the main risk factors of cardiovascular disease ( cvd ) are well known , and reversing the exposure to these risk factors is associated with a significant reduction of cvd risk . this is particularly evident when hypercholesterolemia is treated : a 1  mmol / l decrease in low - density lipoprotein ( ldl)-cholesterolemia is associated with a 20% risk reduction of cvd events . however , not all recent literature agrees on the cost - benefit ratio associated with statin treatment in subjects in primary prevention for cvd . a certain number of patients therefore refuse to continue the standard treatment due to intolerance to it , or look for alternative treatments because of their fear of statin - related side effects . a large amount of literature suggests that numerous natural products could have interesting preventive activities in the management of human hyperlipidemia . based on the positive results reported in literature , the european food safety authority ( efsa ) recognized that there is a cause - and - effect relationship between the consumption of monacolin k from red yeast rice ( daily dose about 10  mg monacolin k ) and the maintenance of normal blood low - density lipoprotein cholesterol ( ldl - c ) concentrations , and between omega-3 polyunsaturated fatty acid ( pufa ) intake ( eicosapentaenoic acid [ epa ] and docosahexaenoic acid [ dha ] about 250  mg per day ) and normal cardiac function . in this context , our aim was to carry out an open clinical trial comparing the metabolic effects of a combined nutraceutical containing both red yeast rice and pufas and a phytosterol - based approach in patients affected by primary polygenic hypercholesterolemia and metabolic syndrome . we consecutively enrolled 107 pharmacologically untreated subjects ( m : 58 , f : 49 ) affected by primary polygenic hypercholesterolemia and metabolic syndrome , nondiabetic , in primary prevention for cvd . all patients were already followed for dyslipidemia by specialized lipid clinics , and as they already followed an overall correct diet , they were therefore directly assigned to an 8-week therapy with the combined treatment being tested , containing red yeast rice ( dif1stat , including 5  mg monacolin k ) and 610  mg pufas ( of which , 183  mg epa , 122 dha ) , provided by difass international srl . a parallel group of 30 subjects affected by primary polygenic hypercholesterolemia and metabolic syndrome was also enrolled and treated for 8 weeks with phytosterols 1600  mg / die , administered in the form of a yogurt with added phytosterols ( danacol , danone italia ) . the choice of phytosterols as a treatment for the control group was based on suggestions made by italian and european guidelines for dyslipidemia management , and the dosage of 1600  mg / day was based on the widely available marketed yogurt with this dosage , also considered as risk effective . the two groups of patients resulted cross - matched by baseline age , blood pressure , lipid , and glucose metabolism parameters . baseline main characteristics of the subjects included in the two treatment groups bmi , body mass index ; cpk , creatinine - phosphokinase ; got , glutamate oxaloacetate transaminase ; gpt , glutamate piruvate transaminase ; hdl - c , high - density lipoprotein cholesterol ; ldl - c , low - density lipoprotein cholesterol ; tc , total cholesterol ; tg , triglycerides ; wc , waist circumference . safety monitoring included physical examination , vital sign assessment , weight and height measurements , questioning about adverse events , and laboratory tests . medication compliance was assessed by counting the number of drug doses returned at clinic visits . adverse events , intercurrent diseases , and compliance were also checked at the end of the study . the whole study was carried out in the field of the routine clinical practice of the units involved in the research , following the internal guidelines of the service , and in line with the principles outlined in the declaration of helsinki ( recommendations guiding physicians in biomedical research involving human subjects ) . for the statistical analysis , we excluded those patients who were not compliant with the diet and/or the treatment , so that the final sample included 84 subjects ( m : 41 , f : 43 ) . the data were entered in an apposite database and statistically analyzed with the help of spss 21.0 , version for windows . a complete descriptive analysis of all studied parameters was carried out ( range , mean , standard deviation , mean standard error , kurtosis , skewness ) , followed by a kolmogorov - smirnov normality test . the comparative analysis was carried out applying the anova test followed by post - hoc tukey 's test to evaluate treatment associated changes , while the t - test for unpaired samples was used to evaluate possible differences between genders or between patients with and without metabolic syndrome . to be more prudent , both treatments were well tolerated , and no patients had side effects or withdrew from the study . no safety parameters ( got , gpt , and cpk ) changed significantly during the study . no significant body changes were observed during the study in either of the treatment groups . the main changes that occurred in lipid profile during the study following both treatments are resumed in figure 1 . in the combined nutraceutical group , compared with the baseline level , we observed a significant decrease in total cholesterol ( tc ; 42.50    18.1  mg / dl , p  <  .001 ) , ldl - c ( 37.6  13.6  mg / dl , p  <  .001 ) , triglyceride ( tg ; 19.8    25.1  mg / dl , p  <  .001 ) , and non - hdl - c ( 43.1    17.7  mg / dl , p  < main % changes occurred during the study in lipid profile after treatment with the combined nutraceutical being tested and phytosterols . in the phytosterol - treated group , compared with the baseline level , we observed a significant decrease in tc ( 13.7  4.3  mg / dl , p  <  .001 ) , ldl - c ( 17.6    8.5  mg / dl , p  < .001 ) , and non - hdl - c ( 14.1    5.6  mg / dl , p  < high - density lipoprotein cholesterol ( hdl - c ) level was not significantly modified in either the combined nutraceutical or the phytosterol - treated groups . in comparing the combined nutraceutical effect with that of phytosterols , we observed that the combined nutraceutical intake was associated with a significantly higher decrease in tc ( p  <  .001 ) , ldl - c ( p  < , 75% of subjects reached an ldl - c target of less than 160  mg / dl and 25% of less than 130  mg / dl . in the placebo group , 50% of subjects reached an ldl - c target of less than 160  mg / dl , and none less than 130  mg / dl . repeating the analysis by subgroups , similar trends were observed in men and women and in subjects with or without metabolic syndrome . we noted a greater decrease in tg levels only in subjects with baseline tg  >  150  mg / dl treated with the combined nutraceutical being tested , who reached a 11% reduction ( p  <  .001 vs. subjects with baseline tg <  150  mg / dl ) . cvds are still the most common cause of death and one of the main causes of disability in industrialized countries , and despite efforts toward primary prevention , many patients still remain at risk . lifestyle interventions such as diet and/or physical activity remain the most cost - effective approach in delaying or preventing the onset of cvds , especially in relatively healthy subjects . weight loss ( reduction of 710% of weight ) and moderate intensity exercise , such as walking 57 days per week , could be useful tools to help blood pressure , ldl - c , and blood glucose control . however , lifestyle programs are often difficult to follow for long periods , and some risk parameters , such as cholesterolemia , are relatively resistant to changes in dietary habits and physical activity . on the other hand , a relatively large number of dietary supplements and nutraceuticals have been studied for their supposed or demonstrated ability to safely improve lipid patterns in humans . in our study , carried out on moderately hypercholesterolemic subjects with metabolic syndrome , we observed that the intake of a combined nutraceutical containing red yeast rice and pufas was associated with a significant reduction of tc ( 16%    2% ) , ldl - c ( 22%    3% ) , tg ( 9%    5% ) , and non - hdl - c ( 21%    3% ) , and a significant increase in hdl - c ( + 1.5%    0.5% ) , without the modification of safety parameters . the observed improvement in tc , ldl - c , and non - hdl - c was also significant when compared with that registered in a parallel group of patients treated with phytosterols . based on current evidence , we could estimate that an ldl - c reduction of 20% is associated with a reduction in cvd events of about 20% in the following 10 years . naturally , this is only an indirect estimation , but it supports a potential role for the use of efficacious nutraceuticals in cvd risk reduction . the improvement in ldl - cholesterolemia is quantitatively similar to that observed in other studies carried out on combined nutraceuticals with lipid - lowering activity , containing either statin - like substances or other components . the lack of a significant improvement in tg level is probably related to the large spontaneous variation of this parameter , the relatively normal level of tg in the patients studied , and the small amount of epa / dha included in the tested nutraceutical , aimed more at improving the dietary intake of epa / dha for an adequate cvd prevention than at reducing triglyceridemia . the first are the relatively small sample of enrolled patients and the short duration of observation . this was , however , just a preliminary study aiming to evaluate efficacy and tolerability . a further limitation is that we did not test the lipid - lowering efficacy of the single components of the nutraceutical to be tested . these are , however , known from available literature . furthermore , our evaluation of efficacy is based on a limited quantity of laboratory data and on no instrumental data . another problem is that the study we designed was not a randomized , double - blind clinical trial , although the considered control group had characteristics similar to the main one , and treatment with phytosterols is currently suggested as a first step nutraceutical treatment by a number of experts . this choice was also related to the technical difficulty in creating an active comparator similar to a mix of red yeast rice and pufas . in fact , our aim was not to compare the effect of the combined nutraceutical being tested with a placebo ( the lipid - lowering effect of both red yeast rice and pufas being widely known from available literature ) , but with an active compound also known for its cholesterol - lowering effect . in conclusion , in the short term the tested combined nutraceutical is well tolerated and efficacious in reducing plasma lipid levels in subjects affected by primary polygenic hypercholesterolemia and metabolic syndrome .
abstractthe main guidelines for cardiovascular disease prevention suggest that nutraceuticals could be an efficacious tool to improve lipid pattern . 
 our aim was to carry out a clinical trial comparing the metabolic effects of a combined nutraceutical containing both red yeast rice and polyunsaturated fatty acids ( pufas ) and a phytosterol - based approach in a setting of clinical practice . 
 this was a multicenter open study with parallel control . 
 we consecutively enrolled 107 pharmacologically untreated subjects affected by primary polygenic hypercholesterolemia and metabolic syndrome , assigned to 8-week treatment with a combined treatment with red yeast rice ( dif1stat , including 5  mg monacolin k ) and 610  mg pufas . 
 a parallel group of 30 subjects with similar characteristics was treated with phytosterols 1600  mg / die . in the combined nutraceutical group , 
 compared with the baseline level , we observed a significant decrease in total cholesterol ( tc ; 42.50    18.1  mg / dl ) , low - density lipoprotein cholesterol ( ldl - c ; 37.6    13.6  mg / dl ) , triglycerides ( tg ; 19.8    25.1  mg / dl ) , and non - hdl - c ( 43.1    17.7  mg / dl ) ( all p  < 
 .001 ) . in the phytosterol - treated group , 
 compared to the baseline level , we observed a significant decrease in tc ( 13.7    4.3  mg / dl ) , ldl - c ( 17.6    8.5  mg / dl ) , and non - hdl - c ( 14.1    5.6  mg / dl ) ( all p  <  .001 ) . 
 when comparing the combined nutraceutical effect with that of phytosterols , we observed that the combined nutraceutical intake was associated with a significantly higher decrease in tc , ldl - c , tg , and non - hdl - c ( all p  < 
 .001 ) . in the short term 
 , a combined nutraceutical containing red yeast rice and pufas is well tolerated and efficacious in reducing plasma lipid levels in subjects affected by primary polygenic hypercholesterolemia and metabolic syndrome .