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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 56:M186-M193 (2001)
© 2001 The Gerontological Society of America

Effects of Policosanol in Older Patients With Type II Hypercholesterolemia and High Coronary Risk

Gladys Castañoa, Rosa Másb, J.C. Fernándezb, J. Illnaitb, Lilia Fernándezb and Estrella Alvarezb

a Medical Surgical Research Center, National Center for Scientific Research, Havana City, Cuba
b Center of Natural Products, National Center for Scientific Research, Havana City, Cuba

Rosa Más, Center of Natural Products, National Center for Scientific Research, P.O. Box 6880 or 6990, Cubanac\|[aacute]\|n, Havana City, Cuba E-mail: dalmer{at}ip.etecsa.cu.

Decision Editor: John E. Morley, MB, BCh


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background. The present study was undertaken to investigate the effects of policosanol in older patients with type II hypercholesterolemia and more than one concomitant atherosclerotic risk factor.

Methods. After 6 weeks on a lipid-lowering diet, 179 patients randomly received a placebo or policosanol at doses of 5 followed by 10 mg per day for successive 12-week periods of each dose. Policosanol (5 and 10 mg/d) significantly (p < .001) reduced low-density lipoprotein cholesterol (LDL-C; 16.9% and 24.4%, respectively) and total cholesterol (TC; 12.8% and 16.2%, respectively), while significantly (p < .01) increasing (p < .001) high-density lipoprotein cholesterol (HDL-C) by 14.6% and 29.1%, respectively.

Results. Policosanol significantly decreased (p < .01) the ratios of LDL-C to HDL-C (29.1%) and TC to HDL-C (28%) at study completion, although triglycerides remained unchanged. Policosanol, but not the placebo, significantly improved (p .01) cardiovascular capacity, which was assessed using the Specific Activity Scale. No serious adverse experiences occurred in policosanol patients (p < .01), compared with seven adverse experiences (7.9%) reported by placebo patients.

Conclusions. This study shows that policosanol is effective, safe, and well tolerated in older hypercholesterolemic patients.

CORONARY artery disease (CAD) is a major cause of morbidity and mortality in middle-aged and older patients, and its prevalence increases remarkably with age (1)(2)(3)(4). Clinical studies have convincingly proved the clinical benefits resulting from lowering total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in both primary and secondary prevention (5)(6)(7).

The elderly population is among the fastest growing segments of the worldwide population in this decade and, consequently, its major causes of morbidity and mortality represent a current health care problem. The acceptance of hypercholesterolemia as an important coronary risk factor in elderly persons has been controversial (8), because the influence of TC as a predictor of the relative risk of CAD decreases with age (3)(9). In addition, pharmacological intervention of hypercholesterolemia in elderly persons has been carefully managed, taking into account that there are not enough data demonstrating the clinical benefits of cholesterol-lowering drugs in this population and the potential hazards of their use in such cases. Thus, older patients are especially susceptible to drug-related adverse effects caused by age-induced modifications in drug metabolism and simultaneous diseases requiring concomitant medications (10)(11)(12).

Nevertheless, although the influence of elevated TC levels to coronary risk lowers with age, this factor, together with increased LDL-C and low high-density lipoprotein cholesterol (HDL-C) levels, is a strong predictor of absolute risk in both older men and women (3)(4)(9), thus indicating that hypercholesterolemia is also a major coronary risk factor in the elderly population. In addition, the results of the Scandinavian Survival Simvastatin Study (5), conducted in patients with a previous history of CAD and type II hypercholesterolemia, demonstrated a 27% decrease in total mortality and a 29% decrease in major coronary events in men aged 60 to 70 years, thus extending the benefits of lowering LDL-C in secondary coronary prevention in older patients.

For these reasons, management of dyslipidemia in elderly persons is necessary, but requires special considerations, including lifestyle modifications and an individualized cholesterol-lowering diet (13)(14). Drug therapy must be managed with caution because these patients are more susceptible to drug-related adverse effects (10)(11)(12), and only up-to-date fibrates and statins have been referred as generally well tolerated in this population subset. Therefore, the need to characterize the effects of any lipid-lowering drug in this population is supported. Policosanol is a cholesterol-lowering drug consisting of a mixture of eight higher aliphatic alcohols purified from sugar cane (Saccharum officinarum, L.) wax, and whose main component is octacosanol, followed by triacontanol and hexacosanol; the other alcohols (tetracosanol, heptacosanol, nonacosanol, dotriacontanol, and tetratriacontanol) are minor components. Policosanol inhibits cholesterol biosynthesis from acetate-14C or tritiated water, but not from mevalonic acid 14C, and also increases the LDL receptor-dependent processing by increasing the number of LDL receptors (15)(16). The cholesterol-lowering effects of policosanol have been demonstrated in healthy volunteers (17), patients with type II hypercholesterolemia (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29), and patients with dyslipidemia associated with non-insulin-dependent diabetes mellitus (30)(31). Likewise, previous short- and long-term studies conducted in older patients with hypercholesterolemia have shown that policosanol is effective, safe, and well tolerated in this population (32)(33)(34), but they have not focused on older patients with high coronary risk, which is a population amenable to receiving cholesterol-lowering therapy.

Taking into account that the individual evaluation of the risk-to-benefit ratio is an important clinical matter of dyslipidemia management in elderly persons, drug safety and tolerability profiles are crucial for its use. In this regard, preclinical toxicology (35)(36)(37)(38) and clinical studies (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) have shown that policosanol is very safe and better tolerated than other drugs of the same therapeutic category.

The present study was undertaken to evaluate the effects of policosanol (5 and 10mg/d) in older patients with type II hypercholesterolemia and high coronary risk.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
The study was a randomized, double-blind, placebo-controlled, multicenter clinical study with two treatment arms: diet plus placebo and diet plus policosanol at 5 (first step) and 10 mg per day (second step). The study patients were enrolled and observed at the Medical Surgical Research Center and the Ramón González Coro and Elpidio Berovides policlinical centers in Havana City, Cuba.

The study protocol was approved by the ethics committee of the Ramón Gonzalez Coro and Elpido Berovides policlinical centers, and patients of both sexes, aged 60 to 78 years, were enrolled in the study after giving their written informed consent (first visit). The age range selected was based on the available evidence that supported the validity of managing hypercholesterolemia in older patients where life expectancy is still considerable. Enrolled patients had diagnosed hypercholesterolemia and one or more additional coronary risk factors as defined in the study protocol (i.e., documented history of myocardial infarction or angina, family history of CAD, hypertension, cigarette smoking, diabetes mellitus, and obesity).

Patients were excluded if active renal diseases, diagnosed neoplastic diseases, severe hypertension (diastolic pressure >=120 mm Hg), uncontrolled diabetes, or poor cognitive function were present, or if they had experienced a myocardial infarction, stroke, or had coronary surgery in the 3 months prior to the study.

Any other lipid-lowering therapy had to be discontinued from the recruitment period up to study completion. Patients were instructed to follow a step-one cholesterol-lowering diet for 6 weeks. After this diet-only period, two lipid profiles were done within 15 days. To be included in the trial, the percentage of change in the consecutive determinations of TC and LDL-C were restricted to <10%. Baseline levels of lipid profiles were considered as the average of the successive determinations, and those cases with serum levels (mmol/l) of LDL-C >3.4, TC >5.2, and triglycerides <4.52 after dietary stabilization were included in the study, if exclusion criteria were not present. When blood samples for the second determination were drawn, aliquots for other laboratory analyses were also obtained.

Patients were randomized to receive, under double-blind conditions, 5 mg of policosanol or placebo tablets (second visit), which had to be taken once daily with the evening meal for 12 weeks. After 6 weeks on therapy, an interim check-up was performed. At 12 weeks, all the controls were repeated, and patients received 10 mg of policosanol or placebo tablets for the next 12 weeks. Another interim check-up was done at week 18, and all the controls were repeated at the completion of the study (week 24). Physical examinations were performed at each visit. Meanwhile, requests for adverse experiences (AE) and assessments for drug compliance were performed between the third and sixth visits. Lipid profile determinations, laboratory safety analysis, and assessment of cardiovascular function were performed at baseline and after 12 and 24 weeks on therapy.

No special restrictions for any other concomitant medication other than the lipid-lowering drugs were defined in the study protocol, and the consumption of them was recorded at each visit.

Efficacy Variables
The primary efficacy variable considered was the change in LDL-C values. Treatment was considered as effective only if LDL-C levels were reduced by at least 15% compared with the baseline levels (39). The other lipid profile parameters (HDL-C, triglycerides, and LDL-C:HDL-C and TC:HDL-C) were considered as secondary efficacy variables.

Cardiovascular capacity was assessed as a colateral efficacy variable by means of a questionnaire based on the Specific Activity Scale, a method that classifies the patients into four functional classes according to the number of metabolic equivalents (METS) required to perform different activities without the occurrence of symptoms, such as chest pain, tachycardia, fatigue, or dyspnea (40).

Safety and Tolerability
Data from physical examinations, laboratory tests, and requests for AE were included for the analysis of drug safety and tolerability. AE were classified as mild, moderate, or serious (fatal and nonfatal). Mild AE were those not requiring discontinuation of study medication, nor specific treatment of AE; moderate AE were those requiring withdrawal of study medication and treatment; and serious AE were predefined as fatal or otherwise disabling events leading to, or prolonging, hospitalization.

Laboratory Analysis
Blood samples were drawn after an overnight fasting of 12 hours. TC and triglycerides were determined by colorimetric enzymatic methods using reagent kits from Boehringer Mannheim (Germany). Levels of HDL-C were determined according to the cholesterol content in the supernatant obtained after ß-lipoprotein precipitation (41). LDL-C values were calculated using the Friedewald equation (42).

Laboratory safety tests, including glucose, creatinine, aspartate amino transferase (AST), and alanino amino transferase (ALT), were performed in a Hitachi 705 autoanalyzer (Tokyo, Japan) located at the laboratory of the Medical Surgical Research Center in Havana, Cuba. A systematic quality control was performed.

Statistical Analysis
The data were analyzed according to the intention-to-treat approach. Within-group comparisons of continuous variables were made using the paired t test; comparisons between groups were performed using the t test for independent samples. Comparisons between groups of categorical data were made by the {chi}2 test. All statistical tests were two-tailed, with significance at {alpha} = 0.05. Statistical analyses were performed using the CSS (Stat Soft, Tulsa, OK) statistical package program.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Baseline Characteristics
Both groups were well matched at baseline (Table 1 ). There was a high frequency of nonlipid coronary risk factors among study patients. The most frequent (>30%) of these were hypertension (83.2%), family history of CAD (62.0%), low levels of HDL-C (35.2%), and peripheral vascular disease (33.5%). The frequency of concomitant medications was very high (91.6%) and statistically similar in both groups.


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  		Table 1. Baseline Characteristics of the Study Patients

 
Efficacy Analysis
Table 2 summarizes the effects of policosanol on lipid profile. Comparisons of the baseline and placebo levels showed that policosanol administered at 5 and 10 mg per day significantly reduced (p < .001) LDL-C (16.9% and 24.4%, respectively), TC (19.8% and 16.2%, respectively), as well as the ratios of LDL-C to HDL-C (19.0% and 28.8%, respectively) and TC to HDL-C (15.6% and 27.4%, respectively). In addition, HDL-C levels significantly (p < .001) increased by 14.6% (p < .01) and 29% (p < .001) respectively; at study completion, triglycerides remained unchanged, compared with baseline, although final values of the treated group were slightly lower (p < .05) than in the placebo group. No significant changes in lipid profiles were obtained in the placebo group. At study completion, 77 policosanol patients (86.5%) achieved reductions of LDL-C (>15%), compared with only 10 (11.2%) patients in the placebo group (p < .0001).


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  		Table 2. Effects of Policosanol (5 and 10 mg/d) on Lipid Profile (mmol/l) of Older Patients With Type II Hypercholesterolemia and High Coronary Risk

 
Cardiovascular capacity, assessed using the Specific Activity Scale (40), significantly increased in the policosanol (5 and 10 mg/d) group, compared with baseline levels (p < .0001), and remained unchanged in the placebo group. Comparisons between groups showed that at the study's completion, the mean number of METS able to be developed by policosanol-treated patients was significantly higher than in placebo-treated patients. This agrees with the improvement on the frequency of cases classified within each functional class. Therefore, at study completion, the frequency of policosanol patients who corresponded to the worst functional class (class IV) was significantly lower (p < .05) than in the placebo group (Fig. 1).



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  		Figure 1. Effects of policosanol (5 and 10 mg/d) on the cardiovascular capacity of older patients with type II hypercholesterolemia, assessed by the Specific Activity Scale questionnaire (40). Step 1, policosanol at 5 mg/d; step 2, policosanol at 10 mg/d. B = baseline. Solid bars represent the placebo-treated group; striped bars represent the policosanol-treated group. A, Effects on the maximal number of metabolic equivalents (METS) developed asymptomatically by study patients. *p < .01, comparison with baseline (t test for paired samples); {dagger}p < .05, comparison with placebo (t test for independent samples). B, Distributions of patients within the four functional classes. *p < .05, comparison with placebo ({chi}2 test).

 
Safety and Tolerability
Table 3 summarizes the effects of policosanol on safety indicators. No significant change on any parameter occurred in the placebo group. Policosanol significantly reduced (p < .01) systolic and diastolic blood pressure, compared with the baseline and placebo levels. It also reduced serum transaminases, compared with baseline (p < .01), but not with placebo levels, thus not clinically relevant.


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  		Table 3. Effects of Policosanol on Safety Indicators of Study Patients

 
Of 179 randomized patients, 13 (7.3%) discontinued the trial (5 policosanol- (5.6%) and 8 placebo-treated (8.9%) patients). Seven placebo-treated patients (7.9%), but none of the policosanol patients, discontinued the study because of serious AE. One placebo-treated patient died during the study because of a sudden cardiac arrest and another 6 placebo-treated patients suffered serious nonfatal AE; none of the policosanol patients experienced serious AE (p < .05; Table 4 ). Five of the seven serious AE that occurred in the placebo group were of vascular etiology (one fatal sudden cardiac arrest, one myocardial infarction, one congestive heart failure, and two cases of hypertensive status requiring hospitalization). The other serious AE was the result of glaucoma surgery. In addition, the overall frequency of AE was higher in placebo (14.6%) than in policosanol groups (4.4%; p < .01).


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  		Table 4. Adverse Experiences (AE) Reported During the Study

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The current preventive efforts regarding CAD morbidity and mortality underline that patients at high risk are those expected to receive the greatest benefit from cholesterol-lowering therapy (13)(14)(39)(40).

For the present study, high-risk conditions were those defined by the National Cholesterol Education Program guidelines (13)(14) and included secondary prevention cases and those without such conditions but with type II hypercholesterolemia and two or more concomitant atherosclerotic risk factors, representative of populations who need to be treated with lipid-lowering therapy to lower levels of LDL-C and TC more stringently than patients with isolated hypercholesterolemia. Because all patients were older than 60 years, age-associated risk factors (men, >45 years, and women, >55 years) were common to both study groups.

Although the treatment of dyslipidemia in elderly persons has been managed with caution and even questioned (8)(10), the absolute risk for morbidity and mortality from CAD increases steeply with age. The major coronary risk factors for CAD continue beyond the age of 60 and even beyond the age of 70 in both sexes, and the contribution of high LDL-C and low HDL-C levels as predictors of CAD rates still continues into the age of 85 (43). Moreover, in Scandinavian Simvastatin Survival Study patients >=60 years old, risk for all-cause mortality and major coronary events was significantly reduced (5).

The present study shows that policosanol was effective in lowering LDL-C and TC, as well as increasing HDL-C, in older patients with type II hypercholesterolemia and high coronary risk. Hence, the ratios of LDL-C to HDL-C and TC to HDL-C were reduced by policosanol therapy.

These results agree with previous data of policosanol efficacy in middle-aged and elderly patients (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Nevertheless, the increases in HDL-C levels obtained in the present study are larger than those reported in previous short- and long-term studies in this population (32)(33)(34), a fact that could be related to the high frequency of patients with low baseline levels of HDL-C (<0.9 mmol/l), which is in agreement with previous data obtained in other high-risk patients (28)(29).

Cardiovascular capacity, evaluated using the Specific Activity Scale, improved in policosanol-treated patients, a finding that agrees with previous data obtained in a long-term open study conducted in middle-aged and older patients with hypercholesterolemia and high coronary risk (29). This result cannot have been simply explained by the cholesterol-lowering properties of policosanol. Therefore, the contribution of other pleiotropic effects (44) must be considered. Policosanol inhibits platelet aggregation in experimental models and in humans (45)(46)(47)(48)(49), reducing serum levels of thromboxane A2, an effect that can exert a beneficial impact on the endothelium wall functioning, normally impaired with age. In addition, policosanol also prevents lipid peroxidation of LDL (50). Therefore, in addition to its cholesterol-lowering properties, both the antiplatelet and antioxidant effects of policosanol contribute to reinforce this drug's antiatherosclerotic effect.

This study corroborates the very good safety and tolerability of policosanol. No drug-related impairment of any safety indicator was observed. As in previous studies (24)(29), a significant decrease in AST and ALT levels was detected, but the lack of significance between both groups suggests that this finding is clinically nonrelevant. However, this finding corroborates that policosanol does not induce increases on serum transaminases as reported for other lipid-lowering drugs (51).

Policosanol, but not the placebo, significantly reduced systolic and diastolic blood pressure, which agrees with some previous results (23)(28)(29). This finding has not been considered as a drug-related AE because the lowest levels we obtained did not reach hypotensive values. However, because the coexistence of hypertension and hypercholesterolemia potentiates global coronary risk, and its frequency also increases with age, this finding could be potentially beneficial in a population of older hypercholesterolemic patients with a high frequency of hypertension. Although the mechanism whereby policosanol induces such reductions has not been demonstrated, it could be related to the potentiation of antihypertensive effects of ß-blockers induced by policosanol (52).

The frequency of AE in policosanol patients was lower than in the placebo group (p < .01). More specifically, all serious AE (one fatal and six nonfatal events) occurred in the placebo group; most of them were of vascular etiology. Although the study was not designed to follow clinical end points, they were collected as a part of AE record. So, although the exact definition of myocardial infarction, unstable angina, cardiac arrest, cardiac congestive failure, and hypertensive crisis were not predefined in study protocol, as the study was double-blind and placebo-controlled, clinical events were assessed similarly in both groups.

The finding that policosanol improves cardiovascular capacity of these patients and that the extent of AE and, primarily, serious AE was lesser in policosanol than in placebo patients indicates a policosanol-induced improvement of the study patients' quality of life.

Although, at first glance, the occurrence of such differences in a relatively short time (6 mo) could be remarkable, similar results have been obtained in population subsets of hypercholesterolemic patients with high coronary risk, not only with policosanol (29)(53), but also with pravastatin (54). Results of the major statins trials have also revealed clinical benefits so dramatic and relatively fast that they cannot simply be due to the reduction of LDL-C levels (4)(5)(6) and the contribution of pleiotropic effects (44), which have been argued to explain these findings. In addition to its cholesterol-lowering properties, policosanol also shows antiplatelet and antioxidant effects that could contribute to the present results.

Therefore, even though the supporting mechanism that fully explains our results is not completely available, the results indicate that policosanol therapy is useful in managing type II hypercholesterolemia in older patients with high coronary risk, not only because of its cholesterol-lowering efficacy, but also, from the clinical point of view, because the treated group showed a lesser extent of AE than did placebo-treated patients and, specifically, did not suffer serious AE. Because all the older patients of the present study were of high coronary risk, they represented a population who, according to the prevention programs, is amenable to receiving lipid-lowering therapy.


   Acknowledgments
 
This work was presented in the poster session of the meeting of Gerontovida held in Havana, Cuba, September 27th to October 1st, 1999.

Received December 19, 1999

Accepted April 12, 2000


   References
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 Methods
 Results
 Discussion
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