objectives: “hypercholesterolemia: pathophysiology...

““Hypercholesterolemia: Hypercholesterolemia: Pathophysiology and Therapeutics”Pathophysiology and Therapeutics”

Robert J. Straka, Pharm.D. FCCPAssociate ProfessorCollege of Pharmacy

University of [email protected]

Objectives: “Hypercholesterolemia: “Hypercholesterolemia: Pathophysiology and Therapeutics”Pathophysiology and Therapeutics”

By the end of this presentation, learners should be able to:1. Discuss the epidemiology and pathophysiology of

atherosclerosis

2. Describe the risk factors for developing (ASCVD)

3. Discuss NCEP ATP III treatment algorithms for patients with hyperlipidemia (and optional goals based on the white paper)

4. Compare antihyperlipidemic medications in terms of efficacy, side effects, cost, outcomes, major study results and implications regarding education of the patient

4. Based on a patient case, provide and defend a rational approach to selecting a pharmacotherapeutic treatment plan incorporating clinical evidence and cost data where applicable (10 yr risk, therapeutic goals etc.)

Hyperlipidemia Epidemiology

Lipids:Estimated 105 M American adults have hyperlipidemia (cholesterol levels of > 200 mg/dL)39% males (15% F) have HDL-C < 40mg/dL42M have cholesterol levels of > 240 mg/dLA 10% decrease in total-C may reduce by 30% the incidence of CHDRisk of AMI in Male and Female is highest at lower HDL-C (<37mg/dL in M and 47mg/dL in F) regardless of total-C, conversely those with higher HDL-C (>53mg/dL in M or >67mg/dL in F) are at lower risks for AMI

CAD Risk Is Incremental

(Adapted from Neaton et al.)

LipoproteinsComposition:

Phospholipid, free cholesterol & protein on surface and a core made up of primarily triglyceride & cholesterol estersApolipoproteins are proteins on the surface which regulate their transport and metabolism

Apo AApo B

Function of Cholesterol and role of lipoproteins: Cell membranes, bile acid synthesis, steroid hormone precursor

LipoproteinsClasses

ChylomicronsVery-low-density (VLDL)Intermediate density lipoprotein (IDL)Low-density (LDL)High-density (HDL)

SignificancePremature coronary artery disease (CAD)Pancreatitis (hypertriglyceridemia)

(VLDL + IDL + LDL-C) = “non HDL-C” Apo B particles

Low HDL-C as a Potent Predictor of CHDAlthough strong epidemiological evidence that HDL-C protects against CHD exists, there has not been a cause and effect relationship provedFrom analysis of 4 epi trials, for each 1mg/dL increase in HDL-C, a 2% decrease in CHD risk in men and 3% decrease in women may occur

11% of US men have isolated Low HDL-C levels (NHANES III), but up to 17-36% of high risk pts.

LDL-C management does not completely remove the risk imparted by low HDL-C

Harper C Jacobson T Arch Intern Med 1999;159:1049-1057.

Risk of CHD by HDL and LDL Levels: Framingham Heart Study

100 (2.59) 160 (4.14) 220 (5.67)

85 (2.20)

65 (1.68)

45 (1.16)

25 (0.65)

Rel. R

isk of

CHD

LDL-C, mg/dl (mmol/L)

HDL-C, m

g/dl (m

mol/L)

Arch Intern Med. 1999;159:1049-57

Relative Risk of CHD over 4 years follow-up in men 50-70 yrs old

3x

2x 1x

0.5

Lipoprotein & Lipid Concentrations

Handbook of lipoprotein Testing 2nd Ed 2000 AACC Press Washington DC

VLDLVLDL--CC(TG/5)(TG/5)

V6 V5 V4 V3 V2 V1

HDLHDL--CCH5 H4 H3 H2 H1

IDLIDL--CC LDLLDL--CCL3 L2 L1

ApoBApoB--lipoproteinslipoproteins ApoAIApoAI--lipoproteinslipoproteins

Total CholesterolTotal Cholesterol

++

Reported LDLReported LDL--CC

TC = LDLTC = LDL--C + HDLC + HDL--C + VLDLC + VLDL--CCNon HDLNon HDL--C = TC C = TC –– HDLHDL--CC

(Adapted from (Adapted from GlagovGlagov et al.)et al.)

Coronary Remodeling

NormalNormalvesselvessel

MinimalMinimalCADCAD

ProgressionProgression

Compensatory expansionCompensatory expansionmaintains constant lumenmaintains constant lumen

Expansion overcome:Expansion overcome:lumen narrowslumen narrows

SevereSevereCADCAD

ModerateModerateCADCAD

GlagovGlagov et al, et al, N N EnglEngl J MedJ Med, 1987., 1987.

Lipid-Rich Plaque

With permission from Davies. In: Colour Atlas of Cardiovascular Pathology. 1986;86.

Most Myocardial Infarctions Are Caused by Low-Grade Stenosis

Pooled data from 4 studies: Ambrose et al, 1988; Little et al, 1988; Nobuyoshi et al, 1991; and Giroud et al, 1992.(Adapted from Falk et al.)

Falk E et al, Circulation, 1995.

NCEP ATP IIIObjectives:By the end of this section, learners should be able to:1) Be able to recommend a treatment approach for a

patient with hypercholesterolemia according to current NCEP ATP III guidelines

2) Be able to apply the guidelines to a specific patient case (calculating 10 yr risk, identifying LDL-C and non HDL-C goals etc.)

3) Demonstrate familiarity with key therapeutic optionsfor managing hypercholesterolemia and results of key studies and novel approaches to therapy

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

New Features of ATP IIIBuilt on ATP II

Designation of a CHD risk equivalent category for aggressive LDL-C loweringDeployment of a Framingham based 10-year CHD risk assessment to identify certain patients with ≥ 2 risk factors for more intensive treatmentIdentification of patients with multiple metabolic risk factors (the metabolic syndrome) who become candidates for intensified therapeutic lifestyle changes (TLC)

ATP III: FeaturesContinues to identify LDL-C as the primary target of cholesterol-lowering therapyIncreased emphasis on:

CHD risk status and CHD risk equivalents Diabetes: CHD risk equivalentFramingham projections of 10-y CHD riskMetabolic syndromeHDL-C as a risk factor for CHDIntensified therapeutic lifestyle changes (TLC)Adherence to therapy


Step #1 Determine Fasting Lipid Levels of LDL-C, HDL-C, TG, TC


LDL-C (mg/dL) TG (mg/dL)<100 Optimal <150 Normal100 – 129 Above, near optimal 150 – 199 Borderline high130 – 159 Borderline high 200 – 499 High160 – 189 High ≥500 Very high≥190 Very high TC (mg/dL)HDL-C (mg/dL) <200 Desirable<40 Low 200 – 239 Borderline high≥60 High ≥240 High

Step #2 Identify Presence of CHD or CHD Risk Equivalents

Myocardial infarctionMyocardial ischemiaStable anginaUnstable anginaPTCACoronary by-pass surgery

Peripheral artery diseaseAbdominal aortic aneurysmThrombotic strokeTransient ischemic attacksDiabetes10-year CHD risk >20%

CHD CHD risk equivalents

All of these listings are associated with >20% risk of a CHD event in 10 yearsLDL-C goal is < 100mg/dL

Patients With Diabetes Are at Even Greater Risk for CHD

45%

20.2%18.8%

3.5%

0%

10%

20%

30%

40%

50%

DiabetesNo diabetes

MI = myocardial infarction.

Haffner SM et al. N Engl J Med. 1998;339:229–234.

CHD No CHD

N=2,432

7-Year MI Incidence,

%

Patients With Diabetes Without History of CHD Have Incidence of MI Comparable to Patients Without Diabetes With CHD History

Step #3 Determine Major CHD Risk Factors Other Than LDL-C According to ATP-III

Positive risk factorsAge

Men ≥45Women ≥55

Family history of premature CHD (first-degree relative)

Male relative age <55 yearsFemale relative age <65 years


Cigarette smokingHypertension: BP ≥140/90 mm Hg or on antihypertensive medicationLow HDL-C: <40 mg/dL

* Negates one other risk factor

Negative risk factorHigh HDL-C: ≥60 mg/dL*

Step #4 Framingham Point Scale for Estimating 10-Year CHD Risk if > 2 risk factors (Men/Women)

Age20 – 34 = -9/-735 – 39 = -4/-340 – 44 = 0/045 – 49 = 3/350 – 54 = 6/655 – 59 = 8/860 – 64 = 10/1065 – 69 = 11/1270 – 74 = 12/1475 – 79 = 13/16

Total cholesterolAge Age Age Age Age

20–39 40–49 50–59 60–69 70–79<160 0/0 0/0 0/0 0/0 0/0 160 – 199 4/4 3/3 2/2 1/1 0/1200 – 239 7/8 5/6 3/4 1/2 0/1240 – 279 9/11 6/8 4/5 2/3 1/2≥ 280 11/13 8/10 5/7 3/4 1/2

HDL-C≥60 = -1/-1

50 – 59 = 0/040 – 49 = 1/1

<40 = 2/2

Total points: <0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 >1710-year CHD risk (%) for men: <1 1 1 1 1 1 2 2 3 4 5 6 8 10 12 16 20 25 ≥30Total points: <9 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 ≥2510-year CHD risk (%) for women: <1 1 1 1 1 2 2 3 4 5 6 8 11 14 17 22 27 ≥30

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497.

Systolic blood pressureIf Untreated If Treated

<120 0/0 0/0120 – 129 0/1 1/3130 – 139 1/2 2/4140 – 159 1/3 2/5≥160 2/4 3/6

SmokerAge Age Age Age Age

20–39 40–49 50–59 60–69 70–79No 0/0 0/0 0/0 0/0 0/0Yes 8/9 5/7 3/4 1/2 1/1

Patient Risk Categories Based on the 10-year Risk Assessment

<10%

10% – 20%

Low risk

Moderate risk

High risk – risk equivalent


>20%

Step #5 Establish Risk Category and Determine Goal:

*Determined using the Framingham Risk Scoring system. † Therapeutic lifestyle changes.‡Some experts will use drug therapy is TLC does not achieve LDL-C <100 mg/dL; others usedrugs to modify HDL-C and triglycerides.Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

≥130: 10-y risk 10%-20%≥160: 10-y risk <10%≥130<1302+ Risk factors (10-

y risk <20%*)

≥130(100-129: drug optional)≥100<100

CHD or CHD risk equivalents

(10-y risk >20%)

≥190 (160-189: LDL-C-lowering

drug optional)≥160<1600-1 Risk factor

LDL-C Level for Consideration of

Drug Therapy (mg/dL)

LDL-C Level for Initiation

of TLC (mg/dL)

LDL-C Goal (mg/dL)

RiskCategory

Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult

Treatment Panel III GuidelinesScott M. Grundy, James I. Cleeman,C. Noel Bairey Merz, H. Bryan Brewer, Jr, Luther T. Clark, Donald

B. Hunninghake, Richard C. Pasternak, Sidney C. Smith, Jr, Neil J. Stone

For the Coordinating Committee of the National Cholesterol Education Program

Endorsed by the NHLBI, ACC, and AHA

Circulation. 2004;110:227-239.

ATP III LDL cholesterol cutoffs for lifestyle interventions and drug therapy in different risk categories

>190 mg/dL (consider drug options if LDL-C 160-189 mg/dL)

>160 mg/dL<160 mg/dLLow risk: <1 risk factor

>160 mg/dL>130 mg/dL<130 mg/dLModerate risk: two or more risk factors (10-year risk <10%)

>130 mg/dL (consider drug options if LDL-C 100-129 mg/dL)

>130 mg/dL<130 mg/dL (with an optional goal of <100 mg/dL)

Moderately high risk: two or more risk factors (10-year risk 10%-20%)

>100 mg/dL (consider drug options if LDL-C <100 mg/dL)

>100 mg/dL<100 mg/dL (with an optional goal of <70 mg/dL)

High risk: CHD or CHD risk equivalents (10-year risk >20%)

Consider drug therapyInitiate therapeutic lifestyle changes

LDL cholesterol goal

Risk category

Grundy SM et al. Circulation; available at http://circ.ahajournals.org


Step #6 Therapeutic Lifestyle Changes (TLC) and/or Step #7 Consider Drug TherapyTLC

Reduce saturated fat intake to <7% of total calories and cholesterol to <200 mg/dayUtilize other therapeutic options for LDL-C lowering such as plant stanols/sterols (2 g/day) and (soluble) fiber (10–25 g/day)Maintain an appropriate body weightEstablish a regular exercise plan

Pharmacologic interventionDrug therapy may be started simultaneously

Nutritional Components of TLC Diet


* Trans fatty acids also raise LDL-C and should be kept at a low intake.

Nutrient Recommended intake

Saturated fat* <7% of total caloriesPolyunsaturated fat Up to 10% of total caloriesMonounsaturated fat Up to 20% of total caloriesTotal fat 25% to 35% of total caloriesCarbohydrates (esp. complex carbs) 50% to 60% of total caloriesFiber 20 – 30 grams/dayProtein ~ 15% of total caloriesCholesterol <200 mg/day

Step # 8 Identify Patients With The Metabolic Syndrome*(Any 3 or more of the following are needed for diagnosis)(Any 3 or more of the following are needed for diagnosis)

* Diagnosis is established when ≥3 of these risk factors are present.† Abdominal obesity is more highly correlated with metabolic risk factors than is ↑ BMI.‡ Some men develop metabolic risk factors when circumference is only marginally ↑.

Risk category Defining level Abdominal obesity† (Waist circumference‡)

Men >102 cm (>40 in)Women >88 cm (>35 in)

TG ≥150 mg/dL

HDL-CMen <40 mg/dLWomen <50 mg/dL

Blood pressure ≥130 / ≥85 mmHg

Fasting glucose* ≥100 mg/dL

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.*Updated based on Grundy et al, Circulation 2005;112:2735-2752


Treatment of the Metabolic Syndrome

Weight controlPhysical activityRx of hypertensionASA for patients with CHDRx of elevated TGsRx of low HDL-C

Relative Risk of Death in Patients With Metabolic Syndrome Compared With Those Without Metabolic

Syndrome†

**PP<.05.<.05.††Subjects with metabolic syndrome (n=106Subjects with metabolic syndrome (n=106--179) 179) vsvs subjects without metabolic syndrome (n=1037subjects without metabolic syndrome (n=1037--1103).1103).LakkaLakka HH--M et al. M et al. JAMAJAMA. 2002;288:2709. 2002;288:2709--2716. 2716.

CHD mortalityCVD mortalityAll-cause mortality

0.0NCEP

Waist >102 cmNCEP

Waist >94 cmWHO

WHR >0.90 orBMI ≥30

WHOWaist ≥94 cm

**

**

* *

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Rel

ativ

e ris

k

Step # 9 Treat Elevated Triglycerides

Classification of Serum Triglycerides

Normal <150 mg/dLBorderline high 150–199 mg/dLHigh 200–499 mg/dLVery high ≥500 mg/dL

Primary aim to lower LDL-CIntensify weight management, increase physical activity, if LDL target is reached and TG still exceed 200mg/dL, then set secondary goal for non-HDLFibrate or nicotinic acid if TG > 500mg/dL

Elevated Triglycerides (≥200 mg/dL)

* Non-HDL-C = Total Cholesterol – HDL-C

Risk category Non-HDL-C goal*(mg/dL)

CHD and CHD risk equivalent <130

≥2 risk factors <160

0 – 1 risk factors <190


Non–HDL-Cholesterol

Strongly correlated with CHD events

Strongly correlated with apo B levelsTakes into account all atherogenic lipoproteins

VLDL-CIDL-Cremnant particlesLDL-C

Non–HDL-C = total-C - HDL-C

Same LDL-C Levels, Different Cardiovascular Risk

Large LDL Small, Dense LDL

Apo B

LDL=130 mg/dL

Fewer Particles More Particles

CholesterolEster

More Apo B

Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i.

Correlates with:TC 198 mg/dLLDL-C 130 mg/dLTG 90 mg/dLHDL-C 50 mg/dLNon-HDL-C 148 mg/dL

Correlates with:TC 210 mg/dLLDL-C 130 mg/dLTG 250 mg/dLHDL-C 30 mg/dLNon-HDL-C 180 mg/dL

Management of Low HDL-CLow HDL-C: <40 mg/dL (no specific goal defined for raising HDL-C)

Targets of therapyAll persons with low HDL-C: achieve LDL-C goal; then set non–HDL-C goal decrease weight, increase physical activity (if metabolic syndrome is present)

Those with TG 200-499 mg/dL: achieve non-HDL-C goal* as secondary priority

Those with TG <200 mg/dL: consider drugs for raising HDL-C (fibrates, niacin)

* Non-HDL-C goal is set at 30 mg/dL higher than LDL-C goal.Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

Patient Case

53 yo WM 6’1”, 210 lbs (95.5Kg) waist circumference 40” with a BMI 27.7kg/sqm with a family history positive for CHD on both father and mother’s side is seen 12/02 by Family physician secondary to a suggestion by a colleagueBP 153/98, smoker 1ppd (>20yrs)Lipid Panel: Tot. C 230mg/dL, LDL 187mg/dL, HDL-C 26mg/dL, TG 84 mg/dL Recommendations?

Framingham Point Scale for Estimating 10-Year CHD Risk (Men/Women)

Age20 – 34 = -9/-735 – 39 = -4/-340 – 44 = 0/045 – 49 = 3/350 – 54 = 6/655 – 59 = 8/860 – 64 = 10/1065 – 69 = 11/1270 – 74 = 12/1475 – 79 = 13/16

Total cholesterolAge Age Age Age Age

20–39 40–49 50–59 60–69 70–79<160 0/0 0/0 0/0 0/0 0/0 160 – 199 4/4 3/3 2/2 1/1 0/1200 – 239 7/8 5/6 3/4 1/2 0/1240 – 279 9/11 6/8 4/5 2/3 1/2≥ 280 11/13 8/10 5/7 3/4 1/2

HDL-C≥60 = -1/-1

50 – 59 = 0/040 – 49 = 1/1

<40 = 2/2

Total points: <0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 >1710-year CHD risk (%) for men: <1 1 1 1 1 1 2 2 3 4 5 6 8 10 12 16 20 25 ≥30Total points: <9 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 ≥2510-year CHD risk (%) for women: <1 1 1 1 1 2 2 3 4 5 6 8 11 14 17 22 27 ≥30


Systolic blood pressureIf Untreated If Treated

<120 0/0 0/0120 – 129 0/1 1/3130 – 139 1/2 2/4140 – 159 1/3 2/5≥160 2/4 3/6

SmokerAge Age Age Age Age

20–39 40–49 50–59 60–69 70–79No 0/0 0/0 0/0 0/0 0/0Yes 8/9 5/7 3/4 1/2 1/1

Patient Risk Categories Based on the 10-year Risk Assessment

<10%

10% – 20%

Low risk

Moderate risk

High risk – risk equivalent


>20%

Classification of LDL-C, HDL-C, TG, TC


LDL-C (mg/dL) TG (mg/dL)<100 Optimal <150 Normal100 – 129 Above, near optimal 150 – 199 Borderline high130 – 159 Borderline high 200 – 499 High160 – 189 High ≥500 Very high≥190 Very high TC (mg/dL)HDL-C (mg/dL) <200 Desirable<40 Low 200 – 239 Borderline high≥60 High ≥240 High

FormulasFriedwall’s Equation for calculating LDL-C:( LDL ) = ( Total - HDL ) - ( TRG / 5 )Note: not useful or accurate if Trigs exceed 400mg/dLEg: T-Chol=240mg/dL, HDL=50mg/dL, TG= 150mg/dL what is LDL-C? Answer: (240-50)-(150/5)=160mg/dL

Units:-Traditional -- mg / dL-SI -- mmol / LConversion: (mg / dL) x 0.02586 = (mmol / L)eg. 100mg/dL x 0.02586 = 2.59

(NEJM 312:20, 1300. 1985)

objectives: “hypercholesterolemia: pathophysiology...

Documents