1

Hyperlipidemia/DyslipidemiaHyperlipidemia/Dyslipidemia

J.B. Handler, M.D.J.B. Handler, M.D.

Physician Assistant ProgramPhysician Assistant Program

University of New EnglandUniversity of New England

2

AbbreviationsAbbreviations

LDL- low density lipoproteinLDL- low density lipoprotein HDL- high density lipoproteinHDL- high density lipoprotein IDL- intermediate density lipproteinIDL- intermediate density lipprotein VLDL- very low density lipoproteinVLDL- very low density lipoprotein Lp(a)- lipoprotein aLp(a)- lipoprotein a CAD- coronary artery diseaseCAD- coronary artery disease CHD=CAD= coronary heart diseaseCHD=CAD= coronary heart disease CVD- cerebrovascular diseaseCVD- cerebrovascular disease LFT- liver function testLFT- liver function test GI- gastrointestinalGI- gastrointestinal ETOH- alcoholETOH- alcohol D.M.- diabetes mellitusD.M.- diabetes mellitus CK- creatine kinaseCK- creatine kinase

NNT- number needed to treatNNT- number needed to treat ARR- absolute risk reductionARR- absolute risk reduction IVUS- intravascular ultrasoundIVUS- intravascular ultrasound RRR- relative risk reductionRRR- relative risk reduction PAD- peripheral arterial diseasePAD- peripheral arterial disease PVD- peripheral vascular diseasePVD- peripheral vascular disease CVD- cerebrovascular diseaseCVD- cerebrovascular disease ACS- acute coronary syndromeACS- acute coronary syndrome HTN- hypertensionHTN- hypertension TLC- therapeutic lifestyle changesTLC- therapeutic lifestyle changes UAP- unstable angina pectorisUAP- unstable angina pectoris PE- physical examPE- physical exam ACC- American College of ACC- American College of

CardiologyCardiology

3

Lipids and AtherosclerosisLipids and Atherosclerosis

Thickened and hardened lesions of the medium and large Thickened and hardened lesions of the medium and large muscular and elastic arteries; muscular and elastic arteries; lipid richlipid rich. Lesions occur in . Lesions occur in the innermost layer of the artery (intima) and are largely the innermost layer of the artery (intima) and are largely confined to this region of the vessel.confined to this region of the vessel.

Deposition of lipid within the artery is dependent on 2 Deposition of lipid within the artery is dependent on 2 major factors: major factors: – LDL: carries lipid to the arteries (LDL must be oxidized)LDL: carries lipid to the arteries (LDL must be oxidized)– HDL: removes lipid from the arteriesHDL: removes lipid from the arteries

The role triglycerides play is not as well understood, but The role triglycerides play is not as well understood, but considered a risk factor. See below. considered a risk factor. See below.

4

LipoproteinsLipoproteins

Lipoproteins carry lipids - Cholesterol, Triglyceride, Lipoproteins carry lipids - Cholesterol, Triglyceride, Phospholipids.Phospholipids.

Lipoproteins of importance: VLDL, (IDL), LDL, Lipoproteins of importance: VLDL, (IDL), LDL, chylomicrons.chylomicrons.– Apolipoproteins- Protein constituents of lipoproteins that add Apolipoproteins- Protein constituents of lipoproteins that add

structural stability; may help mediate catabolism. structural stability; may help mediate catabolism. Apolipoprotein B (LDL) increases coronary risk.Apolipoprotein B (LDL) increases coronary risk.

Lipid catabolism - 70% LDL removed in liver by LDL Lipid catabolism - 70% LDL removed in liver by LDL receptors.receptors.

5

Cholesterol BiosynthesisCholesterol Biosynthesis

Liver and intestines - major sources of Liver and intestines - major sources of endogenously derived cholesterol.endogenously derived cholesterol.

Diet - exogenously derived cholesterol.Diet - exogenously derived cholesterol. In liver- rate limiting step is In liver- rate limiting step is converting HMG converting HMG

CoA to mevalonic acid by HMG CoA CoA to mevalonic acid by HMG CoA ReductaseReductase (role of “STATINS”). (role of “STATINS”).

Increase intake in dietary cholesterol - down Increase intake in dietary cholesterol - down regulation of LDL receptors regulation of LDL receptors subsequent subsequent elevation of serum LDL cholesterol.elevation of serum LDL cholesterol.

6

HypercholesterolemiaHypercholesterolemia

Diet and drug induced reductions of total and Diet and drug induced reductions of total and LDL Cholesterol can significantly reduce LDL Cholesterol can significantly reduce mortality and morbidity from Coronary Heart mortality and morbidity from Coronary Heart Disease.Disease.

Cholesterol reduction can slow progression of Cholesterol reduction can slow progression of atherosclerosis, and in some cases, halt or reverse atherosclerosis, and in some cases, halt or reverse (isolated cases) its course.(isolated cases) its course.

7

Lipids and AtherogenesisLipids and Atherogenesis

Vascular injury from any source (smoking, Vascular injury from any source (smoking, HTN, DM) can lead to HTN, DM) can lead to uptakeuptake of of lipoproteins.lipoproteins.

Elevation of LDL (oxidized) can lead to Elevation of LDL (oxidized) can lead to vascular injuryvascular injury resulting in premature resulting in premature atherosclerosis.atherosclerosis.

8

Lipids and AtherogenesisLipids and Atherogenesis LDL oxidationLDL oxidation necessary for endothelial damage. necessary for endothelial damage. HDL- Inverse correlation between serum HDL HDL- Inverse correlation between serum HDL

and atherosclerosis; reverse cholesterol transport and atherosclerosis; reverse cholesterol transport and prevents oxidation of LDL- and prevents oxidation of LDL- cardioprotectivecardioprotective..

A A low HDL levellow HDL level (dyslipidemia) is a (dyslipidemia) is a strong riskstrong risk factor for CHDfactor for CHD even when LDL and total even when LDL and total cholesterol are normal.cholesterol are normal.

Next major advance: safe drugs that substantially Next major advance: safe drugs that substantially increase HDL levels, while reducing cardiac increase HDL levels, while reducing cardiac events (MI, Death).events (MI, Death).

9

Hyperlipidemia- Clinical FindingsHyperlipidemia- Clinical Findings

Often asymptomatic.Often asymptomatic. AtherosclerosisAtherosclerosis and disease- CHD, PVD, etc. and disease- CHD, PVD, etc. Eruptive xanthomas- red papules on buttocks seen Eruptive xanthomas- red papules on buttocks seen

with extremely high levels of chylomicrons or with extremely high levels of chylomicrons or VLDL (triglycerides).VLDL (triglycerides).

Tendinous xanthomas- Very high LDL- nodules Tendinous xanthomas- Very high LDL- nodules on tendons (achilles, back of hand, patella).on tendons (achilles, back of hand, patella).

Xanthelasma- yellow placques in skin around the Xanthelasma- yellow placques in skin around the eyes.eyes.

XanthelasmaXanthelasma

Images.google.com

11

Dyslipidemias in AdultsDyslipidemias in Adults

Most cases are Most cases are multifactorialmultifactorial Influenced by diet, lifestyle and genesInfluenced by diet, lifestyle and genes Often detected in Often detected in asymptomaticasymptomatic adults during adults during

routine blood screeningroutine blood screening In patients with atherosclerosis involving the In patients with atherosclerosis involving the

coronary arteries, carotids, aorta or periperal coronary arteries, carotids, aorta or periperal vessels, a high percentage will be found to have a vessels, a high percentage will be found to have a dyslipidemia.dyslipidemia.

12

Secondary DyslipidemiaSecondary Dyslipidemia

Diabetes Mellitus Diabetes Mellitus (discussed in Endocrine (discussed in Endocrine section)section)

Nephrotic Syndrome (Renal system)Nephrotic Syndrome (Renal system) Chronic Renal Failure Chronic Renal Failure Hypothyroidism - high TG, low HDLHypothyroidism - high TG, low HDL

13

Familial DyslipidemiaFamilial Dyslipidemia

At least six documented disorders all with At least six documented disorders all with accelerated accelerated atherosclerosis.atherosclerosis.

Example: Familial hypercholesterolemiaExample: Familial hypercholesterolemiaLDL receptor defect; heterozygous -total cholesterol at LDL receptor defect; heterozygous -total cholesterol at birth> 350 mg/dl;birth> 350 mg/dl;Homozygous - total cholesterol > 700mg/dlHomozygous - total cholesterol > 700mg/dl

PE: Tendon xanthomas, xanthelasma, cutaneous xanthomasPE: Tendon xanthomas, xanthelasma, cutaneous xanthomas Most patients with lipid disorders carry genes that can Most patients with lipid disorders carry genes that can

predispose them to develop dyslipidemia when additional predispose them to develop dyslipidemia when additional factors (diet, obesity, etc.) are present. Likely multiple factors (diet, obesity, etc.) are present. Likely multiple genes involved.genes involved.

14

Rationale for TreatmentRationale for Treatment Primary prevention- Lowering cholesterol/LDL Primary prevention- Lowering cholesterol/LDL

will will prevent new onset CHDprevent new onset CHD. Every 1% drop in . Every 1% drop in cholesterol produces a 2-3% decrease in CHD cholesterol produces a 2-3% decrease in CHD risk. risk.

Secondary prevention - Lowering cholesterol/LDL Secondary prevention - Lowering cholesterol/LDL will will prevent recurrent coronary eventsprevent recurrent coronary events and and decrease coronary and total mortality in the decrease coronary and total mortality in the presence of existing CHD or equivalent(s).presence of existing CHD or equivalent(s).– Angiographic/IVUS trialsAngiographic/IVUS trials retarded progression of of retarded progression of of

coronary lesions; regression in some.coronary lesions; regression in some.

15

Primary PreventionPrimary Prevention

ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial)ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) 10,305 patients with HTN but without heart disease 10,305 patients with HTN but without heart disease

randomized to Placebo vs. Atorvastatin 10 mg/dailyrandomized to Placebo vs. Atorvastatin 10 mg/daily– Baseline LDL-133 mg/dL, treated LDL- 103mg/dLBaseline LDL-133 mg/dL, treated LDL- 103mg/dL

Primary endpoints: Nonfatal MI and fatal CHDPrimary endpoints: Nonfatal MI and fatal CHD– Study ended prematurely at 3.3 yearsStudy ended prematurely at 3.3 years

Results: 36% Results: 36% in primary endpoint (100 vs 154 events) in primary endpoint (100 vs 154 events)

16

Secondary PreventionSecondary Prevention

High risk preventionHigh risk prevention Patients with known Patients with known CHDCHD have a 5-7x risk of have a 5-7x risk of

recurrent MI.recurrent MI. Patients with known Patients with known PAD, Carotid or Aortic PAD, Carotid or Aortic

diseasedisease have a 4-6x incidence of developing CHD have a 4-6x incidence of developing CHD and it’s consequences.and it’s consequences.

Other high risk subsets: DM, others (see below)Other high risk subsets: DM, others (see below) Goal: Goal: lower LDL to <100 mg/dl or less lower LDL to <100 mg/dl or less (below). (below).

17

Heart Protection StudyHeart Protection Study

Patients with documented CHD or equivalent (DM, Patients with documented CHD or equivalent (DM, PAD).PAD).

>20,000 patients; placebo vs 40mg Simvastatin daily.>20,000 patients; placebo vs 40mg Simvastatin daily. Baseline LDL 131-155 mg/dL. Rx with simvastatin Baseline LDL 131-155 mg/dL. Rx with simvastatin

resulted in:resulted in: all cause mortality by 13% all cause mortality by 13% coronary death by 18% coronary death by 18% non fatal MI + coronary death by 27% non fatal MI + coronary death by 27% coronary revascularization procedures by 24%.coronary revascularization procedures by 24%. stroke by 25% .stroke by 25% . major vascular events by 24% major vascular events by 24%

18

Risk Stratification (NCEP)Risk Stratification (NCEP)

Determine number of major risk factors besides elevated Determine number of major risk factors besides elevated lipids. Excludes patients with documented lipids. Excludes patients with documented CHD/PAD/CVD or diabetes (coronary risk equivalent).CHD/PAD/CVD or diabetes (coronary risk equivalent).– Age/gender: men>45, women >55Age/gender: men>45, women >55– FH of premature CHD FH of premature CHD MI or SD in 1MI or SD in 1stst degree relative: degree relative:

male<55, female < 65male<55, female < 65– Hypertension whether treated or notHypertension whether treated or not– Current cigarette smokerCurrent cigarette smoker– Low HDL: < 40 mg/dLLow HDL: < 40 mg/dL

2 or more risk factors2 or more risk factors calculate statistical risk for calculate statistical risk for subsequent MI/death in next 10 years.subsequent MI/death in next 10 years.

19

Risk Stratification (NCEP)Risk Stratification (NCEP)

For patients with 2 or more risk factors and no For patients with 2 or more risk factors and no evidence yet of CHD: Determine 10 year CHD evidence yet of CHD: Determine 10 year CHD risk (for “hard CHD outcomes”- MI or coronary risk (for “hard CHD outcomes”- MI or coronary death) assessment using Framingham risk death) assessment using Framingham risk assessment tool.assessment tool.

Newest guidelines and options: NCEP ATP III, Newest guidelines and options: NCEP ATP III, 7/04; amended in 2007. 7/04; amended in 2007.

20

Risk Assessment ToolRisk Assessment Tool

Estimates 10 yr risk (%) of developing “hard” CHD (MI Estimates 10 yr risk (%) of developing “hard” CHD (MI or coronary death) outcomes in patients without CHD.or coronary death) outcomes in patients without CHD.

Gender and age Gender and age Total or LDL cholesterolTotal or LDL cholesterol HDL cholesterolHDL cholesterol SmokerSmoker Systolic blood pressure; on meds for HTN?Systolic blood pressure; on meds for HTN? Tables based on Framingham Heart StudyTables based on Framingham Heart Study

21

High RiskHigh Risk

Presence of CHD, PAD, CVD or DMPresence of CHD, PAD, CVD or DM (coronary risk (coronary risk equivalent even if no CHD yet documented).equivalent even if no CHD yet documented).

Absence of clinical atherosclerosis with 2 or more risk Absence of clinical atherosclerosis with 2 or more risk factors (such as smoking or HTN) that give a greater than factors (such as smoking or HTN) that give a greater than 20% chance of having an MI or coronary death within 10 20% chance of having an MI or coronary death within 10 years (risk factor tool). Remember IS case: Lenny L.years (risk factor tool). Remember IS case: Lenny L.

GoalGoal: : LDL< 100 mg/dLLDL< 100 mg/dL; initiate meds if > 100mg/dL.; initiate meds if > 100mg/dL. Initiate TLC simultaneously.Initiate TLC simultaneously. Some High Risk patients will fall into the “Very High Risk Some High Risk patients will fall into the “Very High Risk

subset (see below).subset (see below).

22

Very High RiskVery High Risk

Established CHDEstablished CHD withwith: DM, multiple and poorly controlled : DM, multiple and poorly controlled risk factors (such as smoking), metabolic syndrome, risk factors (such as smoking), metabolic syndrome, oror recent ACS (MI or UAP)recent ACS (MI or UAP)..

GoalGoal: : LDL < 70mg/dLLDL < 70mg/dL is a “therapeutic option”- a is a “therapeutic option”- a reasonable therapeutic strategy, on the basis of available reasonable therapeutic strategy, on the basis of available clinical trial evidence.clinical trial evidence.

This will require drug therapy, possibly 2 drugs (see below).This will require drug therapy, possibly 2 drugs (see below). Initiate TLC if not already done.Initiate TLC if not already done. Evidence: PROVE-IT trial (see below). Evidence: PROVE-IT trial (see below).

23

Metabolic Syndrome (3 of 5 Factors) Metabolic Syndrome (3 of 5 Factors) Central obesity: waist circumference>88cm in women, Central obesity: waist circumference>88cm in women,

>102 cm in men. >102 cm in men. Hyperglycemia: FBS Hyperglycemia: FBS 110 mg/dL.110 mg/dL. Hypertension: BP Hypertension: BP 135/85. 135/85. trig: trig: 150 mg/dL. 150 mg/dL. HDL: HDL: 40 for men, 40 for men, 50 for women (any 3 of 5 meets 50 for women (any 3 of 5 meets

criterion).criterion). 3x 3x risk of atherosclerosis. risk of atherosclerosis. Metabolic syndrome often associated with insulin Metabolic syndrome often associated with insulin

resistance- to be discussed in Endocrine system. resistance- to be discussed in Endocrine system.

24

Is Greater Lowering Better?Is Greater Lowering Better?

PROVE IT-TIMIPROVE IT-TIMI 22: Atorvastatin 80 mgs/d vs Pravastatin 22: Atorvastatin 80 mgs/d vs Pravastatin 40 mgs/d in patients with ACS (AMI or UAP). Prospective, 40 mgs/d in patients with ACS (AMI or UAP). Prospective, randomized, double blind study of 4162 patients; 2 yr follow-randomized, double blind study of 4162 patients; 2 yr follow-up. up.

End-points: All cause mortality, MI, UAP, coronary End-points: All cause mortality, MI, UAP, coronary revascularization, stroke.revascularization, stroke.

Pravastatin group: mean LDL- 95mg/dL, 26.3% had primary Pravastatin group: mean LDL- 95mg/dL, 26.3% had primary end-point.end-point.

Atorvastatin group: mean LDL- 62mg/dL, 22.4% had Atorvastatin group: mean LDL- 62mg/dL, 22.4% had primary end point.primary end point.– ARR with Atorvastatin= 3.9%, NNT= 25ARR with Atorvastatin= 3.9%, NNT= 25– RRR 16%RRR 16%

25

Moderately High RiskModerately High Risk

Absence of clinical atherosclerosisAbsence of clinical atherosclerosis 2 or more risk factors for CHD and a 10-20% risk 2 or more risk factors for CHD and a 10-20% risk

of MI/Coronary Death within 10 years (risk factor of MI/Coronary Death within 10 years (risk factor tool).tool).

GoalGoal: : LDL<130mg/dLLDL<130mg/dL– Therapeutic Therapeutic optionoption: : LDL<100mg/dLLDL<100mg/dL

Initiate TLC if not already started.Initiate TLC if not already started. Initiate drug therapy for LDL>130 mg/dL.Initiate drug therapy for LDL>130 mg/dL.

26

Moderate RiskModerate Risk

Absence of clinical atherosclerosisAbsence of clinical atherosclerosis 2 or more risk factors for CHD and a < 10% risk 2 or more risk factors for CHD and a < 10% risk

for MI/coronary death within 10 years (risk factor for MI/coronary death within 10 years (risk factor tool).tool).

Goal: LDL<130mg/dLGoal: LDL<130mg/dL Initiate TLCInitiate TLC Initiate drug therapy if LDLInitiate drug therapy if LDL160 mg/dL160 mg/dL

27

Lower RiskLower Risk

0-1 risk factors0-1 risk factors Do not need to calculate risk score as will be Do not need to calculate risk score as will be

<10%.<10%. Goal: LDL< 160 mg/dLGoal: LDL< 160 mg/dL TLCTLC Initiate drug therapy if: LDLInitiate drug therapy if: LDL190mg/dL190mg/dL Option: Option: Initiate drug therapy if LDL Initiate drug therapy if LDL

160mg/dL160mg/dL

28

Other GoalsOther Goals

Total Cholesterol < 200mg/dLTotal Cholesterol < 200mg/dL HDL HDL 40 (45) mg/dL in men; 40 (45) mg/dL in men; 50 (55) mg/dL 50 (55) mg/dL

in pre-menopausal women.in pre-menopausal women. Bloodwork: Fasting Lipoprotein AnalysisBloodwork: Fasting Lipoprotein Analysis

Total chol, Triglycerides, HDL, LDL Total chol, Triglycerides, HDL, LDL LDL = TC - HDL - (Trig /5). LDL = TC - HDL - (Trig /5).

Can now measure “direct LDL”- does not require Can now measure “direct LDL”- does not require fasting; values usually lower (fasting; values usually lower (10%) than 10%) than calculated LDL levels.calculated LDL levels.

29

Treatment ConsiderationsTreatment Considerations

Age, weight and sex of patientAge, weight and sex of patient Presence or absence of CAD risk factorsPresence or absence of CAD risk factors Socioeconomic factorsSocioeconomic factors Patient compliancePatient compliance Availability of support personnel: dietary,Availability of support personnel: dietary,

educational, administrativeeducational, administrative

30

HypertryglyceridemiaHypertryglyceridemia Risk for developing CAD/CHD from elevated Risk for developing CAD/CHD from elevated

triglycerides alone is controversial; likely contributes triglycerides alone is controversial; likely contributes when LDL-C is when LDL-C is or HDL-C is or HDL-C is ..

Pure hypertriglyceridemia associated with Pure hypertriglyceridemia associated with VLDLVLDL elevations is often accompanied by mild elevations of elevations is often accompanied by mild elevations of total and LDL-C (small dense LDL).total and LDL-C (small dense LDL).

Inverse relationship between VLDL (triglycerides) and Inverse relationship between VLDL (triglycerides) and HDL.HDL.

Tryglycerides (>500 mg/dL) Tryglycerides (>500 mg/dL) s risk of pancreatitiss risk of pancreatitis Consensus: treat hypertriglyceridemia but lowering Consensus: treat hypertriglyceridemia but lowering

LDL-C much more important.LDL-C much more important.

31

HypertriglyceridemiaHypertriglyceridemia Often associated with obesity, type 2 diabetes & Often associated with obesity, type 2 diabetes &

metabolic syndrome; mildly metabolic syndrome; mildly with some drugs: with some drugs: estrogen, corticosteroids, estrogen, corticosteroids, ß-ß-Blockers (Non-Blockers (Non-selective) and thiazides. Increased by alcohol.selective) and thiazides. Increased by alcohol.

Very sensitive to diet, weight reduction and Very sensitive to diet, weight reduction and exercise.exercise.

Triglycerides > 200mg/dL may warrant additional Triglycerides > 200mg/dL may warrant additional Rx. Important to consider Rx if Rx. Important to consider Rx if HDL is very lowHDL is very low..

Rx with fibric acid agents or niacin.Rx with fibric acid agents or niacin.

32

HDLHDL Cardioprotective; facilitates removal of cholesterol Cardioprotective; facilitates removal of cholesterol

in tissues; also has direct protective effects. in tissues; also has direct protective effects. Reduced in presence of obesity, smoking, inactivity.Reduced in presence of obesity, smoking, inactivity. Modest increase with weight reduction, regular Modest increase with weight reduction, regular

exercise, smoking cessation, estrogen therapy in post exercise, smoking cessation, estrogen therapy in post menopausal women (avoid where possiblemenopausal women (avoid where possiblerisks), risks), alcohol in low quantities.alcohol in low quantities.

Increased with some meds: fibric acid derivatives Increased with some meds: fibric acid derivatives and niacin. and niacin. Off label indication in patients with Off label indication in patients with CHD and very low HDL levelsCHD and very low HDL levels

33

Therapeutic Lifestyle Changes (TLC)Therapeutic Lifestyle Changes (TLC)

Smoking cessationSmoking cessation Decrease intake of saturated fats (details below)Decrease intake of saturated fats (details below) Decrease total calories if overweightDecrease total calories if overweight Increase physical activityIncrease physical activity Decrease sodium intakeDecrease sodium intake Treat other risk factors if applicableTreat other risk factors if applicable

34

Treatment of Dyslipidemia: DietTreatment of Dyslipidemia: Diet The “typical” American diet is a major contributor to The “typical” American diet is a major contributor to

lipoproten disorders.lipoproten disorders. Dietary Cholesterol - Raises LDL - Egg yolks, animal Dietary Cholesterol - Raises LDL - Egg yolks, animal

fat, red meat, etc.fat, red meat, etc. Dietary Fat- Saturated fat, saturated fatty acids and Dietary Fat- Saturated fat, saturated fatty acids and

animal fat.animal fat. Ideal Diet: < 30% fat, <7% saturated fat, <200 Ideal Diet: < 30% fat, <7% saturated fat, <200

mgs/day cholesterol. Fat replaced with mgs/day cholesterol. Fat replaced with carbohydrates.carbohydrates.

Obesity - Minimum 10% weight reduction.Obesity - Minimum 10% weight reduction. Result: Result: 10% lowering of LDL, but varies.10% lowering of LDL, but varies.

35

Drug Therapy - HyperlipidemiaDrug Therapy - Hyperlipidemia

HMG CoA reductase inhibitors (statins)HMG CoA reductase inhibitors (statins) Bile Acid sequestrants (resins)Bile Acid sequestrants (resins) Nicotinic Acid (niacin)Nicotinic Acid (niacin) Fibric Acid derivatives (fibrates)Fibric Acid derivatives (fibrates) Cholesterol absorption inhibitor- EzetimibeCholesterol absorption inhibitor- Ezetimibe

36

HMG CoA Reductase InhibitorsHMG CoA Reductase Inhibitors AtorvastatinAtorvastatin (Lipitor) 10-80 mg/D(Lipitor) 10-80 mg/D Simvastatin (Zocor/generic) 10-80 mg/DSimvastatin (Zocor/generic) 10-80 mg/D Rousuvastatin (Crestor) 5-40 mg/D Rousuvastatin (Crestor) 5-40 mg/D Lovastatin (Mevacor/generic) 10-80 mg/DLovastatin (Mevacor/generic) 10-80 mg/D Pravastatin (Pravachol/generic) 10-80 mg/DPravastatin (Pravachol/generic) 10-80 mg/D Fluvastatin (Lescol) 20-40 mg/DFluvastatin (Lescol) 20-40 mg/D

Inhibit rate limiting step in cholesterol synthesis in liver; Inhibit rate limiting step in cholesterol synthesis in liver; up regulate synthesis of LDL receptors - further up regulate synthesis of LDL receptors - further reduction LDL cholesterol; LDL and TC lowered by 30-reduction LDL cholesterol; LDL and TC lowered by 30-55%.55%.

Some statins Some statins triglycerides and triglycerides and HDL but mildly.HDL but mildly.

37

Statins - Side EffectsStatins - Side Effects

Increase in serum transaminase levels- must be Increase in serum transaminase levels- must be monitored closely initial year.monitored closely initial year.

GI disturbance infrequentGI disturbance infrequent MyopathyMyopathy – – Dose relatedDose related skeletal muscle complaints skeletal muscle complaints

are most commonly reported adverse effects.are most commonly reported adverse effects.– Myalgia is most Myalgia is most common common (1-5%) and (1-5%) and benign.benign.

– Myositis with rhabdomyolysisMyositis with rhabdomyolysis is is rarerare but can be life but can be life threatening; threatening; CK confirmation is essential to decision CK confirmation is essential to decision making; making; >10 ULN with myositis or rhabdo >10 ULN with myositis or rhabdo

38

““Statin” Induced MyopathyStatin” Induced Myopathy

Mechanism unknown but dose related. Mechanism unknown but dose related. Evaluate patients Evaluate patients with muscle Sx ASAPwith muscle Sx ASAP hold drug and obtain CK. hold drug and obtain CK. It It may be as simple as lowering the dose.may be as simple as lowering the dose.

Signs and symptoms: myalgia, muscle weakness, Signs and symptoms: myalgia, muscle weakness, CK, rarely CK, rarely progressing to rhabdomyolysis, myoglobinemia, renal failure progressing to rhabdomyolysis, myoglobinemia, renal failure and death.and death.– Cerivistatin (Baycol) was taken off market because of 31 reported Cerivistatin (Baycol) was taken off market because of 31 reported

deaths from rhabdomyolysis.deaths from rhabdomyolysis. Risk of myopathy increased with a variety of drugs that Risk of myopathy increased with a variety of drugs that

inhibit statin metabolisminhibit statin metabolism: niacin, fibrates, bile acid : niacin, fibrates, bile acid sequestrants, ketoconazole, erythromycin, clarithromycin, sequestrants, ketoconazole, erythromycin, clarithromycin, cyclosporin and others.cyclosporin and others.

39

Statins: Pleiotropic EffectsStatins: Pleiotropic Effects

Statins have beneficial effects independent of Statins have beneficial effects independent of lipid lowering:lipid lowering:– Placque stabilizationPlacque stabilization– Anti-inflammatory effectsAnti-inflammatory effects– Reduce C-reactive protein levels Reduce C-reactive protein levels – Protection of vessels subject to invasive coronary Protection of vessels subject to invasive coronary

interventionsinterventions

40

EzetimibeEzetimibe

Relatively new- released in 2003; inhibits Relatively new- released in 2003; inhibits intestinal absorption of dietary and biliary intestinal absorption of dietary and biliary cholesterolcholesterol

As monotherapy (randomized double blind study As monotherapy (randomized double blind study of 893 patients), 10 mg daily lowered LDL by up of 893 patients), 10 mg daily lowered LDL by up to 17%, triglycerides by 6% and increased HDL to 17%, triglycerides by 6% and increased HDL by 1.3by 1.3 (minimal)(minimal) %%..

Very well tolerated but avoid in patients with Very well tolerated but avoid in patients with hepatic insufficiency.hepatic insufficiency.

41

EzetimibeEzetimibe

When When addedadded to a statin there was additional LDL to a statin there was additional LDL cholesterol lowering of up to 25%cholesterol lowering of up to 25% likely a likely a synergistic effect.synergistic effect.

Ezetimibe plus low/moderate dose statin is more Ezetimibe plus low/moderate dose statin is more effective in lowering LDL cholesterol than effective in lowering LDL cholesterol than doubling the dose of the statin. doubling the dose of the statin. ButBut…see …see controversies below.controversies below.

Ezetimibe very low incidence of myopathyEzetimibe very low incidence of myopathy

42

Ezetimibe- Recent ConcernsEzetimibe- Recent Concerns

1/14/08- Enhance Trial (Merck/Schering Plough), 1/14/08- Enhance Trial (Merck/Schering Plough), simvastatin vs simvastatin + ezetimibe.simvastatin vs simvastatin + ezetimibe.

Patients with familial hyperlipidemia: marked Patients with familial hyperlipidemia: marked in LDL- in LDL-C. Simvastatin C. Simvastatin LDL-C by 41% (2 yrs), simvastatin + LDL-C by 41% (2 yrs), simvastatin + ezetimibe ezetimibe LDL-C by 58%. No difference in outcomes LDL-C by 58%. No difference in outcomes (MI or stroke), but study not powered for outcomes.(MI or stroke), but study not powered for outcomes.

But: But: Carotid intima media wall thickness (IMT*) Carotid intima media wall thickness (IMT*) increased faster in group treated with combined therapy increased faster in group treated with combined therapy compared with simvastatin alone. ?Significance.compared with simvastatin alone. ?Significance.

More trials neededMore trials needed. Opinion (ACC): Continue to use if . Opinion (ACC): Continue to use if LDL goal not reached with statin (hi dose) alone.LDL goal not reached with statin (hi dose) alone.

*IMT- surrogate end point for clinical coronary events

43

Bile Acid Sequestrants (Resins)Bile Acid Sequestrants (Resins)

Bind bile in the intestine and stimulate conversion of Bind bile in the intestine and stimulate conversion of cholesterol to bile acids in the liver; up regulate LDL cholesterol to bile acids in the liver; up regulate LDL receptors- result is decrease in LDL cholesterol.receptors- result is decrease in LDL cholesterol.

Cholestyramine and Cholestipol- up to 12 scoops of Cholestyramine and Cholestipol- up to 12 scoops of powder in water daily. Colesevelam (Welchol) tablet powder in water daily. Colesevelam (Welchol) tablet form. Expensive.form. Expensive.

Side effects - Constipation, GI Distress (flatulence, Side effects - Constipation, GI Distress (flatulence, constipation, dyspepsia); less common with colesevelamconstipation, dyspepsia); less common with colesevelam

These drugs can also cause myopathy.These drugs can also cause myopathy.

44

Nicotinic AcidNicotinic Acid

Mechanism of action unclear (hepatic).Mechanism of action unclear (hepatic). Lowers Triglycerides and to a lesser degree LDL Lowers Triglycerides and to a lesser degree LDL

cholesterol.cholesterol. Modest (20-30% increase) elevation HDL. Modest (20-30% increase) elevation HDL. Side effects: Side effects: GI distress; flushing/itchingGI distress; flushing/itching, small , small

elevations of LFT’s.elevations of LFT’s.– Pre-treat with ASA for itching/flushingPre-treat with ASA for itching/flushing– Caution: use in uncontrolled diabetesCaution: use in uncontrolled diabetes blood sugar. blood sugar.– Start with very low doses and work upwardsStart with very low doses and work upwards

Increases the likelihood of myopathy when added to statins Increases the likelihood of myopathy when added to statins or bile acid sequestrants.or bile acid sequestrants.

45

Fibric Acid DerivativesFibric Acid Derivatives

Gemfibrozil 600 mgs. 2x/dayGemfibrozil 600 mgs. 2x/dayPrimary effect - lower triglycerides Primary effect - lower triglycerides

Fenofibrate: Once daily, may be more effective than Fenofibrate: Once daily, may be more effective than gemfibrozil in lowering LDL and triglycerides.gemfibrozil in lowering LDL and triglycerides.

Rx of low HDL Rx of low HDL (off label indication). (off label indication). HDL by 15-20%HDL by 15-20%Consider fibrates in patients with CHD and very low Consider fibrates in patients with CHD and very low (<30 mg/dL) HDL levels(<30 mg/dL) HDL levels. Variable reduction in LDL.. Variable reduction in LDL.

Side effects: GI, myopathy, gallstones.Side effects: GI, myopathy, gallstones.

46

Guidelines for Drug TherapyGuidelines for Drug Therapy Elevations of total and LDL cholesterol:Elevations of total and LDL cholesterol:

StatinStatin (TC and LDL decreased up to 50%) Goal (TC and LDL decreased up to 50%) Goal based on degree of risk; statin dose increased to based on degree of risk; statin dose increased to maximum as necessary (see below).maximum as necessary (see below).

If goal not achieved, the addition of other agents If goal not achieved, the addition of other agents (cholestyramine, niacin, ezetimibe, etc) will need to (cholestyramine, niacin, ezetimibe, etc) will need to be determined on a case by case basis as supported by be determined on a case by case basis as supported by clinical trials, weighing the pros/cons, cost, side-clinical trials, weighing the pros/cons, cost, side-effects, compliance and more.effects, compliance and more.– Most experts recommend adding additional drugs to max Most experts recommend adding additional drugs to max

dose statins to lower LDL to goals if necessary.dose statins to lower LDL to goals if necessary.

47

Guidelines for Drug TherapyGuidelines for Drug Therapy Triglycerides + mild Triglycerides + mild hypercholesterolemia: hypercholesterolemia:

Gemfribrozil, Fenofibrate or Niacin. Must control Gemfribrozil, Fenofibrate or Niacin. Must control Diabetes, reduce smoking, reduce ETOH and lose Diabetes, reduce smoking, reduce ETOH and lose weight if indicated. Add statin if LDL remains above weight if indicated. Add statin if LDL remains above goal.goal.

Combination drugs (Advicor- extended release niacin Combination drugs (Advicor- extended release niacin plus lovastatin in fixed combination; Vytorin- plus lovastatin in fixed combination; Vytorin- simvastatin + ezetimibe) may play a role for some simvastatin + ezetimibe) may play a role for some patients.patients.

Very low HDL with CHD: consider fibric acid agent Very low HDL with CHD: consider fibric acid agent or niacin.or niacin.

48

ReferencesReferences

Grundy, SM, et. Al., Implications of Recent Grundy, SM, et. Al., Implications of Recent Trials for National Cholesterol Education Trials for National Cholesterol Education Program Adult Treatment Panel III Guidelines. Program Adult Treatment Panel III Guidelines. CirculationCirculation, 2004; 110: 227-239, 2004; 110: 227-239

Canon, CP, et. al., PROVE IT TIMI trial; NEJM, Canon, CP, et. al., PROVE IT TIMI trial; NEJM, 2004; 350:1495-15042004; 350:1495-1504