Effects Of Policosanol Combined With Simvastatin On Serum Lipids And Testosterone In Male Patients With Hyperlipidemia

BackgroundMainly due to the changes in lifestyles,the incidence of hyperlipidemia has become more and more prevalent.Lipid lowering therapy,especially the low degree of LDL-C has been proved to play a significant role in preventing both primary and secondary cardiovascular events in patients with dyslipidemia.The3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors(statins) are widely prescribed all over the world since they can significantly reduce the risk of cardiovascular events.Reduction in the level of serum LDL-C is the major reason responsible for this benefit.The main adverse effects(AEs) of statins are the damage to the liver and muscle,featured as increasing levels of transaminases and creatases,myopathy even the rarer rhabdomyolysis.The side-effects of statins are dose dependent,they are rare when statins are administrated at standard doses and increases with use of higher doses.Besides,current data has shown that statin therapy is associated with a9%increase in the risk of new-onset diabetes compared with placebo and that statin intensive therapy is positively correlated with new-onset diabetes incidence. Stopping statin use reverses these side-effects,usually leading to a full recovery.Recent guidelines have suggested an LDL-C treatment goal of<1.8mmol/L(70mg/dL) or a≥50%reduction from baseline in patients with high risks of cardiovascular disease such as ACS.The effect of statin depend on its dosage to some extent. However, the administration of statins at the maximal approved dose provides only limited additional lowering of LDL-C at the expense of an increased incidence of side effects. Concerns about safety may prevent physicians from titrating statin doses high enough to achieve recommended targets. This partly explains the low LDL-C goal attainment in China.Findings suggested that treatment with statins reduces the rate of cardiovascular events in high-risk patients,but residual cardiovascular risk persists despite achieving LDL-C levels at or below recommended targets.It is reported that each1mmol/L LDL-C reduction reduces the risk of main cornary events by about20%, but residual cardiovascular risk remains about77%. The residual cardiovascular risk may in part be attributable to atherogenic dyslipidemia,which indicates dyslipidemia contains low HDL-C,high TG levels and increased small dense low density lipoprotein (sdLDL) particles. Atherogenic dyslipidemia mainly occurs in patients with obesity,MetS and DM.In order to fully modulate dyslipidemia and further reduce residual cardiovascular risk, it is of our interest to investigate novel lipid-modulating compounds.Policosanol is a drug currently in use to reduce elevated LDL-C and total cholesterol levels in combination with dietary therapy in patients with hypercholesterolemia.It was originally developed by Dalmer Laboratories,Havana, Cuba, and was approved for use in Cuba in1991. Currently it is used in>25countries throughout the world, mainly in South America and in the Caribbean region, with approval or registration filed or planned in several other countries.Policosanol is a natural mixture of aliphatic primary alcohols that are isolated from purified sugar cane (Saccharum officinarum L) wax by hydrolytic cleavage and subsequent purification. The chemical formula is CH3-(CH2)n-CH2OH with chain length varying from24to34carbon atoms. Octacosanol (62.9%), triacontanol (12.6%), and hexacosanol (6.2%) are the major components of the mixture. Although both the statin and policosanol showed a definite lipid-lowering effect,data related to the efficacy profiles when them were co-administrated remain unclear.More recently,studies conducted in Europe and US indicated no preferable lipid-modulating effects of statin combined with policosanol when compared with statin alone.To date,no similar data is available in China.Sex hormones play an important role in human’s growth and development.The insufficient of testosterone has been proved to be a risk factor for the development of cardiovascular diseases,metabolic syndrome(MetS),type2diabetes(T2DM) or insulin resistance(IR), prostate cancer,and erectile dysfunction(ED) in men. As we already know,cholesterol is the precursor of testosterone.The cardinal source of this cholesterol is provided from the circulation in the form of LDL-C,the other sources for this pathway may be de novo synthesis and circulating HDL-C,which are considered to be of less important. Some studies found that the levels of T and HDL-C has positive correlation,while negatively correlated with TC and LDL-C values in men. Physiologically,statins may have a subtle adverse effect on testosterone synthesis due to reducing the concentrations of circulating LDL-C and inhibiting de novo cholesterol synthesis.The effects of policosanol combined with statin on testosterone has not been discussed so far. Here, we carried out a randomized trial to explore this subject. ObjectiveTo evaluate the effects and safety of policosanol coadministrated with simvastatin on serum lipids and testosterone in male patients with hyperlipidemia.MethodsPatients populationThis single-center,prospective,randomized,open-label trial recruited120men with documented hyperlipidemia from September2011to June2012in Guangzhou,China.The inclusion criteria contains:(1)age between18to80years,(2)serum TC levels>5.18mmol/L or>200mg/dl,or LDL-C levels>3.37mmol/L or>130mg/dl with or without HDL-C≤1.04mmol/L or≤40mg/dl, for patients with coronary heart diseases or diabetes,LDL-C levels>2.59mmol/L or>100mg/dl is suitable,in order to calculating LDL-C values using Friedewald formula,triglycerides<4.52mmol/L or<400mg/dl is necessary,the enrollment standards of lipids were established according to the Chinese guideline on dyslipidemia(2007edition),(3)no prior lipid-lowering drug use or need to be off statin therapy or any lipid-lowering drug for a minimum of2weeks before study enrollment,(4)liver transaminases (ALT,AST) and CK<1.5X upper limit of normal (ULN) with no active liver disease,(5)expected lifetime>6months.The exclusion criteria are listed as follows:(1)congestive heart failure(NYHA Class III or IV),(2)ACS or coronary artery bypass surgery or angioplasty within6months,(3)impaired renal function (Scr>221mmol/L),(4) active hepatitis,(5) coagulation defects or active bleeding recently,(6)hyperthyroidism or hypothyroidism,(7)warfarin treatment due to valvular replacement or persist atrial fibrillation,(8) use of any medicationthat may interfere with steroidogenesis,(9)hypersensitivity to statins or policosanol,(10)severe psychosis. Study designAll eligible patients were randomly divided into treatment group(group I) or control group(group II) using a1:1ratio. Group I received40mg per day of simvastatin(Merck Sharp&Dohme,Australia) plus20mg per day of policosanol(Dalmer Laboratories,Cuba)) and group II with simvastatin40mg per day and placebo20mg/d for16weeks. The study medication was taken once daily, unchewed,within1hour after dinner.For the purpose of minimizing the interference for our results,all participants were advised to keep their usual dietary habits and maintain the concurrent medications. The present study was approved by the Ethics Committee of Southern Medical University and was conducted in accordance with the Declaration of Helsinki Principles.Informed consent was obtained from each patient before study enrollment.All patients were arranged to a complete physical examination(weight, height and blood pressure measurements) and laboratory analyses(TC, LDL-C, HDL-C,TQ FBG,Scr,ALT,AST,T) at baseline,8th and16th week of treatment. All blood samples were drawn from the antecubital vein between8.00and9.00a.m after a12-hour fasting. Tolerability was assessed by questioning patients about adverse effects and monitoring relevant laboratory parameters(ALT, AST, CK) at the end of4th,8th,and12th week of treatment. Compliance with study medication was assessed at week12by pill counts,patients were considered compliant if they took90%to100%of the prescribed number of tablets. The primary efficacy measures of the study were to determine the changes in lipoproteins (LDL-C, TC) from baseline to8th,16th week, and the secondary efficacy measures of the study were to determine the changes in lipoproteins(TG,HDL-C) and T from baseline to8th,16th week.Safety was evaluated by assessment of laboratory tests,electrocardiograms,physical examinations,and vital signs.Laboratory evaluations included liver function tests,serum creatine phosphokinase,biochemistry,hematology,and urinalysis.Safety and tolerability were evaluated by treatment-emergent AEs.AEs were defined as any adverse clinical and/or laboratory abnormality occurring during the course of the study. We assessed patient-reported clinical AEs,new-onset physical exam AEs,and laboratory AEs at each study visit.Specifically regarding the assessment of laboratory AEs,which were evaluated by the determination of blood biochemical parameters at patients’each study visit in the fasted state.For ALT or AST elevations≥3times the ULN or CK levels≥10times ULN without muscle symptoms,a re-test was mandatory within7days. If consecutive elevations to these degrees were observed on laboratory re-test,the AEs were considered serious and the patient was withdrawn from the study.Any incidence of CK≥5-10times ULN associated with muscle symptoms was classified as a serious AE and the patient was immediately withdrawn from the study. All AEs were recorded on the CRF.Laboratory assaysSamples for serum chemistry and hormone were analyzed by the laboratory ofvNanfang Hospital,Southern Medical University.FBQlipid profiles,biochemical safety parameters levels were measured using an Olympus AU5421automatic biochemical analyzer(Olympus Co.,Japan).TC,HDL-C and LDL-C levels were determined by using an enzymatic colorimetric assay.TG levels was assayed by glycerol phosphate oxidase(GPO-PAP).Testosterone levels was assayed on the Roche cobas e601using chemiluminescence immunoassay (Roche Diagnostics GmbH, Germany).Statistical analysis All data were analyzed using SPSS version13.0(SPSS Inc.,US). Results are showed as mean±SD. Differences in continuous variables within each group were compared using the paired t-test and differences between the2groups were compared using the independent t-test. The incidence of adverse events in the2groups was assessed using descriptive statistical analysis.All tests of significance were two-tailed. Differences were considered statistically significance at P value<0.05.ResultsEffects on lipid profilesTC, LDL-C concentrations were decreased significantly in both groups, but the decreases were more pronounced in the policosanol add-on group with significant between-group differences after a16-week treatment.Plasma TC and LDL-C levels declined significantly in group I at both8th and16th week compared with baseline(P <0.01);there was a significant reduction in TG levels at16th week(P<0.05) rather than8th week(P>0.05),but there were no changes in HDL-C levels at any visit compared with baseline.The lipid-altering regime of group II also resulted in a significant reduction in both TC and LDL-C values at both8th and16th week compared with baseline(P<0.01),while no changes were found toward TG and HDL-C values.The policosanol add-on therapy regimen showed a mean reduction of1.16mmol/L or a19.37%in percentage in TC value and a mean reduction of0.92mmol/L or a24.88%in percentage in LDL-C value.The simvastatin/placebo regimen elicited a mean reduction of0.96mmol/L or a15.36%in percentage in TC value and a mean reduction of0.79mmol/L or a20.33%in percentage in LDL-C value.Group I regimen showed a greater lipid-lowering effect versus group II regimen.Effects on testosterone levels Baseline testosterone levels were similar in2groups.At the end of the study, no significant changes on testosterone values were found in any group.Safety eventsThe safety profile was excellent.No subjects dropped out the experiment due to side effects. There were3patients in group I and3in group II experienced an episode of transient asymptomatic elevation in CK≥3XULN.The values of CK in group I at enrollment and at the end of the study were (75.88±34.62)U/L and (89.36±43.55)U/L,respectively,and values of CK in group Ⅱ at enrollment and at the end of the study were (80.86±34.29)U/L and (91.27±41.43)U/L,respectively.The between-group changes of CK levels were without significance.There were no elevations in ALT or AST≥3XULN or in CK≥10×ULN in either group.There were few subjects in both groups suffered from fatigue,dizziness,nausea or constipation within one week after administrated.Most of the side effects could be relieved over time.No case of rhabdomyolysis(defined as myopathy with a CK>40X ULN) was recorded throughout the study.ConclusionsSimvastatin/policosanol produces greater decreases in TC,LDL-C and TG than simvastatin/placebo along with no more side effests.Both of the combinations have no effects on testosterone level.As confirmed in our study,we recommend the clinical use of the simvastatin/policosanol combination in the hyperlipidemic populations in China.