Consensus statement on management ofdyslipidemia in Indian subjectsK. Sarat Chandraa, Manish Bansalb, Tiny Nairc, S.S. Iyengard,Rajeev Guptae, Subhash C. Manchandaf, P.P. Mohanang,V. Dayasagar Raoh, C.N. Manjunathi, J.P.S. Sawhneyj, Nakul Sinhak,A.K. Pancholial, Sundeep Mishram, Ravi R. Kasliwaln,Saumitra Kumaro,p,q, Unni Krishnanr, Sanjay Kalras, Anoop Misrat,Usha Shrivastavau, Seema Gulativ,waEditor, Indian Heart Journal, Sr. Cardiologist, Indo US Superspeciality Hospital, Ameerpet,Hyderabad 500016, IndiabSenior Consultant e Cardiology, Medanta e The Medicity, Sector 38, Gurgaon, Haryana 122001, IndiacHead, Department of Cardiology, PRS Hospital, Trivandrum, Akashdeep, TC 17/881, Poojapura, Trivandrum,Kerala 695012, IndiadSr. Consultant & HOD, Manipal Hospital, 133, JalaVayu Towers, NGEF Layout, Indira Nagar,Bangalore 560038, IndiaeHead of Medicine and Director Research, Fortis Escorts Hospital, JLN Marg, Malviya Nagar, Jaipur 302017, IndiafSr. Cardiologist, Sir Ganga Ram Hospital, New Delhi, IndiagWestfort H. Hospital, Poonkunnanm, Thrissur 680002, IndiahSr. Cardiologist, Krishna Institute of Medical Science, Minister Road, Secunderabad, IndiaiDirector, Prof & HOD, Sri Jayadeva Institute of Cardiovascular Sciences & Research, Bannerghatta Road, Bangalore560 069, IndiajMD DM FACC, Chairman Department of Cardiology, Sir Ganga Ram Hospital, New Delhi, IndiakSr. Consultant & Chief Interventional Cardiologist, Sahara India Medical Institute, VirajKhand, Gomti Nagar,Lucknow, Uttar Pradesh 226010, IndialHead, Department of Clinical and Preventive Cardiology and Research Centre Arihant Hospital, Indore, MP, IndiamProf. of Cardiology, All India Institute of Medical Sciences, New Delhi 110029, IndianChairman, Clinical and Preventive Cardiology, Medanta e The Medicity, Sector 38, Gurgaon, Haryana 122001, IndiaoProfessor, Vivekanada Institute of Medical Sciences, Kolkata, IndiapChief Co-ordinator, Academic Services (Cardiology), Narayana Hrudayalay, RTIICS, Kolkata, IndiaqConsultant Cardiologist, Fortis Hospital, Kolkata, IndiarChief Endocrinologist & CEO, Chellaram Diabetes Institute, Pune 411021, IndiasConsultant Endocrinology, Bharti Hospital& BRIDE, Karnal, Haryana, IndiatChairman, Fortis-C-DOC Centre of Excellence for Diabetes, Metabolic Diseases and Endocrinology, Chirag Enclave,New Delhi, IndiauHead, Public Health, National Diabetes, Obesity and Cholesterol Foundation (N-DOC), Diabetes Foundation (India),New Delhi, IndiavHead, Nutrition Research Group, Center for Nutrition & Metabolic Research (C-NET) & National Diabetes, Obesityand Cholesterol Foundation (N-DOC), New Delhi, IndiawChief Project Ofcer, Diabetes Foundation (India), C-6/57, Safdarjung Development Area, New Delhi 110 016, IndiaAvailable online at www.sciencedirect.comScienceDirectj ournal homepage: www. el sevi er. com/ l ocat e/ i hji nd i a nhe a r tj o ur na l 6 6( 2 0 1 4 ) S 1 eS 5 1http://dx.doi.org/10.1016/j.ihj.2014.12.0010019-4832/Copyright 2014, Cardiological Societyof India. All rights reserved.1. The need for India specic guidelines forlipidsCardiovascular disease(CVD) isthesinglelargest causeofdeathinthedevelopedcountriesandisamongtheleadingcausesof deathanddisabilityinthedevelopingnationsaswell. Thereareanestimated31.8millionpeoplelivingwithcoronary artery disease (CAD) in India alone.1Furthermore, incontrast todevelopedcountries, CVDtends tooccur at ayounger ageinIndianswith52%of CVDdeathsoccurringunder 70 years and 10% of heart attacks occurring in subjects 3times the ULN occurred in 5.3% of pa-tients taking fenobrate compared to 1.1% on placebo. Hence,liverenzymes shouldbeperiodicallymonitoredduringther-apy and therapy to be discontinued if enzyme levels persist >3times the ULN.Thedosageof coumarinanticoagulantsmayneedtobeadjusted during brate therapy to prevent bleedingcomplications.2204.3.2.6. Clinical evidence. Anumberoftrialshaveevaluatedbrates, either alone or in combination with statin therapy. Inthe FIELDtrial, 9795 diabetics who were not on any statin wererandomized to receive fenobrate or a placebo. After anaveragefollow-upof 5years, nosignicant differencewasseenbetweenthetwogroupsinthecompositeendpointofCHDdeathandnonfatal MI. However, fenobratetherapyresultedinsignicantlylowerriskofnon-fatalMIandcoro-naryrevascularization.221Similarly, intheACCORDtrial, inwhich fenobrate was added on top of open label simvastatin,nooverall benetwasseenwithfenobrateinreducingthecombinedprimaryendpoint of rst nonfatal MI, nonfatalstroke and CHDdeathor individual components, despitereduction of triglycerides and increase in HDL-C.134However,asubgroupanalysisinvolvingpatientswithTGmore than 204 mg/dl and HDL-C 300 mg/dl or those who have type IIIhyperlipoproteinemia.Cholestyramineandcolestipol arepregnancycategoryCdrugs. Their use during pregnancy or lactation, or by womenof childbearing age requires that potential benet be weighedagainst hazard to fetus.Colesevelam is a pregnancy category B drug and should beusedduringpregnancyonlyif clearlyneeded. It isnot ex-pected to be excreted in human milk because it is not absor-bed systemically from the GI tract.4.3.3.6. Adverseeffects. BASmayproducegastro-intestinal(GI) side effects like constipation, dyspepsia and atu-lence. Tominimize GI slide effects withBAS, lowinitialdoses are to be started. For constipation, increased uid anddietaryber intakearerecommendedandstool softenersmay be added as needed. Less frequent adverse effectsinclude abdominal discomfort and/or pain, atulence,nauseaandvomiting. BASs arenot recommendedinpa-tients with gastroparesis, other gastro-intestinal motilitydisorders, those who have had major gastrointestinalmotility tractsurgery, patients who may be at risk ofbowelobstructionandthosewithcompletebiliarytract obstruc-tion. Becauseofthetabletsize, colesevelamandcolestipolshouldbeusedwithcautioninpatientswithdysphagiaorswallowingdisorders, sincetheymaycausedysphagiaoresophagealobstruction.BASs can increase triglycerides. For example, colesevelammayincreasetriglyceridesby5%inpatientswithprimaryhyperlipidemiawhereasmedianincreasesintriglyceridesof18e22%havebeenreportedinclinical studiestreatingpa-tients with type 2 diabetes mellitus. Chronic use of BAS maybe associated with increased bleeding tendency due to hypo-prothrombinemia and vitamin K deciency.BAS may decrease absorption of fat-soluble vitamins.Patients on vitamin therapy should take vitamins at least 4 hbeforetheBAS. If apatient istakingothermedicationsinadditiontocholestyramineorcolestipol, theothermedica-tionsshouldbetaken1hbeforeor4haftertheBAS.Cole-sevelam is a more specic BAS, but may reduce GI absorptionof some drugs. Drugs with a known interaction that should betakenat least 4hprior toacolesevelamdoseare: cyclo-sporine, glyburide, levothyroxine, oral contraceptives andphenytoin.4.3.3.7. Clinical evidence (Table 13). The most signicantoutcome trial was the Lipid ResearchClinics Coronary PrimaryPrevention Trial (LRC-CPPT), which demonstrated a 19%decrease in the risk of combined CHDdeath and nonfatal MI inmen with elevated cholesterol treated with 24 g/day ofcholestyramine.226Incombinationtrials, theadditionof colesevelamtoastatinresultedinanadditional 10e16%reductioninLDL-C.However, the effect of colesevelamonCVmorbidity andmortality has not been determined.4.3.3.8. When to use. If treatment witha statindoes notachieve the LDL-C goal selected for a patient, intensication ofLDL-CloweringdrugtherapywithaBASisreasonable. Inaddition, BAS provides an alternative to statins as initial drugtherapyfor LDL-Clowering. The combinationof BASandezetimibe can have additive effects on LDL-C lowering, and isusefulforpatientswhodonottolerateastatinorforwhomstatins are contraindicated.225Anadvantageofthestatin-BAScombinationisthatheremay be a reduction in blood glucose in diabetic patients.Table 12 e Currently available bile acid sequestrants for clinical use.Bile acidsequestrantInitial dosage Maintenance dosage LDL-C reduction CommentsCholestyramineresin8 g/day individed doses16e24 g/day as monotherapy;lower doses if used with statinsVaries from 8.7% to 28%depending on dosage of resinTake other drugs 1 h before or3 h after, psylium augmentsactionColestipol resin 10 g/day individed doses16e24 g/day as monotherapy;lower doses if used with statinsSimilar to cholestyramine,varies with dosage of resinTake other drugs 1 h before or3 h after, psylium augmentsactionColesevelam Two or three625 mg tabs twicedaily (7 tabs/day max)19% (with 3.8 g/day dose) Take with a large glass ofwater, lowers HbA1C in type2 diabetesi nd i a nhe a r tj o ur na l 6 6( 2 0 1 4 ) S 1 eS 5 1 S254.3.4. NiacinNiacinreducesLDL-C,VLDL-C,TG,Lp(a)andincreasesHDL-C.232,233Itsprimaryeffect is todown-regulatelipolysis andproduction of free fatty acids. This leads to a reduction in theamount of free fatty acids released fromthe adipocyte that areavailable to the liver for TG and VLDL production. Decreasedlevels of VLDL leadtodiminishedhepatic andperipheralproduction of IDL and LDL. At the same time, niacin increasesapo-A1bydecreasingitscellularuptakeresultinginHDL-Cincrease.232,234,235Althoughniacinisamongstthemosteffectiveagentstoraise HDL-C, results of recent largetrials have shownnobenet, andevenharm, withadditionof niacintostatintherapyalone.236,237In addition, niacin has several side effects.Asaresult, niaciniscurrentlynotrecommendedfortreat-ment of any form of dyslipidemia.4.3.5. Omega-3-fatty acidsTheomega-3fattyacids(OFA) includethemarine-derivedlong-chain fatty acids eicosapentaenoic acid (EPA) and doco-sahexaenoicacid(DHA).Theylowertriglyceridesinpatientswith severe hypertriglyceridemia. OFA is available as an 1 gmliquid-lled gel capsule containing at least 900 mg ethyl estersof OFA derived from sh oils (465 mg EPA and 375 mg DHA).4.3.5.1. Mechanismofaction. OFAinterferewithmanytran-scription factors and lower triglycerides.4.3.5.2. Pharmacology. OFA is manufactured by trans-esterication of sh oil. After intestinal absorption andbreakdownof theethyl esters, theresultingEPAandDHAenter the circulation.4.3.5.3. Indications. ForpatientswithmixedhyperlipidemiawhoattainLDLgoalwithstatins,OFAsupplementationisareasonabletherapeuticoptionasanalternativetobratetoachieve non-HDL target goals.For patients withveryhightriglyceride levels >500 mg/dl, theinitial therapeutic goal is to lower triglyceride levels to preventpancreatitis, and OFAs are indicated as an adjunct to diet.4.3.5.4. Dosage. Daily dose of OFA of 4 g/day is recommendedfor severe hypertriglyceridemia. The daily dose may be takenas a single 4 g dose or as two 2 g doses. The capsule should beswallowedwholeandnot brokenopenor chewed. Lowerdoses (1e2 gm/d) may be sufcient for less severehypertriglyceridemia.4.3.5.5. Contraindications.People with sea sh allergy shouldbe careful with OFA.PrescriptionOFAs are pregnancycategory Cdrugs andshould be used during pregnancy only if the potential benetto the patient justies the potential risk to the fetus. It is notknown whether OFAs are excreted in human milk, andthereforecautionshouldbeexercisedwhenadministeringOFAs to a nursing woman.4.3.5.6. Adverse effects. Dyspepsia, and/or tasteperversionhavebeenreportedin3e4%of patientsinclinical studies.SomestudieshavedemonstratedaprolongationofbleedingTable13eClinicaltrialevidencedemonstratingefcacyofbileacidsequestrants.TrialPopulationDrugLDL-CreductionEfcacyinpreventionofCHDLRCCPPT2263806men,noCHDCholestyramine16e24g/day20.3%19%reductioninfatalandnonfatalMInotedat7.4yearsSTARS22790men,CHDCholestyramine16g/day35.7%Improvementseenonangiographyat2yearsNHLBItype2trial228116menandwomen,CHDCholestyramine16g/dayaverage26%Reducedprogression,at5years,oflesionscausing>50%stenosisatbaselineCLAS229162men,CHDColestipol30g/daynicotinicacid4.3g/day43%Patientstreatedhadsignicantlymoreatherosclerosisregressiononangiographyat2yearsFH-SCOR23072menandwomen,familialhypercholesterolemiaColestipol,nicotinicacidandlovastatin39%AngiographicchangecorrelatedwithchangeinLDL-Cat2yearsFATS231120men,CHDColestipol30g/dayandeitherlovastatin20mgbidornicotinicacid4g/day46%(lovastatin),36%(nicotinicacid)NicotinicacidgrouphadhigherHDL-Cthanlovastatingroup,signicantangiographicandclinicalimprovementseenat2.5years*Nodosageavailable.CHD-coronaryheartdisease;CLAS-CholesterolLoweringAtherosclerosisStudy;HDL-C-highdensitylipoproteincholesterol;LDL-C-lowdensitylipoproteincholesterol;LRCCPT-LipidResearchClinicsCoronaryPrimaryPrevention;MI-myocardialinfarction;STARS-ST-ThomasAtherosclerosisRegressionStudy.i nd i a nhe a r tj o ur na l 6 6( 2 0 1 4 ) S 1 eS 5 1 S26time, but the times reported have not exceeded normal limitsand did not produce clinically signicant bleeding episodes.4.3.5.7. Clinical evidence. In patients with severe hyper-triglyceridemia(levels>500mg/dl), 4gprescriptionofOFAdecreased triglyceridesby45%and increased HDLby9>%.Inpatients treated with simvastatin 40 mg/day and havingpersistently elevated triglycerides in the range of 200e499 mg/dl, the addition of 4 g prescription OFA resulted in reductionsin triglyceride levels by 23% and increases in HDL of 4.6%andLDL of 3.5%.Japan EPA Lipid Intervention Study (JELIS), compared a lowdose statin plus either EPA (1.8 g) or placebo. Subgroup anal-ysis of primary prevention patients with baseline triglyceridelevels>150 mg/dl and HDL 90%) bound to plasma proteins. It is neitheran inhibitor nor an inducer of the CYP P450 isoenzymes.4.3.6.3. Dosage. The recommended dose of ezetimibe is 10 mgonce a day. Concomitant food administration has no effect onabsorption, and ezetimibe can be administered with orwithout food. No dosage adjustment is necessary in patientswith mild hepatic or renal impairment.4.3.6.4. Contraindications. EzetimibeisapregnancycategoryCdrugs.Therearenoadequate,wellecontrolledstudiesofezetimibe in pregnant women.4.3.6.5. Adverse effects. Ezetimibe monotherapy does notcausesignicant elevations of hepatictransaminases. Theincidence of increased transaminases is marginally higher inpatients receiving ezetimibe incombinationwitha statin(1.3%) compared to patients treated with a statin alone (0.4%).Whenusedwithastatin,liverfunctiontestsshouldbeper-formedattheinitiationoftherapyandsubsequentlyasrec-ommended for statins.2394.3.6.6. Clinical evidence. As monotherapy, ezetimibe pro-ducesLDL-Creductionsof15e25%butthereisacompensa-tory increase in cholesterol synthesis. Combining it withstatinsresultsingreaterdecreaseinLDL-C,ascomparedtoezetimibe monotherapy. The advantage of the combination isthe low incidence of side effects, but the disadvantage is thelack of clinical outcome data for ezetimibe.225In the Ezetimibe and Simvastatin in HypercholesterolemiaEnhances Atherosclerosis Regression(ENHANCE) trial, theadditionofezetimibetostatintherapydidnotsignicantlychange CIMTcomparedto statinmonotherapy, despite a>50 mg/dl lowering of LDL in the combination therapygroup.2414.3.6.7. When to use. If treatment with a maximally tolerateddose of statin does not achievethe LDL-C goal selected for apatient(ofteninthosewithprimaryhyperlipidemia), inten-sication of LDL lowering drug therapy with ezetimibe may beconsidered. Itisalsoindicatedforuseincombinationwithstatin and fenobrate for the reduction of elevated LDL-C andnon-HDL-C in patients with mixed hyperlipidemia.5. The 2013 ACC/AHA guidelines on lipidmanagement and their relevance to the presentdocumentThe ACC and AHA, in collaboration with the National Heart,Lung andBloodInstitute (NHLBI), have recently releasednewguidelinesforthemanagementofbloodcholesterolinadults.133Theseguidelinesservetoupdatethepreviouslyavailabledocumentforthispurpose, theNCEPATPIIIrec-ommendations.67However,unlikeallthecurrentlyexistingguidelinesonlipidmanagement, includingthosefromtheEuropeanSociety of Cardiology68andthe AmericanDia-betes Association,242thenewdocument proposes acom-plete paradigm shift in the approach towards lipidmanagement and, therefore, has become a subject ofintense controversy. The fundamental reasonunderlyingthisdeparturefromtheconventionalprinciplesisthatthecurrentdocumentispurposefullybasedpredominantlyondata derived fromrandomized controlled trials (RCTs),systematicreviewsandmeta-analysesofRCTs. Theexpertcommittee identied a few critical questions and addressedthem based on such available data, while choosing to makeno recommendation, except in fewcircumstances, if arelevantRCTormeta-analysiswasnotavailabletoanswera particular critical question. As a result,the document hasbecome vastly different and less encompassing than itsprevious iterations. Giventhe far-reaching recommenda-tionsmadeinthenewguidelines, acareful reviewof thesameisrequiredtodeterminetheirrelevancetotheIndianpopulations.i nd i a nhe a r tj o ur na l 6 6( 2 0 1 4 ) S 1 eS 5 1 S275.1. Key features of the new lipid guidelinesFollowing are the key recommendations of the new ACC/AHAlipid guidelines:1. The expert panel found no evidence to support the use ofspecic LDLeC or non-HDLeC targets for either primary orsecondarypreventionofCVDandthereforehasnotrec-ommended any specic lipid targets.2. Four major statin benet groups were identied for whomat least moderate to high-intensity statintherapy wasstrongly recommended-a. Those with clinically manifest atherosclerotic CVD,b. Those with primary elevations of LDLeC >190 mg/dl,c. Diabeticsaged40e75yearswithLDLeC70e189mg/dland without clinical CVD, ord. ThosewithoutclinicallymanifestatheroscleroticCVDor diabetes with LDLeC 70e189 mg/dl and estimated 10-year CVD risk >7.5%.While high-intensity therapy is recommended for the rst3 groups, moderate-to high-intensity statin therapy isconsidered appropriate for the fourth group.3. Regularuseofnon-statinlipid-loweringdrugsisdiscour-aged, placingmajoremphasisonusingappropriatedosestatin therapy only.4. The expert panel made no recommendations regarding theinitiationor discontinuationof statins inpatients withfunctionalclassIIeIVischemic systolic heart failure orinpatients on maintenance hemodialysis.5.2. Relevance to Indian populations5.2.1. Statin doseThenewguidelinesrecommendusinghigh-intensitystatintherapy, andifnot possiblethen atleastmoderate-intensitytherapy,inallthehighriskgroupsidentied.High-intensitystatintherapyis denedas the onethat results in50%reduction in LDL-C frombaseline whereas moderate-intensityistheonethatlowersLDL-Cby30e50%. Theserecommen-dations are based on the fact that the large-scale RCTsshowingbenetwithstatintherapyhadusedthesedosagesonly and had resulted in this much reduction in LDL-C.133It is well knownthat Asians respondmorestronglytostatinsascomparedtotheir westerncounterparts. AmongAsians,atorvastatin10e20mg/dandrosuvastatin5e10mg/d have been shown to result in as much as 40e50% reductionintheLDL-C.243e247IntheIRISstudy(InvestigationofRosu-vastatin In South Asians), the largest statin efcacy trial in anexclusivelySouth-Asianpopulation, 740patientsinUSandCanada received 6 weeks of treatment with rosuvastatin 10 or20 mg/d and atorvastatin 10 or 20 mg/d. Nearly 40%, 47% and45%reductioninLDL-Cwasseenwithatorvastatin10mg,20mgandrosuvastatin10mg/ddose, respectively.247It isbelieved that lower body mass index and slower statinmetabolismarethepossiblereasonsunderlyingheightenedstatin response in Asians.243,248e250Unfortunately,nolarge-scalestudyhasyetcomparedCVevent reductionwithregular doseversus high-dosestatintherapy exclusively in Asian populations. However, it isnoteworthythatinmostofthelarges-scalestatintrials,theobservedbenet onCVriskreductionwasdirectlypropor-tional to the reduction in LDL-C,251suggesting that it may bepossibleto achieve a similar degree of CV event reduction withlower dosages of statins in Asian populations. Indeed, in theMEGA(Management of ElevatedCholesterol inthePrimaryPreventionGroupofAdultJapanese) trial enrolling7832in-dividuals, 10e20mgpravastatineverydayresultedin33%reduction in CHD events as compared to diet alone.252Exaggerated statin response in Asians also raises concernsof increased risk of adverse effects. Although no causal rela-tionshiphasbeenestablished, somestudieshavereportedincreasedriskofhemorrhagicstrokesandcancersinAsianpatients achieving very low serum cholesterol levels.253e257Incontrast, a recent 12-week study in Indian patients presentingwith ACS has demonstrated good safety and tolerability pro-leof intensivestatintherapy.258However, thisstudywassmall and had only a short follow-up. In addition, apart fromthe risk of side effects, high dose statin therapy is also asso-ciatedwithincreasedcost, whichisanimportantconsider-ationinIndianpatientswithlimitednancial affordability.Giventheseobservations, it remainsdebatabletoroutinelyrecommendhighdosestatintherapyforIndianpatientsinwhomthe desiredLDL-Creductioncanbe achievedwithmuchlowerdosages.Amoreprudentapproachwouldbetostarttreatmentwithcommonlyuseddosagesandthenup-titratethedoseifthedesiredmagnitudeofLDL-Creductionis not achieved.5.2.2. LDL-C targetsWhile setting aside xed LDL-C targets, the current guidelinesassume that moderate or high-intensity statin therapy, onceinitiated,willresultinatleast30e50%or >50%reductioninLDL-C, respectively. However, it is well known that individualresponses and tolerability to statin therapy vary considerably,translatingintovariablemagnitudeofLDL-CreductionwithvariabledegreeofCVriskreduction. Apatienthavingsub-optimal response to a particular statin dose is likely tobenet from further intensication of life-style measures, anincrementinthestatindoseand/orchangeofstatinprepa-rationto achieve adequate LDL-Creduction. However, inabsence of a reference value, it becomes difcult to determinewhetheraparticularpatient hasachievedadesiredfall inLDL-Cornot,particularlyifthebaselinelipidvaluesarenotavailable. These issues are especially relevant for Asian pop-ulations in whom lower statin doses are used very frequentlyandbaselinelipidlevelsareoftendifculttotrace.Further-more, successful achievement of LDL-C goal provides the pa-tient with a sense of accomplishment, boosts his/her moraleand motivates him/her further to continue with the treatmentregimen. At the same time, persistently elevated LDL-C abovethegoal canhelpimprovepatientcompliancetothetreat-ment, particularly the adherence to life-style measures.Considering these issues, the present consensus documentadvocates usingahybridapproach. FixedLDL-Cgoals aredened to provide the treating physicians with a perspectiveon the anticipated CV risk in a given individual and to deter-mine the aggressiveness of therapy. At the same time, amongthosehigh-riskpatients whoalreadyhavebaselineLDL-Ci nd i a nhe a r tj o ur na l 6 6( 2 0 1 4 ) S 1 eS 5 1 S28valuesclosetothetargetlevels,itisstronglyrecommendedthat adequate dose statin therapy be prescribed to achieve atleast 40e50% further reduction inLDL-C. This is alsoconsis-tent withthe recent AmericanDiabetes Associationstatementthat continues to recommend xed LDL-C targets for diabeticindividuals.2595.2.3. Non-statin drugsStatinshavethemostprofoundeffectonLDL-C,whilealsoloweringTGtoalesser extent andraisingHDL-C. Asdis-cussedintheprevioussections, of all theavailablelipid-loweringagents,statinsareknowntobethemosteffectiveinreducingCVrisk. However, it isalsobeingincreasinglyrecognized now that persistently elevated non-HDL-C in pa-tients whohaveachievedadequateLDL-CreductionwithstatinsisassociatedwithincreasedCVrisk.74,260Loweringnon-HDL-C in such patients can potentially lead to further CVrisk reduction. As brates have potent action on triglycerides(and therefore non-HDL-C), they have been evaluated for thispurpose. Two large trials-the FIELD and the ACCORD-studiedfenobrate, the most commonly used brate in clinicalpractice, indiabeticpatients.134,221Whilemost patientsinthe FIELD trial were not on any statin, in the ACCORD study,fenobratewasaddedontopofsimvastatin. Inboththesetrials, fenobrate did not result in any signicant reduction intheprimaryend-pointintheoverallstudypopulations,butthosewithatherogenicdyslipidemia(increasedTGandlowHDL-C)derivedsignicantbenet.134,222Furthermore,feno-brate also reduced the risk of microvascular complicationsof diabetes.221Other large brate trials have also shownsimilar CV risk reduction in patients with atherogenic dysli-pidemia.135Theseobservationsrenderfenobrateausefulagent for lipid management in Indians in whom atherogenicdyslipidemiaiswidelyprevalent. Consideringthis, thepre-sent consensus committee advocates useof fenobrateinpatientswhocontinuetohaveelevatednon-HDL-Cdespiteadequate dose of statin therapy and intensive life-stylemeasures. However, at the same time, it must be re-emphasized that treatment with any non-statin lipidlowering agent should not be happen at the cost of adequatestatin therapy.6. Special situations6.1. Diabetes mellitus6.1.1. Type 2 diabetesType2diabetesisacommonco-morbidconditionencoun-tered in the lipidology clinic. It is a major risk factor for CVDandincreasestheriskofCVDbyvetimesinwomen, andthree fold in men. It has been demonstrated that people withdiabetes and no history of MI have a CV risk nearly equivalenttothosewithoutdiabetesandahistoryofMI.67Themecha-nisms postulatedto cause rapiddevelopment of vasculardisease in diabetes include hyperglycemia, hypertension, lowHDL-C, hightriglyceride levels, elevatedsmall-dense LDL,increased pro-coagulant activity and a pro-inammatorymilieu.261Itstandstoreason, therefore, thatlipidmanage-ment is an essential part of diabetes care.6.1.1.1. Screening and investigations. As mentionedabove,peoplewithdiabetesareclassiedashighriskpatientsforvascular events. Hence, irrespective of the presence orabsence of other risk factors on history (age, gender, smoking,hypertension, family history) or physical examination(obesity, hypertension, polycystic ovary syndrome in woman),they should be screened for dyslipidemia.Afastinglipidproleshouldbeperformedannually.TheminimuminvestigationsshouldincludeTC, LDL-C, TG, andHDL-C. Non-HDL-Cshouldberoutinelycalculatedinthesepatients given the higher prevalence of elevated triglyceridesand small-dense LDL among diabetics. In addition, estimationofApo-Blevelsisalsodesirableinthesepatients. However,routine assessment of these markers is not mandatory.6.1.1.2. Goalsoftherapy. As allpatients withtype2diabeteswith evidence of target organ damage or other CV risk factorsandthosewithtype1diabeteswithmicroalbuminuriaareautomatically designatedtohighriskcategory,they requiremanagement whichis similar tothat for secondary preven-tionof CVD.67,68Inotherpatients, formal riskassessmentmay be needed. The treatment approach is broadly same asthat for any high risk individual without diabetes, asdescribed in the previous sections. The primary target is LDL-C, while non HDL-C, HDL-C and apoB are secondary targets.68The present document reiterates the fact that these goals areglobal, i.e. forbothgendersandforall adults. However, inchildren and adolescents, the acceptable LDL-C level isrelaxed to 110 mg%.68,2616.1.1.3. Non-pharmacological therapy. Managementofdysli-pidemiaindiabetesissimilartothatinpeoplewithoutdia-betes. Non-pharmacological therapy viz physical activity,cessation of smoking, and healthy nutrition therapy areimportant aspects of therapyandshouldfollowthesameprinciplesasoutlinedintheprevioussections. However, itshould be noted that dietary fructose leads to hyper-triglyceridemiaifconsumedinexcessof10%oftotalenergyintake, in spite of its low glycemic index. Therefore, a carefuldietaryreviewfocusingonfructoseintakeisrequiredforallpersons with hypertriglyceridemia.6.1.1.4. Pharmacological therapy6.1.1.4.1. Statins.The choice of drug therapy is similar indyslipidemicpersonswithandwithout diabetes.261,262Thepresent guidelines strongly recommend statintherapy despitethefactthatcertainstudiesdocumentariseinincidenceofdiabetes withthese drugs. Meta-analysis has shownthatstatin use is linked to a higher (9%) risk of development of neweonsetdiabetes, especiallyinolderpersons. However, therisk:benet ratioofstatinsisstrongly tiltedinfavorofdruguse.263Although the choice of statin in diabetes is broadly similarto that in people without diabetes, there are some importantdifferences in the impact of different statins on the glycemiccontrol. Glucoseneutral effectshavebeenreportedforpra-vastatin. Simvastatin has been showto inhibit glucose-inducedinsulinsecretionthroughblockadeof L-typeCa2channels in b cells. Atorvastatin is thought to suppressglucose transporter GLUT4 expression in 3T3_L1 adipose cellsi nd i a nhe a r tj o ur na l 6 6( 2 0 1 4 ) S 1 eS 5 1 S29byblockingisoprenoidsynthesis. Cytotoxiceffectsonthebcell have also been reported for atorvastatin. Another postu-lated mechanismis through activation of SREBPs (SterolRegulatoryElement-BindingProteins). Pitavastatinusehasbeen reported to be devoid of the adverse effects on glycemiathat are reported with atorvastatin. Pitavastatin, in fact,demonstratedabenecial effectonHbA1cinsubjectswithdiabetes who were enrolled in the LIVES study.264Differencesinthemetabolicpathwaysforvariousstatinsmayexplainthesedifferentialeffectsonglycemiccontrol. Pitavastatinisminimally metabolized by the CYP3A4 isoenzyme, unlikeother statins, andthismayberesponsiblefor itsglucose-neutral character.The patients with diabetes often have multiple co-morbiditiesandarerecognizedtobeinapoly-medicatedstate. Therefore, lipidtherapyindiabeticsshouldhavelowriskofdrugedruginteractions. Whilemoststatinsaresafe,one shouldbe aware of potential drugedrug interactions.Antifungal agents such as itraconazole, commonly prescribedindiabetes,mayincreaseatorvastatinandsimvastatincon-centrationsbyinhibitingCYP3A4, whichmetabolizesthesestatins.6.1.1.4.2. Fibrates. Fenobrate is the most widely usedbrate compound, and is recommended for use as add-on tostatins.Additionof fenobrate tostatintherapy maybenetpatients with diabetes, hyperglyceridemia and lowHDL-C.134,221Gembrozil canalso be used inpatients withTG>200 mg% and HDL-C 440mg%)shouldbeadmittedifsymptom-atic, or at risk of developing acute pancreatitis, and started oninsulin therapy to achieve tight glycemic control.Althoughpioglitazonehasbeenshowntohavebenecialeffects on lipids,266there have been questions marks about itssafety, particularlytheriskof bladdercancer. Additionally,pioglitazoneisalsonot safeinpatientswithheart failure.Incretin-based therapy, including the glucagon-like peptide 1analogs (liraglutide, exenatide) and gliptins (vildagliptin,alogliptin, sitagliptin) alsoimprovederangedlipidlevelsinpatients with diabetes. This effect is likely mediated throughreduction in lipolysis and an improvement in the metabolismof postprandial intestinal triglyceride-rich lipoproteinparticles.2676.1.1.6. Specialsituationswithindiabetes.Statinsaresafetouseinnon-alcoholicsteatohepatitis,withmildtomoderateelevationofliverenzymes.Obeseindividualswithdiabetesanddyslipidemiashouldbetreatedinamannersimilartothosewithoutotherfeaturesofmetabolicsyndrome. Ator-vastatinhasbeenshowntohaverelativelylessbenet inobesepersonsintheREVERSAL(ReversalofAtherosclerosiswith Aggressive Lipid-Lowering Therapy) study268andCHIBAtrial.269Thelipophilicnatureof thedrugmaypro-mote drug redistribution in the adipose tissue, thus reducingits efcacy. Pitavastatinhas beenreportedtohavebetterresultsinobesepersons. Thiseffect maybeduetoanin-crease in lipoprotein lipase expression in 3T3-L1 pre-adipocytes, which is otherwise suppressed in insulinresistance.6.1.1.7. Monitoring. Inpersonswho experiencedeteriorationof diabetes control and/or considerable weight gain, frequentlipid estimations are advisable. Lipid prole can be checked at6 weekly intervals till goals are achieved. People with suddenworseningofglycemiaafterinitiationorescalationofstatintherapy may benet from temporary cessation of the offend-ingdrug, orsubstitutionwithanotherstatinmoleculewithdifferent metabolism.Liver enzymes should be assessed along with routine dia-betesmonitoring,especiallybeforeand3monthsafteriniti-ation of pharmacotherapy. Creatine Kinase should bemeasuredonlyinpatientswithmyalgia. Bileacidseques-trants(cholestyramine, colestipol, colesevelam) mayreduceblood glucose and increase TG, and careful monitoring shouldbe done in patients with diabetes.6.1.2. Pre diabetesAs theunderlyingpathophysiologyis similar, thepatientswithpre-diabetes(i.e. impairedfastingglucoseorimpairedglucosetolerance)areequallypronetodevelopCVD, asarethose withfrank diabetes. Hence, the treatment strategies andgoals of management are also the same.2616.1.3. Type1 diabetesPatientswithtype1diabetesdevelopatherosclerosisearlierthanothers, withamorerapidprogression, andexperiencehigher premature mortality due to vascular disease. This is inspite of the fact that they enjoy higher HDL-C levels and rarelyexhibit insulinresistance. Thisapparentlyhealthy prole,characteristic of type 1 diabetes, is explained by the action ofexogenous insulin therapy. Insulin increases lipoproteinlipaseactivityinskeletal muscleandadiposetissue, whichcatabolizesVLDL-C, andreducesTGandLDL-C. Thepara-doxical increase in CV mortality is due to atherogenic changesinthecompositionof HDLandLDLparticles.68Thefactorsassociatedwithincreasedrisk of CVDintype 1 diabetesinclude proteinuria, previous history of MI, high HbA1c>10.4%, prolonged duration of disease (>16years), presence ofmetabolic syndrome, and elevated high-sensitive CRP >3.0 mg% levels.67,68,190i nd i a nhe a r tj o ur na l 6 6( 2 0 1 4 ) S 1 eS 5 1 S306.1.3.1. Screening. Screeningfordyslipidemiashouldbecar-ried out from the age of 12 onwards, in fasting state, only afterstabilizingdiabetes.Ifthereisafamilyhistoryofhypercho-lesterolemia,earlyCVDorifthefamilyhistoryisunknown,screeningshouldstartattheageof2yearsitself. Ifnormalresultsareobtained, screeningshouldberepeatedevery5years, till adulthood, and yearly thereafter.2706.1.3.2. Goals. There is a controversy regarding goals for lipidlevelsinchildrenwithtype1diabetes. WhiletheAmericanAcademy of Paediatrics, and American Association of ClinicalEndocrinologists support softer LDL-C targets (normal130 mg/dl, borderline 110e130 mg/dl), theInternational Societyfor PediatricandAdolescent Diabetessuggests that the target for LDL-C should be 40yearswhohaveconcomi-tant diabetes (to keep the LDL-C levels below 100 mg/dl).i nd i a nhe a r tj o ur na l 6 6( 2 0 1 4 ) S 1 eS 5 1 S316.2.4.1. Weight reduction. Weight reductionis the centralpillar of management, both for metabolic syndromeitself andfor dyslipidemia. Weight reductionimprovesinsulinsensi-tivity, andfavorablyaffects lipidlevels. Maximal effect isobservedon TG(20e30%), with HDL-C (0.4mg% increaseperkgbodyweight lost) andLDL-C(0.8mg%fall perkgbodyweightloss)showinglesserbenet. Exercisepersehassig-nicant effects on HDL-C (3.1e6 mg% increase in HDL-C with1500e2200 kcal/week of aerobic exercise), but not on LDL-C.6.2.4.2. Pharmacological management of dyslipidemia. Thechoiceoftherapyfordyslipidemiaisbaseduponthetypeoflipid abnormality and not the presence or absence of variouscomponents of metabolicsyndrome. Thedosagesof lipid-lowering therapy also depend upon the extent of lipid-loweringrequired,notuponbodyweight,bloodpressure,orglycemia.Statinsdonot affect bodyweight andcanbeusedirre-spectiveofbodymassindex.Bileacidsequestrants,suchascolesevalam,improveglycemiaandareapprovedforuseasanti-diabetic drugs as well. However, this alone does not makethemdrug of choice in metabolic syndrome with diabetes anddyslipidemia, as there is a paucity of event-driven randomizedcontrolled trial data with these medications. The presence orotherwise of metabolic syndrome does not impact the choiceof, or dosage of, statins or ezetimibe or brates.Summary. Themetabolic syndromeis acluster of riskfactorsthatheightenCVrisk. Thereisnolargemulticenterrandomized controlled study of CV outcomes in persons withmetabolicsyndrome.Intheabsenceofsuchdata,thetreat-ment of the metabolic syndrome should continue to betailoredaccordingtothevariousindividual componentsofmetabolic syndrome. In subjects with type 2 diabetes, estab-lished atherosclerotic vascular disease, or severe obesity, thediagnosisof metabolicsyndromeisnot reallyrelevant, astreatment, including lipidmanagement, will be basedac-cording to these concomitant conditions.6.3. Acute coronary syndromeAcute coronary syndrome (ACS) continues to present a majorchallenge to clinicians because of its increasing incidence andbecause of the subsequent high risk of recurrent ischemic CVevents. As most of theacutecoronaryevents result fromrupture of non-obstructive plaques, preventive strategies,including lipid management, assume critical importance afterACS and early and intensive lipid modifying therapy isconsidered to be mandatory after an acute coronary event.6.3.1. Effect of recent acute coronary syndrome on lipid andlipoprotein measurementsTodeterminetherelationshipbetweenplasmalipidsandli-poproteinsandprognosisafterACSandtoguidearationalapproach to therapy, lipids and lipoproteins need to be ideallymeasured under steady-state metabolic conditions. However,ACS is often accompanied by an acute systemic inammatoryresponse, manifest by fever, leukocytosis, elevation of eryth-rocyte sedimentation rate,andan alteration inthe prole ofplasmaproteinsknownastheacute-phasereactants. Someacute-phasereactants, suchasCRP, increaseinconcentra-tion,whileHDLandLDL decrease,resulting inadecreaseinHDL-C and LDL-C levels. The time course of lipoproteinchangesafterACShasbeencharacterizedandreviewedbyRosenson.276Thelevelsmaybegintodecreasewithin24hafter anACS event, particularly among those withmoreextensive myocardial necrosis, reach a nadir at approximately1 week and then gradually recover.277,278A metabolic steady-stateisusuallyre-attainedby1monthfollowingACS.279,280The most pronounced lipid changes seen after ACS are-decreased levels of LDL-C, a similar decrement in HDL-C anda smaller increase in TG and Lp(a). The magnitude of changesisvariable&isrelatedtotheextentofmyocardialnecrosis,withthelargestchangesgenerallyobservedafterextensivetransmural MI& smaller to insignicant changes after limitedinfarction or unstable Angina. After an extensive MI, it is notuncommontoobserveanadirinLDL-Cthatis30%ormorebelowbaseline.Concurrentdrugtherapymayalsoinuencelipid measurements after ACS. For example, initiation of beta-blocker therapy may contribute to a rise in TGs. The practicalimplicationsofalltheseacutephaseeffectsisthat,afteranacute coronary event, accurate measurement of lipid levels isbest made either at the time of presentation or several weekslater. Nonetheless, it isfair tosaythat if LDL-Clevelsarehigher than desirable during acute phase following ACS, theywill almost certainlybeundesirablyhighduringmetabolicsteady state.6.3.2. Is there any inuence of lipoprotein and lipids on long &short term prognosis after ACS?There is strong epidemiological data linking elevated levels ofatherogenic lipoproteins particularly LDL-C&reduced levels ofprotectivelipoproteinsparticularlyHDL-Ctoinitialdevelop-mentofCHD.Similarly,inpatientswithstableCHDe.g.pa-tients with stable angina pectoris, remote MI or prior coronaryrevascularization, substantial evidence fromobservationalstudies&placebocontrolledtrialsof statinsindicatesthatlong term prognosis is adversely affected by derangement ofplasmalipoproteins. RelationshipbetweenhighLDL-CandlowHDL-CwithCVeventspersistsamongpatientstreatedwith statins in randomized trials.In ACS, the scenario is different. Each 1 mg/dl increase inLDL-Cmeasured1e4daysafterACS(priortoassignmenttostatin or placebo), the hazard ratio for an ischemic CV eventhasbeen1.0i.e. anull relationship, supportingthelackofrelationship between LDL-C & short term prognosis after ACS.TheabsenceofarelationshipbetweenLDL-Clevels&shorttermriskislikelytobetheresultof2counterbalancingfac-tors.Ononehand,higher levelsofLDL-Cmaybeassociatedwithincreasedrisk throughpromotionof atherosclerosis,while on the other, lower levels of LDL-C may indicate greateracute phase depression of LDL-C resulting from larger infarctsand therefore associated with increased risk.6.3.3. Evidence supporting early and intensive statintreatment after acute coronary syndromeUntil recently, lipid-loweringdrugtherapywasviewedasalong-termstrategytoreduceCVrisk, ratherthananinter-ventiontobeemployedintheshort-termmanagement ofpatients after ACS. The conventional viewpoint was based oni nd i a nhe a r tj o ur na l 6 6( 2 0 1 4 ) S 1 eS 5 1 S32experimental andangiographicevidencethatlipidloweringpromotesgradual removaloflipidfromatheroscleroticpla-ques, leading to gradual, modest regression of arterial steno-ses. The conventional viewwas also based onlandmarkclinical trials that established the efcacy of statin treatmentin reducing CV morbidity and mortality in patients with stablecoronaryheartdisease. TheselandmarktrialsincludedtheScandinavianSimvastatinSurvivalStudy(4S),281CholesterolandRecurrentEvents(CARE) study,279Long-TermInterven-tion with Pravastatin in Ischemic Disease (LIPID) study,280andHeart Protection Study.282In each of these trials, patients withACSwithinpreceding3e6monthswereexcludedand1e2yearsofstatintreatmentwasrequiredbeforeareductioninevents could be discerned. Furthermore, all these trialsemployedmoderateintensitystatintreatmentsuchaspra-vastatin 40 mg daily or simvastatin 20e40 mg daily. However,in ACS population, potentially modiable pathophysiologicalchanges in the vessel wall occur at a much faster pace. Bothexperimental and clinical evidence indicate that statins havethe potential to act rapidly to normalize the interface betweenbloodstreamandthevesselwall.Sucheffectsincludeanti-inammatoryactions, improvementinendothelial integrityandfunction, antithrombotic effects andfavorable plaqueremodeling. These effects are independent of the concurrentreduction of LDL-Cand are the most pronounced at high dosesof statins. It is therefore possible that high intensity treatment(i.e. the highest doses and/or use of the most potent statins),when initiated early after ACS, can result in potential benetin terms of CV risk reduction.6.3.3.1. Observational datasupportingstatintreatment afteracute coronarysyndrome. Theclinical evidencesupportingearlystatintherapyafterACSconsistsofobservationalan-alyses&randomizedcontrolledtrials. Theformercategorygenerallysupportsabenetofearlystatintherapy, butin-dividual analyses vary widely in magnitude of the estimatedeffect. A Swedish cohort of 20,000 patients who suffered rstMI was followed prospectively for 1 year. After adjusting for42 covariates & a propensity score for statin use,prescriptionofastatindrugathospitaldischargewasassociatedwithareduction in 1-year mortality compared with dischargewithout statintreatment (relative risk0.75; p0.001).283Similarndingswereobtainedinamultivariateanalysisofmorethan20,000patientswithACSenrolledintheGUSTO(GlobalUseofStreptokinaseort-PAforOccludedCoronaryArteries) andPURSUIT(PlateletGlycoproteinIIb/IIIainUn-stableAngina: ReceptorSuppressionUsingIntegrilinTher-apy) studies. Use of lipid lowering therapy at hospitaldischarge was associated with odds ratio of 0.67 (P 0.02) fordeath at 6 months compared with no lipid loweringtherapy.2846.3.3.2. Randomized clinical trials of statins in ACS. There aresix large randomized trials conducted in ACS patients (Table14). Out of these, 3 large trials- MIRACL (Myocardial IschemiaReductionwithAggressiveCholesterol Lowering),285A-to-Z(AggrastattoZocor)288andPROVE-ITTIMI22(PravastatinorAtorvastatin Evaluation and Infection TherapyeThrombolysisIn Myocardial Infarction 22)287- provide the foundation for ourcurrent understanding of the role of statins after ACS. None ofthesetrialsimposedalowerlimitontotalorLDL-Catbaseline,andeachhadanupperlimitofTCatrandomizationof240e270 mg/dl. The MIRACL trial showed that early andintensive statin therapy after ACS was an efcient and effec-tive intervention. The 4 months composite endpoint of death,reinfarction, cardiac arrest, or recurrent unstable angina wasreduced from 17.2% in placebo group to 14.6% in the atorvas-tatin80 mggroup.285Inthe PROVE-ITTIMI 22 study, thecompositeendpointofdeath, reinfarction, stroke, recurrentunstableanginaorunanticipatedcoronaryrevascularizationwasreducedfrom26.3%inthepravastatin40mggroupto22.4%intheatorvastatin80mggroupat2years(p 0.005).Thedifferencebetweentheevent ratesinthetwogroupsbecame statistically signicant at 6-months.287Thus, MIRACLtrial demonstratedsuperiorityof highintensitystatinoverplacebo in a 4 month period following ACS whereas PROVE-ITTIMI 22 demonstratedsuperiority of highintensity statintreatment overmoderateintensitytreatment overa2-yearperiodfollowingACS. Incontrast, theresultsofA-to-Ztrialdidnot showanysignicant benet of moderateintensitytreatmentoverplaceboearlyafterACS.Duringthe4monthplacebocontrolledphaseofA-to-Z,eventrateswere8.2%inthesimvastatin40mggroup&8.1%intheplacebogroup.However,intheactivecomparatorphaseofA-to-Z,highin-tensitystatintreatmentprovidedgreaterbenetthanmod-erate intensity statin treatment. Treatment with simvastatin80 mg from 4-months to 2 years resulted in signicantly fewerevents compared with treatment with simvastatin 20 mg overthis period of time. Thus, A-to-Z also supports the efcacy ofhigh intensity statin treatment after ACS.288Table 14 e Major randomized controlled trial of statins after acute coronary syndrome.Trial, year n Statin Comparator Duration Mean LDL-C(mg/dl; statin v/scomparator)% Of primary event(statin v/s comparator)MIRACL, 20012853086 Atorvastatin 80 mg Placebo 4months 72 v/s 135 14.8 v/s 17.4FLORIDA, 2002286540 Fluvastatin Placebo 1 yr 104 v/s 151 33 v/s 36 (NS)PROVE-IT TIMI 22, 20042874162 Atorvastatin 80 mg Pravastatin 40 mg 2 yrs 62 v/s 95 22.4 v/s 26.3A to Z, 20042884497 Simvastatin 40 mg Placebo simvastatin 20 mg4 months 66 v/s 81 14.4 v/s 16.7PACT, 20042893408 Pravastatin 20e40 mg Placebo 1 month Not measured 11.6 v/s 12.4 (NS)Ato Z Aggrastat to Zocor, FLORIDA- Fluvastatin on Risk Diminishing after Myocardial Infarction, MIRACL- Myocardial Ischemia Reduction withAggressiveCholesterol Lowering, NS- not signicant, PACT- PravastatininAcuteCoronaryTreatment, PROVE-ITTIMI 22- PravastatinorAtorvastatin Evaluation and Infection TherapyeThrombolysis In Myocardial Infarction 22.i nd i a nhe a r tj o ur na l 6 6( 2 0 1 4 ) S 1 eS 5 1 S336.3.3.3. Is greater reduction in LDL-Cwith intensive statintreatmentreducesearlyrecurrenteventsafterACS?.Unfortu-nately, data from 3 key randomized trials do not support suchasimpleexplanation. Infact, at 4months of randomizedtreatment intheA-to-Ztrial, averageLDL-Cconcentrationwas 62 mg/dl in the simvastatin 40 mg group & 124 mg/dl inthe placebo group, while at the same time point in the MIRACLtrial, LDL-C averaged 72 mg/dl in the atorvastatin 80 mg group& 135 mg/dl in the placebo group. Thus, the difference in LDL-Cbetweenactive treatment &placebogroups was nearlyidentical in both trials (62-62 mg/dl) but atorvastatin at 80 mgreducedclinical eventsinMIRACLwhilesimvastatin40mgdid not inA-to-Z. Moreover, analysis of MIRACL did notdemonstrate a relationship between LDL-C concentrationduring randomized treatment & risk of an ischemicevent.285,288Thus, it appearsthat factorsotherthanLDL-Creductiondeterminewhetherstatintherapyisbenecial inthe early period after ACS.6.3.4. Should CRP or other inammatory markers be targetsof therapy after ACS in addition to low density lipoproteincholesterol?Theroleofinammationinthepathogenesisofatheroscle-rosis, the relationship between risk after ACS& elevated levelsof inammatory markers such as CRP &the benecial effect ofstatins on CRP levels lead to the question of whether CRP (orother inammatory biomarkers) should be the primary targetof therapy in patients with ACS. Current data do not supportsuch an approach, at least in regard to CRP. The conventionalparadigmisthat inammationinthearterial wall leadstorelease ofnanogramperliterquantitiesofinammatorycy-tokines such as interleukins, which act on the liver to stimu-latesynthesis&releaseof milligramperliterquantitiesofCRP. Thus, the liver amplies inammatory stimuli from sitessuchasthevasculature, whicharethenreectedbycircu-latingCRPconcentrations.Whilethisparadigmmayexplainthe relation between atherosclerosis & elevated levels of CRP,the reduction of CRP with statin therapy may not necessarilyreect suppression of vascular inammation. This is becausestatins exert direct effects on the liver to suppress CRPexpression. Therefore, it is possible that reduction in CRP withstatintherapyprimarilyreectssuppressionofhepaticCRPproduction rather than attenuation of vascular inammation.In sum, CRP has been validated as a risk marker after ACS, butnot yet as a primary target of therapy.6.3.5. Safety of intensive statin therapy in ACSAtorvastatin 80 mg has been proven to be remarkably safe inlarge clinical trials. In the combined atorvastatin 80 mg armsintheMIRACL, PROVE-ITandTNT(Treat eto-New-Target)trials, thereweretotal sixcasesofrhabdomyolysisin59000patient-yearsofassignedtreatment, anincidencenohigherthanthatwithplacebo.Thus,vastmajorityofpatientswithACS can be treated safely with higher doses of statins. How-ever, it is important to recognize the factors that increase therisk of rhabdomyolysis, such as advanced age, renal or hepaticdysfunction, hypothyroidism, etc.Therehavebeenconcernsaboutthesafetyofhigh-dosestatintherapyinAsians. Althoughnocausal linkcouldbeestablished, an increase in cancer mortality and hemorrhagicstroke has been reported in some of the studies, particularlythose involving Japanese populations.253,255e257Recently, ashort-term(12 weeks) randomized study comparing twodifferentdosesofatorvastatin(80mgand40mg) wascon-ducted in Indian patients presenting with ACS.258Both dosesofatorvastatinwerewelltoleratedwithnodose-relateddif-ferences inincidence of adverse events betweenthe twotreatmentgroups. Nopatienthadelevationof(3timesofupperlimitofnormal)liverenzymesorcreatininephospho-kinase whereas only one patient on atorvastatin 80 mg com-plainedofmyalgia. However, asmentionedabove, thiswasonly a short-term study and involved only 236 patients.6.3.5.1. Incident diabetes withintensive statintherapy. Inapooled analysis of data from 5 statin trials (PROVE IT, A-to-Z,TNT, IDEALandSEARCH)intensive-dosestatintherapywasassociated with an increased risk of new-onset diabetescomparedwithmoderate-dosestatintherapy.290Theoddsratioswere1.12(95%condenceinterval 1.04e1.22) forthedevelopment of new-onset diabetes and 0.84 (95% condenceinterval 0.75e0.94) for CVevents inparticipants receivingintensive therapy compared with moderate-dose therapy. Ascomparedwithmoderate-dosestatintherapy, 498patientsneeded to be treated per year withintensive-dose statintherapy to result in one new case of diabetes while the num-ber needed to treat for preventing one new CV event was 155.Thus, the benet clearly outweighed the risk of inducing mildhyperglycemia with intensive statin therapy.6.3.6. Translating clinical trials to clinical practiceBased inpart onthe data fromMIRACL &PROVE ITTIMI 22, theNational Cholesterol EducationProgramrecommendedanoptional target forLDL-Cof lessthan70mg/dl inpatientsconsidered to be at very high risk of CVevents, including thosewith recent ACS.251On the surface, this recommendation ap-pears to be consistent with the nding of the clinical trials inwhich LDL-C averaged 62e70 mg/dl in the Atorvastatin 80 mgarm. However, the PROVE-IT TIMI 22 trial found progressivelylower risk withprogressively lower achieved LDL-Clevel intheatorvastatin 80 mg arm, extending even to those patients withLDL-C level less than 40 mg/dl. Therefore, it would appear tobe illogical to attenuate the intensity of therapy to achieve anLDL-Clevel of70mg/dl whenahigherstatindosagemightdrive LDL-C even lower. Thus, given the data supporting ef-cacy&safetyofhighintensitystatintreatmentafterACS,itwould be reasonable to apply this strategy of initiation of highdose statin therapy to the majority of patients presenting withACS, rather than titrating the intensity of statin treatment toachieve an LDL-C level of 70 mg/dl. In all patients, the goal ofthe treatment should be to achieve at least 40e50% reductionin LDL-C, irrespective of the baseline levels.InIndiansalso, itisrecommendedthathigh-dosestatintherapytobeprescribedtoall patientspresentingwithanacutecoronary event. However, as the data about safety of high-dosestatintherapyinIndians is limitedtoonly3months' period, it isreasonabletoreducestatindose,3monthsafterinitial pre-sentationwithACS, tolevels sufcient enoughtosustaindesired LDL-C reduction (at least 40e50% from baseline).i nd i a nhe a r tj o ur na l 6 6( 2 0 1 4 ) S 1 eS 5 1 S346.4. 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