Efficacy and safety of policosanol in patients with primary hypercholesterolemia

CURRENT THERAPEUTIC RESEARCH VOL. 52, NO. 4, OCTOBER1992

EFFICACY AND SAFETY OF POLICOSANOL IN PATIENTS WITH PRIMARY H Y P E R C H O L E S T E R O L E M I A P. PONS, 1 R. MAS,2 J. ILLNAIT,2 L. FERNANDEZ,2 M. RODRIGUEZ,1 C. ROBAINA,3 AND J. C. FERNANDEZ2

1Plaza Policlinical Center, 2National Center for Scientific Research, and 3General Hospital "Calixto Garcia," Havana City, Cuba

ABSTRACT A double-blind, placebo-controlled study was c o n d u c t e d in patients with primary hypercholesterolemia to examine the effects of policosanol on plasma lipids and lipoproteins. A f t e r a d h e r i n g to a cholesterol-lowering diet for 6 weeks, 56 p a t i e n t s were r a n d o m i z e d to receive placebo or policosanol 5 m g once daily in t h e e v e n i n g for 8 weeks. Total cholesterol and low-density lipoprotein cholesterol decreased significantly, by an average of 13.1% and 17.7%, respectively. No significant c h a n g e s were observed for triglycerides, very-low-density li-

poprotein cholesterol, or high-density lipoprotein cholesterol. No significant d i f f e r e n c e s in clinical and b i o c h e m i c a l safety indicators were seen in th e t r e a t e d patients compared with those r e c e i v i n g placebo. T h e r e were no adverse effects attributable to t r e a t m e n t , and no patient was w i t h d r a w n from the trial. These d a t a indicate that policosanol t h e r a p y is effective and very well tolerated. INTRODUCTION

Epidemiologic data have established a positive relationship between increased levels of total cholesterol and low-density lipoprotein (LDL) cholesterol and coronary heart disease. 1-3 Although dietary management is accepted as first-line treatment for hypercholesterolemia, patients with moderate or severe hypercholesterolemia m a y not be able to control their total and LDL cholesterol levels with diet alone, and cholesterol-lowering drugs m a y be necessary. Policosanol* is a mixture of high-molecular-weight (MW) aliphatic primary alcohols isolated from sugar cane; octacosanol (MW, 410.77 Ixm) is the primary component of this mixture. Policosanol has been shown to reduce elevated total and LDL cholesterol levels in healthy volunteers a and in patients with primary hyperlipoproteinemia type II. 5'6 These shortterm studies also showed that the treatment was very well tolerated. Address correspondenceto: Dr. Rosa M~s,National Center for ScientificResearch, P.O. Box 6990, Havana, Cuba. Received for publication on April 1, 1992. Printed in the U.S.A. Reproduction in whole or part is not permitted. * Trademark: ATEROMIXOL(Laboratorios Dalmer, Havana, Cuba). 507

0011-393xj92/$3.50

POLICOSANOL FOR PRIMARY HYPERCHOLESTEROLEMIA

The purpose of this 8-week, double-blind, placebo-controlled, parallelgroup trial was to evaluate the efficacy and safety ofpolicosanol in patients with elevated serum cholesterol and LDL cholesterol levels. PATIENTS AND METHODS A total of 56 outpatients of both sexes ages 37 to 69 years with primary type II hypercholesterolemia were recruited for the study. Patients with type III, IV, or V hypercholesterolemia were excluded from the trial, as were those with diabetes, thyroid dysfunction, active hepatic or renal diseases, and neoplastic disease. Pregnant women and those planning to become pregnant, patients with blood pressure >160/100 mmHg, and those who had a myocardial infarction within the past 6 months were also excluded. Use of other lipid-lowering drugs was prohibited, but other medications were continued unchanged during the study period. Informed consent was obtained from all study patients. The study protocol was approved by the institutional review committee. After 6 weeks of dietary stabilization, plasma lipids were measured a minimum of two times at 15-day intervals. Patients entered the doubleblind phase if the mean of the two measurements of plasma LDL cholesterol was at least 4 mmol/L, the mean total cholesterol values were at least 6 mmol/L, and the triglyceride concentration was <4.52 mmol/L. Values obtained at the end of the diet-only period represent the baseline data. Patients were randomly assigned to receive identical policosanol 5 mg (n = 27) or placebo (n = 29) film-coated tablets taken with the evening meals. All patients were instructed to continue following a low-cholesterol diet with an approximate polyunsaturated:saturated fatty acid ratio of 0.75 and a cholesterol content ~<300 mg/day. A clinical history and laboratory tests were performed at baseline and at week 8. Patients were also interviewed regarding health status, use of non-study drugs, compliance, and adverse experiences. Venous blood samples were obtained after an overnight fast of at least 12 hours. Laboratory evaluation included alanine aminotransferase, glucose, and creatinine determinations. Total cholesterol and triglycerides were analyzed by microenzymatic procedures. High-density lipoprotein (HDL) cholesterol was determined by quantifying the cholesterol content in the supernatant obtained after LDL and very-low-density lipoprotein (VLDL) cholesterol precipitation. 7 LDL cholesterol was calculated using Friedewald's formula, s All tests were performed using kit reagents purchased from Boehringer-Mannheim (Mannheim, Federal Republic of Germany) on a Hitachi autoanalyzer model 705 (General Hospital "Calixto Garcia," H a v a n a City, Cuba). The primary variables of interest were total and LDL cholesterol. 508

P, PONS ET AL.

The efficacy criteria applied was a reduction i>10% in the total or LDL cholesterol after 8 weeks of treatment. 9

Statistical Analysis The nonparametric Wilcoxon test was used to analyze serum lipid and lipoprotein changes from baseline. The Mann-Whitney U test was used to compare lipid profile values and percent changes between groups. The same test was used to compare body weight, blood pressure, and blood biochemical parameters between the treated and placebo groups. Comparisons of categoric data (adverse experience reports) between groups were done using Fisher's exact probability test. RESULTS

Fifty-six patients (7 men, 49 women; mean age, 60 years) who met the entrance criteria were included in the trial. The two groups were similar with regard to general baseline characteristics, except for serum glucose levels, which were significantly higher (P < 0.05) in the treated group than in the placebo group. Lipid variables were also similar at baseline between the groups, except for triglycerides and VLDL cholesterol values, which were higher in the placebo group than in the policosanol group. The effects of policosanol and placebo on serum lipids and lipoproteins are summarized in Table I. Compared with baseline, total cholesterol and

Table I. Effects of policosanol on serum lipids and lipoproteins (mmol/L) in hypercholesterolemic patients after 8 weeks of treatment. Policosanol (n = 27)

Total cholesterol mean _ SD) LD (mean +_ SO) HDL (mean _+ SD) Triglycerides median (D~sD) VL (median +_ SD)

Placebo (n = 29)

Baseline

Week 8

Baseline

Week 8

7.28 _+ 0.66

6.33 -+ 0.72*$

7.22 ___0.79

7.29 - 0.87

5.09 _+ 0.67

4.19 _+ 0.72":~

4.91 ___0.80

5.09 +- 0.94

1.51 -+ 0.24

1.46 +- 0.26

1.39 _+ 0.26

1.39 _+ 0.17

1.75 _+ 0.771"

1.51 _+ 0.80t

2.24 __+1.04

2.18 _+ 0,84

0.80 +_ 0.351-

0.69 _+ 0.36t

1.02 _+ 0.47

0.99 - 0.38

LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol; VLDL = very-lowdensity lipoprotein cholesterol. * P < 0.0001 versus baseline (Wilcoxon test). t P < 0.05 versus placebo (Mann-Whitney U test). :~ P < 0,001 versus placebo (Mann-Whitney U test). 509

POLICOSANOL FOR PRIMARY HYPERCHOLESTEROLEMIA

M e a n

P e r C

15

5 0

•

-5

t

-10

C h a

-16

n

n

g e 8

WEEK 8

10

÷÷÷÷

-20

-25

CHOLESTEROL

LDL-C

I n n ATEROMIXOL 6 mg

~

Placebo

Figure. Mean percent changes in total cholesterol and low-density lipoprotein cholesterol (LDL-C) ****P < 0.00001 versus placebo (Mann-Whitney U test) in hypercholesterolemic patients.

LDL cholesterol decreased significantly (P < 0.0001), by 13.1% and 17.7%, respectively, 8 weeks after the start of treatment. The differences between groups were also significant (P < 0.001) (Table I). The percent changes in serum lipids and lipoproteins in both groups are shown in the figure. No significant changes in HDL cholesterol, triglycerides, or VLDL cholesterol were observed when compared with baseline. However, at week 8, a significant difference (P < 0.05) was obtained when triglycerides and VLDL cholesterol data were compared with placebo. Mean ratios of LDL:HDL cholesterol and total cholesterol:HDL cholesterol were significantly reduced compared with baseline and placebo (Table II). No patient discontinued the trial. No significant differences were observed between the placebo and policosanol groups in body weight, h e a r t

Table II. Effects of policosanol on lipid ratios (mean -4- SD) of hypercholesterolemic patients after 8 weeks of treatment. Policosanol (n = 27)

LDL:HDL Total cholesterol:HDL

Placebo (n -- 29)

Baseline

Week 8

Baseline

Week 8

3.47 _+ 0.80 4.93 -+ 0.83

2.98 _+ 0.88"14.48 -+ 1.01"$

3.68 _+ 0.94 5.38 -+ 1.18

3.76 +_ 1.08 5.35 -+ 1.16

LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol. * P < 0.01 versus baseline (Wilcoxon test). i P < 0.01 versus placebo (Mann-Whitney U test). :~ P < 0.001 versus placebo (Mann-Whitney U test).

510

P. PONS ET AL.

Table III. Safety indicators (mean -+ SD) in hypercholesterolemic patients. Treatment

n

Policosanol Placebo

27 28

Policosanol Placebo

26 28

Policosanol Placebo

27 28

Policosanol Placebo

27 28

Policosanol Placebo

26 26

Policosanol Placebo

22 24

Policosanol Placebo

25 23

Baseline Body Weight (kg) 66.70 -+ 11.26 68.44 _+ 13.13 Heart Rate (beats/min) 74.00 -+ 4.66 73.93 _+ 5.70 Systolic Blood Pressure (mmHg) 128.89 _+ 16.49 135.71 +_ 19.89 Diastolic Blood Pressure (mmHg) 85.37 _+ 10.28 85.00 _+ 11.30 ALAT (U/L) 18.23 _+ 6.01 17.91 _+ 6.12 Glucose (mmol/L) 5.59 -+ 0.63* 5.14 -+ 0.68 Creatinine (~mol/L) 97.80 _+ 17.91 94,74 _+ 19.48

n

Week 8

26 27

66.21 +_ 11.34 68.76 _ 13.04

26 28

75.00 _+ 4.87 73.93 _ 6.43

26 29

127.69 _+ 16.08 133.28 _+ 16.60

26 29

83.85 +_ 8.98 83.45 +_ 10.01

27 28

19.95 +__6.28 20.27 _ 5.39

27 28

5.10 _+ 0.55 5.10 _+ 0.56

27 28

87.67 _+ 8.55 84.7t +_ 11.22

ALAT = alanine aminotransferase. * P < 0.05 versus placebo (Mann-Whitney U test),

rate, and blood pressure or any laboratory test (Table III). Moreover, none of the patients showed abnormal values of the blood biochemical parameters tested. Although at baseline the policosanol-treated patients showed significantly higher mean glucose values than the placebo patients, after 8 weeks of treatment both groups were statistically indistinguishable. Table IV shows the adverse effects reported in this study. Differences between groups were not significant and thus not attributable to drug therapy. Paradoxically, more adverse experiences were reported in the placebo group.

Table IV. Adverse experiences reported by hypercholesterolemic patients treated with placebo or policosanol for 8 weeks.

Cephalea Dizziness Insomnia Nervousness Flatulence Arthralgia Muscle cramps Pruritus

Placebo (n = 29)

Policosanol (n = 27)

3.45 6.90 6.90 3.45 10.34 10.34 3.45 3.45

3.70 0 3.70 0 0 0 3.70 0

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POLICOSANOLFOR PRIMARYHYPERCHOLESTEROLEMIA

DISCUSSION AND CONCLUSIONS

These results demonstrate that policosanol significantly reduced total cholesterol and LDL cholesterol when administered for 8 weeks to patients with p r i m a r y hypercholesterolemia type II. There were no significant changes in HDL cholesterol, plasma triglycerides, or VLDL cholesterol levels compared with the placebo values. As a consequence of the reduction in both LDL cholesterol and total cholesterol levels, the mean LDL:HDL cholesterol and total cholesterol:HDL cholesterol ratios were also significantly reduced. Similar data have been reported in an open clinical trial with 17 hyperlipoproteinemic type II patients receiving policosanol 5 mg daily for 8 weeks. 5 Moreover, except for H D L cholesterol changes, the same efficacy results were obtained in a multicenter clinical trial conducted in patients with elevated total cholesterol and LDL cholesterol levels who received policosanol 5 mg once-a-day for 12 weeks6; these authors found a significant increase in HDL cholesterol values in the treated group. Our study also shows that the drug therapy was well tolerated. Safety indicators such as heart rate and arterial blood pressure measurements and reports of adverse experiences showed no significant differences between groups. No patient discontinued the trial, and none of the patients showed abnormal blood biochemical values. These data demonstrate that policosanol 5 mg once-a-day is a safe treatment when administered for short-term periods. Similar results have been obtained in healthy volunteers 4 and hypercholesterolemic patients treated with policosanol. 5'6 Since cholesterol-lowering drugs must be administered for long-term periods, safety and tolerability are essential aspects for their definitive acceptance. The safety data for policosanol treatment suggests that this aspect could be an advantage of this therapy. These clinical results agree with those of toxicologic preclinical studies indicating that policosanol can be considered a safe drug. 1°-12 Our results demonstrate that policosanol is an effective cholesterollowering agent in patients with primary hypercholesterolemia type II. Policosanol was well tolerated over the 8-week study, and there were no clinically significant side effects or adverse biochemical effects. References:

1. Consensus Conference. Lowering blood cholesterol to prevent h e a r t disease. JAMA 1985; 253:2080-2086. 2. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results: Reduction in incidence of coronary h e a r t disease. JAMA 1984; 251:351-364. 512

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3. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results: The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. J A M A 1984; 251:365-374. 4. Hern~ndez F, Illnait J, M~s R, et al. Effect of policosanol on serum tipids and lipoproteins in healthy volunteers. Curr Ther Res 1992; 51(4):568-575. 5. Illnait J, Castafio G, Nodarse M, et al. Efectos del Ateromixol (PPG) sobre la hiperlipoproteinemia tipo II. Rev CENIC Ciencias Biol6gicas 1991; 22:74-76. 6. Castafio G, Zardoya R, Illnait J, et al. Efectos del tratamiento con Ateromixol (PPG) (5 mg) en pacientes con hiperlipoproteinemia Tipo II. PCM 1991; 5:21-28. 7. Seigler L, Wu WT. Separation of serum high-density lipoproteins for cholesterol determination: Ultracentrifugation vs precipitation with sodium phosphotungstate and magnesium chloride. Clin Chem 1981; 27:838-841. 8. Friedewald WT, Levy RI, Frederickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 1972; 18:499-502. 9. Illingworth R. An overview of lipid-lowering drugs. Drugs 1988; 36(Suppl 3):63-71. 10. Alem~n CL, M~s R, Rodeiro I, et al. Toxicologia aguda del Ateromixol (PPG) en roedores. Rev CENIC Ciencias Biol6gicas 1991; 22:102-105. 11. Fern~indez SI, Rend6n A, De las Cajigas A, L6pez M. Estudio genot6xico del Ateromixol (PPG), un nuevo medicamento hipolipemiante. Rev CENIC Ciencias Biol6gicas 1991; 22:98-101. 12. Alemdn CL, M~s R, Rodeiro I, Men~ndez R. Estudio de la toxicidad subcr6nica del Ateromixol (policosanol). Arch Venez Farmacol Toxicol 1992 (in press).

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