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Efficacy and tolerability of a nutraceutical combination (red yeast rice, policosanols and berberine) in low-moderate risk hypercholesterolemic patients: a double-blind, placebo controlled study Stefano Gonnelli, Carla Caffarelli, Kostantinos Stolakis, Claudia Cuda, Nicola Giordano, Ranuccio Nuti www.elsevier.com/locate/cuthre
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S0011-393X(14)00016-2 http://dx.doi.org/10.1016/j.curtheres.2014.07.003 CUTHRE458
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Current Therapeutic Research
Cite this article as: Stefano Gonnelli, Carla Caffarelli, Kostantinos Stolakis, Claudia Cuda, Nicola Giordano, Ranuccio Nuti, Efficacy and tolerability of a nutraceutical combination (red yeast rice, policosanols and berberine) in lowmoderate risk hypercholesterolemic patients: a double-blind, placebo controlled study, Current Therapeutic Research, http://dx.doi.org/10.1016/j. curtheres.2014.07.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Efficacyandtolerabilityofanutraceuticalcombination(redyeastrice,policosanolsand berberine)inlowmoderateriskhypercholesterolemicpatients:adoubleblind,placebo controlledstudy StefanoGonnelli,CarlaCaffarelli,KostantinosStolakis,ClaudiaCuda,NicolaGiordano, RanuccioNuti DepartmentofMedicine,SurgeryandNeuroscience,UniversityofSiena,Italy CorrespondingAuthor StefanoGonnelli,MD DepartmentofMedicine,SurgeryandNeuroscience UniversityofSiena PoliclinicoLeScotte, VialeBracci2 53100Siena,Italy Ph+390577585468 Fax+390577233446 email:
[email protected] Keywords:Hypercholesterolemia,Monacolin,Redyeastrice,Berberine,Policosanols, Tolerability
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Abstract Background:Statinsareattheforefrontofstrategiestomanagehypercholesterolemia. However,1015%ofpatientsresulttobeintoleranttoanystatins,evenatlowdailydoses andalmostonethirdofstatinusersdiscontinuetherapywithinoneyear.Some nutraceuticalsareprescribedaslipidloweringsubstances,butdoubtsremainabouttheir efficacyandtolerability.Thisstudyaimedtoinvestigatetheefficacyandthesafetyofa nutraceuticalcombinationconsistingmainlyofredyeastriceextract200mg(equivalentto 3mgmonacolins),berberine500mgandpolicosanols10mg(MBPNC)inlowmoderaterisk hypercholesterolemicpatients. Methods:Inthissinglecentre,randomized,doubleblind,placebocontrolledstudy60 consecutiveoutpatients(29malesand31females;agerange:1860years),withnewly diagnosedprimaryhypercholesterolemianotpreviouslytreated,afteraruninperiodof3 weeksonastablehypolipidicdiet,wererandomizedtoreceiveapillofMBPNC(N=30)or placebo(N=30)onceadayafterdinner,inadditiontothehypolipidicdiet.Theefficacyand thetolerabilityoftheproposednutraceuticaltreatmentwerefullyassessedafter4,12and 24weeksoftreatment. Results:IntheMBPNCgroupbothTotalCholesterol(TC)andLDLCholesterol(LDLC) alreadyshowedasignificantreductionatweek4(30.3±33.9%and29.4±35.3%, respectively)whichremainedsubstantiallyunchangedatweek12(26.7±33.1%and 25.6±31.5%,respectively)andatweek24(24.6±32.1%and23.7±32.6%,respectively).The betweengroupsdifferencesweresignificantatalltimepointsforbothTCandLDLC.There werenosignificantchangesinHDLC,fastingglucoseandtriglyceridesserumlevelsineither group.MBPNCnutraceuticalcombinationwasalsosafeandwelltolerated.
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Conclusions:InlowtomoderateriskhypercholesterolemicpatientstheMBPNC nutraceuticalcombinationinassociationwithahypolipidicdiet,significantlyreducesTCand LDLCandmayfavorthereachingtherecommendedcholesteroltargets. RegisteredinClinicalTrials.govIdentifier:NCT02078167
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Introduction Manyepidemiologicalstudieshaveshownthatserumcholesterollevelsarestronglyrelated tocardiovascularrisk[1,2].Consequentlyloweringcholesterollevelsisafundamental prognosticgoalintheprimaryandsecondarypreventionofcardiovascularevents.The3 hydroxy3methylglutarylcoenzimeA(HMGCoA)reductaseinhibitors,commonlyknownas “statins”arethedrugsoffirstchoicetolowerserumcholesterol,especiallyinpatientsat highorveryhighriskofcardiovasculardiseases,inviewoftheirestablishedefficacyin reducingcardiovascularmortalityandmorbidityinbothprimaryandsecondaryprevention [3,4].Statinsaregenerallywelltoleratedandincontrolledtrialstheadverseeventswere similarinpatientstreatedwithstatinsandthosetreatedwithplacebo[4].However,in clinicalpractice,1015%ofpatientsresulttobeintoleranttoanystatins,evenatlowdaily dosesandalmostonethirdofstatinusersdiscontinuetherapywithinoneyear[5]. Furthermore,someotherpatients,especiallyinprimaryprevention,refusestatinsbecause ofthefearofpossiblesideeffects.Somenutraceuticalproductsmayrepresentan alternativetreatmenttobeconsideredfortheabovementionedcases,aboveallinpatients withmarginallyhighhypercholesterolemia[4,6].Sincetheuseoffulldosenutraceuticals entailssometolerabilityconcerns,acombinationofnutraceuticalswithdifferentbut synergicmechanismsofactionatlowerandsaferdosagescouldbepreferable.Inparticular, inrecentyearstherehasbeenagrowinginterestinanutraceuticalcombinationcontaining monakolin(thebiologicallyactivecomponentofredyeastrice),berberineandpolicosanols (MBPNC).ThecholesterolloweringeffectofMBPNCconsumedinconjunctionwitha standardMediterraneanhealthydiethasbeenobservedinalargeItalianstudycarriedout bygeneralpractitioners(GPs)[7],inpatientsintoleranttomorethanonestatin[8],in patientswithmetabolicsyndromeorwhoareoverweight[9,10]andinelderly 4
hypercholesterolemicsubjects[11].Moreover,MBPNCmixturehasbeenreportedtohave somedirectprotectivevasculareffects,similartopharmacologicallipidloweringagents, suchasimprovementinendothelialdysfunction[12]andimprovementinaorticstiffness [13].Anotherrecentstudyhasreportedthata2monthtreatmentwithMBPNCimproved insulinsensitivityinpatientswithmetabolicsyndrome[14]. However,hithertothecholesterolloweringeffectofMBPNChasnotbeenevaluatedinlong termdoubleblindplacebocontrolledstudies.Theaimofthissinglecentre,randomized, doubleblind,placebocontrolledstudywastoevaluatetheefficacyandthesafetyofa24 weektreatmentwithMBPNCmixtureinlowmoderateriskhypercholesterolemicpatients.
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MaterialsandMethods Population Acohortof66consecutiveoutpatientswithnewlydiagnosedprimaryhypercholesterolemia notpreviouslytreatedwhoappliedtotheLipidClinicoftheDepartmentofInternal MedicineattheUniversityofSiena(Italy),wereconsideredforenrolmentinthisstudy.The inclusioncriteriawere(1)agebetween18and60years,(2)bodymassindex(BMI)between 18,5ad29,9Kg/m2,(3)serumlowdensitylipoproteincholesterol(LDLC)above150mg/dL andanestimated10yearcardiovascularrisk40g/day,(4)estimated10yearcardiovascularrisk>20% accordingtoFraminghamriskscoring,(5)musculardiseasesorabnormallyelevatedcreatine phosphokinase(CPK)levelsordrugtreatmentwithantiplatelet,antiinflammatory, hypolipidemicagentsorhormonereplacementtherapy,eitherongoingoranytimeinthe previous2months.Instead,thepatientsonstableantihypertensivetreatmentforatleast3 monthswereincluded.Allthepatientswereinstructedtomaintaintheirhabitualphysical activityduringthestudyperiod. Atthescreeningvisit,allpatientswereinstructedtofollowahypolipidicdiet(low cholesterol/lowsaturatedfatdietapproximatelyconsistingof55%carbohydrates,20% proteins,and25%lipids)duringaruninperiodof3weeks,afterwhichallpatientswhomet theinclusioncriteria(29malesand31females),wererandomizedtoreceiveapillofMBP NC(N=30)orplacebo(N=30)onceadayafterdinner,inadditiontothehypolipidicdiet.The placebopills,identicalintasteandappearancetotheMBPNCpills,consistedofinactive compound.RandomisationandblindingwereprovidedbyRottapharmMadausS.p.A 6
(Monza,Italy).Thecompositionofthepatentedproprietarycombinationofnutraceuticals investigatedwasasfollows:redyeastriceextract200mg(equivalentto3mgmonacolins), berberine500mg,policosanol10mg,folicacid0.2mg,coenzymeQ102mgandasthaxantin 0.5mg(ArmolipidPlus,RottapharmMadausS.p.A,Italy). ThestudywasconductedinaccordancewiththeguidelinesoftheDeclarationofHelsinki,as revisedin2000and2008,andthestudyprotocolwasapprovedbytheEthicsCommitteeof theUniversityHospitalofSiena.Writteninformedconsentwasobtainedfromeachpatient. Clinicalandanthropometricevaluation Allpatientsunderwentphysicalexaminationatbaselineandafter4,12,and24weeksof treatment.AllthedeterminationsweremadeattheLipidClinicat09.00AM,afteran overnightfastof12h.Heightandweightweremeasuredtothenearest0.1cmand0.1Kg, respectively.BMIwascalculatedasweightinkilogramsdividedbyheightsquaredinmeters. Brachialbloodpressurewasmeasuredbyaphysicianwithamercurysphygmomanometer afterpatienthadbeenseatedforatleast10minandtheaverageof3measurementswas consideredfortheanalysis.Waistcircumferencewasalsomeasuredateachvisitmidway betweenthelowestribandtheiliaccrestusingananthropometrictape. Inallpatients,bodycomposition[fatmass(FM)percentage,fatfreemass(FFM)andfatfree mass/fatmassratio(FFM/FM)]wasassessedbyanthropometryandbioelectricalimpedance analysis(BIA)usingasinglefrequency50kHzbioelectricalimpedanceanalyzer(BIA101 RJL,AkernBioresearch,Florence,Italy).AllBIAmeasurementswerecarriedoutbythesame operatoraccordingtothestandardtetrapolartechnique,withpatientsinasupineposition foratleast20min.Theelectrodeswereplacedonthedorsalsurfaceoftherightfootand ankleand therightwristandhand. 7
Biochemicalmeasurements Inallpatientsfastingvenousbloodsamplesweredrawnatbaselineandafter4,12and24 weeksinordertoassessserumlevelsoftotalcholesterol(TC),triglycerides(TG),high densitylipoproteincholesterol(HDLC)andlowdensitylipoproteincholesterol(LDLC).All lipidparameters(TC,TG,HDLCandLDLC)weremeasuredusingacolorimetricmethod (AutoanalyzerMenarini,Florence,Italy).Inourinstitutiontheintraandinterassay coefficientsofvariationwere,respectively,1.8%and3.8%forTC,2.0%and3.0%forHDLC, 1.7%and2.9%forTG,and1.5%and2.3%forLDLCassessment.Inordertomonitorthe safetyoftheMBPNCinallpatients,atthesametimepoints,serumlevelsofglucose,uric acid,CPKw,gammaglutamiltranferase( GT)andtransaminaseswerealsoassessed. Tolerabilitywasmonitoredbyrecordingsymptoms.Medicationcompliancewasassessedby countingthenumberofpillsreturnedattheclinicvisits. Statisticalanalysis Allvalueswereexpressedasmean±SD.Clinicaldataandinitialvaluesofthevariables measuredinthestudygroupswerecomparedusingStudent’sttestforunpaireddata.The KolmogorovSmirnovtestwasusedtoverifythenormalityofthedistributionoftheoutcome variables.Forallparameterstheabsolutechangesovertimeforeachpatientwere expressedasapercentageofthebaselinevalues.PairedttestandWilcoxonmatchedpairs signedrankstestwereused,whereappropriate,tocomparethechangeswithbaseline values.Twowaysanalysisofvarianceforrepeatedmeasureswasusedtocomparethe responseofthestudyvariablestothetwodifferenttreatments.Alltestsweredonetwo sided,andp
