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Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2804_Библиотеки_им_академика_М_И_Перельмана

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loweringtherapywithastatin,itmaybereasonabletocontinuethestatin. In adultswith advancedkidneydisease whorequire dialysis treatment,initiation of a statinisnot recommended. InpatientswithHFwithreducedejectionfractionattributabletoischemicheartdiseasewhohavea reasonablelifeexpectancy(3–5years)andarenotalreadyonastatinbecauseofASCVD,clinicians may consider initiation of moderate-intensity statin therapy to reduce the occurrence of ASCVD events.
66
LDL-Creductionbeyondstatintherapy
WhenstatinsareinsufficientforLDL-Creduction,furthertherapywithnonstatinsmaybeindicated. Thiswouldgenerallyincludeezetimibe,bileacidsequestrants,andPCSK9monoclonalantibodies.
88
Hypertriglyceridemia
Hypertriglyceridemiamaybeanindependentcardiovascularriskfactor.
65,89-91
Hypertriglyceridemia is often observed inthemetabolic syndrome,91 and there are many potential etiologies for hypertriglyceridemia, including obesity, DM, renal insufficiency, genetic dyslipidemias,andtherapywithoralestrogen,glucocorticoids,β-blockers,tamoxifen,cyclosporine, antiretrovirals,andretinoids. Theclassificationofserumtriglyceridelevelsisasfollows:normal:<150mg/dL;borderlinehigh: 150–199mg/dL;high:200–499mg/dL;veryhigh: ≥500mg/dL;severe:1000–1999mg/dL (greatly increasestheriskofpancreatitis);andverysevere:≥2000mg/dL.
69,91
Treatmentofhypertriglyceridemiadependsonthedegreeofseverity.
Forpatientswithveryhightriglyceridelevels,triglyceridereductionthroughavery-low-fatdiet (≤15%ofcalories),exercise,weightloss,anddrugs(fibrates,ω-3fattyacids)istheprimarygoal oftherapytopreventacutepancreatitis. Whenpatientshavea lesser degreeofhypertriglyceridemia, controlling theLDL-C level is the primaryaimofinitialtherapy.Lifestylechangesareindicatedtolowertriglyceridelevels.
69
LowHDLcholesterol
LowHDLcholesterolisanindependentASCVDriskfactorthatisidentifiedasanon–LDL-Crisk andisincludedasacomponentoftheACC/AHAASCVDriskscoringalgorithm.
92
Etiologies of low HDL cholesterol includegenetic conditions, physical inactivity, obesity, insulin resistance, DM, hypertriglyceridemia, cigarette smoking, high-carbohydrate (>60% of calories) diets,andcertainmedications(β-blockers,anabolicsteroids/androgens,progestins).Acquiredlow HDLcanalsooccurwithplasmacelldyscrasiasduetointerferenceofparaproteinswiththeassay.
93
Because therapeutic interventions for low HDL cholesterol are oflimited efficacy, the guidelines recommendconsideringlowHDLcholesterolasacomponentofoverallrisk,ratherthanaspecific therapeutictarget. There are no clinical trial data showing a benefit of pharmacologic methods of elevating HDL cholesterol.
Startingandmonitoringtherapy
Before starting therapy, guidelines recommend checking alanine aminotransferase (ALT), hemoglobin A1C (if diabetes status is unknown), labs for secondary causes (if indicated), and creatinekinase(ifindicated). Evaluate for patientcharacteristics thatincrease the risk ofadverse eventsfrom statins,including impaired hepatic and renal function, history of statin intolerance, history of muscle disorders, unexplained elevations of ALT >3× the upper limit of normal, drugs affecting statin metabolism, Asianethnicity,andage>75years.
79
Arepeatfastinglipidpanelisindicated4–12weeksafterstartingtherapytoassessadherence,with reassessmentevery3–12monthsasindicated.
https://t.me/med1917
In patients without the anticipated level of LDL-C reduction based on intensity of statin therapy (≥50% for high intensity, 30%–50% for moderate intensity), assess adherence to therapy and lifestylemodifications,evaluateforintolerance,andconsidersecondarycauses.Afterevaluation,if thetherapeuticresponseisstillinsufficientonmaximallytoleratedstatintherapy,itisreasonableto consideraddinganonstatinagent.
88
Creatinekinase should not be routinelychecked in patients onstatin therapy butis reasonable to measureinpatientswithmusclesymptoms. In2012,theFDAstatedthatliverenzymetestsshouldbeperformedbeforestartingstatintherapyand onlyas clinicallyindicatedthereafter. TheFDA concludedthatseriousliverinjury withstatinsis rareandunpredictableandthatroutinemonitoringofliverenzymesdoesnotappeartobeeffective indetectingorpreventingseriousliverinjury.Elevationsoflivertransaminases2–3×theupperlimit of normal are dose-dependent, may decrease on repeat testing even with continuation of statin therapy,andarereversiblewithdiscontinuationofthedrug.
TreatmentofElevatedLDLCholesterol
HMG-CoAreductaseinhibitors(statins)
Statins(seeTable3-10)arethetreatmentofchoiceforelevatedLDL-Candusuallylowerlevelsby 30%–50%withmoderate-intensityand≥50%withhigh-intensitystatintherapy.
79,94,95
Thelipid-loweringeffectofstatinsappears withinthe firstweekof useandbecomes stable after approximately4weeksofuse. Statintherapyiseffectiveinbothmenandwomen.
96
Common side effects (5%–10% of patients) include gastrointestinal upset (e.g., abdominal pain, diarrhea, bloating,constipation) andmuscle pain or weakness, which can occur without creatine kinaseelevations.Otherpotentialsideeffectsincludemalaise,fatigue,headache,andrash.
95,97-99
Myalgias are themostcommoncauseofstatindiscontinuationandare often dose-dependent.They occurmoreoftenwithincreasingageandnumberofmedicationsanddecreasingrenalfunctionand bodysize.
98-100
Discontinue statins in patients who develop muscle symptoms until they canbe evaluated. For severesymptoms,acreatinekinaselevelcanbemeasured.
79
Formildtomoderatesymptoms,evaluateforconditionsincreasingtheriskofmusclesymptoms, including renal or hepatic impairment, hypothyroidism, vitamin D deficiency, rheumatologic disorders, andprimarymuscledisorders. Statin-inducedmyalgiasare likelytoresolve within2 monthsofdiscontinuingthedrug. Ifsymptomsresolve,thesameorlowerdoseofthestatincanbereintroduced. Ifsymptomsrecur,usealowdoseofadifferentstatinandincreaseastolerated.
Ifthecauseofsymptomsisdeterminedtobeunrelated,restarttheoriginalstatin. StatinshavebeenassociatedwithanincreasedincidenceofDM.However,thetotalbenefitofstatin useusuallyoutweighsthepotentialadverseeffectsfromanincreaseinbloodsugar.
101
Thereisnoaggregatedevidencethatstatinshaveanynegativeimpactoncognitivefunction.
102
Because a number ofdrug interactionsarepossible dependingonthestatinandother medications beingused,druginteractionprogramsandpackageinsertsshouldbeconsulted.
103
Because some statins undergo metabolism by the cytochrome P450 enzyme system, taking these statins in combination with other drugs metabolized by this enzyme system increases the risk of rhabdomyolysis.
95,97,98
Amongthesedrugsarefibrates(greaterriskwithgemfibrozil),itraconazole,
ketoconazole,erythromycin,clarithromycin,cyclosporine,nefazodone,andproteaseinhibitors.
98
Statinsmayalsointeractwithlargequantitiesofgrapefruitjuicetoincreasetheriskofmyopathy.
https://t.me/med1917
Simvastatin can increase the levels of warfarin and digoxin and has significant dose-limiting interactions with amlodipine, amiodarone, dronedarone, verapamil, diltiazem, and ranolazine. Rosuvastatinmayalsoincreasewarfarinlevels. Theuseofstatinsiscontraindicatedduringpregnancyandlactation.
Bileacidsequestrantresins
Currentlyavailablebileacidsequestrantresinsincludethefollowing:
Cholestyramine:4–24g/dPOindivideddosesbeforemeals.
Colestipol:tablets,2–16g/dPO;granules,5–30g/dPOindivideddosesbeforemeals.
Colesevelam: 625 mg tablets, threetablets PObid or sixtablets PO daily(maximumofseven
tabletsdaily)withfood,oronepacketoforalsuspensiondaily. BileacidsequestrantstypicallylowerLDL-Clevelsby15%–30%andtherebylowertheincidence ofCHD.
95,104
These agents should not be used as monotherapy inpatients with triglyceride levels >250 mg/dL becausetheycanraisetriglyceridelevels.Theymaybecombinedwithstatinsornicotinicacid. Commonsideeffectsofresinsincludeconstipation,abdominalpain,bloating,nausea,andflatulence. Bile acid sequestrants may decrease oral absorption of many other drugs, including warfarin, digoxin,thyroidhormone,thiazidediuretics,amiodarone,glipizide,andstatins.
Colesevelam interactswith fewerdrugsthandotheolder resinsbutcanaffecttheabsorptionof
thyroxine.
Othermedicationsshouldbegivenatleast1hourbeforeor4hoursafterresins.
Nicotinicacid(niacin)
NiacincanlowerLDL-Clevelsby≥15%,lowertriglyceridelevelsby20%–50%,andraise HDL cholesterollevelsbyupto35%.
89,105
Theuseofniacinislimitedbyitssideeffectprofile. Crystallineniacinis given1–3g/dPOintwotothreedivideddoseswithmeals.Extended-release niacinisdosedatnight,withastartingdoseof500mgPO,andthedosemaybetitratedmonthlyin 500 mg increments to a maximum of 2000 mg PO (administer dose with milk, applesauce, or crackers). Common side effects of niacin include flushing, pruritus, headache, nausea, and bloating. Other potentialsideeffectsincludeelevationoflivertransaminases,hyperuricemia,andhyperglycemia.
Flushingmaybedecreasedwiththeuseofaspirin325mg30minutesbeforethefirstfewdoses. Hepatotoxicity associated with niacin is partially dose-dependent and appears to be more
prevalentwithsomeover-the-countertime-releasepreparations. Avoiduseofniacininpatientswithgout,liverdisease,activepepticulcerdisease,anduncontrolled DM.
Niacincanbeusedwithcareinpatientswithwell-controlledDM(hemoglobinA1Clevel≤7%).
Serumtransaminases,glucose,anduricacidlevelsshouldbemonitoredevery6–8weeksduring
dosetitrationandthenevery4months Theuseofniacininpatientswithwell-controlledLDL-Clevels(withstatins)hasnotbeenshownto be of benefit in clinical trials.
106,107
 Niacin can be useful as an additional agent in patients with
severelyelevatedLDL-Clevels.
Ezetimibe
Ezetimibe is currently the only available cholesterol-absorptioninhibitor. Itappears to act at the brushborderofthesmallintestineandinhibitscholesterolabsorption. Ezetimibemayprovideanadditional25% meanreduction inLDL-C whencombinedwithastatin andprovidesanapproximately18%decreaseinLDL-Cwhenusedasmonotherapy.
107-111
The recommended dosing is 10 mg PO once daily. No dosage adjustment is required for renal insufficiencyandmild hepatic impairmentor inelderlypatients.It isnot recommendedforusein
https://t.me/med1917
patientswithmoderatetoseverehepaticimpairment. Side effects are infrequent and include gastrointestinal symptoms (e.g., diarrhea, abdominal pain) andmyalgias. Inclinicaltrials,therewasnoexcessofrhabdomyolysisormyopathywhencomparedwithstatinor placeboalone. Liverenzymesshouldbemonitoredwhenusedinconjunctionwithfenofibratebutarenotrequiredin monotherapyorwithastatin. Aclinicaloutcometrialshoweddecreasedreductionofcardiovasculareventswiththecombination ofsimvastatin andezetimibe compared with placebo inpatientswithchronic renal failure.
112
 The IMPROVE-ITtrialshowedareduction incardiovascularendpointswhenezetimibewasaddedto simvastatininhigh-riskpatientswithalreadylowLDLlevels.
113
EzetimibeisusefulinpatientswithFHwhodonotachieveadequateLDL-Creductionswithstatin therapyalone.
114
Bempedoicacid
Bempedoicacid is aninhibitorofadenosinetriphosphatecitratelyase, anenzymeupstreamofthe targetofstatins(3-hydroxy-3-methylglutaryl-CoAreductase)inthecholesterolbiosynthesispathway. Bempedoicacid aloneorincombinationwithastatinorezetimibe (combinationbempedoicacid­ezetimibe tablet withFDA approval is available) safely lowers LDL-C as shown inthe CLEAR HarmonyandCLEARWisdomrandomizedcontrolledtrialsin2019.
115,116
Inpatientswithgout,serumuricacidlevelsshouldbemeasuredandstabilizedpriortoinitiation.
PCSK9inhibitors
MonoclonalantibodieshavebeendevelopedthatlowerLDL-C.TheyworkbyinhibitingthePCSK9 enzyme,whichisinvolvedinbreakingdowntheLDL-Creceptor.Theiruseincreasesthenumberof available cell surfaceLDL receptors andsubsequently removemoreLDL fromcirculation. Major studies have shown significant reductionin LDL-C when PCSK9 inhibitors were added to statin therapy.
117
These agents have shown great ability in further reducing LDL-C in high-risk patients and are approved for use as adjuncts in patients with clinical ASCVD and heterozygous FH and as monotherapyforhomozygousFH. TwoPCSK9inhibitorsareapproved forclinicaluse,evolocumabandalirocumab.Evolocumabis dosedat140mgsubcutaneouslyevery2weeksor420mgevery4weeks.Alirocumabisdosedat75 or150mgevery2weeksor300mgevery4weeks. Evolocumab has been shown to decrease major cardiovascular events.
117
 The more recent ODYSSEYOUTCOMES trial showed alirocumab significantlyreducesischemicevents,all-cause mortality,andMIamongpatientswithanacutecoronarysyndromeeventwithinthepreceding1–12 months.
118
Evinacumab
Evinacumab is a human monoclonal antibody against ANGPTL3, a angiopoietin-like protein (ANGPTLs)thatregulateslipoproteinmetabolism. A recentphase2trial in2020showedreductioninhepaticVLDL-Cproductionandsecretionand consequently loweredLDL-Cwhensafelyusedincombinationwith a PCSK9inhibitorandstatin, withorwithoutezetimibe.
119
TreatmentofHypertriglyceridemia
Nonpharmacologictreatment
Nonpharmacologictreatmentsareimportantinthetherapyofhypertriglyceridemia.Approachesinclude
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thefollowing:
Changingoralestrogenreplacementtotransdermalestrogen Decreasingalcoholintake Encouragingweightlossandexercise ControllinghyperglycemiainpatientswithDM Avoidingsimplesugarsandvery-high-carbohydratediets
69,91
Pharmacologictreatment
Pharmacologictreatmentofseverehypertriglyceridemiaconsistsoffibricacidderivative(fibrates), niacin,orω-3fattyacids. Patientswithseverehypertriglyceridemia(>1000mg/dL)shouldbetreatedwithpharmacotherapyin addition to reduction of dietary fat, alcohol, and simple carbohydrates to decrease the risk of pancreatitis. Statins may be effective for patientswith mild to moderatehypertriglyceridemia andconcomitant LDL-Celevation.
69,91,120
Fibricacidderivatives
Currently availablefibric acidderivativesincludethe following(bezafibrateis notavailable in theUnitedStates):
□ Gemfibrozil:600mgPObidbeforemeals □ Fenofibrate:availableinseveralforms,dosagetypically48–145mg/dPO
Fibratesgenerallylowertriglyceridelevelsby30%–50%andincreaseHDLcholesterollevelsby 10%–35%.TheycanlowerLDL-Clevelsby5%–25%inpatientswithnormaltriglyceridelevels butmayactuallyincreaseLDL-Clevelsinpatientswithelevatedtriglyceridelevels.
120,121
Commonsideeffectsincludedyspepsia,abdominalpain,cholelithiasis,rash,andpruritus. Fibrates maypotentiate the effects ofwarfarin.95 Gemfibrozil given in conjunctionwith statins mayincreasetheriskofrhabdomyolysis.
99,122-124
ω-3fattyacids
Highdosesofω-3fattyacidsfromfishoilcanlowertriglyceridelevels.
125,126
Theactiveingredientsareeicosapentaenoicacid(EPA)anddocosahexaenoicacid(DHA). Tolowertriglyceridelevels,1–6gofω-3fattyacids,eitherEPAaloneorwithDHA,isneeded daily. Mainsideeffectsareburping,bloating,anddiarrhea. Prescriptionformsofω-3fattyacidsareavailableandareindicatedfortriglyceridelevels>500 mg/dL.OnepreparationcontainsEPAandDHA;fourtabletscontainabout3.6gofω-3acidethyl esters andcanlower triglyceride levels by30%–40%. Other preparationscontainonlyEPA or containunesterifiedEPAandDHA. Threerecentlargecardiovascularoutcomestrials(ASCEND,VITAL,REDUCE-IT)showedclear benefitsforω-3fattyacidintakeforCVD,includingriskreductionforheartattack, other major cardiovascularevents,anddeathfromCVD.
127-130
Applying the results of thesetrials to clinical practice, the addition of 4 g/d of EPA should be consideredforstatin-treatedpatientswhohaveCVDordiabetespluselevatedtriglycerides.All adults should consume at least one to two servings of fish/seafood per week, with additional primarypreventionbenefitsconferredbyconsuming1g/dofEPAandDHA. Inaddition,EPAandDHAmayhelppreservephysicalfunctioninCADpatients.
131
Thecombinationofω-3fattyacidsplusastatinhastheadvantageofavoidingtheriskofmyopathy seenwithstatin–fibratecombinations.
132,133
TreatmentofLowHDLCholesterol
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Low HDL cholesterol often occurs in the setting of hypertriglyceridemia and metabolic syndrome. Management of accompanying high LDL-C, hypertriglyceridemia, and the metabolic syndrome may resultinimprovementofHDLcholesterol.
134
Nonpharmacologictherapiesarethemainstayoftreatment,includingthefollowing:
Smokingcessation Exercise Weightloss
In addition, medications known to lower HDL levels, such as β-blockers (except carvedilol), progestins,andandrogeniccompounds,shouldbeavoidedifpossible. Noclinical outcomes trials haveshown a clear benefitto pharmacologictreatment for raising HDL cholesterol.
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