Approach to Approach to DyslipidemiaDyslipidemia

Dr Zuhair M ShawagfehDr Zuhair M Shawagfeh

FRCPIFRCPI

Covered TopicsCovered Topics

Physiology of Lipid MetabolismPhysiology of Lipid Metabolism Role of lipoproteins in atherosclerosisRole of lipoproteins in atherosclerosis Hypolipidemic Agents ,indications, and Hypolipidemic Agents ,indications, and

side effectsside effects Screening and Risk AssessmentScreening and Risk Assessment Treatment ParadigmsTreatment Paradigms Treatment of Special PopulationTreatment of Special Population

Exogenous Pathway of Lipid Exogenous Pathway of Lipid MetabolismMetabolism

Vessel wall

Cholest

AA

FA

P,

glycerol

Endogenous Pathway of Lipid Endogenous Pathway of Lipid MetabolismMetabolism

Key Enzymes and Cofactors in Key Enzymes and Cofactors in Lipid MetabolismLipid Metabolism

HMG-CoA reductase-reduces HMG-HMG-CoA reductase-reduces HMG-CoA to mevalonic acid in the rate-CoA to mevalonic acid in the rate-limiting step of cholesterol limiting step of cholesterol biosynthesis (mainly liver and biosynthesis (mainly liver and intestine)intestine)

Lipoprotein Lipase- digests TG core Lipoprotein Lipase- digests TG core of CMC and VLDLof CMC and VLDL

LDL Oxidation and LDL Oxidation and AtherosclerosisAtherosclerosis

Increased Atherogenicity of Increased Atherogenicity of Small Dense LDLSmall Dense LDL

Direct AssociationDirect Association– Longer residence time in Longer residence time in

plasma than normal sized plasma than normal sized LDL due to decreased LDL due to decreased recognition by receptors in recognition by receptors in liverliver

– Enhanced interaction with Enhanced interaction with scavenger receptor scavenger receptor promoting foam cell promoting foam cell formationformation

– More susceptible to More susceptible to oxidation due to decreased oxidation due to decreased antioxidants in the coreantioxidants in the core

– Enter and attach more Enter and attach more easily to arterial wall easily to arterial wall

– Endothelial cell dysfunctionEndothelial cell dysfunction

Indirect AssociationIndirect Association– Inverse relationship with Inverse relationship with

HDLHDL– Marker for atherogenic TG Marker for atherogenic TG

remnant accumulationremnant accumulation– Insulin resistanceInsulin resistance

High Density Lipoprotein and High Density Lipoprotein and AtherosclerosisAtherosclerosis

Reverse cholesterol transportReverse cholesterol transport

Maintenance of endothelial functionMaintenance of endothelial function

Protection against thrombosisProtection against thrombosis– With With Apo A-IApo A-I inhibits generation of calcium- inhibits generation of calcium-

induced procoagulant activity on erythrocytes by induced procoagulant activity on erythrocytes by stabilizing cell membranestabilizing cell membrane

Low blood viscosity via permitting red cell Low blood viscosity via permitting red cell deformabilitydeformability

Anti-oxidant properties-may be related to enzymes Anti-oxidant properties-may be related to enzymes called paraoxonasecalled paraoxonase

Lipoprotein (a)Lipoprotein (a) Specialized form of LDL Specialized form of LDL

(apolipoprotein (a) covalently bound (apolipoprotein (a) covalently bound to apo B by disulfide bridge)to apo B by disulfide bridge)

Structural similarity to plasminogen, Structural similarity to plasminogen, thus interfering with fibrinolysisthus interfering with fibrinolysis

Macrophage binding and cholesterol Macrophage binding and cholesterol depositiondeposition

Measured by ELISAMeasured by ELISA Cross-sectional and retrospective Cross-sectional and retrospective

epidemiologic studies have shown epidemiologic studies have shown association between excess Lp (a) association between excess Lp (a) and CHD while prospective results and CHD while prospective results are conflictingare conflicting

Associated with unstable angina and Associated with unstable angina and presence of complex coronary lesionspresence of complex coronary lesions

Commonly detected in premature Commonly detected in premature CHDCHD

Possible role in target organ damage Possible role in target organ damage in presence of HTNin presence of HTN

Indications for screening:Indications for screening:– CHD and no other identifiable CHD and no other identifiable

dyslipidemiadyslipidemia– Strong CHD family history and Strong CHD family history and

no other dyslipidemiano other dyslipidemia– HTN and early premature HTN and early premature

target organ damagetarget organ damage– Hypercholesterolemia Hypercholesterolemia

refractory to statins and bile refractory to statins and bile acid sequestrantsacid sequestrants

Treatment guidelinesTreatment guidelines– Primary goal is to lower LDL to Primary goal is to lower LDL to

target and lowering to <80 target and lowering to <80 may reduce riskmay reduce risk

– If LDL cannot become If LDL cannot become optimized, then Lpa loweing optimized, then Lpa loweing with nicotinic acid (38%) with nicotinic acid (38%) shoud be triedshoud be tried

– Goal <20 in whites Goal <20 in whites

Primary Disorders of Primary Disorders of LDL-Cholesterol MetabolismLDL-Cholesterol Metabolism

Familial hypercholesterolemia-Familial hypercholesterolemia- defect in gene coding for apo B/E LDL receptor defect in gene coding for apo B/E LDL receptor thus reduced clearance of LDL from circulationthus reduced clearance of LDL from circulation– Homozygotes with higher LDL-C levelsHomozygotes with higher LDL-C levels– Excess LDL deposited in arteries as atheroma and in tendons and skin as Excess LDL deposited in arteries as atheroma and in tendons and skin as

xanthomata and xanthelasmaxanthomata and xanthelasma– Hypercholesterolemia, normal TG, genetic or cellular confirmation of LDL Hypercholesterolemia, normal TG, genetic or cellular confirmation of LDL

receptor defectreceptor defect– Usually serum cholesterol levels AND premature CHD in first-degree or 2 second-Usually serum cholesterol levels AND premature CHD in first-degree or 2 second-

degree relativesdegree relatives– Usually requires multiple drugs for treatmentUsually requires multiple drugs for treatment

Familial combined hyperlipidemiaFamilial combined hyperlipidemia– Usually associated with metabolic syndromeUsually associated with metabolic syndrome– 1-2% general population1-2% general population– 1/3-1/2 familial causes of CHD and 10% of premature cases1/3-1/2 familial causes of CHD and 10% of premature cases– Overproduction of hepatically derived apo-B 100 associated with VLDL +/- Overproduction of hepatically derived apo-B 100 associated with VLDL +/-

decreased LDL receptor activitydecreased LDL receptor activity– LDL phenotype B, increased TG, decreased HDL (atherogenic dyslipidemia) LDL phenotype B, increased TG, decreased HDL (atherogenic dyslipidemia) – Phenotypic heterogeneity depends on problems with VLDL or LDL metabolismPhenotypic heterogeneity depends on problems with VLDL or LDL metabolism

Elevated TG and cholesterolElevated TG and cholesterol Elevated LDLElevated LDL Isolated hypertriglyderidemia (rise in VLDL)Isolated hypertriglyderidemia (rise in VLDL)

StatinsStatins Competitive inhibitors of HMG CoA reductase, rate-limiting Competitive inhibitors of HMG CoA reductase, rate-limiting

step in cholesterol biosynthesisstep in cholesterol biosynthesis

Reduction in intrahepatic cholesterol leading to increased Reduction in intrahepatic cholesterol leading to increased LDL receptor turnoverLDL receptor turnover

Most powerful for lowering LDL cholesterolMost powerful for lowering LDL cholesterol

Modest effect on raising HDLModest effect on raising HDL

Reduction in TG due to decreased VLDL synthesis and Reduction in TG due to decreased VLDL synthesis and clearance of VLDL remnants by apo B/E (LDL) receptorsclearance of VLDL remnants by apo B/E (LDL) receptors

Reduction in oxidized and small dense LDL subfractions Reduction in oxidized and small dense LDL subfractions and reduce remnant lipoprotein cholesterol levels and reduce remnant lipoprotein cholesterol levels (reduction of CE transfer from LDL to VLDL)(reduction of CE transfer from LDL to VLDL)

Comparable Efficacy of Statins

Special considerations:

No renal dosing: Atorvastatin and Fluvastatin

Use in chronic liver disease: pravastatin or rosuvastatin

Less drug interactions: pravastatin, fluvastatin, rosuvastatin (not metabolized via CYP3A4)

Less muscle toxicity: Pravastatin and Fluvastatin

Cost-effectiveness: Rosuvastatin, atorvastatin, fluvastatin

Evidence in Primary Evidence in Primary PreventionPrevention

Name of Name of StudyStudy

DesignDesign OutcomeOutcome

West of Scotland West of Scotland Coronary Prevention Coronary Prevention Study (WOSCOPS)Study (WOSCOPS)

6595 men6595 men

Mean TC 272; Mean TC 272; LDL>155LDL>155

diet + placebodiet + placebo

Diet + pravastatinDiet + pravastatin

31 %31 % risk reduction in risk reduction in coronary deaths and coronary deaths and nonfatal MInonfatal MI

Benefit >treating mild Benefit >treating mild HTN but 3 x less than HTN but 3 x less than that in 4S studythat in 4S study

Air Force/Texas Air Force/Texas Coronary Coronary Atherosclerosis Atherosclerosis Prevention StudyPrevention Study

5614 Men; 991 5614 Men; 991 womenwomen

45-73 y.o.45-73 y.o.mean TC 221; LDL mean TC 221; LDL 150 (130-190)150 (130-190)

Diet + placebo Diet + placebo

Diet + lovastatinDiet + lovastatin

37 %37 % risk reduction in risk reduction in coronary eventscoronary events

Evidence in Secondary Evidence in Secondary PreventionPrevention

Name of Name of StudyStudy

DesignDesign OutcomeOutcome

Scandinavian Simvastatin Scandinavian Simvastatin Survival Study (4S)Survival Study (4S)

4444 patients (angina or h/o 4444 patients (angina or h/o MI)MI)

TC 212-309; 5 year f/uTC 212-309; 5 year f/u

Placebo v. simvastatin 20-Placebo v. simvastatin 20-40 qd40 qd

Goal TC <200Goal TC <200

Total mortality (8 v.12%)Total mortality (8 v.12%)

Major events (19 v. 28%)Major events (19 v. 28%)

CHD deaths 42% lowerCHD deaths 42% lower

Revascularization 37%Revascularization 37%

CVA (2.7 vs 4.3)CVA (2.7 vs 4.3)

1% LDL decrease=1.7% RR1% LDL decrease=1.7% RR

CARECARE 4159 h/o MI 2 yrs prior4159 h/o MI 2 yrs prior

Borderline Average TC Borderline Average TC 209209; ; LDL 139; HDL 39LDL 139; HDL 39

Pravastatin 40 qhs x 5 yrsPravastatin 40 qhs x 5 yrs

Coronary death/MI 10.2 v. Coronary death/MI 10.2 v. 13.213.2

Revascularization 14.1 v. Revascularization 14.1 v. 18.818.8

Stroke frequency 2.6 v. 3.8Stroke frequency 2.6 v. 3.8

% LDL reduction % LDL reduction unrelated to eventsunrelated to events

LIPIDLIPID 9014 men and women with 9014 men and women with recent MI or unstable recent MI or unstable anginaangina

TC 155-270TC 155-270

Pravastatin or placeboPravastatin or placebo

CHD deaths 6.4 v. 8.3CHD deaths 6.4 v. 8.3

Total mortality 11 v. 14Total mortality 11 v. 14

Stroke 20% decreaseStroke 20% decrease

Bypass 8.9 v. 11.3Bypass 8.9 v. 11.3

Heart Protection StudyHeart Protection Study 20,536; simvastatin 40 qd; 20,536; simvastatin 40 qd; 33% LDL<116;25% 116-33% LDL<116;25% 116-135; 42% LDL>135 h/o CVD, 135; 42% LDL>135 h/o CVD, DM, or treated HTN; 5.5 yrsDM, or treated HTN; 5.5 yrs

All cause mortality RRR 13%All cause mortality RRR 13%

CHD death RRR 17%CHD death RRR 17%

Major events RRR 24%Major events RRR 24%

Similar in 3 tertiles of Similar in 3 tertiles of LDL and in those with LDL and in those with LDL<100LDL<100

Mechanism of Benefit of Mechanism of Benefit of Statins in Secondary Statins in Secondary

PreventionPrevention Regression of atherosclerosisRegression of atherosclerosis Plaque stabilizationPlaque stabilization Reduced inflammationReduced inflammation Decreased thrombogenicityDecreased thrombogenicity Reversal of endothelial dysfunctionReversal of endothelial dysfunction OthersOthers

– Reduced monocyte adhesion to endotheliumReduced monocyte adhesion to endothelium– Reduced oxidative modification of LDLReduced oxidative modification of LDL– Increased mobilization and differentiation of Increased mobilization and differentiation of

endothelial progenitor cells leading to new endothelial progenitor cells leading to new vessel formationvessel formation

Adverse Effects of StatinsAdverse Effects of Statins In general, less than with other agents. Fairly tolerable and safeIn general, less than with other agents. Fairly tolerable and safe MyopathyMyopathy

– Ranges from myalgias (2-11%), myositis(0.5%) to rhabdomyolysis (<0.1%) (possibly ARF)Ranges from myalgias (2-11%), myositis(0.5%) to rhabdomyolysis (<0.1%) (possibly ARF)– Few weeks-4 months onsetFew weeks-4 months onset– Symptoms and CK should normalize over days to one month after d/cSymptoms and CK should normalize over days to one month after d/c– Pravastatin and Fluvastatin less riskPravastatin and Fluvastatin less risk– Increased risk in Increased risk in

ARF/CRFARF/CRF Obstructive liver diseaseObstructive liver disease HypothyroidismHypothyroidism Concomittant use of drugs interfering with CYP3A4Concomittant use of drugs interfering with CYP3A4???? Gemfibrozil combined therapyGemfibrozil combined therapy

HepaticHepatic– 0.5 to 3% persistent elevations in amino-transferases in first 3 months and dose-0.5 to 3% persistent elevations in amino-transferases in first 3 months and dose-

dependentdependent– Several randomized trials have found no difference compared with placeboSeveral randomized trials have found no difference compared with placebo– FDA recommends LFTs before and 12 weeks after starting and with any dose elevation FDA recommends LFTs before and 12 weeks after starting and with any dose elevation

and periodicallyand periodically CNSCNS

– Case reports of memory loss associated with statins (mainly lipophilic)Case reports of memory loss associated with statins (mainly lipophilic)– If memory loss and recent initiation of statin, then d/c and use a hydrophilic statin such as If memory loss and recent initiation of statin, then d/c and use a hydrophilic statin such as

pravastatin or rosuvastatinpravastatin or rosuvastatin– No significant difference with placebo in trialsNo significant difference with placebo in trials

Fibric Acid DerivativesFibric Acid Derivatives

Decrease Triglycerides (35-50%)Decrease Triglycerides (35-50%)– Reduced hepatic secretion of VLDL through activation of PPAR-alpha receptors in Reduced hepatic secretion of VLDL through activation of PPAR-alpha receptors in

liverliver– Stimulate lipoprotein lipase and thus clearance of TG-rich lipoproteinsStimulate lipoprotein lipase and thus clearance of TG-rich lipoproteins

Raise HDL (15-25%)Raise HDL (15-25%)– Direct stimulation of HDL apolipoprotein synthesis A-I,IIDirect stimulation of HDL apolipoprotein synthesis A-I,II– Increased transfer of apo A-I with diminished cholesterol transfer from HDL to Increased transfer of apo A-I with diminished cholesterol transfer from HDL to

VLDLVLDL Increases LDL buoyancyIncreases LDL buoyancy May also improve endothelial function and favorable effect on macrophage responses May also improve endothelial function and favorable effect on macrophage responses

(possible reduction in CHD risk independent of effect on lipoproteins)(possible reduction in CHD risk independent of effect on lipoproteins) AgentsAgents

– Gemfibrozil- 600 mg po BID (11% raise in HDL). Modest LDL reduction but little Gemfibrozil- 600 mg po BID (11% raise in HDL). Modest LDL reduction but little effect in combined hyperlipidemia. Can increase LDL in pure hypertriglyderidemiaeffect in combined hyperlipidemia. Can increase LDL in pure hypertriglyderidemia

– Fenofibrate 200 mg capsules or iii caps 67 mg qd (renal dosing and can decrease Fenofibrate 200 mg capsules or iii caps 67 mg qd (renal dosing and can decrease Cyclosporin levels). Better for LDL loweringCyclosporin levels). Better for LDL lowering

Side effectsSide effects– Gallstone formationGallstone formation– Dyspepsia, diarrhea, nausea, vomiting, abdominal pain, eczema, rash, vertigo and Dyspepsia, diarrhea, nausea, vomiting, abdominal pain, eczema, rash, vertigo and

myalgiasmyalgias Adverse drug interactionAdverse drug interaction

– Gemfibrozil- inhibits glucuronidation of lipophilic statins and increases levels thus Gemfibrozil- inhibits glucuronidation of lipophilic statins and increases levels thus increasde risk of myopathy. Also decreases warfarin by 30%increasde risk of myopathy. Also decreases warfarin by 30%

Bile Acid SequestrantsBile Acid Sequestrants Lower LDL (10-15%)Lower LDL (10-15%)

BINDING BILE ACIDS IN INTESTINE CAUSING A DECLINE IN HEPATIC CHOLESTEROL BINDING BILE ACIDS IN INTESTINE CAUSING A DECLINE IN HEPATIC CHOLESTEROL POOL; THUS SYNTHESIS OF apo B/E (LDL) RECEPTORSPOOL; THUS SYNTHESIS OF apo B/E (LDL) RECEPTORS

Max doses cause 30% reductionMax doses cause 30% reduction– Raise HDLRaise HDL

Intestinal formation of nascent HDLIntestinal formation of nascent HDL

Available agents Available agents – Cholestyramine 8 grams/day. 24-30 grams/day can lower LDL up to 24%Cholestyramine 8 grams/day. 24-30 grams/day can lower LDL up to 24%– Colestipol 10 grams/dayColestipol 10 grams/day– Colesevelam 1.5-4.5 grams/dColesevelam 1.5-4.5 grams/d

Adverse effectsAdverse effects– Usually limit useUsually limit use– Mainly GI (nausea, bloating, cramping)- least problematic with colesevelamMainly GI (nausea, bloating, cramping)- least problematic with colesevelam– Increased liver enzymesIncreased liver enzymes– Also drug interactions (impair absorption)Also drug interactions (impair absorption)

Digoxin, warfarin, and fat soluble vitamins (give one hour before or 4 hours after bile Digoxin, warfarin, and fat soluble vitamins (give one hour before or 4 hours after bile acid sequestrant)acid sequestrant)

Contraindications: pts with elevated TGContraindications: pts with elevated TG

Nicotinic AcidNicotinic Acid Mechanism of ActionMechanism of Action

– Inhibits hepatic VLDL production and its metabolite LDLInhibits hepatic VLDL production and its metabolite LDL– Raises HDL by reducing lipid transfer of cholesterol from HDL to VLDL and by delaying HDL clearanceRaises HDL by reducing lipid transfer of cholesterol from HDL to VLDL and by delaying HDL clearance– Increase in LDL sizeIncrease in LDL size– Reduction in plasma fibrinogen levelsReduction in plasma fibrinogen levels

Formulations and dosingFormulations and dosing– Immediate release (crystalline): 100 TID and titrated to toleranceImmediate release (crystalline): 100 TID and titrated to tolerance– Sustained release Sustained release

NiacorNiacor Niaspan: 500 mg qhs x one month and then titrated to 1000 mg usually given daily after evenng Niaspan: 500 mg qhs x one month and then titrated to 1000 mg usually given daily after evenng

mealmeal

– 1-1.5 grams/day for HDL raising1-1.5 grams/day for HDL raising– 3 grams/day for VLDL and LDL lowering and possibly lowering lipoprotein a levels3 grams/day for VLDL and LDL lowering and possibly lowering lipoprotein a levels– OTC IR preps are cheaper and effectiveOTC IR preps are cheaper and effective– OTC preps labeles “NO FLUSH” usually not efficaciousOTC preps labeles “NO FLUSH” usually not efficacious

Side effectsSide effects– Flushing (less common with controlled release) minimized with ASA 30 minutes before and limited in Flushing (less common with controlled release) minimized with ASA 30 minutes before and limited in

7-10 days7-10 days– Nausea, paresthesias, pruritis (20% each)Nausea, paresthesias, pruritis (20% each)– Elevation of hepatocellular enzymes and possible hepatotoxicity, jaundice and fulminant hepatitis Elevation of hepatocellular enzymes and possible hepatotoxicity, jaundice and fulminant hepatitis

(generally less common with Niaspan and crystalline niacin)(generally less common with Niaspan and crystalline niacin)– Insulin resistance and worsening hyperglycemia (less with crystalline Niaspan)Insulin resistance and worsening hyperglycemia (less with crystalline Niaspan)– Hyperuricemia (AVOID IF H/O GOUT)Hyperuricemia (AVOID IF H/O GOUT)– Hypotension in combination with other vasodialtors (can increase unstable angina)Hypotension in combination with other vasodialtors (can increase unstable angina)

EzetimibeEzetimibe(Zettia)(Zettia)

Mechanism:Mechanism: – impairs dietary and biliary cholesterol absorption at the brush border of impairs dietary and biliary cholesterol absorption at the brush border of

the intestines without affecting TG or fat-soluble vitaminsthe intestines without affecting TG or fat-soluble vitamins– possible Niemann-Pick C1 like protein involved in cholesterol transportpossible Niemann-Pick C1 like protein involved in cholesterol transport– LDL decrease 15-20%LDL decrease 15-20%– Trivial effects on HDL and TGTrivial effects on HDL and TG

Also adjunctive therapy to statins but same effect with higher dose of statin as Also adjunctive therapy to statins but same effect with higher dose of statin as in one study 10 zettia and 10 atorvastatin same effect as 80 atorvastatinin one study 10 zettia and 10 atorvastatin same effect as 80 atorvastatin

IndicationsIndications– Avoiding high doses of statinsAvoiding high doses of statins– Very high LDL (FCH) not sufficiently controlled on statinsVery high LDL (FCH) not sufficiently controlled on statins

Adverse effectsAdverse effects– Only 20% absorption so lower side-effect profileOnly 20% absorption so lower side-effect profile– Higher incidence of myopathy and elevated transaminases when Higher incidence of myopathy and elevated transaminases when

coadministered with a statincoadministered with a statin

Should not be used as the first-line agent in lowering LDLShould not be used as the first-line agent in lowering LDL Check LFTs prior to starting in combo with statinsCheck LFTs prior to starting in combo with statins No definite clinical outcome studies availableNo definite clinical outcome studies available

Effect of Lifestyle ModificationEffect of Lifestyle Modification DietDiet

– Decreased saturated fat (decrease LDL)Decreased saturated fat (decrease LDL)– Replacing saturated and trans unsaturated fats with unhydrogenated Replacing saturated and trans unsaturated fats with unhydrogenated

monounsaturated or polyunsaturated fatsmonounsaturated or polyunsaturated fats– Recommended dietRecommended diet

Dietary cholesterol <200 mg/d; total fat <30%; saturated fat <7%Dietary cholesterol <200 mg/d; total fat <30%; saturated fat <7% CHO (whole grains, fruits,veggies) 50-60% total caloriesCHO (whole grains, fruits,veggies) 50-60% total calories Dietary fiber 20-30 g/dDietary fiber 20-30 g/d Protein 10-25 g/dayProtein 10-25 g/day Plant stanols/sterols 2 grams/dayPlant stanols/sterols 2 grams/day

– Effect of LDL lowering should be evident in 6-12 monthsEffect of LDL lowering should be evident in 6-12 months– Elevated BMI associated with decreased dietary responseElevated BMI associated with decreased dietary response– Referral to dietitian helpfulReferral to dietitian helpful

ExerciseExercise– In a prospective study of 111 sedentary men and women with dyslipidemia In a prospective study of 111 sedentary men and women with dyslipidemia

randomized to different levels of exercise, decrease in VLDL TG and increase in LDL randomized to different levels of exercise, decrease in VLDL TG and increase in LDL size observed. Increase in HDL and size and largest effect on LDL seen with high size observed. Increase in HDL and size and largest effect on LDL seen with high amount high intensity exerciseamount high intensity exercise

– Mechanisms of benefit: reduction in CETP, elevation in LCAT, reduced hepatic lipase Mechanisms of benefit: reduction in CETP, elevation in LCAT, reduced hepatic lipase and elevated LPL activityand elevated LPL activity

– Possible effect on LDL particle sizePossible effect on LDL particle size– Moderate intensity exercise (3-4 mi/hr) for 30 minutes on most days of the weekModerate intensity exercise (3-4 mi/hr) for 30 minutes on most days of the week

Diet SupplementsDiet Supplements Fish Oil (source of omega-3 polyunsaturated fatty acids)Fish Oil (source of omega-3 polyunsaturated fatty acids)

– Salmon, flaxseed, canola oil, soybean oil and nutsSalmon, flaxseed, canola oil, soybean oil and nuts– At high doses > 6 grams/day reduces TG by inhibition of VLDL-TG synthesis and At high doses > 6 grams/day reduces TG by inhibition of VLDL-TG synthesis and

apolipoprotein B apolipoprotein B – Possibly decreases small LDL (by inhibiting CETP)Possibly decreases small LDL (by inhibiting CETP)– Several studies have shown lower risk of coronary eventsSeveral studies have shown lower risk of coronary events– 2 servings of fish/week recommended??2 servings of fish/week recommended??– Pharmacologic use restricted to refractory hypertriglyceridemia Pharmacologic use restricted to refractory hypertriglyceridemia – Number of undesirable side effects (mainly GI)Number of undesirable side effects (mainly GI)

Soy Soy – Source of phytoestrogens inhibiting LDL oxidationSource of phytoestrogens inhibiting LDL oxidation– 25-50 grams/day reduce LDL by 4-8%25-50 grams/day reduce LDL by 4-8%– Effectiveness in postmenopausal women is questionableEffectiveness in postmenopausal women is questionable

GarlicGarlic– Mixed results of clinical trialsMixed results of clinical trials– In combination with fish oil and large doses (900-7.2 grams/d), decreases in LDL observedIn combination with fish oil and large doses (900-7.2 grams/d), decreases in LDL observed

Cholesterol-lowering MargarinesCholesterol-lowering Margarines– Benecol and Take Control containing plant sterols and stanolsBenecol and Take Control containing plant sterols and stanols– Inhibit cholesterol absorption but also promote hepatic cholesterol synthesisInhibit cholesterol absorption but also promote hepatic cholesterol synthesis– 10-20% reduction in LDL and TC however no outcome studies10-20% reduction in LDL and TC however no outcome studies– AHA recommends use only in hypercholesterolemia pts or those with a cardiac event AHA recommends use only in hypercholesterolemia pts or those with a cardiac event

requiring LDL treatmentrequiring LDL treatment Other agents include soluble fiber, nuts (esp. walnuts), green teaOther agents include soluble fiber, nuts (esp. walnuts), green tea Overall a combination diet with multiple cholesterol-lowering agents causes much more Overall a combination diet with multiple cholesterol-lowering agents causes much more

significant LDL reductions significant LDL reductions

Measurement of Measurement of LipoproteinsLipoproteins

Lipoprotein analysis 12-14 hours fasting Lipoprotein analysis 12-14 hours fasting TC and HDL-C can be measured fasting or non-fastingTC and HDL-C can be measured fasting or non-fasting LDL-Cholesterol = Total cholesterol –VLDL (1/5 TG)-HDLLDL-Cholesterol = Total cholesterol –VLDL (1/5 TG)-HDL

– Validity depends on TG <400 mg/dLValidity depends on TG <400 mg/dL– Measured directly if patients have profound hypertrigMeasured directly if patients have profound hypertrig– Errors in TC, HDL, and TG can affect valuesErrors in TC, HDL, and TG can affect values

Non-HDL cholesterol= TC – HDL-CNon-HDL cholesterol= TC – HDL-C– All cholesterol in atherogenic lipoproteins incl LDL, Lipoprotein a, IDL, All cholesterol in atherogenic lipoproteins incl LDL, Lipoprotein a, IDL,

VLDLVLDL Acute phase response (i.e. MI, surgical trauma or infection)Acute phase response (i.e. MI, surgical trauma or infection)

– Can reduce levels of TC, HDL, LDL, apo A+B through impairment of Can reduce levels of TC, HDL, LDL, apo A+B through impairment of hepatic lipoprotein production and metabolismhepatic lipoprotein production and metabolism

– Raise Lpa and TGRaise Lpa and TG– Lipoprotein analysis should be done as outpatient one month after Lipoprotein analysis should be done as outpatient one month after

eventevent

Risk AssessmentRisk Assessment CHD equivalents:CHD equivalents:

– Symptomatic carotid artery diseaseSymptomatic carotid artery disease– Peripheral arterial diseasePeripheral arterial disease– AAAAAA– DM DM – Multiple risk factors that confer a 10-year risk of CHD > 20%Multiple risk factors that confer a 10-year risk of CHD > 20%

Identify Identify major risk factorsmajor risk factors other than LDL: other than LDL:– SmokingSmoking– HTN BPHTN BP > >140/90 or on anti-hypertensive medication140/90 or on anti-hypertensive medication– Low HDL <40 mg/dLLow HDL <40 mg/dL– Family history premature CHD (CHD in men 1Family history premature CHD (CHD in men 1stst degree relative <55; women degree relative <55; women

<65 y.o.)<65 y.o.)– Age (men > or =45; women >or =55)Age (men > or =45; women >or =55)

Other potential risk factorsOther potential risk factors– Chronic renal insufficiency (Cr > 1.5 mg/dL OR GFR <60 cc/min) per Up-To-Chronic renal insufficiency (Cr > 1.5 mg/dL OR GFR <60 cc/min) per Up-To-

DateDate– Obesity, physical inactivity, impaired fasting glucose, markers for Obesity, physical inactivity, impaired fasting glucose, markers for

inflammationinflammation HDL > 60 mg/dL is a negative risk factorHDL > 60 mg/dL is a negative risk factor If patient without CHD or equivalent has 2 or more major risk factors, then If patient without CHD or equivalent has 2 or more major risk factors, then

calculate the Framingham risk (age,TC,HDL,smoking,SBP)calculate the Framingham risk (age,TC,HDL,smoking,SBP)

Validation study found Framingham CHD predictor worked well in white and black population but overestimated risk in Japanese American, Hispanic men and native American women and other studies have shown possible overestimation in European and Asian populations

New Guidelines for LDL GoalNew Guidelines for LDL Goal

Risk categoryRisk category Goal LDL (mg/Dl)Goal LDL (mg/Dl)

CHD (CHD risk equivalent)CHD (CHD risk equivalent) <100 <100

<70 optional<70 optional

2 or more major risk factors + 2 or more major risk factors + 10 yr >20%10 yr >20%

<100 <100

<70 optional<70 optional

2 or more major risk factors 2 or more major risk factors +10 yr 10-20%+10 yr 10-20%

<130<130

<100 optional<100 optional

2 or more major risk factors 2 or more major risk factors +10 yr risk <10%+10 yr risk <10%

0-1 major risk0-1 major risk

<130<130

<160<160

Elevated LDLElevated LDL

Statins are first choice and selection is based on extent of Statins are first choice and selection is based on extent of LDL reduction, cost and reduction in clinical CHD events as LDL reduction, cost and reduction in clinical CHD events as well as presence of renal impairmentwell as presence of renal impairment

30-35% decrease in LDL-C with equivalent doses30-35% decrease in LDL-C with equivalent doses

Titrate statin dose at 3-4 week intervalsTitrate statin dose at 3-4 week intervals

Doubling statin dose reduced LDL an additional 6%Doubling statin dose reduced LDL an additional 6% Consider adding second agent instead of dose increaseConsider adding second agent instead of dose increase Variable drug response depending on endogenous v. Variable drug response depending on endogenous v.

exogenous hypercholesterolemiaexogenous hypercholesterolemia

Second agents may include bile acid resins (15%), Second agents may include bile acid resins (15%), ezetimibe (20%), or plant stenol/sterol margarine (10%)ezetimibe (20%), or plant stenol/sterol margarine (10%)

Niacin may be added as a third agent if neededNiacin may be added as a third agent if needed

Mixed (Combined Mixed (Combined Hyperlipidemia)Hyperlipidemia)

Elevated LDL and/ or triglyceridesElevated LDL and/ or triglycerides

Objective is to achieve LDL goalsObjective is to achieve LDL goals

With very high TG> 400, start with fibrate or niacinWith very high TG> 400, start with fibrate or niacin

Then treat LDL with statinThen treat LDL with statin

If LDL-C goal achieved, but TG>200, non-HDL-C should be If LDL-C goal achieved, but TG>200, non-HDL-C should be targetedtargeted

Non-HDL goal 30 above LDL goal Non-HDL goal 30 above LDL goal

Statin titration dose OR Statin-fibrate OR Statin-Niacin Statin titration dose OR Statin-fibrate OR Statin-Niacin combinations more effective in this type of dyslipidemia but combinations more effective in this type of dyslipidemia but adverse reactions more common with combined treatment so adverse reactions more common with combined treatment so benefit/risk ratio consideredbenefit/risk ratio considered– Titration for mild TG elevationsTitration for mild TG elevations– Combination TX for moderate to severe TG elevationsCombination TX for moderate to severe TG elevations

Isolated Low HDLIsolated Low HDL Treatment Indications of Treatment Indications of

Isolated low HDLIsolated low HDL– CHD OR CHD equivalentCHD OR CHD equivalent– if first-degree relative early if first-degree relative early

onset CHD and similar lipid onset CHD and similar lipid profileprofile

Weight management, exercise, Weight management, exercise, and smoking cessationand smoking cessation

Niacin +/- gemfibrozilNiacin +/- gemfibrozil CETP inhibitors (NEW and CETP inhibitors (NEW and

investigational)investigational)

Treatment GuidelinesTreatment Guidelines Always Consider secondary causes of dyslipidemia (DM, hypothyroidism, Always Consider secondary causes of dyslipidemia (DM, hypothyroidism,

obstructive liver disease, CRF or nephrotic syndrome or drugs)obstructive liver disease, CRF or nephrotic syndrome or drugs) All patients with LDL above goal start with adequate trial of lifestyle modification All patients with LDL above goal start with adequate trial of lifestyle modification

only but concomitant drug therapy may be appropriate if:only but concomitant drug therapy may be appropriate if:– LDL >220 or LDL >220 or > > 190 if >= 2 risk factors190 if >= 2 risk factors– Pre-existing CHD or CHD equivalentPre-existing CHD or CHD equivalent

If CHD or risk equivalent and? significantly above goal, then start If CHD or risk equivalent and? significantly above goal, then start pharmacotherapy (preferably statin) immediatelypharmacotherapy (preferably statin) immediately

If CHD or equivalent and LDL goal <100 not achieved on maximal statin If CHD or equivalent and LDL goal <100 not achieved on maximal statin (atorvastatin 80 or rosuvastatin 40), then additional agent should be added (atorvastatin 80 or rosuvastatin 40), then additional agent should be added based on abnormalities in other lipoproteinsbased on abnormalities in other lipoproteins

In no CHD or CHD equivalent, consider drug therapy with statin if after adequate In no CHD or CHD equivalent, consider drug therapy with statin if after adequate lifestyle trial:lifestyle trial:– LDL >190 if 0 or 1 risk factor LDL >190 if 0 or 1 risk factor – LDL >160 if 2 or more risk factors if 10 yr risk <10%; 130 if risk 10-20%LDL >160 if 2 or more risk factors if 10 yr risk <10%; 130 if risk 10-20%

If persistent elevation in LDL purely, then add bile acid sequestrant or zettiaIf persistent elevation in LDL purely, then add bile acid sequestrant or zettia In patients with ACS, atorvastatin 80 mg/day should be started soon after In patients with ACS, atorvastatin 80 mg/day should be started soon after

hospitalizationhospitalization– PROVE-IT TIMI 22 Trial, MIRACLE, A to Z trialPROVE-IT TIMI 22 Trial, MIRACLE, A to Z trial

When LDL goal reached but TG >200, then consider non-HDL cholesterol and treat When LDL goal reached but TG >200, then consider non-HDL cholesterol and treat to goal 30 above LDLto goal 30 above LDL

In patients with ACS, atorvastatin 80 mg/day should be started soon after In patients with ACS, atorvastatin 80 mg/day should be started soon after hospitalization (event reduction and LDL lowering effect)hospitalization (event reduction and LDL lowering effect)– PROVE-IT TIMI 22 Trial, MIRACLE, A to Z trialPROVE-IT TIMI 22 Trial, MIRACLE, A to Z trial

ElderlyElderly Should be individualized based on chronologic and physiologic ageShould be individualized based on chronologic and physiologic age Secondary prevention studies support treatmentSecondary prevention studies support treatment

– CARE :50% patients >60 derived similar benefits as in younger CARE :50% patients >60 derived similar benefits as in younger patientspatients

– HPS :% reduction in events similar in < or > 65 y.o.HPS :% reduction in events similar in < or > 65 y.o. Cardiovascular Health Study showed benefit in primary prevention Cardiovascular Health Study showed benefit in primary prevention

in >65 y.o.in >65 y.o. All major statin trials and VA-HIT trial have shown reduction of All major statin trials and VA-HIT trial have shown reduction of

atherothrombotic stroke with lipid-loweringatherothrombotic stroke with lipid-lowering ATP III recommends diet as first line of primary intervention but ATP III recommends diet as first line of primary intervention but

drugs can be considered if multiple risk factors possibly with LDL drugs can be considered if multiple risk factors possibly with LDL >160>160

Underutilization of lipid-lowering drugs in elderly due toUnderutilization of lipid-lowering drugs in elderly due to– Concern for safety (hapatic/renal impairment)Concern for safety (hapatic/renal impairment)– Time course to benefit Time course to benefit

Adults With DMAdults With DM Both primary and secondary intervention trials have shown benefit Both primary and secondary intervention trials have shown benefit

and reduction of CVD in diabetic subgroups treated with lipid-and reduction of CVD in diabetic subgroups treated with lipid-lowering agents (HPS and CARE trial showed significant outcome lowering agents (HPS and CARE trial showed significant outcome improvement with statins even at LDL <116)improvement with statins even at LDL <116)

Despite their often elevated TG and low HDL due to insulin Despite their often elevated TG and low HDL due to insulin resistance, etc. LDL should be primary goalresistance, etc. LDL should be primary goal

Niacin-Statin combination can be particularly effectiveNiacin-Statin combination can be particularly effective LDL goal <100 and threshold for drug tx is 130 and optional 100-LDL goal <100 and threshold for drug tx is 130 and optional 100-

129 if diet effective129 if diet effective ADA 2004 guidelines: adults >40 y.o. and TC >135, statin to lower ADA 2004 guidelines: adults >40 y.o. and TC >135, statin to lower

LDL by 30%LDL by 30% Based on HPS, drug therapy should not be postponed if LDL goal Based on HPS, drug therapy should not be postponed if LDL goal

unlikely achieved by nonpharmacologic meansunlikely achieved by nonpharmacologic means TZDs are insulin sensitizers and affect adipose tissue distribution TZDs are insulin sensitizers and affect adipose tissue distribution

by decrease in intraabdominal fat; shown to increase HDL and by decrease in intraabdominal fat; shown to increase HDL and peak LDL buoyancy; rosiglitazone/atorvastatin led to reduction in peak LDL buoyancy; rosiglitazone/atorvastatin led to reduction in TG/LDL and elevation in HDL (Promising but more studies TG/LDL and elevation in HDL (Promising but more studies required)required)

Hyperlipidemia in Nephrotic Hyperlipidemia in Nephrotic SyndromeSyndrome

Marked hypercholesterolemiaMarked hypercholesterolemia– Increased apo B lipoprotein synthesis by liver due to decreased oncotic Increased apo B lipoprotein synthesis by liver due to decreased oncotic

pressurepressure– Decreased catabolismDecreased catabolism

HypertriglyceridemiaHypertriglyceridemia– Slow conversion of VLDL to IDL then LDLSlow conversion of VLDL to IDL then LDL– Decreased LDL-receptor clearance of LDL and IDLDecreased LDL-receptor clearance of LDL and IDL

Associated RisksAssociated Risks– Small study showed RR 5.5 for MI and 2.8 for coronary deathSmall study showed RR 5.5 for MI and 2.8 for coronary death– Possible progression of glomerular diseasePossible progression of glomerular disease

Treatment rationaleTreatment rationale– Tx of underlying disease (i.e. steroids in minimal change disease)Tx of underlying disease (i.e. steroids in minimal change disease)– Little benefit in diet therapy (vegetable soy diet rich in MUFA/PUFA) and low Little benefit in diet therapy (vegetable soy diet rich in MUFA/PUFA) and low

protein with 20-30 % reduction in lipidsprotein with 20-30 % reduction in lipids– Best drug tx is statinsBest drug tx is statins– ACE-Inhibitor or ARB by decreasing protein excretion cause 10-20% ACE-Inhibitor or ARB by decreasing protein excretion cause 10-20%

reduction in TC and LDLreduction in TC and LDL

Thank youThank you