Drug Treatment of HyperlipidemiaPhilip Marcus, MD MPH0

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Atherosclerotic Cardiovascular Disease and Hypercholesterolemia7 Million Americans with symptomatic ASCVD1:2 deaths in US attributed to ASCVD$120 billion spent to treat ASCVD1/500 has genetic predisposition leading to premature ASCVDHeterozygous familial hypercholesterolemiaLifestyle is contributing factor in remainder31% of Americans have borderline to high total cholesterol20% of Americans have high total cholesterol0

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Ischemic Heart Disease:Plaques of atheroma in coronary arteriesPartially occludeMay rupture exposing subendotheliumFocus for thrombosesCan result in Myocardial InfarctionPrevention of Myocardial InfarctionReduce progression of atheromaProduce regression of existing plaques0

Development of Atheromatous Plaque0

Ischemic Heart Disease: AtheromaCoronary ArteriesMyocardial InfarctionCerebral ArteriesStrokePeripheral ArteriesPeripheral Vascular Disease (PVD)Renal ArteriesHypertensionRenal failure

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Atheromatous Disease: Risk FactorsFamily HistoryHypertensionCigarette SmokingHyperglycemiaObesityPhysical InactivityHigh serum cholesterol (LDL)Hyperhomocysteinemia 0

Lipoproteins and ASCVD:LipoproteinsPlay essential role in transporting lipids between tissuesLipids insoluble in plasma and therefore require lipoproteins for transportComposition of LipoproteinsCentral CoreContains lipid (Triglyceride or cholesterol esters)HydrophobicHydrophilic CoatPolarContains Phospholipids, Free Cholesterol, Apolipoproteins0

Lipoprotein Classification:HDLLDLVLDLChylomicrons0

Chylomicrons:Largest, lightest of particlesSynthesized in intestinal mucosaCarry Triglyceride of dietary originAppear after a fatty mealMilky plasmaCleared in 8 to 12 hoursVia lipoprotein lipaseConverts TG to FFA and GlycerolHeparin and Apo C-II cofactorsType I HyperlipoproteinemiaFamilial Lipoprotein Lipase DeficiencyDelayed chylomicron clearance, elevated serum TGNo increase in coronary artery disease0

Very Low Density Lipoprotein (VLDL)Smaller and denser particlesSecreted by liverSynthesized from carbohydrate, fatty acids and othersPrincipal carrier of endogenous TriglycerideMajor lipid is TG, also contains CholesterolExcess VLDL = Elevated TGContains Apo B100Metabolized by lipoprotein lipaseTG converted to FFA (cell permeable)Elevated LDL results from increased VLDL secretion or from decrease in LDL catabolism0

Low Density Lipoprotein (LDL):Smaller, denser and more solublePrincipal lipid is cholesterol (up to 75%) to 1/3 of total cholesterol carried by LDLLow in TG, no turbidityDerived mainly from VLDL catabolism via IDLContains Apo B100Allows binding to LDL receptorLDL particles, on binding to LDL receptors on hepatocytes and peripheral cells, deliver cholesterol for synthesis of cell membranes and steroid hormones0

Low Density Lipoprotein (LDL):Some cholesterol, upon presentation to LDL receptors, undergo esterification by fatty acids and are reincorporated into HDLHalf-Life = 2.5 daysType IIA HyperlipoproteinemiaFamilial hypercholesterolemiaElevated LDL with normal VLDL levelsDue to block in LDL degradationCaused by decreased number of LDL receptorsAssociated with accelerated coronary artery disease0

High Density Lipoprotein (HDL):Smallest, most dense and most solubleProduced by liver and small intestine in nascent form (HDL3)Discoidal HDL3 acquires protein from catabolism of TG rich lipoproteins to become mature, spheroidal HDL2 particlesApo AI major protein component of HDLActivates lecithin cholesterol acetyltransferaseHDL acts in transport of cholesterol between cells and plasmaProvides mechanism for removing cholesterol from tissueInverse relationship between HDL and coronary artery diseaseProtective effect via HDL20

Major Enzymes in Lipoprotein MetabolismLipoprotein LipaseLocated in muscle and adipose tissueHydrolyzes chylomicron and VLDL TriglycerideLecithin-Cholesterol AcetyltransferaseFound in plasmaEsterifies free cholesterol on HDL surfaceTriglyceride LipaseLocated in liverHydrolyzes TG within IDL and HDL particles0

Hyperlipidemias: PrimaryType IFamilial HyperchylomicronemiaElevated TG, Mildly elevated CHOLTreated by LOW FAT dietType IIAFamilial HypercholesterolemiaElevated CHOL, Normal TGElevated LDLTreatment with low cholesterol and low saturated fat diet. Drug therapy effective.0

Hyperlipidemias: PrimaryType IIBFamilial combined hyperlipidemiaSimilar to IIA, but elevated VLDL alsoElevated CHOL and TGCaused by overproduction of VLDL by liverTreatment with low cholesterol and low saturated fat diet. Avoidance of alcohol. Low CHO.Type IIIFamilial dysbetalipoproteinemiaIncreased levels of IDLIncreased TG and CHOLOverproduction/underutilization of IDL, abnormal ApoEAccelerated coronary artery diseaseTreatment similar to IIB

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Hyperlipidemias: PrimaryType IV Familial hypertriglyceridemiaMarked increase in VLDL, normal LDLRelatively commonOften associated with hyperuricemia, obesity, diabetesAccelerated coronary disease notedTreatment with low CHO diet, weight reduction, avoidance of alcoholType VFamilial mixed hypertriglyceridemiaType I + Type IVElevated VLDL + chylomicronsLow fat and low CHO diet0

Hyperlipidemia: SecondaryDisease statesDiabetes mellitusAlcoholismNephrotic syndromeChronic renal failureHypothyroidismLiver diseaseDrugsThiazidesEstrogensb-blockersIsotretinoin0

Drugs for LipidsLipid-regulating drugs must be taken indefinitelyPlasma lipid levels return to pretreatment levels within 2-3 weeks when stoppedShould NOT be a substitute for lifestyle changesDiet + Exercise + Lipid-lowering drugs optimal for treatment/prevention0

Drugs Used in Treatment: Past and PresentThyroid hormonesDextrothyroxineEstrogensNeomycinBile Acid Binding ResinsEzetimibeFibric Acid DerivativesNiacinProbucolHMG-CoA-Reductase inhibitors (statins)0

Natural AlternativesDietary SupplementsGarlicPlant SterolsBenecolAlso as margarine productRed Rice YeastContains LovastatinFDA attempting to regulate as drugNiacin0

Bile Acid Binding Resins:Cholestyramine, Colestipol, Colesevelam Anion exchange resinsLarge polymeric cationsInsoluble chloride saltIon exchange sites are trimethyl-benzyl-ammonium groupsBind negatively charged bile acids and bile salts in small intestinePrevents absorption of bile acids and cholesterolChloride exchanged for bile acidsResin itself not absorbed

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Cholestyramine (Questran, LoCHOLEST)Colestipol (Colestid)

Colesevelam (Welchol)-hydrophilic polymerResins0

Cholestyramine: Bile acid effects

Bile Acid Binding Resins:Bile acids normally 95% reabsorbed in jejunum10 fold excretion of bile acids notedBile acids are metabolites of cholesterolLowering bile acids causes hepatocytes to increase conversion of cholesterol to bile acidsIntracellular cholesterol concentration decreasesActivates hepatic uptake of LDL and fall in serum LDLIncreased uptake mediated by up-regulation of cell surface LDL receptors

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Bile Acid Binding Resins:Drugs of choice in treating IIA and IIBFor homozygous IIA, no effect since LDL receptors lacking20-25% reduction in LDL-C after 2 to 4 weeksIncrease in HDL-CToxicityUnpleasant textureNausea, constipation, bloating, flatulenceNeed large amount of fluids, high bulk dietImpaired absorption of fat-soluble vitaminsUseful also in itching associated with partial biliary obstruction0

Bile Acid Binding Resins:Drug InteractionsInterfere with intestinal absorption of anionic drugsThiazidesDigoxinWarfarinThyroxinTetracyclineDrugs to be taken 2 hours before or 4 hours after cholestyramine or colestipolLarge Doses neededCholestyramine 8 grams three times dailyColesevelam 3 tablets (1875 mg) twice a day0

Ezetimibe (Zetia)Localizes and acts at brush border of small intestineInhibits absorption of cholesterolLeads to decrease in delivery of intestinal cholesterol to the liverCauses reduction of hepatic cholesterol stores and increase in clearance of cholesterol from the blood0

Ezetimibe (Zetia)Mechanism of action is complementary to that of HMG-CoA reductase inhibitorsResults in reductions in:Total cholesterolLDL-C (18%)Apolipoprotein BTriglyceridesResults in increase in HDL-cholesterol0

Ezetimibe (Zetia)Inhibits intestinal absorption of cholesterol by 54%No effect on plasma concentrations of Vitamins A, D or ENo impairment of steroid hormone synthesis0

Ezetimibe (Zetia)Well-absorbed orallyExtensively conjugated to pharmacologically active glucuronideHighly bound to plasma proteinsMetabolized in liver and small bowel via glucuronide conjugationBiliary and renal excretion0

Ezetimibe (Zetia)Well toleratedAdverse reactions no different than placeboAntacids and cholestyramine decrease effect of ezetimibe10 mg once daily0

Fibric Acid DerivativesActivate the nuclear transcription factor peroxisome proliferator activated receptor alpha (PPAR-alpha) which relates genes that control lipid metabolismStimulates lipoprotein lipaseResults in hydrolysis of TG in chylomicrons and VLDLAccelerates removal of VLDL and chylomicrons Does not alter secretion of VLDL from liverAlso lower fibrinogen levels

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Fibric Acid Derivatives0

Fibric Acid DerivativesClofibrate (Atromid-S )First agent used in clinical practiceCaused 22% lowering of TG, 6% lowering of cholesterolLong-term use associated with complicationsThromboembolic diseaseCholelithiasis and pancreatitisIncreased malignanciesNo beneficial effects on progression of heart disease0

Fibric Acid DerivativesGemfibrozil (Lopid )Same mechanism of actionMore commonly usedUsed in hypertriglyceridemia Useful in Type III Adjunct to diet in Type IVCompletely absorbedExtensively bound to albumin

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Fibric Acid DerivativesGemfibrozilAdverse effectsGI effectsMyositis syndromeElevated CK, ASTPatients with renal disease at greatest riskMyopathy reported in conjunction with statinsHepatotoxicityElevated transaminase levelsReversible upon discontinuationCholelithiasisDrug interactionsCompetes with highly bound drugs to albuminMajor problem with warfarin (Coumadin )0

Fibric Acid DerivativesFenofibrate (Tricor)Adjunctive therapy Adult patientsElevated serum triglyceridesAt risk of pancreatitisNo response to dietary manipulationInhibits TG synthesisDecreases VLDLStimulates catabolism of VLDLOnce daily administration0

Niacin (Nicotinic Acid):Found to lower cholesterol levels in large doses as early as 1955Gram doses rather than mg doses used as vitaminNiacin, not niacinamide (nicotinamide)Vitamin B3Acts to decrease VLDL and LDLLowers cholesterol(10%) and TG (30%)Maximal effects in 3 to 5 weeksRaises HDL0

Niacin (Nicotinic Acid):Mechanism of Action:Inhibits lipolysis in adipose tissueAdipose tissue primary producer of FFAFFA major precursor for TG synthesisDecreases esterification of TG in liverIncreases lipoprotein lipase activityInhibits VLDL secretion and synthesis in liverDecreases LDL productionIncreases secretion of tPA and lowers fibrinogenReverses endothelial cell dysfunction contributing to thrombosis and atherosclerosisDecreases HDL catabolismChanges LDL particles from small, dense ones to ones that are large and buoyant0

Niacin (Nicotinic Acid):PharmacokineticsOrally administeredRapidly absorbedPeak levels in under one hourConverted to nicotinamideIncorporated into cofactor NADExcreted in urine88% excreted unchangedTherapeutic UseType IIB and Type IVRaises HDL (most effective agent)Used with bile acid resins in Type IIB (heterozygotes)0

Niacin (Nicotinic Acid): ToxicityMany untoward effects limit usefulnessFlushingCutaneous vasodilatation in almost allAccompanied by warmth and itchingTolerance within one to two weeksBlunted by use of aspirin hour earlierGI distressLiver dysfunctionHyperuricemiaInhibits tubular secretion of uric acidImpaired glucose toleranceAcanthosis appearance associated with insulin resistance0

NiacinImmediate release, quickly-absorbedExtended release, absorbed over 8 hrsSustained release, absorbed over 12-24 hoursCombination of extended release niacin and immediate release lovastatin0

Probucol (Lorelco )Lowers LDL, up to 15%Also lowers HDL, up to 30%Mechanism of action:Inhibits oxidation of cholesterolPrevents ingestion of cholesterol by macrophagesMay slow development of atherosclerosisEffects on cholesterol in 1 to 3 monthsLipophilic compoundPersists in adipose tissues for monthsProlongs cardiac action potentialAvoid in long QT intervalAvoid Amiodarone, Sotalol, Quinidine, etcNot shown to prevent or retard atherosclerosisRemoved from Market

In-vivoCholesterolSynthesis0

HMG-CoA-Reductase Inhibitors:Inhibit first step rate-limiting in sterol (cholesterol) synthesisStructural analogs of natural substrate3-hydroxy-3-methyl-glutaric acidBlock hydroxy-methyl-glutaryl-Coenzyme A reductaseReduces conversion of HMG-CoA to mevalonic acidMost compounds are related to compounds occurring naturally in fungiLovastatin first agent in classInhibit de novo cholesterol synthesisDeplete intracellular supply of cholesterolIncrease LDL receptors0

HMG-CoA-Reductase Inhibitors:Lovastatin (Mevacor) 1987Simvastatin (Zocor) 1991Pravastatin (Pravachol) 1991Fluvastatin (Lescol) 1993Atorvastatin (Lipitor) 1996Cerivastatin (Baycol) Withdrawn because of toxicityRosuvastatin (Crestor) 20030

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HMG-CoA-Reductase Inhibitors:Lovastatin and simvastatin are lactones which are hydrolyzed to active drugPravastatin, fluvastatin, atorvastatin are activeAgents differ primarily in bioavailability, half-life and metabolismHighly protein bound (>95%)Biotransformed in liverMetabolites mostly activeExcretion mostly through bile and feces (83%)0

HMG-CoA-Reductase Inhibitors:Adverse EffectsGenerally well tolerated; few adverse effectsPatients who dont tolerate one statin may tolerate anotherHepatic dysfunctionElevation in transaminase levels>3x ULN increase occurs in 1-2%Symptomatic hepatitis rareContraindicated in pregnancy0

HMG-CoA-Reductase Inhibitors:Adverse EffectsMuscleMyalgia and muscle weaknessWith or without increases in CKMyopathy and rhabdomyolysis (rare)May lead to renal failure; dose relatedRenal insufficiency predisposing factorMyopathy often caused by drug interactionsConcurrent use of CYP3A4 inhibitors increase levelsItraconazole, ketoconazole, erythromycin, clarithromycin, teilithromycin, HIV antiviralsGrapefruit juiceCyclosporineDrug interactionsGemfibrozil inhibits metabolism of all statinsInhibits statin glucuronidationIncreases risk of rhabdomyolysisIncreased anticoagulant effect when used with warfarin

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HMG-CoA-Reductase Inhibitors:See dose related decrease in LDL-cholesterolOccurs within 3 daysPeaks at one month25 to 45% reduction in cholesterolReduces Apo BAlso causes reduction in TG (up to 25%)Raises HDL up to 10%Effective in all HyperlipoproteinemiasLess effective in familial homozygous Type IIALack LDL receptorsOften combined with other agents to increase effectAdminister once daily in the evening0

HMG-CoA-Reductase Inhibitors:Pravastatin and atorvastatin indicated for childrenLovastatin indicated for primary prevention of coronary artery disease0

Beneficial Effects of Statins:Angiogenic rolePromote formation of new blood vesselsReduction in mortality independent of effect on cholesterol concentrationActivates protein kinase AktLeads to NO productionPromotes endothelial cell survivalEnhances revascularization of ischemic tissue? Inhibits cell apoptosis rather than stimulation of vessel growth Nature Med 2000;6:1004-100

Beneficial Effects of Statins:Individuals of 50 years and older who were prescribed statins had a substantially lowered risk of developing dementia, independent of the presence or absence of untreated hyperlipidemia, or exposure to non statin LLAs. The available data do not distinguish between Alzheimers disease and other forms of dementia. Adjusted relative risk for those prescribed statins was 0.29 (0.13-0.63; p=0.002)Nested case-control study (UK)Jick, et al, Lancet 2000; 356: 1627-310

Beneficial Effects of Statins:Reduction in plasma viscosityDecrease in platelet aggregation and thrombin formationReduction in inflammationDecrease in CRPReduction in fractures0