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Clinical Efficacy, Safety, and Tolerability of PolicosanolPlus for Hypercholesterolemia.
I. Introduction:
Cardiovascular disease is a leading cause of morbidity and mortality in the United States. Systematic reviews have found that lowering cholesterol in people at high risk of ischemic coronary events substantially reduces the risk of cardiovascular mortality and morbidity. Hypercholesterolemia is a major independent risk factor for coronary heart disease. Reduction of LDL-C levels in clinical trials for secondary prevention has been demonstrated to produce favorable effects on atherosclerotic coronary artery disease, resulting in the retardation of the progression of stenotic lesions, regression of lesions, and prevention of formation of new lesions, and prevention of thrombotic events associated with non-stenotic lesions. Reduction of the LDL-C level has also been associated with a reduced incidence of fatal and nonfatal myocardial infarction, angina pectoris, angioplasty, and coronary artery bypass surgery. PolicosanolPlus® is a natural mixture of high molecular-weight aliphatic alcohols and omega-3, omega-6 and omega-9 polyunsaturated fatty acids, which are extracted from natural waxes. There are several scientific papers demonstrating that policosanol may inhibit hepatic cholesterol synthesis at a step before mevalonate generation and policosanol may enhance the processing of LDL-cholesterol. Consumption of omega-3 fatty acids is strongly associated with a reduced risk of coronary heart disease(CHD) in women and men and particularly CHD deaths. This breakthrough in the development of PolicosanolPlus®, combining policosanol and omega-3, omega-6 and omega-9 fatty acids may prove to be the utmost cardiovascular protective supplement.
II. Objective:
To evaluate the effect of PolicosanolPlus® on total cholesterol, low- density lipoprotein(LDL) cholesterol, ,triglycerides, high density lipoprotein(HDL) cholesterol levels and the LDL:HDL ratios over a 9 week study period with no modification of diet. Also, to evaluate the tolerability and side effects of the supplement at the 20 mg total daily dose.
IlI Study design, Participants, Setting, Methods and Study End Points
The study will be conducted from an open label, single center study enrolling 18 participants. Men and women between the ages of 20-70 years of age will be enrolled. Participants will be enrolled during the Thanksgiving and Christmas Holiday season and no dietary restrictions will be placed on the study group. All participants had a history of having elevated total cholesterol on previous routine screening. All enrollees were educated on the purpose and safety of the study and then subjected to an informed consent. Participants must not be taking any cholesterol lowering agents nor have a history of: Active renal disease Diagnosed with neoplastic disease Severe hypertension diastolic p >l20 mmHg Uncontrolled diabetes Active hepatic disease Nephrotic syndrome Thyroid dysfunction Three months prior to study participants must not have had a Myocardial infarction Stroke Cardiovascular surgery The treatment group participants will have a baseline lipid profile after a 12 hour overnight fast. The lipid profile will consist of serum levels of: total cholesterol , triglycerides(TG), and HDL-C to be measured using enzymatic methods. LDL-C concentrations will be calculated using the Friedewald formula. All lipid measurements to be performed in the same laboratory, using the same methods. Participants will receive PolicosanolPlus® 10mg twice daily, one dose in the morning and one dose in the evening, for a period of 9 consecutive weeks beginning after the first laboratory visit. Laboratory tests will be repeated at 3, 6 and 9 weeks during the study period using the same methodology as mentioned above.
Study End Points: Reduction changes in LDL-C and total cholesterol levels were considered as primary efficacy variables. Furthermore, changes in HDL-C, triglycerides and ratios of total cholesterol to HDL-C and LDL-C to HDL-C, were also analyzed.
IV Results: The data included are for the 11 participants completing the study. Seven participants dropped out of the study because of poor compliance. Lipid measurements were obtained at baseline, 3 weeks, 6 weeks and the 9th week, which was the endpoint of the study. Per visit analysis is submitted with the data in appendix A. Overall, data shows a reduction in Total cholesterol from a mean of 267mg/dl to 225mg/dl. This represents an 15.8% reduction over the 9 week course of treatment with no dietary changes. The LDL-C cholesterol was reduced from a mean of 174mg/dl to 143mg/dl which represents an 17.4% reduction.
Appendix A. will show the Full Study Data. T1 = (November 20, 2001) 0 weeks Baseline (before taking PolicosanolPlus) T2 = (December 11, 2001) 3 weeks of 10 mg PolicosanolPlus twice a day T3 = (January 3, 2002) 6 weeks of 10 mg PolicosanolPlus twice a day T4 = (January 24, 2002) 9 weeks of 10 mg PolicosanolPlus twice a day Comparison with baseline by Wilcoxon statistical analysis
Notes: We plan on conducting a future clinical study enrolling participants with elevated LDL-C levels. These participants would be studied over a six month period with dietary restrictions. Participants would take the PolicosanolPlus® in the evening before bedtime because of the possible enhanced effect. Most cholesterol synthesis occurs at night. Results would be submitted for publication.
To conduct further studies looking at the combination effect of PolicosanolPlus® and low fat diet on selected Hyperlipidemia patients.
Further clinical studies looking at the potential effect of PolicosanolPlus® on platelet aggregation. We also plan on conducting future research with PolicosanolPlus® and drugs in clinical studies for: - Strategies for combination therapy - Combination-Synergistic at lowering LDL-C, total cholesterol and improving LDL/HDL ratio - Conjugated-Synergistic at render the conjugated more lipophilic than the drug - Bioavalability and factors that might enhance or inhibit its absorption - Mixture combination or fractionate ingredient (fractions) for run bioassay on specific effects
PolicosanolPlus® Clinical Study Conclusion: Hyperlipidemia increases the risk of developing Coronary Artery Disease (CAD) substantially in patients with two or more risk factors and a total Cholesterol level in excess of 200 mg/dl, a low density lipoprotein (LDL)-cholesterol level greater than 130 mg/dl, or a high-density lipoprotein (HDL)-cholesterol level of less than 35 mg/dl. Treatment of hyperlipidemia can reduce the incidence of CAD by 25 – 60 % and the risk of death from CAD by up to 30 %.Our study, conducted in a random population without diet restrictions and regardless their risk factors (smoking, alcohol intake, medications, life style, etc) showed: 1. A decrease in Total Cholesterol from a mean of 267 mg/dl to 225 mg/dl at the end of the ninth week, which represent an 15.8 % reduction. If this study is continued the Total Cholesterol level is expected to reach levels below 200 mg/dl by the end of the thirteenth week of treatment. 2. The Low Density Lipoprotein (LDL-C) was reduced by 17.4 %, as it was expected. Notice that at the end of the 3rd week there was a significant decrease of 11.3%. The lowest level was 130 mg/dl (mean 143 mg/dl) at the end of study. 3. The HDL-Cholesterol increased by 5.75 % (48.5 mg/dl) at the end of the 3rd week and 10.1 % (50.5 mg/dl) at the end of the study. Notice that it coincides with the holidays of Christmas and New Year. 4. Triglyceride levels, similar to HDL, had a significant change by the end of the 3rd week of treatment (reduction of 8.2 %) and (reduction of 16.1 %) at the end of the study. In our clinical trial, the Total and LDL-C were reduced to levels associated with a significant decrease in coronary artery disease (CAD risk < 23.7%), less than 200 mg/dl and 130 mg/dl respectively. HDL-C was increased to levels ( > 35 mg/dl ) were there is a strong inverse relationship with coronary disease, related to the heightened capacity of the HDL molecules to transport cholesterol from cells. PolicosanolPlus® therapy, 10 mg twice a day, demonstrated excellent short-term safety and efficacy in reducing total and low-density lipoprotein cholesterol levels in patients with primary hypercholesterolemia.
Open Label, Single Center Study
Our study was conducted from open label, single center study, in a random population of men and women between the ages of 20 – 70 years of age, without diet restrictions and regardless of their risk factors (smoking, alcohol intake, medications, life style, etc). All enrollees were educated on the purpose and safety of the study and then subjected to an informed consent. Reduction changes in LDL-C and total cholesterol levels were considered as primary efficacy variables. Furthermore, changes in HDL-C, triglycerides and ratios of total cholesterol to HDL-C and LDL-C to HDL-C, were also analyzed. All data is reported in mg/dL.
Appendix A.
TOTAL CHOLESTEROL SUBJECT T1 T2 %Chg T3 %Chg T4 %Chg 1 251 227 -9.56 216 -13.94 206 -17.93 2 252 215 -14.68 228 -9.52 217 -13.89 3 248 199 -19.11 199 -19.11 209 -15.04 4 329 279 -15.20 312 -5.17 270 -17.93 5 289 272 -5.88 253 -12.46 241 -16.61 6 261 218 -16.48 215 -17.62 209 -19.92 7 258 228 -11.63 226 -12.40 220 -14.73 8 253 250 -1.19 215 -15.02 220 -13.04 9 258 247 -3.52 241 -5.86 221 -13.67 10 261 237 -9.20 223 -14.56 212 -18.77 11 279 254 -8.96 247 -11.47 245 -12.19 Average 267 239 -10.53 234 -12.27 225 -15.84
T1: Baseline before taking the mixture aliphatic alcohols-saturated-polyunsaturated fatty acids (AA-SPFA) T2: 3 weeks of 10 mg (AA-SPFA) twice a day T3: 6 weeks of 10 mg (AA-SPFA) twice a day T4: 9 weeks of 10 mg (AA-SPFA) twice a day
TRIGLYCERIDES SUBJECT T1 T2 %Chg T3 %Chg T4 %Chg 1 178 239 34.27 134 -24.72 146 -0.9 2 136 109 -19.85 129 -5.15 129 17.04 3 284 298 4.93 283 -0.35 267 -17.83 4 108 119 10.19 109 0.93 108 -13.67 5 139 146 5.04 107 -23.02 106 19.81 6 156 137 -12.18 112 -28.21 115 14.57 7 175 143 -18.29 118 -32.57 139 4.67 8 239 195 -18.41 198 -17.15 221 -24.05 9 154 125 -18.83 115 -25.32 129 -9.45 10 128 108 -15.63 124 -3.13 105 -35.88 11 176 99 -43.75 166 -5.68 106 6.0
Average 170 156 -8.28 145 -14.84 143 -16.12
T1: Baseline before taking the mixture aliphatic alcohols-saturated-polyunsaturated fatty acids (AA-SPFA) T2: 3 weeks of 10 mg (AA-SPFA) twice a day T3: 6 weeks of 10 mg (AA-SPFA) twice a day T4: 9 weeks of 10 mg (AA-SPFA) twice a day
HDL-CHOLESTEROL SUBJECT T1 T2 %Chg T3 %Chg T4 %Chg 1 46 47 2.17 50 8.70 50 8.70 2 48 49 2.08 51 6.25 51 6.25 3 49 50 2.04 51 4.08 52 6.12 4 45 46 2.22 48 6.67 49 8.89 5 45 48 6.67 48 6.67 50 11.11 6 44 47 6.82 51 15.91 50 13.64 7 48 51 6.25 50 4.17 51 6.25 8 46 49 6.52 48 4.35 50 8.70 9 43 50 16.28 51 18.60 52 20.93 10 46 49 6.52 50 8.70 50 8.70 11 44 47 6.82 50 13.64 50 13.64
Average 45.8 48.5 5.75 49.8 8.73 50.5 10.12
T1: Baseline before taking the mixture aliphatic alcohols-saturated-polyunsaturated fatty acids (AA-SPFA) T2: 3 weeks of 10 mg (AA-SPFA) twice a day T3: 6 weeks of 10 mg (AA-SPFA) twice a day T4: 9 weeks of 10 mg (AA-SPFA) twice a day
LDL-CHOLESTEROL SUBJECT T1 T2 %Chg T3 %Chg T4 %Chg 1 165 145 -12.12 144 -12.73 136 -17.58 2 167 125 -25.15 133 -20.36 130 -22.16 3 162 168 3.70 155 -4.32 136 -16.05 4 202 203 0.50 210 3.96 168 -16.83 5 178 159 -10.67 165 -7.30 153 -14.04 6 161 146 -9.32 139 -13.66 140 -13.04 7 162 122 -24.69 118 -27.16 138 -14.81 8 184 146 -20.65 128 -30.43 147 -20.11 9 169 149 -11.83 128 -24.26 144 -14.79 10 189 168 -11.11 156 -17.46 149 -21.16 11 171 163 -4.68 148 -13.45 136 -20.47
Average 174 154 -11.31 148 -14.97 143 -17.43
T1: Baseline before taking the mixture aliphatic alcohols-saturated-polyunsaturated fatty acids (AA-SPFA) T2: 3 weeks of 10 mg (AA-SPFA) twice a day T3: 6 weeks of 10 mg (AA-SPFA) twice a day T4: 9 weeks of 10 mg (AA-SPFA) twice a day
CHOLESTEROL/HDL (CAD RISK) SUBJECT T1 T2 %Chg T3 %Chg T4 %Chg 1 5.5 4.8 -11.5 4.3 -20.8 4.1 -24.5 2 5.3 4.4 -16.4 4.5 -14.8 4.3 -19.0 3 5.0 4.0 -20.7 3.9 -22.3 4.0 -19.9 4 7.3 6.1 -17.0 6.5 -11.1 5.5 -24.6 5 6.4 5.7 -11.8 5.3 -17.9 4.8 -24.9 6 5.9 4.6 -21.8 4.2 -28.9 4.2 -29.5 7 5.4 4.5 -16.8 4.5 -15.9 4.3 -19.7 8 5.5 5.1 -7.2 4.5 -18.6 4.4 -20.0 9 6.0 4.9 -17.0 4.7 -20.6 4.3 -28.6 10 5.7 4.8 -14.8 4.5 -21.4 4.2 -25.3 11 6.3 5.4 -14.8 4.9 -22.1 4.9 -22.7
Average 5.8 4.9 -15.4 4.7 -19.4 4.5 -23.7 T1: Baseline before taking the mixture aliphatic alcohols-saturated-polyunsaturated fatty acids (AA-SPFA) T2: 3 weeks of 10 mg (AA-SPFA) twice a day T3: 6 weeks of 10 mg (AA-SPFA) twice a day T4: 9 weeks of 10 mg (AA-SPFA) twice a day Results: All 11 enrolled patients completed the study. Lipid measurements were obtained at baseline, in the 3rd, 6th and the 9th weeks, which was the endpoint of the study. Overall, data shows a reduction in total cholesterol from a mean of 267mg/dl to 225mg/dl. This represents a 15.84% reduction over the 9 week course of treatment with no dietary changes. The LDL-C cholesterol was reduced from a mean of 174mg/dl to 143mg/dl which represents a 17.43% reduction. HDL-C levels increased during the period of active treatment Triglycerides levels decreased throughout the study period from a baseline value of 170 mg/dl to 143 mg/dl.
Discussion: Hyperlipidemia increases the risk of developing Coronary Artery Disease (CAD) substantially in patients with two or more risk factors and a total cholesterol level in excess of 200 mg/dl, a low density lipoprotein (LDL)-cholesterol level greater than 130 mg/dl, or a high-density lipoprotein (HDL)-cholesterol level of less than 35 mg/dl. Treatment of hyperlipidemia can reduce the incidence of CAD by 25 – 60 % and the risk of death from CAD by up to 30 %.Our study, conducted in a random population without diet restrictions and regardless their risk factors (smoking, alcohol intake, medications, life style, etc) showed: 3. A decrease in total cholesterol from a mean of 267 mg/dl to 225 mg/dl at the end of the 9th week, which represent a 15.84 % reduction. If this study is continued the total cholesterol level is expected to reach levels below 200 mg/dl by the end of the thirteenth week of treatment. 4. The Low Density Lipoprotein (LDL-C) response to PolicosanolPlus® showed a marked decrease over the first 3 weeks of treatment and a continuing downward trend thereafter. The 9-week value of 143 mg/dl represented a statistically significant (p <0.001) reduction over the baseline level of 174 mg/dl. 5. The HDL-Cholesterol levels were elevated by 5.75 % and 10.12 % at the end of the 3rd week and the 9th week, respectively. 6. Triglyceride levels had a significant change by the end of the 9th week of treatment (reduction of 16.12 %). In our clinical trial, the total cholesterol and LDL-cholesterol were reduced to levels associated with a significant decrease in coronary artery disease (CAD risk < 19.4%) and (CAD risk < 23.7%), less than 200 mg/dl and 130 mg/dl respectively. HDL-Cholesterol was increased to levels (> 35 mg/dl) where there is a strong inverse relationship with coronary disease, related to the heightened capacity of the HDL molecules to transport cholesterol from cells. The aliphatic alcohols-saturated-polyunsaturated fatty acids mixture therapy, (PolicosanolPlus®) 10 mg twice a day, demonstrated excellent short-term safety and efficacy in reducing total and low-density lipoprotein cholesterol levels in patients with primary hypercholesterolemia and without diet restrictions. Cardiovascular disease is a leading cause of morbidity and mortality in the United States. Systematic reviews have found that lowering cholesterol in people at high risk of ischemic coronary events substantially reduces the risk of cardiovascular mortality and morbidity. Hypercholesterolemia is a major independent risk factor for coronary heart disease. Reduction of LDL-C levels in clinical trials for secondary prevention has been demonstrated to produce favorable effects on atherosclerotic coronary artery disease, resulting in the retardation of the progression of stenotic lesions, regression of lesions, and prevention of formation of new lesions, and prevention of thrombotic events associated with non-stenotic lesions. Reduction of the LDL-C level has also been associated with a reduced incidence of fatal and nonfatal myocardial infarction, angina pectoris, angioplasty, and coronary artery bypass surgery. Having multiple therapeutic effects the aliphatic alcohols and saturated-polyunsaturated fatty acids (AA-SPFA) mixture from natural vegetable wax such as sugar cane wax and/or by blending of selected natural sugar cane waxes from continental United States sugar cane varieties can enhance current treatment for hyperlipidemia and hypercholesterolemia and may be as indicated new strategies for safe combination therapy with statins, this combination may have some synergistic triglyceride-lowering and HDL-C-raising effects; actions that may improve outcomes independent of their effect on LDL-C. That allows patients to reduce their dosage of statins, and also reduces risk of side effects associated with statins, and may also serve as a bridge toward new dimensions in cholesterol control.
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