hypercholesterolemia, hypertriglyceridemia,dignosis, management, complications, prevention

1. DYSLIPIDEMIADYSLIPIDEMIA

2. Dr. Md. Toufiqur RahmanDr. Md. Toufiqur Rahman
MBBS(DMC),MBBS(DMC), FCPS(Medicine),FCPS(Medicine),
MD(Cardiology),MD(Cardiology), FACCFACC,, FRCP,FRCP, FESC,FESC,
FAHAFAHA,, FAPSICFAPSIC,, FAPSCFAPSC
Associate Professor of CardiologyAssociate Professor of Cardiology
National Institute of CardiovascularNational Institute of Cardiovascular
Diseases(NICVD), Dhaka.Diseases(NICVD), Dhaka.

3. 1.20
1.100
1.063
1.019
1.006
0.95
5 10 20 40 60 80
1000
Chylomicron
Remnants
VLDL
LDL-R
HDL2
HDL3DL3
Particle Size (nm)
Density(g/ml)
Chylomicron
VLDL
Remnants
Lipoprotein ParticlesLipoprotein Particles
Lp(a)
IDL
Only these lipoprotein particles
found in plaque at biopsy.
1.050

4. Rationale for therapeutic lowering of Apo B lipoproteins: decrease the
probability of inflammatory response to retention
High Plasma Apo BHigh Plasma Apo B
Lipoprotein Levels PromoteLipoprotein Levels Promote
AtherogenesisAtherogenesis
Blood
Apo B lipoprotein
particles
Modification
Macrophage
Monocytes bind to
adhesion molecules
Smooth muscle
Foam cell
Inflammatory
response

5. 5
Intestinal Cholesterol AbsorptionIntestinal Cholesterol Absorption
Bays H et al. Expert Opin Pharmacother 2003;4:779-790.
IntestinalIntestinal
epithelial cellepithelial cell
BiliaryBiliary
cholesterolcholesterol
DietaryDietary
cholesterolcholesterol
LuminalLuminal
cholesterolcholesterol
MicellarMicellar
cholesterolcholesterol
BileBile
acidacid
Cholesteryl esters
Free
cholesterol
excretion
uptakeuptake
ACATACAT
ABCG5ABCG5
ABCG8ABCG8
(esterification)
MTPMTP
CMCM
ThroughThrough
lymphaticlymphatic
system tosystem to
the liverthe liver

6. Exogenous Pathway of LipidExogenous Pathway of Lipid
MetabolismMetabolism
Vessel
wall
Cholest
AA
FA
P,
glycerol

7. Endogenous Pathway of LipidEndogenous Pathway of Lipid
MetabolismMetabolism

8. HDL MetabolismHDL Metabolism

9. Key Enzymes and Cofactors inKey Enzymes and Cofactors in
Lipid MetabolismLipid Metabolism
• HMG-CoA reductase-reduces HMG-CoA to mevalonic acid in theHMG-CoA reductase-reduces HMG-CoA to mevalonic acid in the
rate-limiting step of cholesterol biosynthesis (mainly liver andrate-limiting step of cholesterol biosynthesis (mainly liver and
intestine)intestine)
• Lipoprotein Lipase- digests TG core of CMC and VLDLLipoprotein Lipase- digests TG core of CMC and VLDL
• Hepatic Lipase-conversion of IDL to LDLHepatic Lipase-conversion of IDL to LDL
• CETP-transfers cholesteryl esters from HDL to other lipoproteins inCETP-transfers cholesteryl esters from HDL to other lipoproteins in
exchange for TGexchange for TG
• LCAT(lecithin cholesterol acyl transferase) conversion of cholesterolLCAT(lecithin cholesterol acyl transferase) conversion of cholesterol
to cholesterol estersto cholesterol esters
• Apolipoprotein A-major protein of HDL activating many reactionsApolipoprotein A-major protein of HDL activating many reactions
• Apo-B-major protein of VLDL, IDL, and LDLApo-B-major protein of VLDL, IDL, and LDL
• Apo-CII and Apo E obtained from HDL by CMC and VLDL forApo-CII and Apo E obtained from HDL by CMC and VLDL for
activation of LPL and receptor recognition respectivelyactivation of LPL and receptor recognition respectively

10. LDL Oxidation and AtherosclerosisLDL Oxidation and Atherosclerosis

11. Mechanism of AtherogenicMechanism of Atherogenic
DyslipidemiaDyslipidemia
Insulin resistance
increased NEFA and
glucose flux to liver
Insulin resistance
and decreased
apo-B
degradation
Insulin
resistance
and
decreased
LPL
IR impairs
LDLR
Increased
VLDL
FCHL
DM II
Metabolic
syndrome

12. Increased Atherogenicity of SmallIncreased Atherogenicity of Small
Dense LDLDense LDL
• Direct AssociationDirect Association
– Longer residence time inLonger residence time in
plasma than normal sized LDLplasma than normal sized LDL
due to decreased recognitiondue to decreased recognition
by receptors in liverby receptors in liver
– Enhanced interaction withEnhanced interaction with
scavenger receptor promotingscavenger receptor promoting
foam cell formationfoam cell formation
– More susceptible to oxidationMore susceptible to oxidation
due to decreased antioxidantsdue to decreased antioxidants
in the corein the core
– Enter and attach more easilyEnter and attach more easily
to arterial wallto arterial wall
– Endothelial cell dysfunctionEndothelial cell dysfunction
• Indirect AssociationIndirect Association
– Inverse relationship withInverse relationship with
HDLHDL
– Marker for atherogenic TGMarker for atherogenic TG
remnant accumulationremnant accumulation
– Insulin resistanceInsulin resistance

13. High Density Lipoprotein andHigh Density Lipoprotein and
AtherosclerosisAtherosclerosis
• Reverse cholesterol transportReverse cholesterol transport
• Maintenance of endothelial functionMaintenance of endothelial function
• Protection against thrombosisProtection against thrombosis
– WithWith Apo A-IApo A-I inhibits generation of calcium-inducedinhibits generation of calcium-induced
procoagulant activity on erythrocytes by stabilizingprocoagulant activity on erythrocytes by stabilizing
cell membranecell membrane
• Low blood viscosity via permitting red cell deformabilityLow blood viscosity via permitting red cell deformability
• Anti-oxidant properties-may be related to enzymes calledAnti-oxidant properties-may be related to enzymes called

14. Lipoprotein (a)Lipoprotein (a)
• Specialized form of LDLSpecialized form of LDL
(apolipoprotein (a) covalently bound to(apolipoprotein (a) covalently bound to
apo B by disulfide bridge)apo B by disulfide bridge)
• Structural similarity to plasminogen,Structural similarity to plasminogen,
thus interfering with fibrinolysisthus interfering with fibrinolysis
• Macrophage binding and cholesterolMacrophage binding and cholesterol
depositiondeposition
• Measured by ELISAMeasured by ELISA
• Cross-sectional and retrospectiveCross-sectional and retrospective
epidemiologic studies have shownepidemiologic studies have shown
association between excess Lp (a) andassociation between excess Lp (a) and
CHD while prospective results areCHD while prospective results are
conflictingconflicting
• Associated with unstable angina andAssociated with unstable angina and
presence of complex coronary lesionspresence of complex coronary lesions
• Commonly detected in premature CHDCommonly detected in premature CHD
• Possible role in target organ damagePossible role in target organ damage
in presence of HTNin presence of HTN
• Indications for screening:Indications for screening:
– CHD and no other identifiableCHD and no other identifiable
dyslipidemiadyslipidemia
– Strong CHD family history and noStrong CHD family history and no
other dyslipidemiaother dyslipidemia
– HTN and early premature targetHTN and early premature target
organ damageorgan damage
– Hypercholesterolemia refractory toHypercholesterolemia refractory to
statins and bile acid sequestrantsstatins and bile acid sequestrants
• Treatment guidelinesTreatment guidelines
– Primary goal is to lower LDL toPrimary goal is to lower LDL to
target and lowering to <80 maytarget and lowering to <80 may
reduce riskreduce risk
– If LDL cannot become optimized,If LDL cannot become optimized,
then Lpa loweing with nicotinicthen Lpa loweing with nicotinic
acid (38%) shoud be triedacid (38%) shoud be tried
– Goal <20 in whitesGoal <20 in whites

15. CHOLESTEROLCHOLESTEROL
• A soft waxy substance found among lipidsA soft waxy substance found among lipids
(fats) in the bloodstream and all cells(fats) in the bloodstream and all cells
• Needed for digesting fats, makingNeeded for digesting fats, making
hormones, building cell wallshormones, building cell walls
• Carried in particles calledCarried in particles called lipoproteinslipoproteins thatthat
act as transport vehicles deliveringact as transport vehicles delivering
cholesterol to various body tissues to becholesterol to various body tissues to be
used, stored or excretedused, stored or excreted
• Excess circulating cholesterol can lead toExcess circulating cholesterol can lead to
plaque formation- Atherosclerosisplaque formation- Atherosclerosis

16. DYSLIPIDEMIADYSLIPIDEMIA
(A consequence of abnormal lipoprotein(A consequence of abnormal lipoprotein
metabolism)metabolism)
• Elevated Total Cholesterol (TC)Elevated Total Cholesterol (TC)
• Elevated Low-density lipoproteins (LDL)Elevated Low-density lipoproteins (LDL)
• Elevated triglycerides (TG)Elevated triglycerides (TG)
• Decreased High-density lipoproteins (HDL)Decreased High-density lipoproteins (HDL)

17. PRIMARY DYSLIPIDEMIAPRIMARY DYSLIPIDEMIA
ETIOLOGYETIOLOGY
• SINGLE OR MULTIPLE GENE MUTATION –SINGLE OR MULTIPLE GENE MUTATION –
RESULTING IN DISTURBANCE OF LDL, HDLRESULTING IN DISTURBANCE OF LDL, HDL
AND TRIGYLCERIDE, PRODUCTION ORAND TRIGYLCERIDE, PRODUCTION OR
CLEARANCE.CLEARANCE.
• Should be suspected in patients withShould be suspected in patients with
• premature heart diseasepremature heart disease
• family hx of atherosclerotic dx.family hx of atherosclerotic dx.
• Or serum cholesterol level >240mg/dl.Or serum cholesterol level >240mg/dl.
• Physical signs of hyperlipidemia.Physical signs of hyperlipidemia.

18. SECONDARY DYSLIPIDEMIASECONDARY DYSLIPIDEMIA
(Most adult cases of dyslipidemia are secondary in nature in western(Most adult cases of dyslipidemia are secondary in nature in western
civilizations)civilizations)
• Sedentary lifestyleSedentary lifestyle
• Excessive consumption of cholesterol –Excessive consumption of cholesterol –
saturated fats and trans-fatty acids.saturated fats and trans-fatty acids.

19. Secondary DyslipidemiaSecondary Dyslipidemia
((Medical Conditions AssociatedMedical Conditions Associated
with dyslipidemia)with dyslipidemia)
• DiabetesDiabetes
• HypothyroidismHypothyroidism
• Cholestatic liver disease.Cholestatic liver disease.
• Nephrotic syndromeNephrotic syndrome
• cigarette smokingcigarette smoking

20. SECONDARY DYSLIPIDEMIASECONDARY DYSLIPIDEMIA
(Drugs causing mild to moderate degrees of(Drugs causing mild to moderate degrees of
dyslipidemia)dyslipidemia)
• Beta-blockersBeta-blockers
• Thiazide diureticsThiazide diuretics
• Antiretroviral drugsAntiretroviral drugs
• Hormonal agentsHormonal agents

21. Types of CholesterolTypes of Cholesterol
LDL-LDL- (“bad” cholesterol) The major cholesterol carrier in the blood.(“bad” cholesterol) The major cholesterol carrier in the blood.
Excess most likely to lead to plaque formation. Goal:Excess most likely to lead to plaque formation. Goal: LLOWOW
HDL-HDL- (“good” cholesterol) Transports cholesterol away from(“good” cholesterol) Transports cholesterol away from
arteries and back to the liver to be eliminated. Removes excessarteries and back to the liver to be eliminated. Removes excess
cholesterol from plaques, slowing growth. Goal:cholesterol from plaques, slowing growth. Goal: HHIGHIGH
Triglycerides-Triglycerides- the chemical form in which most fat exists inthe chemical form in which most fat exists in
foods as well as in the body. Present in blood plasma and togetherfoods as well as in the body. Present in blood plasma and together
with cholesterol, form the plasma lipids. Made in the body from otherwith cholesterol, form the plasma lipids. Made in the body from other
energy sources like carbohydrates. Calories ingested in a meal andenergy sources like carbohydrates. Calories ingested in a meal and
not immediately used by tissues are converted to triglycerides.not immediately used by tissues are converted to triglycerides.
Hormones regulate the release from fat tissue to meet the body’sHormones regulate the release from fat tissue to meet the body’s
needs for energy between meals.needs for energy between meals.

22. Why Do We Care?Why Do We Care?
According to theAccording to the Third Report ofThird Report of
the National Cholesterolthe National Cholesterol
Education Program ExpertEducation Program Expert
Panel on Detection, EvaluationPanel on Detection, Evaluation
and Treatment of Highand Treatment of High
Cholesterol in AdultsCholesterol in Adults
(NCEP ATP-III):(NCEP ATP-III):
High LDL levels are a leadingHigh LDL levels are a leading
cause of coronary heartcause of coronary heart
disease (CHD) and should bedisease (CHD) and should be
the main target of anythe main target of any
cholesterol lowering regimencholesterol lowering regimen

23. ATP III Lipid and LipoproteinATP III Lipid and Lipoprotein
ClassificationClassification
LDL Cholesterol (mg/dl) HDL CholesterolLDL Cholesterol (mg/dl) HDL Cholesterol
(mg/dl)(mg/dl)
<100<100 OptimalOptimal < 40 Low< 40 Low
100-129 Near/Above Optimal100-129 Near/Above Optimal >> 60 High (Desirable)60 High (Desirable)
130-159 Borderline High130-159 Borderline High
160-189 High160-189 High
>>190190 Very HighVery High
Categories of Risk that Modify LDL GoalsCategories of Risk that Modify LDL Goals
CHD and CHD risk equivalentsCHD and CHD risk equivalents <100<100
Multiple (2+) risk factorsMultiple (2+) risk factors <130<130
Zero to one risk factorZero to one risk factor <160<160

24. Major Risk Factors For CHDMajor Risk Factors For CHD
That Modify LDL GoalsThat Modify LDL Goals
Cigarette smokingCigarette smoking
Hypertension (BPHypertension (BP >>140/90 or on BP med)140/90 or on BP med)
Low HDL cholesterol (<40mg/dl)Low HDL cholesterol (<40mg/dl)
Family Hx premature CHDFamily Hx premature CHD
- CHD in male 1CHD in male 1stst
degree relative <55 years olddegree relative <55 years old
- CHD in female 1CHD in female 1stst
degree relative <65 years olddegree relative <65 years old
Age (menAge (men >>45 yrs. women45 yrs. women >>55 yrs)55 yrs)
 HDLHDL >>60 counts as a “negative” risk factor. It’s presence removes one60 counts as a “negative” risk factor. It’s presence removes one
risk factor from the total countrisk factor from the total count

25. Risk Assessment for CHDRisk Assessment for CHD
DM regarded as a CHD equivalentDM regarded as a CHD equivalent
For patients with multiple (2+) risk factorsFor patients with multiple (2+) risk factors
-Perform 10 year risk assessment-Perform 10 year risk assessment
For patients with 0-1 risk factorFor patients with 0-1 risk factor
-Most have 10 year risk assessment <10%;-Most have 10 year risk assessment <10%;
risk assessment scoring unnecessaryrisk assessment scoring unnecessary

26. Framingham Heart Study 10-yearFramingham Heart Study 10-year
CHD Risk Prediction Score SheetCHD Risk Prediction Score Sheet

27. Current ATP III Guidelines forCurrent ATP III Guidelines for
Treating LDL CholesterolTreating LDL Cholesterol
RiskRisk
CategoryCategory
LDL GoalLDL Goal
(mg/dl)(mg/dl)
LDL level toLDL level to
initiate TLCinitiate TLC
LDL level toLDL level to
consider Rxconsider Rx
therapytherapy
CHD orCHD or
EquivalentsEquivalents
<100<100
<70 Ideal<70 Ideal
> 100> 100 >> 130130
(100-129 Rx(100-129 Rx
optional)optional)
2+ Risk2+ Risk
FactorsFactors
<130<130 > 130> 130 >> 130 (10 Year130 (10 Year
risk 10-20%)risk 10-20%)
>> 160 (Risk <10%)160 (Risk <10%)
0-1 Risk0-1 Risk
FactorFactor
<160<160 > 160> 160 >> 190190
(160-189 Rx(160-189 Rx
optional)optional)

28. A Model of Steps in TherapeuticA Model of Steps in Therapeutic
Lifestyle Changes (TLC)Lifestyle Changes (TLC)
Visit 1
Begin TLC
•Emphasize
reduction in
saturated fat
& chol.
•Encourage
moderate
Physical
activity
•Consider
referral to
dietician
Visit 2 (6 wks)
Eval. LDL response
Intensify Tx if not to
goal
•Reinforce dietary
recommendations
•Consider adding
plant stanols/sterols
•Increase fiber
intake
•Consider dietician
Visit 3 (6 wks)
Eval LDL response
Consider adding Rx
if not to goal
•Evaluate for
Metabolic syndrome
•Intensify wt mgmt &
physical activity
•Consider dietician
Visit N
Monitor
adherence to
TLC Q4-6
mos

29. Nutrient Recommendations of TLCNutrient Recommendations of TLC
DietDiet
NutrientNutrient
Recommended IntakeRecommended Intake
• Saturated fatSaturated fat < 7% of total calories< 7% of total calories
• Polyunsaturated fatPolyunsaturated fat Up to 10% of total caloriesUp to 10% of total calories
• Monounsaturated fatMonounsaturated fat Up to 20% of total caloriesUp to 20% of total calories
• Total fatTotal fat 25-30% of total calories25-30% of total calories
• CarbohydratesCarbohydrates 50-60% of total calories50-60% of total calories
• FiberFiber 20-30 grams/day20-30 grams/day
• ProteinProtein Approx. 15% of total caloriesApprox. 15% of total calories
• CholesterolCholesterol <200 mg/day<200 mg/day
• Total caloriesTotal calories Balance energy intake andBalance energy intake and
expenditure to maintainexpenditure to maintain
desirable body weight/ preventdesirable body weight/ prevent
weight gainweight gain

30. Specific Dyslipidemias:Specific Dyslipidemias:
Very High LDL (Very High LDL ( > 190mg/dl)> 190mg/dl)
Causes and DiagnosisCauses and Diagnosis
• Genetic disordersGenetic disorders
Monogenic familial hypercholesterolemiaMonogenic familial hypercholesterolemia
Familial defective apolipoprotein B-100Familial defective apolipoprotein B-100
(Apo B)(Apo B)
Polygenic hypercholesterolemiaPolygenic hypercholesterolemia
• Family testing to detect affected relativesFamily testing to detect affected relatives

32. Specific Dyslipidemias: Low HDLSpecific Dyslipidemias: Low HDL
Causes of Low HDL (<40 mg/dl)Causes of Low HDL (<40 mg/dl)
• Elevated triglyceridesElevated triglycerides
• Overweight and obesityOverweight and obesity
• Physical InactivityPhysical Inactivity
• Type 2 diabetesType 2 diabetes
• Cigarette smokingCigarette smoking
• Very high carb. intakes (>60% energy)Very high carb. intakes (>60% energy)
• Medications (some beta blockers, anabolicMedications (some beta blockers, anabolic
steroids, progestational agents)steroids, progestational agents)

33. Specific Dyslipidemias: ElevatedSpecific Dyslipidemias: Elevated
TriglyceridesTriglycerides
Classification of Serum TriglyceridesClassification of Serum Triglycerides
NormalNormal <150 mg/dl<150 mg/dl
Borderline HighBorderline High 150-199 mg/dl150-199 mg/dl
HighHigh 200-499mg/dl200-499mg/dl
Very HighVery High >>500 mg/dl500 mg/dl

34. Specific Dyslipidemias: ElevatedSpecific Dyslipidemias: Elevated
TriglyceridesTriglycerides
Causes of Elevated TriglyceridesCauses of Elevated Triglycerides
• Obesity and overweightObesity and overweight
• Physical InactivityPhysical Inactivity
• Cigarette smokingCigarette smoking
• Excess alcohol intakeExcess alcohol intake
• High carb. dietsHigh carb. diets
• Several diseases (Type 2 DM, chronic renal failure,Several diseases (Type 2 DM, chronic renal failure,
nephrotic syndromenephrotic syndrome
• Medications (corticosteroids, estrogens, retinoids, higherMedications (corticosteroids, estrogens, retinoids, higher
doses of beta blockersdoses of beta blockers

35. Specific Dyslipidemias: ElevatedSpecific Dyslipidemias: Elevated
TriglyceridesTriglycerides
Management of Very High Triglycerides (>500Management of Very High Triglycerides (>500
mg/dl)mg/dl)
• Goal of therapy: Prevent acute pancreatitisGoal of therapy: Prevent acute pancreatitis
• Very low fat diets (Very low fat diets (<< 15% of caloric intake)15% of caloric intake)
• Triglyceride-lowering drug usually required (fibrate orTriglyceride-lowering drug usually required (fibrate or
nicotinic acid)nicotinic acid)
• Reduce triglyceridesReduce triglycerides beforebefore lowering LDLlowering LDL

36. Advanced Lipid Analysis:Advanced Lipid Analysis:
SizeSize DoesDoes MatterMatter

37. Advanced Lipid AnalysisAdvanced Lipid Analysis
• LDL type “floats” around in theLDL type “floats” around in the
bloodblood
• Most LDL around 260Most LDL around 260
AngstromsAngstroms
• 5% smaller diameter LDL5% smaller diameter LDL
particle leads to a 50%particle leads to a 50%
increase in rate of uptake byincrease in rate of uptake by
the arterial wallthe arterial wall
• LDL particle <258 AngstromsLDL particle <258 Angstroms
more atherogenicmore atherogenic
• Large LDL: Pattern ALarge LDL: Pattern A
• Small LDL: Pattern B (bad)Small LDL: Pattern B (bad)
• Not measured in traditionalNot measured in traditional
lipid profileslipid profiles

38. Advanced Lipid Analysis: Lp(a)Advanced Lipid Analysis: Lp(a)
• Fairly large molecule butFairly large molecule but
easily oxidized (moreeasily oxidized (more
toxic)toxic)
• Protein “tail” canProtein “tail” can
stimulate blood clottingstimulate blood clotting
• Not affected by foods;Not affected by foods;
appears to be geneticappears to be genetic
• Not affected much byNot affected much by
“statins” or fibrates“statins” or fibrates
• Niacin, vitamin E combatNiacin, vitamin E combat
tendency to be oxidizedtendency to be oxidized
• Lowering LDL to <80-100Lowering LDL to <80-100
also minimizes toxicityalso minimizes toxicity

39. Advanced Lipid AnalysisAdvanced Lipid Analysis
(Berkeley Heart Labs/ NMR(Berkeley Heart Labs/ NMR
LipoProfile)LipoProfile)
Who Needs
Advanced lipid
analysis?
•CHD, DM, or CHD equivalent
•Metabolic Syndrome
•Multiple Risk Factors
•Family Hx premature CHD
•Isolated low HDL cholesterol

40. Lipid Lowering DrugsLipid Lowering Drugs
HMG-CoA Reductase Inhibitors (Statins)HMG-CoA Reductase Inhibitors (Statins)
• Partially block an enzyme necessary for formation ofPartially block an enzyme necessary for formation of
cholesterolcholesterol
• Speed removal of LDL from bloodSpeed removal of LDL from blood
• 18%-60% reduction in LDL18%-60% reduction in LDL
• Most effective at lowering LDL; esp. HS dosingMost effective at lowering LDL; esp. HS dosing
• Liver enzymes MUST be monitored. Check baseline,Liver enzymes MUST be monitored. Check baseline,
3mos., then semi-annually (D/C if > 3x normal limits)3mos., then semi-annually (D/C if > 3x normal limits)
• Side effects: Myalgias (D/C if total CK >10x normal),Side effects: Myalgias (D/C if total CK >10x normal),
rhabdomyolysisrhabdomyolysis
• Metabolized by CP450 (watch for drug interactions)Metabolized by CP450 (watch for drug interactions)

41. Dr.Sarma@works
41
Dual InhibitionDual Inhibition
DuodenumDuodenum
JejunumJejunum
IleumIleum
CM
apoB48
LiverLiver
CM
Remnant
apoB48
VLDL
apoB100
Ezetimibe
XX
LDL
apoB100
XX
StatinStatin
ColonColon

42. 42
Statins – Mechanism of ActionStatins – Mechanism of Action
1.1. Reduce hepatic cholesterol synthesis (HMG CoA),Reduce hepatic cholesterol synthesis (HMG CoA),
2.2. lowering intracellular cholesterol,lowering intracellular cholesterol,
3.3. Upregulation of LDL receptor andUpregulation of LDL receptor and
LDL receptorLDL receptor––mediatedmediated
hepatic uptake of LDLhepatic uptake of LDL
and VLDL remnantsand VLDL remnants
Serum VLDL remnantsSerum VLDL remnants
Serum LDL-CSerum LDL-C
CholesterolCholesterol
synthesissynthesis
LDL receptorLDL receptor
(B(B––E receptor)E receptor)
synthesissynthesisIntracellularIntracellular
CholesterolCholesterol
Apo BApo B
Apo EApo E
Apo BApo B
Systemic CirculationSystemic CirculationHepatocyteHepatocyte
LDLLDL
Serum IDLSerum IDL
VLDLVLDLRRVLDLVLDLRR
VLDLVLDL
HMGCoA

43. 43
Time course of Statin effectsTime course of Statin effects
* Time course established
DaysDays YearsYears
LDL-CLDL-C
lowered*lowered*
InflammationInflammation
reducedreduced
VulnerableVulnerable
plaquesplaques
stabilizedstabilized
EndothelialEndothelial
functionfunction
restoredrestored
IschemicIschemic
episodesepisodes
reducedreduced
Cardiac eventsCardiac events
reduced*reduced*

44. Lipid Lowering DrugsLipid Lowering Drugs
Bile Acid SequestrantsBile Acid Sequestrants
• Convert cholesterol to bile acidsConvert cholesterol to bile acids
• Bind bile acids and prevent reabsorptionBind bile acids and prevent reabsorption
in the gutin the gut
• May increase triglyceride levelsMay increase triglyceride levels
• Most common side effects: GI-constipationMost common side effects: GI-constipation
• Alternative for statinsAlternative for statins

45. Bile Acid Resins: MechanismBile Acid Resins: Mechanism
of Actionof Action
Net Effect -Net Effect - ↓↓ LDL-CLDL-CNet Effect -Net Effect - ↓↓ LDL-CLDL-C
Gall BladderGall Bladder
↑ LDL ReceptorsLDL Receptors
↑ VLDL and LDL removalVLDL and LDL removal
↑↑↑ Cholesterol 7-Cholesterol 7-αα hydroxylasehydroxylase
↑ Conversion of cholesterol to BAConversion of cholesterol to BA
↑ BA SecretionBA Secretion
LiverLiver
↑ BA ExcretionBA Excretion
Terminal IleumTerminal Ileum
Bile AcidBile Acid
Enterohepatic RecirculationEnterohepatic Recirculation
Reabsorption ofReabsorption of
bile acidsbile acids

46. Lipid Lowering DrugsLipid Lowering Drugs
Cholesterol Absorption Inhibitor: ZetiaCholesterol Absorption Inhibitor: Zetia
• Monotherapy or in combination with statinMonotherapy or in combination with statin
• Not recommended with fibratesNot recommended with fibrates
• Reduces LDL number : esp. Lp(a)Reduces LDL number : esp. Lp(a)
Lipid-Regulating Agent: Omega 3 acid ethylLipid-Regulating Agent: Omega 3 acid ethyl
esters (Lovaza)esters (Lovaza)
• Omega 3 Fish oil (salmon, herring, mackerel, swordfish,Omega 3 Fish oil (salmon, herring, mackerel, swordfish,
albacore tuna, sardines, lake trout)albacore tuna, sardines, lake trout)
• Only FDA approved supplement for tx of dyslipidemiasOnly FDA approved supplement for tx of dyslipidemias
• Decreases hepatic production of TG and VLDLDecreases hepatic production of TG and VLDL
• Increases LDL size to large buoyant particlesIncreases LDL size to large buoyant particles

47. Lipid Lowering DrugsLipid Lowering Drugs
Nicotinic Acid/NiacinNicotinic Acid/Niacin
• Reduces production and release of LDLReduces production and release of LDL
• Effective in reduction of triglyceridesEffective in reduction of triglycerides
(<400mg/dl)(<400mg/dl)
• Increases HDLIncreases HDL
• Very effective in increasing LDL particle sizeVery effective in increasing LDL particle size
• Monitor liver enzymes and glucoseMonitor liver enzymes and glucose
• Most common side effect: FLUSHING (takeMost common side effect: FLUSHING (take
ASA/ibuprofen 30 min. prior and take with lightASA/ibuprofen 30 min. prior and take with light
snack). Decreased with time released formulassnack). Decreased with time released formulas
(Niaspan)(Niaspan)

48. Dr.Sarma@works
48Nicotinic Acid – Mechanism ofNicotinic Acid – Mechanism of
ActionAction
LiverLiver CirculationCirculation
HDLHDL
Serum VLDLSerum VLDL
results in reducedresults in reduced
lipolysis to LDLlipolysis to LDL
Serum LDLSerum LDL
VLDL
Decreases hepatic production of VLDL and of apo BDecreases hepatic production of VLDL and of apo B
VLDLVLDL
secretionsecretion
Apo BApo B
HepatocyteHepatocyte Systemic CirculationSystemic Circulation
Mobilization of FFAMobilization of FFA
TGTG
synthesissynthesis
VLDL
LDL

49. Lipid Lowering DrugsLipid Lowering Drugs
Fibric Acid Derivatives/FibratesFibric Acid Derivatives/Fibrates
• VeryVery effective in reducing triglycerides (>400)effective in reducing triglycerides (>400)
• Increase HDLIncrease HDL
• Containdications: Gallbladder disease, hepaticContaindications: Gallbladder disease, hepatic
disease, renal dysfunctiondisease, renal dysfunction
• Increase LDL particleIncrease LDL particle size but not quantitysize but not quantity
• Caution with statinsCaution with statins

52. Comparison of LipidComparison of Lipid
Lowering DrugsLowering Drugs

54. Cholesterol Control WithCholesterol Control With
Foods and HerbsFoods and Herbs
• Fiber: Decreases LDL; increases HDLFiber: Decreases LDL; increases HDL
• Carrots/Grapefruit: Fiber and pectin (whole fruits mostCarrots/Grapefruit: Fiber and pectin (whole fruits most
beneficial)beneficial)
• Avocado: monounsaturated fatAvocado: monounsaturated fat
• Beans: High in fiber, low fat; contain lecithinBeans: High in fiber, low fat; contain lecithin
• Phytosterols: sesame, safflower, spinach, okra,Phytosterols: sesame, safflower, spinach, okra,
strawberries, squash, tomatoes, celery, ginger.strawberries, squash, tomatoes, celery, ginger.
• Shiitake mushrooms: contain lentinan (25% reduction inShiitake mushrooms: contain lentinan (25% reduction in
animal studies)animal studies)
• Garlic, onion oil: lowers chol. 10-33%Garlic, onion oil: lowers chol. 10-33%
• Omega 3 fish oilsOmega 3 fish oils
• Red Yeast Rice: a natural substance that inhibits HMG-Red Yeast Rice: a natural substance that inhibits HMG-
CoA reductase. Same ingredient in Lovastatin.CoA reductase. Same ingredient in Lovastatin.

55. What Is On the Horizon?What Is On the Horizon?
• GlabridinGlabridin (licorice root/anise plants):(licorice root/anise plants): InhibitsInhibits
oxidation of LDLoxidation of LDL
• Study of genetic alterationsStudy of genetic alterations : cholesterol: cholesterol
medications tailored to specific genetic profilesmedications tailored to specific genetic profiles
• Microsomal triglyceride transfer protein (MTP):Microsomal triglyceride transfer protein (MTP):
the gene for MTP provides blueprint for production of thethe gene for MTP provides blueprint for production of the
protein that helps assemble LDL. Those who carry 2protein that helps assemble LDL. Those who carry 2
copies of a variant form of the gene had LDL levels 22%copies of a variant form of the gene had LDL levels 22%
lower than those who had one or no copy of the variant.lower than those who had one or no copy of the variant.
Some drug companies have already begun looking atSome drug companies have already begun looking at
MTP inhibitors to help lower LDLMTP inhibitors to help lower LDL
• Lecithin-cholesterol acetyltransferase (LCAT):Lecithin-cholesterol acetyltransferase (LCAT):
an enzyme bound to HDL acts as a powerful antioxidantan enzyme bound to HDL acts as a powerful antioxidant
(reduce oxidation of chol.)(reduce oxidation of chol.)
• Thyroid hormonesThyroid hormones: Molecules similar to thyroid: Molecules similar to thyroid
hormones could assist with weight loss and cholesterolhormones could assist with weight loss and cholesterol
reduction. 2 kinds of receptors that receive the hormonereduction. 2 kinds of receptors that receive the hormone
and pass its signal to the body.and pass its signal to the body.

56. Cholesterol Meds in theCholesterol Meds in the
NewsNews
VytorinVytorin (Zocor + Zetia)(Zocor + Zetia)
• ENHANCE trialENHANCE trial
• New England Journal of MedicineNew England Journal of Medicine
• 720 FH patients over one year720 FH patients over one year
• Endpoint: Carotid artery intima-media thickness (CIMT)Endpoint: Carotid artery intima-media thickness (CIMT)
per ultrasoundper ultrasound
• Findings: Vytorin did not reduce CIMT compared toFindings: Vytorin did not reduce CIMT compared to
Zocor aloneZocor alone
• TAKE HOME: It’s NOT just about the numbersTAKE HOME: It’s NOT just about the numbers

57. Cholesterol Meds in theCholesterol Meds in the
NewsNews
CrestorCrestor
• JUPITER trialJUPITER trial
• Does Crestor reduce major CV events in pts withDoes Crestor reduce major CV events in pts with
no existing symptoms, low-normal LDL butno existing symptoms, low-normal LDL but
higher CRP (c-reactive protein: marker ofhigher CRP (c-reactive protein: marker of
inflammation)?inflammation)?
• Study D/C’d: early findings confirm reducedStudy D/C’d: early findings confirm reduced
deaths and CV risksdeaths and CV risks
• TheThe ONLYONLY statinstatin shown to reduceshown to reduce
Atherosclerotic plaqueAtherosclerotic plaque

58. Other Interesting StudiesOther Interesting Studies
Atherosclerosis:Atherosclerosis: Maternal smoking disturbs lipidMaternal smoking disturbs lipid
profiles in adult offspringprofiles in adult offspring
• Children ages 5-19 years (N=350)Children ages 5-19 years (N=350)
• Total chol. in children whose mothers smokedTotal chol. in children whose mothers smoked
increased by 4.6mg/dl more each decade thanincreased by 4.6mg/dl more each decade than
total chol. levels in other children.total chol. levels in other children.
• Could lead to an increase of 10mg over a 30Could lead to an increase of 10mg over a 30
year periodyear period

59. Other Interesting StudiesOther Interesting Studies
The American Journal of Human GeneticsThe American Journal of Human Genetics ::
Researchers have identified a novel geneticResearchers have identified a novel genetic
determinant of dyslipidemia and possibly CVDdeterminant of dyslipidemia and possibly CVD
• Genotyping of 1955 volunteers with HTNGenotyping of 1955 volunteers with HTN
• 25 serum and urine biochemical tests25 serum and urine biochemical tests
• Compared with genome-wide data from 2 otherCompared with genome-wide data from 2 other
studies of individuals with DMstudies of individuals with DM
• Found 2 proteins that were associated with a 6%Found 2 proteins that were associated with a 6%
increase in non-fasting serum levels of LDL chol.increase in non-fasting serum levels of LDL chol.

60. Other Interesting StudiesOther Interesting Studies
American Journal of Medicine:American Journal of Medicine:
Framingham Offspring Study suggests that at leastFramingham Offspring Study suggests that at least
HALF of U.S. citizens will develop dyslipidemia at someHALF of U.S. citizens will develop dyslipidemia at some
point in their livespoint in their lives
• 4701 participants who were ages 30-54 yrs in 19714701 participants who were ages 30-54 yrs in 1971
• During the following 30 years, 6 in 10 developedDuring the following 30 years, 6 in 10 developed
borderline-high (borderline-high (>> 130) LDL and 4 in 10 developed high130) LDL and 4 in 10 developed high
((>>160) LDL160) LDL
• Study possible suggests that over 70% of AmericansStudy possible suggests that over 70% of Americans
may be eligible for statin treatment at some stage of theirmay be eligible for statin treatment at some stage of their
liveslives

61. Other Studies: The GOOD NewsOther Studies: The GOOD News
Nutrition,Metabolism and CardiovascularNutrition,Metabolism and Cardiovascular
Diseases:Diseases: Drinking moderate amounts of beerDrinking moderate amounts of beer
appears to improve the lipid profile of healthy adultsappears to improve the lipid profile of healthy adults
(esp. women)(esp. women)
• 57 healthy Spanish volunteers (29 women)57 healthy Spanish volunteers (29 women)
• Abstain for 30 day wash out period, then drink moderateAbstain for 30 day wash out period, then drink moderate
(330ml for women, 660ml for men) amounts of beer for(330ml for women, 660ml for men) amounts of beer for
30 days30 days
• HDL increased from 60.7-66.8 mg/dl in women and fromHDL increased from 60.7-66.8 mg/dl in women and from
44.2-46.5 mg/dl in men44.2-46.5 mg/dl in men
• HDL decreased during the 30 day wash out periodHDL decreased during the 30 day wash out period

62. Other Studies: The GOOD NewsOther Studies: The GOOD News
Journal of Nutrition:Journal of Nutrition: People with dyslipidemia canPeople with dyslipidemia can
improve their lipid profiles by drinking cocoaimprove their lipid profiles by drinking cocoa
• 160 volunteers drank 10.0, 19.5 or 26 g/day of cocoa or placebo160 volunteers drank 10.0, 19.5 or 26 g/day of cocoa or placebo
• After 4 weeks, all groups but placebo had lower LDL levelsAfter 4 weeks, all groups but placebo had lower LDL levels
• Most significant reductions in those with baseline LDLMost significant reductions in those with baseline LDL >> 125125
• LDL decreased from 160 to 152LDL decreased from 160 to 152
• HDL increased from 57 to 62HDL increased from 57 to 62
• Decrease in (apo) B and oxidized LDL cholesterolDecrease in (apo) B and oxidized LDL cholesterol
• Polyphenols in cocoa, tea, wine, fruit and vegetables may lead toPolyphenols in cocoa, tea, wine, fruit and vegetables may lead to
decrease in atherosclerotic diseasedecrease in atherosclerotic disease

63. Case Study 1Case Study 1
35 YO male, a police officer. 5’11’’,35 YO male, a police officer. 5’11’’,
weight=258 (BMI=35, obese)weight=258 (BMI=35, obese)
Hx: hypertension, anxiety. Has takenHx: hypertension, anxiety. Has taken
testosterone supplements in past, nowtestosterone supplements in past, now
uses “body building” shakes.uses “body building” shakes.
Family Hx: Father, paternal grandfather-DMFamily Hx: Father, paternal grandfather-DM
Labs: FBS=79, TSH normalLabs: FBS=79, TSH normal

64. Case Study 1Case Study 1
Visit 1 Visit 2Visit 1 Visit 2
Visit 3Visit 3
TC= 167 164 158TC= 167 164 158
TG=539 288TG=539 288 260260
HDL= 18 24 28HDL= 18 24 28
LDL= ? 95 88LDL= ? 95 88
Tricor started Niaspan LevazaTricor started Niaspan Levaza
(intolerant)(intolerant)

65. Case Study 2Case Study 2
39 YO male (hasn’t been in for 2 years) c/o39 YO male (hasn’t been in for 2 years) c/o
frequent urination, excessive thirst, blurredfrequent urination, excessive thirst, blurred
vision.vision.
Hx: Mod. Obesity, BMI= 33Hx: Mod. Obesity, BMI= 33
Family Hx: Mother DMFamily Hx: Mother DM
Meds: NoneMeds: None
Non-fasting Accucheck= 297 (3 hrs PP)Non-fasting Accucheck= 297 (3 hrs PP)

66. Case Study 2Case Study 2
TCTC 705705 252252 212212 195195 144144
TrigTrig 67106710 149149 146146 128128 123123
HDLHDL 170170 3333 3636 3939 4242
LDLLDL ?? 190190 140140 131131 8282
A1CA1C 11.911.9 5.65.6 5.65.6
MedsMeds TricorTricor
andand
DM txDM tx
ZocorZocor
20mg20mg
ZocorZocor
40mg40mg
AddAdd
ZetiaZetia

67. Case Study 3Case Study 3
62 YO Female with CHD s/p CABG wanted me to62 YO Female with CHD s/p CABG wanted me to
manage lipids. Also has Hypertension.manage lipids. Also has Hypertension.
Meds: Plavix, Atenolol, lisinopril, AtorvastatinMeds: Plavix, Atenolol, lisinopril, Atorvastatin
(stopped by pt.-myalgias)(stopped by pt.-myalgias)
Current labs:Current labs:
TC= 248TC= 248
Trig= 144Trig= 144
HDL= 41HDL= 41
LDL= 156LDL= 156

68. Case Study 3Case Study 3
• Changed atenolol to CoregChanged atenolol to Coreg
• Started Pravachol 20mgStarted Pravachol 20mg
• Disease management/diet counselingDisease management/diet counseling
• Resume walking 3-4 days/weekResume walking 3-4 days/week
• Repeat labs:Repeat labs:
TC=190 Increase Pravachol …178TC=190 Increase Pravachol …178
Trig= 130Trig= 130 to 40mgto 40mg …128…128
HDL= 39HDL= 39 …41…41
LDL= 112LDL= 112 …98…98

69. Framingham Risk PredictionFramingham Risk Prediction
ScoreScore
• 47 YO Female47 YO Female
• Labs: TC= 178 Trig= 133 LDL= 110 HDL= 35Labs: TC= 178 Trig= 133 LDL= 110 HDL= 35
• BP: 162/98BP: 162/98
• Hx: Smoker, non-diabeticHx: Smoker, non-diabetic
What is 10 Year CHD Risk?What is 10 Year CHD Risk?

70. Framingham Risk PredictionFramingham Risk Prediction
ScoreScore
• 47 YO Female47 YO Female
• Labs: TC= 178 Trig= 133 LDL= 110 HDL= 35Labs: TC= 178 Trig= 133 LDL= 110 HDL= 35
• BP: 162/98BP: 162/98
• Hx: Smoker, non-diabeticHx: Smoker, non-diabetic
What is 10 Year CHD Risk?What is 10 Year CHD Risk?
10% Compared to average of 5% for10% Compared to average of 5% for

71. Treatment of DyslipidemiasTreatment of Dyslipidemias
(Medication Comparison Chart)(Medication Comparison Chart)
Which Medication(s) slows coronaryWhich Medication(s) slows coronary
athersclerosis, lowers LDL, increases HDLathersclerosis, lowers LDL, increases HDL
but has no effect on triglycerides?but has no effect on triglycerides?

72. Treatment of DyslipidemiasTreatment of Dyslipidemias
(Medication Comparison Chart)(Medication Comparison Chart)
Which Medication(s) slows coronaryWhich Medication(s) slows coronary
athersclerosis, lowers LDL, increases HDLathersclerosis, lowers LDL, increases HDL
but has no effect on triglycerides?but has no effect on triglycerides?
MevacorMevacor

73. NCEP ATP III Lipid GoalsNCEP ATP III Lipid Goals
What is the recommended LDL goal for aWhat is the recommended LDL goal for a
healthy normo-tensive, non-smoking 46healthy normo-tensive, non-smoking 46
year old male whose father died of ayear old male whose father died of a
massive MI at the age of 52?massive MI at the age of 52?

74. NCEP ATP III Lipid GoalsNCEP ATP III Lipid Goals
What is the recommended LDL goal for aWhat is the recommended LDL goal for a
healthy normo-tensive, non-smoking 46healthy normo-tensive, non-smoking 46
year old male whose father died of ayear old male whose father died of a
massive MI at the age of 52?massive MI at the age of 52?
<130 for 2 risk factors<130 for 2 risk factors
(age >45 and father with premature(age >45 and father with premature
CAD)CAD)

75. Final Question!!!!!Final Question!!!!!
58 Year old Male (smoker)58 Year old Male (smoker)
Fam. Hx: Mother with NIDDM, sister died age 70 from MIFam. Hx: Mother with NIDDM, sister died age 70 from MI
BP= 156/86 Pulse 78BP= 156/86 Pulse 78
Labs: TC= 310, TG= 250, HDL=29, LDL=156, FBS=88Labs: TC= 310, TG= 250, HDL=29, LDL=156, FBS=88
• What is Framingham 10 year Risk score?What is Framingham 10 year Risk score?
• Based on score, what is LDL goal?Based on score, what is LDL goal?
• Name 2 cholesterol medications (Brand) that would beName 2 cholesterol medications (Brand) that would be
most appropriate for his treatment.most appropriate for his treatment.

76. Final Question!!!!!Final Question!!!!!
58 Year old Male (smoker)58 Year old Male (smoker)
Fam. Hx: Mother with NIDDM, sister died age 70 from MIFam. Hx: Mother with NIDDM, sister died age 70 from MI
BP= 156/86 Pulse 78BP= 156/86 Pulse 78
Labs: TC= 310, TG= 250, HDL=29, LDL=156, FBS=88Labs: TC= 310, TG= 250, HDL=29, LDL=156, FBS=88
• What is Framingham 10 year Risk score?What is Framingham 10 year Risk score? 27%27%
• Based on score, what is LDL goal?Based on score, what is LDL goal? <100<100
• Name 2 cholesterol medications (Brand) that would beName 2 cholesterol medications (Brand) that would be
most appropriate for his treatment.most appropriate for his treatment. Niaspan, anyNiaspan, any
“statin” except Mevacor, any of the combination“statin” except Mevacor, any of the combination
medsmeds

77. Thank YouThank You
•Questions?Questions?

78. Stepwisw managementStepwisw management

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