length from six weeks to one year. Most trials involved a four- to 12-week period of a standard step 1 National Cholesterol Education Program (NCEP) diet prior to randomization; only individuals who had failed to respond satisfactorily to dietary modification were enrolled. In all of these studies, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) improved significantly in the treated groups compared to the placebo groups and to baseline (P £ 0.05 when stated; some early studies failed to state significance level). Most trials also found statistically significant benefits for treatment (compared to both baseline and placebo) in LDL-C: high-density lipoprotein cholesterol (HDL-C) ratio and TC:HDL-C ratio (P £ 0.05 when stated; some early studies failed to state significance level). Most trials did not find significant HDL-C changes from baseline; however, in the two largest trials, treatment significantly increased HDL-C compared to baseline and was significantly better than placebo (P < 0.001).2,8 Most studies did not find statistically significant changes in trigly-cerides as compared to baseline, although some (including the largest trials) did find significant inter-group differences in triglyceride levels (P < 0.001).

The largest of these was a double-blind, placebo- controlled trial that enrolled 437 individuals with type II hypercholesterolemia.2 Potential participants first were placed on a step 1 diet for five weeks. Lipid profiles were taken twice within the next two weeks and averaged to provide a baseline value. Only participants with serum levels of LDL-C > 133 mg/dL (3.4 mmol/L), TC > 203 mg/dL (5.2 mmol/L) and triglycerides (TG) < 176 mg/dL (4.52 mmol/L) after dietary stabilization were included. Exclusion criteria consisted of active renal disease, diagnosed neoplastic disease, severe hypertension, uncontrolled diabetes, or recent history of myocardial infarction or coronary surgery. Pregnant and lactating women also were excluded.

Participants were randomized to placebo or policosanol at 5 mg/d for 12 weeks. At that point, the dose increased to 10 mg/d in both groups, and the study continued for an additional 12 weeks. Thirty-six patients discontinued participation in the study, and final data were not completely available for six others. An intention-to-treat (ITT) analysis was not reported.

On a per-protocol basis, only the policosanol group improved in TC, LDL, HDL, TG, and lipid ratios (see Table). Changes from baseline were significant in the treated group (P < 0.001), as were inter-group differences. At study completion, 83% in the treated group were considered total responders (defined as more than a 10% reduction in LDL-C) compared to 15.5% in the placebo group, a significant difference (P < 0.00001). Significant changes between the treatment and placebo groups already had been seen at the end of the lower-dose, 12-week period in all measured parameters except TG. Both doses of policosanol were well tolerated.

A study of substantially identical design enrolled 244 postmenopausal women with type II hypercholesterolemia.8 In this case, an ITT analysis was utilized. Again, only the policosanol group benefited (see Table). Except for TG, the changes in the policosanol group were significant compared to baseline (P < 0.001). Inter-group differences were significant for all variables (P < 0.0001). Responder rate (defined by LDL-C reduction of at least 15%) was 80.2% in the treated group vs. 13.5% in the placebo group (P value not stated).

Four double-blind, placebo-controlled, one-year studies of policosanol enrolled about 250 individuals and also reported positive results.5-7,13 The largest of these trials enrolled 74 individuals with type II hypercholesterolemia.5 A 12-week period of stabilization on a low-fat, low-cholesterol diet was followed by 12 months of treatment with either placebo or policosanol (5 mg twice daily). Nine participants dropped out, five from the placebo group and four from the policosanol group. Although the authors state that changes in TC and LDL-C were significantly better in the treatment group compared to the placebo group and were evident as early as two months into the trial, P values are not given, nor are changes in the placebo group reported (see Table). They further stated that HDL-C values were increased significantly as compared to placebo, but only at 12 months. TG levels did not change significantly.

One double-blind, placebo-controlled trial of policosanol was performed in Argentina, although Rosa Mas is a coauthor.16 After six weeks of stabilization on a step 1 diet, 56 patients received either placebo or policosanol 5 mg/d for eight weeks, then 10 mg/d for an additional eight weeks. After 16 weeks, an ITT analysis showed significant benefit of treatment over placebo (P < 0.01) in all measures except TG (see Table, below).

Table

Lipid changes in cited policosanol studies (policosanol vs. control)

Total Cholesterol  LDL-C HDL-C  Triglycerides LDL-C:HDL-C TC:HDL-C
Mas2 (PC)   -17.4% vs. -0.2%  -25.6% vs. -0.4%   +28.4% vs. +2.9% -5.2% vs. +16.8%   -32.5% vs. +7.2%  -28.8% vs. +5.6%
Castano5 (PC)  -17.2%   -26.4%  -33.3% -25.3%
Castano8 (PC) -16.7% vs. +0.5%   -25.4% vs. +0.4%   +29.3% vs. +3.3% -4.6% vs. +17.4%   -29.6% vs. +7.5%   -27.3% vs. +5.9%
Mirkin16 (PC) -19.5% vs. -1.0%   -26.7% vs. +1.0% +7.4% vs. -6.2% -26.5% vs. +6.7% -21.0% vs. +6.8%
Ortensi17 (TC) 14.7% vs. -15.2% -17.9% vs. -19.8% -13.8% vs. -8.7%
Fernandez18 (TC) -19.3% vs. -16.7%   -29.2% vs. -22.9% +19.8% vs. +9.2% -39.8% vs. -28.4%   -31.6% vs. -22.8%

Key: PC = placebo-controlled; TC = treatment-controlled

Comparative Trials

A literature search and query to the Cuban researchers identified seven randomized, double-blind trials, enrolling about 400 individuals, that compared policosanol to simvastatin, fluvastatin, lovastatin, pravastatin, or acipimox.17-23 The results of each trial indicated that policosanol was at least as effective as the comparator drug.

The most recent study compared 10 mg of policosanol to 20 mg of fluvastatin in 70 women with type II hypercholesterolemia.18 After a four-week run-in period, during which participants discontinued lipid-lowering therapy and followed a step 1 NCEP diet, 70 women were randomized to enter the trial. A total of 65 women completed the trial. According to ITT analysis, the effect of policosanol was statistically greater than that of fluvastatin (P < 0.01) in all measures except TG (for which the two treatments were equivalent). (See Table.) In all measurements, the responder rate (defined as decrease in LDL-C of greater than 15%) was 100% in the policosanol group and 90% in the fluvastatin group, again a statistically equivalent outcome. Both drugs were well tolerated, except that on average, an increase in transaminases was seen in the fluvastatin group.

In the one double-blind, comparative trial of policosanol that was conducted outside of Cuba, Argentine researchers compared policosanol and simvastatin, both at a dose of 10 mg/d, for eight weeks.17 Fifty-three elderly individuals were enrolled; 50 completed the study. The treatments were equivalent for TC, LDL-C, and TG (see Table) and both treatments were well tolerated.

Mechanism of Action

The mechanism of action of policosanol is not known. Some evidence suggests that policosanol does not inhibit HMG-CoA reductase.24,25 Rather, it may impair cholesterol synthesis between the acetate and mevalonate production steps and/or increase receptor-dependent LDL-C processing.24,26 Policosanol also may reduce lipid peroxidation.17,27,28

Dosage

In published trials, policosanol was given at a dose of 5-20 mg daily for at least six weeks. Doses of 10 mg or more were given in two divided doses.

Safety Issues

Policosanol generally is well tolerated. A drug monitoring study followed 27,879 patients who were taking policosanol (primarily at a dose of 5 mg/d) for 2-4 years, and reported adverse effects in only 0.31% of participants.29 These consisted primarily of weight loss, excessive urination, and insomnia. Two double-blind, placebo-controlled trials in which 10 mg/d of policosanol was given for 12 weeks to more than 300 individuals found no significant side effects attributable to policosanol.2,8 Two double-blind, placebo controlled trials in which 20 mg/d of policosanol was given to 28 individuals for six and eight weeks, respectively, reported no significant adverse effects attributable to treatment.4,11

A 12-week randomized, double-blind, placebo- controlled (RDBPC) trial of 46 patients with hyper- cholesterolemia and serum biochemical indicators of hepatic dysfunction (ALT > 45 U/L, GGTP > 55 U/L) found no deterioration of liver function attributable to policosanol use.30 Similarly, two 12-week RDBPC trials of hypercholesterolemic diabetic individuals involving a total of 49 individuals found no deterioration in glycemic control.9,14

No signs of toxicity were observed in a one-year study of beagles given policosanol at a dose of 180 mg/kg/d for 52 weeks.31 Other one-year studies in rats and monkeys also failed to detect signs of short- or long-term toxicity with high doses of policosanol.32,33

Policosanol exhibits dose-dependent antiplatelet action comparable to 100 mg of aspirin daily.21,34,35 Caution should be exercised in individuals with impaired coagulation homeostasis. Policosanol also should be avoided before and after surgery or labor and delivery.

Safety in Pregnancy and Lactation

Oral doses of policosanol (up to 1,000 mg/kg/d) in pregnant rabbits and rats resulted in no teratogenic or embryotoxic effects.36 However, the antiplatelet effects of policosanol raise potential concerns. The maximum safe dose in pregnant or nursing women have not been established.

Drug Interactions

A one-year, double-blind trial of 58 individuals with hypertension treated with beta-blockers, diuretics, and/or calcium channel antagonists found no evidence of drug interactions with policosanol.7 However, policosanol potentiates the antiplatelet effects of aspirin.37 Caution should be exercised when combining policosanol with any antiplatelet or anticoagulant agent, including garlic, ginkgo, and high-dose vitamin E.

According to one small trial, octacosanol can potentiate the action of levodopa, causing increased dyskinesia side effects.37

Conclusion

Numerous published double-blind, placebo-controlled and comparative trials support the use of policosanol as a hypolipidemic agent. However, all but two of these trials were performed by a single research group in Cuba. This lack of independent verification significantly detracts from what would otherwise be an impressive level of evidence.

Only sugar cane-derived policosanol has been evaluated as a hypolipidemic agent. Despite their use in the popular product "new" Cholestin™ (see sidebar), beeswax extracts have not been shown effective in double-blind controlled trials.

Dr. Bratman is Medical Director and Senior Editor of TNP.com.

References

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4. Aneiros E, et al. Effect of policosanol in lowering cholesterol levels in patients with type II hypercholesterolemia. Curr Ther Res 1995;56:176-182.

5. Castano G, et al. Efficacy and tolerability of policosanol in elderly patients with type II hypercholesterolemia: A 12-month study. Curr Ther Res 1995;56:819-828.

6. Castano G, et al. One-year study of the efficacy and safety of policosanol (5 mg twice daily) in the treatment of type II hypercholesterolemia. Curr Ther Res 1995;56:296-304.

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27. Menendez R, et al. Oral administration of policosanol inhibits in vitro copper ion-induced rat lipoprotein peroxidation. Physiol Behav 1999;67:1-7.

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