Meta-Analysis of Natural Therapies for Hyperlipidemia: Plant Sterols and Stanols Versus Policosanol

Judy T. Chen, Pharm.D.; Robert Wesley, Ph.D.; Robert D. Shamburek, M.D.; Frank Pucino, Pharm.D.; Gyorgy Csako, M.D.

Pharmacotherapy. 2005;25(2):171-183. 

Abstract and Introduction

Study Objective: To compare the efficacy and safety of plant sterols and stanols as well as policosanol in the treatment of coronary heart disease, as measured by a reduction in low-density lipoprotein cholesterol (LDL) levels.
Design: Systematic review and meta-analysis of randomized controlled trials.
Patients: A total of 4596 patients from 52 eligible studies.
Measurements and Main Results: We searched MEDLINE, EMBASE, the Web of Science, and the Cochrane Library from January 1967-June 2003 to identify pertinent studies. Reduction of LDL levels was the primary end point; effects on other lipid parameters and withdrawal of study patients due to adverse effects were the secondary end points. Weighted estimates of percent change in LDL were -11.0% for plant sterol and stanol esters 3.4 g/day (range 2-9 g/day [893 patients]) versus -2.3% for placebo (769 patients) in 23 eligible studies, compared with -23.7% for policosanol 12 mg/day (range 5-40 mg/day [1528 patients]) versus -0.11% for placebo (1406 patients) in 29 eligible studies. Cumulative p values were significantly different from placebo for both (p<0.0001). The net LDL reduction in the treatment groups minus that in the placebo groups was greater with policosanol than plant sterols and stanols (-24% versus -10%, p<0.0001). Policosanol also affected total cholesterol, high-density lipoprotein cholesterol (HDL), and triglyceride levels more favorably than plant sterols and stanols. Policosanol caused a clinically significant decrease in the LDL:HDL ratio. Pooled withdrawal rate due to adverse effects and combined relative risk for patients who withdrew were 0% and 0.84, respectively (95% confidence interval [CI] 0.36-1.95, p=0.69), for plant sterols and stanols across 20 studies versus 0.86% and 0.31, respectively (95% CI 0.20-0.48, p<0.0001), for policosanol across 28 studies.
Conclusion: Plant sterols and stanols and policosanol are well tolerated and safe; however, policosanol is more effective than plant sterols and stanols for LDL level reduction and more favorably alters the lipid profile, approaching antilipemic drug efficacy.

Coronary heart disease (CHD) remains the leading cause of death in industrialized nations. Elevated low-density lipoprotein cholesterol (LDL) level is a major risk factor for CHD, hence it is the primary target of lipid-lowering therapy.[1] Due to concerns regarding adverse effects and patient reluctance to comply with chemically derived drug therapies, alternative natural therapies have become increasingly popular over the last decade.[2,3]

Plant (phyto) sterols are naturally occurring cholesterol derivatives (e.g., sitosterol, campesterol, brassicasterol, stigmasterol) from vegetable oils, nuts, soy, corn, woods, and beans. Hydrogenation of plant sterols produces stanols. Esterification produces sterol and/or stanol esters. The generic term phytosterols often is used to describe both sterols and stanols and their esters. The LDL-lowering efficacy of plant stanols is considered comparable with that of plant sterols.[4-8] The United States National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III endorses plant sterol and stanol esters 2 g/day as an essential feature of therapeutic lifestyle changes along with diet modifications, weight reduction, intake of viscous fibers, and increased physical activity to reduce risk for CHD.[1]

Another natural product, policosanol, is an antilipemic agent that includes mixtures of aliphatic primary alcohols extracted from sugarcane ( Saccharum officinarum L) wax. Its main components are octacosanol (62.9%), triacontanol (12.6%), and hexacosanol (6.2%).[9] Policosanol is used for reduction of LDL levels in more than 25 countries, mainly in the Caribbean and South America. Clinical studies have demonstrated consistent LDL-lowering activity of policosanol without apparent toxicity concerns.[9,10]

Methods

A systematic review of the published literature from January 1967-June 2003 was performed using MEDLINE, EMBASE, the Web of Science, and the Cochrane Library. The following indexing terms were used: plant stanol esters, plant sterols, plant stanols, sitosterols, phytosterols, policosanol, octacosanol, hypercholesterolemia, hyperlipidemia, cholesterol, lipoprotein, LDL cholesterol, and LDL. A manual review of the bibliographies of seminal primary and review articles was also performed to identify any additional relevant studies.

Only randomized, double-blind, placebo-controlled trials were retrieved, and only if they met the following criteria: LDL levels were reported, treatment duration was 4 weeks or longer, study patients were aged 18 years or older, and dosages used were plant sterol and stanol ester equivalents of 2 g/day or greater or policosanol 5 mg/day or greater. The minimal dosage for plant sterol and stanol esters was based on NCEP ATP III recommendations,[1] whereas the minimal dosage for policosanol was derived from our dose-response treatment duration analysis of published data (Figure 1).[11-39]

Dose and treatment duration response with policosanol.[11-39] For policosanol, studies are represented by an average of 1.5 doses (range 1-3 doses) and 1.8 treatment intervals (range 1-5 intervals), corresponding to an average of 2.4 data points (range 1-5 data points)/study. LDL = low-density lipoprotein cholesterol; m = placebo; s = policosanol 5 mg; u = policosanol 10 mg; and n = policosanol 20-40 mg.

Dose-comparison trials using parallel or crossover designs were analyzed by combining the LDL level reduction from each treatment group.[5-7,12,15,22,26,31,34,36,38,40-42] The summation of each time interval of receiving active therapy was considered the treatment duration in cases of vehicle changes[7] and dose-escalation studies.[13,14,18-21,43,44] For the latter, the final dosage and the associated LDL level change were used. For policosanol trials that provided only a dosage range, mean dosage was considered (e.g., 7.5 mg/day for 5-10 mg/day).[28,30] Trials were excluded if they lacked extractable LDL data, interindependence with other trials included in the meta-analysis, or peer review (e.g., meeting abstracts), or if they included a combination with other antilipemic therapy. Data were retrieved by consensus of three investigators (JTC, FP, and GC).

The quality of evidence for each eligible study was assessed for applicability to the general population, bias and confounding, treatment description, outcomes and follow-up, and statistical quality and interpretation. A modified question-naire from the Johns Hopkins Evidence-Based Practice Center (available from http://www. ahrq.gov/clinic/epcix.htm) was used. The quality of evidence was scored by consensus of three investigators (JTC, FP, and GC) on a scale of 0-100% (worst-best).

For each qualifying study, the percent change in LDL level and secondary end points (total cholesterol, high-density lipoprotein cholesterol [HDL], and triglyceride levels, and LDL:HDL ratio) was calculated from the baseline mean or median (usually after a diet run-in phase) to the end-of-study mean or median values. Thus the most complete data could be obtained. The percent difference was weighted by the number of patients and the baseline and/or end-of-study variability for patients treated with plant sterols and stanols, policosanol, and placebo.

In addition, the Fisher method of combining p values from separate studies was used to provide an overall stratified result for comparing plant sterols and stanols and policosanol with placebo (cumulative p value). For studies reporting nonsignificant findings with no p value, a p value was calculated using an unpaired t test from the posttreatment means and standard deviations. An unpaired t test was used to compare net changes (treatment minus placebo) and baseline lipid parameters of plant sterols and stanols with those of policosanol. Statistical significance for the two-tailed p values was set, a priori, at less than 0.05.

The combined relative risk and corresponding 95% confidence interval (CI) of patients who withdrew from studies due to adverse effects were calculated using the Mantel-Haenszel test. We substituted 0.5 for each cell of the stratum that contained zero to determine the relative risk for studies that reported no dropouts. Homogeneity across studies was assessed with the Breslow-Day test ( X[2] test statistic). This test assesses whether the distribution of effect sizes is compatible with the assumption that any interstudy differences are attributable to random sampling alone. This test would be nonsignificant if studies were homogeneous (e.g., similar risk of withdrawal due to adverse effects from study to study). Thus, with this method, if the heterogeneity (interstudy variability) were large, confidence intervals would be wider than those derived by a simpler type of analysis, such as the inverse-variance weighted average comparison method.

All statistical analyses were performed using OnlineDoc software, version 8 (SAS Institute Inc., Cary, NC).

Results

We identified 42 plant sterol and stanol trials and 30 policosanol trials that were randomized, double-blind, and placebo-controlled and met the initial eligibility criteria. Subsequently, we excluded trials that compared treatment combined with other antilipemic agents (four plant sterol and stanol trials and one policosanol trial). In addition, seven plant sterol and stanol trials were excluded because LDL data were not presented in an extractable format; eight trials were excluded due to lack of independent data. Thus, only 23 (55%) of 42 available plant sterol and stanol trials but 29 (97%) of 30 policosanol trials qualified for the meta-analysis. All studies had comparatively high quality of evidence scores (Figures 2 and 3).[4-7,11-59]

Meta-analysis of clinical trials of plant sterols and stanols. LDL = low-density lipoprotein cholesterol; HC = hypercholesterolemia; DM = diabetes mellitus type 2; NC = normocholesterolemia; PMW, MI = postmenopausal women with previous myocardial infarction. aEquivalent esterified dose (1 g of plant sterol or stanol = 1.7 g of plant sterol or stanol ester); bcrossover trial (summation of each time interval of active therapy was considered treatment duration); ccombined average dosage.

Meta-analysis of clinical trials of policosanol. For dose-escalation studies, the summation of each time interval of active therapy was considered treatment duration. LDL = low-density lipoprotein cholesterol; HC = hypercholesterolemia; DM = diabetes mellitus type 2; NC = normocholesterolemia; PMW = postmenopausal women; HTN = hypertension; AHF = abnormal hepatic function (alanine aminotransferase level > 45 U/L and g-glutamyl transpeptidase level > 55 U/L); ACV = atherosclerosis (carotid-vertebral); CAD = coronary artery disease. aCombined average dosage.

Plant Sterols and Stanols. Of the 23 plant sterol and stanol trials, 17 were parallel in design and 6 were crossover studies.[4,7,45-48] Reduced LDL levels were evaluated in patients with normocholesterolemia,[5,49,50] hypercholes-terolemia,[4,6,7,40-45,47,48,50-59] and type 2 diabetes mellitus,[59] as well as in postmenopausal women with a history of myocardial infarction.[46] The average daily dose of plant sterol and stanol esters was 3.4 g (range 2-9 g) over a mean treatment period of 8.6 weeks (range 4-52 wks). In most studies, plant sterols and stanols were incor-porated into regular margarine[6,7,48,54,57,58] or rapeseed-oil margarine.[5,41,46] Other dietary vehicles used to deliver plant sterols and stanols were rapeseed-oil mayonnaise,[44,51,52] reduced-fat spread and salad dressing,[40] chocolate,[55] butter,[4] ground beef,[56] low-fat yogurt,[49] reduced-fat spread,[42,53,59] "spread,"[45,47] and beverages.[50] Another delivery method was a diet of enriched bread, meat (sausage, meatballs, cold cuts), jam, and yogurt.[43]

Although studies differed considerably, the weighted percent LDL level reduction was greater with plant sterols and stanols (-11%) than placebo (-2.3%) (Figure 2, ).[4-7,40-59] The cumulative p value across all studies was less than 0.0001 when plant sterols and stanols were compared with placebo.

  Summary Comparison Between Plant Sterol and Stanol Studies and Policosanol Studies

  Plant Sterol and Stanol Studies[4-7,40-59] Policosanol Studies[11-39]
Placebo Treatment Cumulative p Valuea Placebo Treatment Cumulative p Valuea
Total cholesterol level
Baseline (mg/dl [mmol/L]) 238 (6.16)b 239 (6.18)c <0.0001 257 (6.65)b 262 (6.78)c <0.0001
% change (weighted mean) -0.2 -7.7 -0.6 -16.2
% change (range) -10.4 to 4.6 -2.8 to -19.5 -7.0 to 6.1 -8.8 to -28.8
No. of patients 769 893 1406 1528
No. of studies 23 23 29 29
LDL level
Baseline (mg/dl [mmol/L]) 159 (4.11)b 158 (4.08)c <0.0001 180 (4.66)b 186 (4.80)c <0.0001
% change (weighted mean) -2.3 -11.0 -0.1 -23.7
% change (range) -11.6 to 4.3 -4.6 to -24.3 -7.2 to 11.5 -12.6 to -42.1
No. of patients 769 893 1406 1528
No. of studies 23 23 29 29
HDL level
Baseline (mg/dl [mmol/L]) 52 (1.35) 52 (1.36)c 0.0590 48 (1.24) 47 (1.21)c <0.0001
% change (weighted mean) -0.5 <-0.1 -3.3 10.6
% change (range) -6.9 to 5.8 -10.7 to 6.5 -15.2 to 18.3 -3.3 to 33.9
No. of patients 734 857 1406 1528
No. of studies 22 22 29 29
LDL:HDL ratio
Baseline 3b 3.2c 0.0025 4b 4.3c <0.0001
% change (weighted mean) 3.8 -11.9 1.1 -32.5
% change (range) -9.1 to 7.2 -10.4 to -16.1 -17.6 to 34.4 -9.8 to -53.8
No. of patients 168 193 1353 1438
No. of studies 6 6 26 26
Triglyceride level
Baseline (mg/dl [mmol/L]) 134 (1.51)b 136 (1.54)c 0.6500 172 (1.94)b 180 (2.03)c 0.0530
% change (weighted mean) -0.8 3.8 2.4 -12.4
% change (range) -20.8 to 15.3 -11.1 to 6.7 -19.1 to 31.3 -35.1 to 17.5
No. of patients 656 790 1406 1528
No. of studies 21 21 29 29

None of the baseline lipid parameters differed significantly (p>0.05) between placebo and treatment arms.

LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol.

aSee definition in Methods section for cumulative p value.

bSignificant difference (p<0.04) between placebo groups.

cSignificant difference (p<0.01) between treatment groups.

Policosanol. All 29 policosanol trials were of parallel design and evaluated the efficacy of policosanol in volunteers with normocholesterolemia[22,34,38]; patients with hypercholesterolemia[11-21,23-33,35,36]; postmenopausal women with hypercholes-terolemia[18,19]; and patients with carotid-vertebral atherosclerosis,[37] coronary artery disease,[39] type 2 diabetes mellitus,[11,27] hypertension,[30] and abnormal hepatic function.[31] The mean policosanol daily dose was 12 mg (range 5-40 mg) over an average treatment period of 29.6 weeks (range 4-104 wks; Figure 3). With a single exception,[39] all studies reported use of tablet formulations.

Although the effect size varied among different studies, the weighted percent LDL level reduction was much greater with policosanol (-23.7%) than placebo (-0.1%) (Figure 3, ).[11-39] The cumulative p value across all studies was less than 0.0001 when policosanol was compared with placebo.

  Summary Comparison Between Plant Sterol and Stanol Studies and Policosanol Studies

  Plant Sterol and Stanol Studies[4-7,40-59] Policosanol Studies[11-39]
Placebo Treatment Cumulative p Valuea Placebo Treatment Cumulative p Valuea
Total cholesterol level
Baseline (mg/dl [mmol/L]) 238 (6.16)b 239 (6.18)c <0.0001 257 (6.65)b 262 (6.78)c <0.0001
% change (weighted mean) -0.2 -7.7 -0.6 -16.2
% change (range) -10.4 to 4.6 -2.8 to -19.5 -7.0 to 6.1 -8.8 to -28.8
No. of patients 769 893 1406 1528
No. of studies 23 23 29 29
LDL level
Baseline (mg/dl [mmol/L]) 159 (4.11)b 158 (4.08)c <0.0001 180 (4.66)b 186 (4.80)c <0.0001
% change (weighted mean) -2.3 -11.0 -0.1 -23.7
% change (range) -11.6 to 4.3 -4.6 to -24.3 -7.2 to 11.5 -12.6 to -42.1
No. of patients 769 893 1406 1528
No. of studies 23 23 29 29
HDL level
Baseline (mg/dl [mmol/L]) 52 (1.35) 52 (1.36)c 0.0590 48 (1.24) 47 (1.21)c <0.0001
% change (weighted mean) -0.5 <-0.1 -3.3 10.6
% change (range) -6.9 to 5.8 -10.7 to 6.5 -15.2 to 18.3 -3.3 to 33.9
No. of patients 734 857 1406 1528
No. of studies 22 22 29 29
LDL:HDL ratio
Baseline 3b 3.2c 0.0025 4b 4.3c <0.0001
% change (weighted mean) 3.8 -11.9 1.1 -32.5
% change (range) -9.1 to 7.2 -10.4 to -16.1 -17.6 to 34.4 -9.8 to -53.8
No. of patients 168 193 1353 1438
No. of studies 6 6 26 26
Triglyceride level
Baseline (mg/dl [mmol/L]) 134 (1.51)b 136 (1.54)c 0.6500 172 (1.94)b 180 (2.03)c 0.0530
% change (weighted mean) -0.8 3.8 2.4 -12.4
% change (range) -20.8 to 15.3 -11.1 to 6.7 -19.1 to 31.3 -35.1 to 17.5
No. of patients 656 790 1406 1528
No. of studies 21 21 29 29

None of the baseline lipid parameters differed significantly (p>0.05) between placebo and treatment arms.

LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol.

aSee definition in Methods section for cumulative p value.

bSignificant difference (p<0.04) between placebo groups.

cSignificant difference (p<0.01) between treatment groups.

Almost all studies allowed assessment of changes in total cholesterol, HDL, and triglyceride levels with both treatments; only assessment of the LDL:HDL ratio with plant sterol and stanol treatment was limited ( ). As with LDL, the effect sizes varied considerably with both treatments for these lipid parameters among different trials. Nevertheless, compared with placebo, treatment with plant sterols and stanols significantly reduced total cholesterol level and LDL:HDL ratio and caused a borderline increase in HDL but had no effect on triglyceride levels. The LDL:HDL ratio was reduced in all six plant sterol and stanol studies amenable to evaluation (Figure 4). In addition to reducing total cholesterol level and the LDL:HDL ratio significantly, and significantly increasing HDL, policosanol caused a borderline decrease in triglyceride level ( ).

  Summary Comparison Between Plant Sterol and Stanol Studies and Policosanol Studies

  Plant Sterol and Stanol Studies[4-7,40-59] Policosanol Studies[11-39]
Placebo Treatment Cumulative p Valuea Placebo Treatment Cumulative p Valuea
Total cholesterol level
Baseline (mg/dl [mmol/L]) 238 (6.16)b 239 (6.18)c <0.0001 257 (6.65)b 262 (6.78)c <0.0001
% change (weighted mean) -0.2 -7.7 -0.6 -16.2
% change (range) -10.4 to 4.6 -2.8 to -19.5 -7.0 to 6.1 -8.8 to -28.8
No. of patients 769 893 1406 1528
No. of studies 23 23 29 29
LDL level
Baseline (mg/dl [mmol/L]) 159 (4.11)b 158 (4.08)c <0.0001 180 (4.66)b 186 (4.80)c <0.0001
% change (weighted mean) -2.3 -11.0 -0.1 -23.7
% change (range) -11.6 to 4.3 -4.6 to -24.3 -7.2 to 11.5 -12.6 to -42.1
No. of patients 769 893 1406 1528
No. of studies 23 23 29 29
HDL level
Baseline (mg/dl [mmol/L]) 52 (1.35) 52 (1.36)c 0.0590 48 (1.24) 47 (1.21)c <0.0001
% change (weighted mean) -0.5 <-0.1 -3.3 10.6
% change (range) -6.9 to 5.8 -10.7 to 6.5 -15.2 to 18.3 -3.3 to 33.9
No. of patients 734 857 1406 1528
No. of studies 22 22 29 29
LDL:HDL ratio
Baseline 3b 3.2c 0.0025 4b 4.3c <0.0001
% change (weighted mean) 3.8 -11.9 1.1 -32.5
% change (range) -9.1 to 7.2 -10.4 to -16.1 -17.6 to 34.4 -9.8 to -53.8
No. of patients 168 193 1353 1438
No. of studies 6 6 26 26
Triglyceride level
Baseline (mg/dl [mmol/L]) 134 (1.51)b 136 (1.54)c 0.6500 172 (1.94)b 180 (2.03)c 0.0530
% change (weighted mean) -0.8 3.8 2.4 -12.4
% change (range) -20.8 to 15.3 -11.1 to 6.7 -19.1 to 31.3 -35.1 to 17.5
No. of patients 656 790 1406 1528
No. of studies 21 21 29 29

None of the baseline lipid parameters differed significantly (p>0.05) between placebo and treatment arms.

LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol.

aSee definition in Methods section for cumulative p value.

bSignificant difference (p<0.04) between placebo groups.

cSignificant difference (p<0.01) between treatment groups.

  Summary Comparison Between Plant Sterol and Stanol Studies and Policosanol Studies

  Plant Sterol and Stanol Studies[4-7,40-59] Policosanol Studies[11-39]
Placebo Treatment Cumulative p Valuea Placebo Treatment Cumulative p Valuea
Total cholesterol level
Baseline (mg/dl [mmol/L]) 238 (6.16)b 239 (6.18)c <0.0001 257 (6.65)b 262 (6.78)c <0.0001
% change (weighted mean) -0.2 -7.7 -0.6 -16.2
% change (range) -10.4 to 4.6 -2.8 to -19.5 -7.0 to 6.1 -8.8 to -28.8
No. of patients 769 893 1406 1528
No. of studies 23 23 29 29
LDL level
Baseline (mg/dl [mmol/L]) 159 (4.11)b 158 (4.08)c <0.0001 180 (4.66)b 186 (4.80)c <0.0001
% change (weighted mean) -2.3 -11.0 -0.1 -23.7
% change (range) -11.6 to 4.3 -4.6 to -24.3 -7.2 to 11.5 -12.6 to -42.1
No. of patients 769 893 1406 1528
No. of studies 23 23 29 29
HDL level
Baseline (mg/dl [mmol/L]) 52 (1.35) 52 (1.36)c 0.0590 48 (1.24) 47 (1.21)c <0.0001
% change (weighted mean) -0.5 <-0.1 -3.3 10.6
% change (range) -6.9 to 5.8 -10.7 to 6.5 -15.2 to 18.3 -3.3 to 33.9
No. of patients 734 857 1406 1528
No. of studies 22 22 29 29
LDL:HDL ratio
Baseline 3b 3.2c 0.0025 4b 4.3c <0.0001
% change (weighted mean) 3.8 -11.9 1.1 -32.5
% change (range) -9.1 to 7.2 -10.4 to -16.1 -17.6 to 34.4 -9.8 to -53.8
No. of patients 168 193 1353 1438
No. of studies 6 6 26 26
Triglyceride level
Baseline (mg/dl [mmol/L]) 134 (1.51)b 136 (1.54)c 0.6500 172 (1.94)b 180 (2.03)c 0.0530
% change (weighted mean) -0.8 3.8 2.4 -12.4
% change (range) -20.8 to 15.3 -11.1 to 6.7 -19.1 to 31.3 -35.1 to 17.5
No. of patients 656 790 1406 1528
No. of studies 21 21 29 29

None of the baseline lipid parameters differed significantly (p>0.05) between placebo and treatment arms.

LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol.

aSee definition in Methods section for cumulative p value.

bSignificant difference (p<0.04) between placebo groups.

cSignificant difference (p<0.01) between treatment groups.

Mean end ratios of LDL:HDL in plant sterol and stanol and policosanol clinical trials. Data are presented in decreasing order of end LDL:HDL ratios in the treatment groups. LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol. *Standard deviation data not available.

Net Changes. On average, patients allocated to policosanol treatment had higher baseline total cholesterol, LDL, and triglyceride levels and LDL:HDL ratios, but lower HDL levels compared with patients allocated to plant sterols and stanols (p<0.01; ). However, baseline comparison for all lipid parameters between treatment and placebo groups was nonsignificant. Patients receiving policosanol treatment were treated longer than those receiving plant sterols and stanols (29.6 vs 8.6 wks, p=0.0006).

  Summary Comparison Between Plant Sterol and Stanol Studies and Policosanol Studies

  Plant Sterol and Stanol Studies[4-7,40-59] Policosanol Studies[11-39]
Placebo Treatment Cumulative p Valuea Placebo Treatment Cumulative p Valuea
Total cholesterol level
Baseline (mg/dl [mmol/L]) 238 (6.16)b 239 (6.18)c <0.0001 257 (6.65)b 262 (6.78)c <0.0001
% change (weighted mean) -0.2 -7.7 -0.6 -16.2
% change (range) -10.4 to 4.6 -2.8 to -19.5 -7.0 to 6.1 -8.8 to -28.8
No. of patients 769 893 1406 1528
No. of studies 23 23 29 29
LDL level
Baseline (mg/dl [mmol/L]) 159 (4.11)b 158 (4.08)c <0.0001 180 (4.66)b 186 (4.80)c <0.0001
% change (weighted mean) -2.3 -11.0 -0.1 -23.7
% change (range) -11.6 to 4.3 -4.6 to -24.3 -7.2 to 11.5 -12.6 to -42.1
No. of patients 769 893 1406 1528
No. of studies 23 23 29 29
HDL level
Baseline (mg/dl [mmol/L]) 52 (1.35) 52 (1.36)c 0.0590 48 (1.24) 47 (1.21)c <0.0001
% change (weighted mean) -0.5 <-0.1 -3.3 10.6
% change (range) -6.9 to 5.8 -10.7 to 6.5 -15.2 to 18.3 -3.3 to 33.9
No. of patients 734 857 1406 1528
No. of studies 22 22 29 29
LDL:HDL ratio
Baseline 3b 3.2c 0.0025 4b 4.3c <0.0001
% change (weighted mean) 3.8 -11.9 1.1 -32.5
% change (range) -9.1 to 7.2 -10.4 to -16.1 -17.6 to 34.4 -9.8 to -53.8
No. of patients 168 193 1353 1438
No. of studies 6 6 26 26
Triglyceride level
Baseline (mg/dl [mmol/L]) 134 (1.51)b 136 (1.54)c 0.6500 172 (1.94)b 180 (2.03)c 0.0530
% change (weighted mean) -0.8 3.8 2.4 -12.4
% change (range) -20.8 to 15.3 -11.1 to 6.7 -19.1 to 31.3 -35.1 to 17.5
No. of patients 656 790 1406 1528
No. of studies 21 21 29 29

None of the baseline lipid parameters differed significantly (p>0.05) between placebo and treatment arms.

LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol.

aSee definition in Methods section for cumulative p value.

bSignificant difference (p<0.04) between placebo groups.

cSignificant difference (p<0.01) between treatment groups.

Figure 5 shows the net change comparisons for plant sterols and stanols versus policosanol for each lipid parameter. The net reduction (treatment minus placebo) was significantly greater with policosanol than plant sterols and stanols (p ≤ 0.0006) in LDL (-14.0%), total cholesterol (-9.1%), LDL:HDL ratio (-22.1%), and triglyceride (-10.9%), and the net increase was significantly greater (p<0.0001) in HDL (+12.4%).

Net percent change comparison between plant sterols and stanols and policosanol for each lipid parameter.[4-7,11-59] Numbers in parentheses are number of patients receiving placebo/number of patients receiving treatment. TC = total cholesterol; LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol; TG = triglyceride.

Overall, plant sterols and stanols were well tolerated. The pooled dropout rate due to adverse effects was 0% with treatment (0 of 777 patients) versus 0.15% (1 of 647) with placebo in 20 studies that provided interpretable data.[4-7,40-42,44-53,55-58] The combined relative risk of patients who withdrew due to adverse effects was 0.84 (95% CI 0.36-1.95, p=0.69). Dropout rates were homogeneous across these studies (p=1.00).

Tolerability of policosanol was also high. Overall frequency of adverse effects was higher with placebo than policosanol. Of 28 inter-pretable studies, the pooled withdrawal rate due to adverse effects was 0.86% with policosanol (13 of 1513 patients) and 4.81% with placebo (67 of 1392).[11-38] The combined relative risk for withdrawals was 0.31 (95% CI 0.20-0.48, p<0.0001); dropout rates were homogeneous across these studies (p=1.00).

Even though plant sterols and stanols needed to be fortified into fat-soluble vehicles, patients receiving them did not experience a statistically significant increase in total body weight[4-6,40-48,51,52,56,58,59] or body mass index.[4,7,44,55,58,59] In addition, no elevations in blood pressure,[7,40,60] pulse,[40] or aspartate aminotransferase,[40,42,49,54,56,57] alanine aminotransferase,[7,42,49,54,56,57] alkaline phosphatase,[40,42] total protein,[42,56] glucose,[40,42,57] blood urea nitrogen,[40,42] creatinine,[7,49,56,57] uric acid,[42] γ-glutamyl transferase,[40,49] or C-reactive protein[49] levels were reported in patients randomized to plant sterols and stanols.

However, a statistically significant increase was noted in mean thyroid-stimulating hormone (thyrotropin).[7] Another study reported no changes in white or red blood cell counts or in platelet counts.[49] Reported complaints were predominantly gastrointestinal, such as dyspepsia, diarrhea, and constipation, and were typically mild. Other adverse effects -- flatulence, discoloration of feces, gastroesophageal reflux, appetite changes, leg cramps, leukopenia, and skin changes -- may have been dose related.[40]

Regarding policosanol, no increases were noted in aspartate aminotransferase,[12,18,22,26,30,32] alanine aminotransferase,[12,14,16,18,22,32,38] alkaline phosphatase,[18,31] or total bilirubin[18,31] levels. Policosanol treatment in patients with abnormal hepatic function resulted in a statistically significant decrease in transaminase levels.[31] Of 17 studies,[11-14,16-18,20-24,26,29-32] serum glucose level was unchanged in 13,[11-13,17,18,20-22,26,29-32] and of 16 studies,[12-14,16-18,20-24,26,29-32] creatinine concentration remained unchanged in 13.[12,13,16-18,20-23,26,30-32] Only one[29] of four[14,27,29,31] studies that assessed serum uric acid showed a significant increase. Similar to plant sterols and stanols, policosanol resulted in no significant increase of total body weight[11-13,16-18,20-23,26,30-32] or body mass index.[26] In addition, no statistically signifi-cant increase was observed in blood pressure[11,16-18,22-24,26,30-32] or pulse.[12,13,16-18,20,21,23,24,26,30-32]

The safety of policosanol has been assessed for up to 2 years of treatment.[23] Frequently reported adverse effects were central nervous system symptoms (somnolence, nervousness, dizziness, insomnia), gastrointestinal problems (polydipsia, polyphagia, diarrhea, nausea, epigastric pain), and hypotension; these effects were mild and transient. Asthenia, pruritus, arthralgia, and muscle cramps occasionally have been observed.

Discussion

Therapeutic lifestyle changes remain the cornerstone of treatment for patients with hyperlipidemia. Although neither the NCEP ATP III[1] nor the European task force[61] recommends policosanol, the NCEP ATP III does recommend plant sterol and stanol esters as an essential feature of therapeutic lifestyle changes. Our finding of an 11% LDL level reduction with plant sterol and stanol esters 3.4 g (average daily dose) is similar to the approximate 10% LDL level reduction reported in a 2003 review of plant stanols 4.2 g (mean daily dose as ester in 27 trials) and sterols 3.9 g (mean daily dose as ester in 21 trials).[62] Based on 41 clinical trials, plant sterol and stanol ester dosing above 3.4 g/day added little benefit.[62]

Our meta-analysis further suggested that, at the doses evaluated, policosanol may be more effective by an additional 14% in lowering LDL levels than plant sterols and stanols (p<0.0001). Reports have suggested that antilipemic therapy is effective when a 10-15% reduction in LDL level is achieved.[63,64] Therefore, treatment would be considered efficacious in 61% and 22% of the plant sterol and stanol studies and 100% and 97% of the policosanol studies, reporting LDL reductions of at least 10% and 15%, respectively (Figures 2 and 3). The overall 23.7% reduction in LDL level and 10.6% increase in HDL level achieved with policosanol are similar to those observed with antilipemic drug therapies ( [1,61,65-68]). Studies directly comparing LDL level reduction with policosanol 10 mg/day versus other antilipemic agents suggest that policosanol is slightly more effective than fibric acid derivatives[9] and similar in efficacy to low-dose statins.[9,69]

  Comparison of the Effect of Various Interventions on Serum Lipid Profile as Estimated from the Literature and Our Meta-Analysis

  Lipid Level (% change)
TC LDL HDL TG LDL:HDL Ratio
Therapeutic lifestyle changesa
Dietary modification
Saturated fat < 7% of calories ND 8-10 ND ND ND
Dietary cholesterol < 200 mg/day ND 3-5 ND ND ND
Weight reduction of 10 lbs ND 5-8 ND ND ND
Viscous fiber 5-10 g/day 5-10 3-5 ND
Plant sterol and stanol esters 3.4 g/dayb 7.7 11 3.8 11.9
Policosanol 5-40 mg/dayb, c 16.2 23.7 10.6 12.4 32.5
Drug therapy[1,65-68]
HMG-CoA reductase inhibitors (statins) 5-52 18-55 5-15 7-30 27-52
Bile acid sequestrants 7-26 15-30 3-5 or 27-52
Niacin 2-12 5-25 15-35 20-50 41
Fibric acid derivatives 9-22 5-20d 10-20 20-50 18-21
2-Azetidinone (ezetimibe) 13 18 1 8 ND

TC = total cholesterol; LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol; TG = triglyceride; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; ND = no data; = increase; = decrease; = no change.

aAs suggested by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III).[1]

bNot recommended by the European task force.[61]

cNot recommended by the NCEP ATP III.[1]

dMay be increased in patients with high triglyceride levels.

If 10% reduction of total cholesterol level may reduce the 5-year risk of ischemic heart disease by approximately 25%,[70] the 24% net reduction observed with policosanol in our meta-analysis would be expected to reduce CHD risk by at least as much. In a meta-analysis of eight clinical trials of lipid-lowering therapy, every 10% reduction in serum total cholesterol level significantly reduced the risk of CHD mortality by 15% and total mortality by 11%.[71] Only six[6,7,46,48,57,58] out of 23 plant sterol and stanol studies but 28[11-38] of 29 policosanol studies from our meta-analysis had at least a 10% reduction in serum total cholesterol level.

In addition to LDL and total cholesterol level reduction, our meta-analysis revealed a more favorable effect of policosanol over plant sterols and stanols for increasing HDL (12.7% vs 0.3%) and reducing both LDL:HDL ratio (-33.8% vs -11.7%) and triglycerides (-15.7% vs -4.8%; Figure 5). The efficacy of policosanol approaches that of antilipemic drug therapies ( ). Of particular importance, policosanol simulta-neously reduced LDL (and total cholesterol) levels and increased HDL levels, resulting in marked improvement of the LDL:HDL ratio and cardiovascular risk (Figure 4). For all five studies[14,19-21,29] in our meta-analysis in which the mean baseline LDL:HDL ratios for the policosanol groups were considered high risk (ratio ≥ 5),[72] policosanol reduced the ratio to a medium-risk range (ratio > 3 to < 5). Policosanol also reduced the ratio to a low-risk category (ratio ≤ 3) in 9[11-13,16,17,24,28,30,35] of 18 studies[11-13,16-18,23-26,28,30-33,35,37,39] in which the baseline ratios were in the medium-risk range.

  Comparison of the Effect of Various Interventions on Serum Lipid Profile as Estimated from the Literature and Our Meta-Analysis

  Lipid Level (% change)
TC LDL HDL TG LDL:HDL Ratio
Therapeutic lifestyle changesa
Dietary modification
Saturated fat < 7% of calories ND 8-10 ND ND ND
Dietary cholesterol < 200 mg/day ND 3-5 ND ND ND
Weight reduction of 10 lbs ND 5-8 ND ND ND
Viscous fiber 5-10 g/day 5-10 3-5 ND
Plant sterol and stanol esters 3.4 g/dayb 7.7 11 3.8 11.9
Policosanol 5-40 mg/dayb, c 16.2 23.7 10.6 12.4 32.5
Drug therapy[1,65-68]
HMG-CoA reductase inhibitors (statins) 5-52 18-55 5-15 7-30 27-52
Bile acid sequestrants 7-26 15-30 3-5 or 27-52
Niacin 2-12 5-25 15-35 20-50 41
Fibric acid derivatives 9-22 5-20d 10-20 20-50 18-21
2-Azetidinone (ezetimibe) 13 18 1 8 ND

TC = total cholesterol; LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol; TG = triglyceride; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; ND = no data; = increase; = decrease; = no change.

aAs suggested by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III).[1]

bNot recommended by the European task force.[61]

cNot recommended by the NCEP ATP III.[1]

dMay be increased in patients with high triglyceride levels.

The precise mechanism of action for these natural antilipemic agents remains unclear. Regarding plant sterols and stanols, sitostanol is apparently unabsorbable,[44] and only about 5% of ß-sitosterol was absorbed.[73,74] Plant sterols and stanols inhibit up to 50% of intestinal cholesterol absorption and increase fecal elimination of both dietary and biliary cholesterol[46] without a significant shift from larger to smaller, more atherogenic LDL particles in the plasma.[56] These effects may be due to displacing cholesterol from bile salt micelles, hindering cholesterol esterification in the intestinal wall, and limiting transmembrane transport.[58,75]

However, these effects may be balanced by up to a 39% increase in cholesterol synthesis.[46] In vitro studies suggest that policosanol may inhibit cholesterol synthesis at a step before mevalonate formation, and increase hepatic LDL uptake and catabolic rates.[9] Combination therapy of statins with plant sterols and stanols provided an additive effect on reducing LDL levels,[54,76] whereas combination therapy of statins with policosanol has not been reported.

In addition to the cholesterol-lowering effect, plant sterols and stanols have demonstrated efficacy in the treatment of mild-to-moderate benign prostatic hyperplasia,[77] and they may decrease the risk of colon cancer.[78] Policosanol exhibits antiplatelet and cytoprotective effects[79] and has demonstrated efficacy in patients with intermittent claudication.[10] Because policosanol seems to be an efficient inhibitor of platelet aggregation -- policosanol 20 mg/day is equivalent to aspirin 100 mg/day -- caution may be indicated with concomitant use of anticoagulants or antiplatelet agents.[9]

Additional cardiovascular benefits observed with policosanol therapy are reduced oxidation susceptibility of LDL,[22,33,34] improved hemo-dynamic abnormalities in patients with mild carotid vertebral atherosclerosis,[37] and improved maximum oxygen uptake and left ventricular ejection fraction in patients with coronary artery disease.[39]

In the studies assessed in this meta-analysis, adverse effects with plant sterols and stanols and policosanol were often mild and transient. Dropout rates due to adverse events were less than 1% across studies for both of these natural therapies, and mean dropout rates were comparable to or better than those for placebo. In turn, withdrawal rates reported in the product labeling for antilipemic drugs range from more than 1% to 21%.[68] No serious biochemical or clinical adverse effects were reported with either natural therapy. The most frequently reported adverse events with plant sterols and stanols were gastrointestinal symptoms.

A pharmacoepidemiologic study evaluated 3602 treated patients, 97.6% of whom received policosanol 5 mg/day, and 3009 controls for a mean follow-up of 3.1 years.[80] The most commonly reported adverse effects in the policosanol-treated patients were weight loss in 63 (1.75%) patients, polyuria in 24 (0.68%), headache in 22 (0.61%), dizziness in 16 (0.44%), and polyphagia in 13 (0.36%), without signifi-cant differences in frequency between treatment and control groups.[80] Other reported adverse effects in policosanol-treated patients were somnolence, nervousness, and insomnia.

Although phytosterols are not associated with mutagenic effects in animals, high doses may act as an abortifacient and reduce sperm concen-tration and testicular weight.[78] Since information regarding teratogenetic and reproductive effects of plant sterols and stanols in humans is not available, their use for treatment in pregnant and lactating women is not recommended. In vitro and in vivo policosanol studies in rats have revealed no carcinogenic or mutagenic potential.[9] However, in the absence of human data, therapy with policosanol during pregnancy or lactation also is not advisable.

A primary limitation of our meta-analysis is the lack of independence in authorship; most of the trials originated from the same group of investigators in Cuba.[11-39] However, studies conducted in Argentina,[18,81] Chile,[82] and Russia[83] with policosanol 10 mg/day found similar LDL level reductions, ranging from 11-27% over 6-8 weeks of treatment.

Another limitation was the use of different vehicles for delivery of plant sterols and stanols. Several studies used vehicles containing rapeseed oil[5,41,44,46,51,52] that may have LDL-lowering properties on their own,[44,51,52] thereby potentially enhancing the antilipemic efficacy of phyto-sterols. In this case, the net LDL level reduction may have been a more accurate estimate of the effect of plant sterols and stanols. Although the percent LDL level reduction was derived from mean rather than actual data, the consistent and dramatic reduction observed with these treatments would not be expected to change our final results.

We are also aware of the small sample sizes used in many of the studies in our meta-analysis. Therefore, we used a weighted percent change to correct for small samples.

General limitations associated with any meta-analysis are selection and publication bias, and variability in the quality of evidence supporting each study. Since our search technique attempted to include all available published studies, we are unlikely to have introduced selection bias. Although publication bias is possible, the consistency of the LDL level reduction observed with plant sterols and stanols and with policosanol disfavor such an effect. Finally, based on consensus of three investigators, the quality of evidence for all eligible studies was scored as moderate to high.

In the United States, two margarines containing phytosterols are approved by the Food and Drug Administration (FDA) to lower cholesterol. Benecol (McNeil Nutritionals, Fort Washington, PA) contains plant stanols, whereas Take Control (Unilver/Lipton, Englewood, NJ) contains plant sterols. The NCEP ATP III advocates plant sterol and stanol esters 2 g/day, which equates to approximately 2 tablespoons/day. Although taste of these fortified margarines is not compromised, they cost 3-4 times more than regular spread, ranging from $14/month for Take Control to $24/month for Benecol.

Plant stanols are also available as a softgel formulation (Benecol). However, efficacy of the softgel formulation is not well established; one report suggests no cholesterol level reduction, possibly due to altered solubilization of phytosterols.[84] A 2003 study demonstrated that a 4-week diet high in plant sterols (1 g/1000 kcal), viscous fiber, soy protein, and almonds (similar to the NCEP ATP III recommendations) leads to significant LDL level reduction.[85] The reduction with this diet (-28.6%) was comparable to the effect of lovastatin 20 mg/day (-30.9%), and both demonstrated a reduction greater than that of the control group (-8%). As an additional benefit, C-reactive protein levels were also decreased with this diet (-28.2%) versus lovastatin (-33.3%).

However, patients may have difficulty complying with such strict, intensive dietary interventions on a long-term basis. Therefore, policosanol may be a more feasible alternative for patients than plant sterol and stanol supple-mentation as a therapeutic lifestyle change.[1] Policosanol is not FDA approved for reduction of LDL levels in the United States, but many consumers purchase policosanol as a nutritional supplement over the counter or through various Internet sources. A bottle of 30 softgels costs approximately $7, and 120 tablets of policosanol 10 mg cost approximately $35 (~$7-9/month) on the Internet and in health nutrition stores. Prices of both plant sterols and stanols and policosanol compare favorably with retail costs for a 30-day supply (using daily doses) of statins (~$49-131), bile acid sequestrants (~$51-139), niacin (~$14-88), fibric acid derivatives (~$35-92), and ezetimibe (~$71).[86]

Conclusion

Although both plant sterols and stanols and policosanol are well tolerated and safe, policosanol offers advantages of greater efficacy, convenience in dose formulation and adminis-tration, cost and, potentially, other nonlipid cardiovascular benefits. Based on these features, policosanol is a valuable addition to the usual therapeutic lifestyle changes and may be an attractive alternative to conventional lipid-lowering drugs. This is relevant, considering that more than half of the U.S. population may benefit from therapeutic lifestyle changes and/or antilipemic therapy. However, large, randomized, double-blind, placebo-controlled trials directly comparing the various products are needed to confirm these findings.

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