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Objectives: Hypercholesterolemia:

Pathophysiology and Therapeutics


Hypercholesterolemia: By the end of this presentation, learners should be able to:
Pathophysiology and Therapeutics 1. Discuss the epidemiology and pathophysiology of
atherosclerosis
2. Describe the risk factors for developing (ASCVD)
Robert J. Straka, Pharm.D. FCCP 3. Discuss NCEP ATP III treatment algorithms for patients with
Associate Professor hyperlipidemia (and optional goals based on the white
paper)
College of Pharmacy 4. Compare antihyperlipidemic medications in terms of efficacy,
University of Minnesota side effects, cost, outcomes, major study results and
implications regarding education of the patient
Strak001@umn.edu 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 CAD Risk Is Incremental


Epidemiology
)Lipids:
)Estimated 105 M American adults have hyperlipidemia
(cholesterol levels of > 200 mg/dL)
)39% males (15% F) have HDL-C < 40mg/dL
)42M have cholesterol levels of > 240 mg/dL
)A 10% decrease in total-C may reduce by 30% the
incidence of CHD
)Risk 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
(Adapted from Neaton et al.)

Lipoproteins Lipoproteins
)Classes
)Composition:
) Chylomicrons
)Phospholipid, free cholesterol & protein on surface and a ) Very-low-density (VLDL)
core made up of primarily triglyceride & cholesterol
) Intermediate density lipoprotein (IDL)
esters
) Low-density (LDL)
)Apolipoproteins are proteins on the surface which
) High-density (HDL)
regulate their transport and metabolism
)Significance
) Apo A
) Premature coronary artery disease (CAD)
) Apo B
) Pancreatitis (hypertriglyceridemia)
)Function of Cholesterol and role of lipoproteins: (VLDL + IDL + LDL-C) = non HDL-C Apo B particles
Cell membranes, bile acid synthesis, steroid
hormone precursor
Low HDL-C as a Potent Predictor of CHD
)Although strong epidemiological evidence that HDL-C protects
against CHD exists, there has not been a cause and effect
relationship proved
)From 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: Lipoprotein & Lipid Concentrations
Framingham Heart Study ApoB-
ApoB-lipoproteins ApoAI-
ApoAI-lipoproteins
D
CH
of
isk
R

V6 V5 V4 V3 V2 V1 L3 L2 L1 H5 H4 H3 H2 H1
el.
R

IDL-C + LDL-
LDL-C HDL-
HDL-C
)

3x VLDL-
VLDL-C IDL-
/L

25 (0.65)
ol

0.5
m

2x
(m

45 (1.16) (TG/5)
1x Reported LDL-
LDL-C
dl
g/

65 (1.68)
m

Total Cholesterol
,
-C

85 (2.20)
DL

TC =Non
LDLHDL-
LDL--C + -HDL-
HDL C = TC
HDL -C + VLDL-
HDL-
HDL-C
VLDL-C
H

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


LDL-C, mg/dl (mmol/L) Arch Intern Med. 1999;159:1049-57
Relative Risk of CHD over 4 years follow-up in men 50-70 yrs old Handbook of lipoprotein Testing 2nd Ed 2000 AACC Press Washington DC

Coronary Remodeling
Lipid-Rich Plaque
Progression
Expansion overcome:
Compensatory expansion lumen narrows
maintains constant lumen

Normal Minimal Moderate Severe


vessel CAD CAD CAD
(Adapted from Glagov et al.)
With permission from Davies. In: Colour Atlas of Cardiovascular Pathology. 1986;86.
Glagov et al, N Engl J Med,
Med, 1987.
Most Myocardial Infarctions Are NCEP ATP III
Caused by Low-Grade Stenosis
Objectives:
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 options
for managing hypercholesterolemia and results of key
studies and novel approaches to therapy
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.

New Features of ATP III ATP III: Features


Built on ATP II
) Continues to identify LDL-C as the primary target of
cholesterol-lowering therapy
) Designation of a CHD risk equivalent category for
aggressive LDL-C lowering ) Increased emphasis on:
) CHD risk status and CHD risk equivalents
) Deployment of a Framingham based 10-year CHD ) Diabetes: CHD risk equivalent
risk assessment to identify certain patients with 2
) Framingham projections of 10-y CHD risk
risk factors for more intensive treatment
) Metabolic syndrome
) Identification of patients with multiple metabolic ) HDL-C as a risk factor for CHD
risk factors (the metabolic syndrome) who become
) Intensified therapeutic lifestyle changes (TLC)
candidates for intensified therapeutic lifestyle
) Adherence to therapy
changes (TLC)
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486-2497. JAMA. 2001;285:2486-2497.

Step #1 Determine Fasting Lipid Levels of


LDL-C, HDL-C, TG, TC Step #2 Identify Presence of CHD or
CHD Risk Equivalents
LDL-C (mg/dL) TG (mg/dL)
<100 Optimal <150 Normal CHD CHD risk equivalents
100 129 Above, near optimal 150 199 Borderline high )Myocardial infarction ) Peripheral artery disease
130 159 Borderline high 200 499 High )Myocardial ischemia ) Abdominal aortic aneurysm
160 189 High 500 Very high )Stable angina ) Thrombotic stroke
190 Very high TC (mg/dL) )Unstable angina ) Transient ischemic attacks
HDL-C (mg/dL) <200 Desirable )PTCA ) Diabetes
<40 Low 200 239 Borderline high )Coronary by-pass ) 10-year CHD risk >20%
60 High 240 High surgery

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. All of these listings are associated with >20% risk of a CHD event in 10 years
JAMA. 2001;285:2486-2497. LDL-C goal is < 100mg/dL
Patients With Diabetes Are at Even Greater Step #3 Determine Major CHD Risk Factors
Risk for CHD
Other Than LDL-C According to ATP-III
Patients With Diabetes Without History of CHD Have Incidence of MI
Comparable to Patients Without Diabetes With CHD History
Positive risk factors
50% 45% ) Age ) Cigarette smoking
) Men 45 ) Hypertension: BP 140/90 mm
Diabetes Women 55 Hg or on antihypertensive
40% )
No diabetes ) Family history of premature CHD medication
7-Year MI 30% (first-degree relative) ) Low HDL-C: <40 mg/dL
Incidence, ) Male relative age <55 years
% 20.2%
18.8% ) Female relative age <65 years
20%
N=2,432

10% Negative risk factor


3.5%
) High HDL-C: 60 mg/dL*
0%
CHD No CHD * Negates one other risk factor
MI = myocardial infarction. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486-2497.
Haffner SM et al. N Engl J Med. 1998;339:229234.

Step #4 Framingham Point Scale for Estimating 10-Year Patient Risk Categories Based on
CHD Risk if > 2 risk factors (Men/Women)
Age Total cholesterol HDL-C the 10-year Risk Assessment
20 34 = -9/-7 Age Age Age Age Age 60 = -1/-1
35 39 = -4/-3 2039 4049 5059 6069 7079 50 59 = 0/0
40 44 = 0/0 <160 0/0 0/0 0/0 0/0 0/0 40 49 = 1/1
45 49 = 3/3 160 199 4/4 3/3 2/2 1/1 0/1 <40 = 2/2
50 54 =
55 59 =
6/6
8/8
200 239 7/8
240 279 9/11
5/6
6/8
3/4
4/5
1/2
2/3
0/1
1/2 >20% High risk risk equivalent
60 64 = 10/10 280 11/13 8/10 5/7 3/4 1/2
65 69 = 11/12
Systolic blood pressure Smoker
70 74 = 12/14
If Untreated If Treated Age Age Age Age Age
75 79 = 13/16
<120 0/0 0/0
120 129 0/1 1/3
2039 4049 5059 6069 7079
No 0/0 0/0 0/0 0/0 0/0 10% 20% Moderate risk
130 139 1/2 2/4 Yes 8/9 5/7 3/4 1/2 1/1
140 159 1/3 2/5
160 2/4 3/6
Total points:
10-year CHD
<0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 >17
<10% Low risk
risk (%) for men: <1 1 1 1 1 1 2 2 3 4 5 6 8 10 12 16 20 25 30
Total points: <9 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
10-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;285:24862497.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:24862497.

Step #5 Establish Risk Category and Implications of Recent Clinical Trials for the
Determine Goal: National Cholesterol Education Program Adult
LDL-C Level
LDL-C Level for
Treatment Panel III Guidelines
Risk LDL-C Goal for Initiation
Consideration of
Category (mg/dL) of TLC Scott M. Grundy, James I. Cleeman,C. Noel Bairey
Drug Therapy (mg/dL)
(mg/dL) Merz, H. Bryan Brewer, Jr, Luther T. Clark, Donald
B. Hunninghake, Richard C. Pasternak, Sidney C.
CHD or CHD risk
130 Smith, Jr, Neil J. Stone
equivalents <100 100
(100-129: drug optional)
(10-y risk >20%) For the Coordinating Committee of the National
Cholesterol Education Program
2+ Risk factors (10- 130: 10-y risk 10%-20%
<130 130
y risk <20%*) 160: 10-y risk <10%

190 Endorsed by the NHLBI, ACC, and AHA


0-1 Risk factor <160 160 (160-189: LDL-C-lowering
drug optional)
Circulation. 2004;110:227-239.
*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.
ATP III LDL cholesterol cutoffs for lifestyle interventions Step #6 Therapeutic Lifestyle Changes (TLC)
and drug therapy in different risk categories and/or Step #7 Consider Drug Therapy
Risk category LDL cholesterol Initiate Consider drug therapy
goal therapeutic )TLC
lifestyle changes
)Reduce saturated fat intake to <7% of total calories and
High risk: CHD or CHD risk <100 mg/dL (with >100 mg/dL >100 mg/dL (consider
equivalents (10-year risk an optional goal of drug options if LDL-C cholesterol to <200 mg/day
>20%) <70 mg/dL) <100 mg/dL)
)Utilize other therapeutic options for LDL-C lowering such as plant
Moderately high risk: two or <130 mg/dL (with >130 mg/dL >130 mg/dL (consider
more risk factors (10-year risk an optional goal of drug options if LDL-C stanols/sterols (2 g/day) and (soluble) fiber (1025 g/day)
10%-20%) <100 mg/dL) 100-129 mg/dL)
Moderate risk: two or more <130 mg/dL >130 mg/dL >160 mg/dL )Maintain an appropriate body weight
risk factors (10-year risk
)Establish a regular exercise plan
<10%)
Low risk: <1 risk factor <160 mg/dL >160 mg/dL >190 mg/dL (consider )Pharmacologic intervention
drug options if LDL-C
160-189 mg/dL) )Drug therapy may be started simultaneously

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
Grundy SM et al. Circulation; available at JAMA. 2001;285:24862497.
http://circ.ahajournals.org

Step # 8 Identify Patients With The Metabolic Syndrome*


Nutritional Components of TLC Diet (Any 3 or more of the following are needed for diagnosis)
Risk category Defining level
Nutrient Recommended intake Abdominal obesity (Waist circumference)
Men >102 cm (>40 in)
Saturated fat* <7% of total calories Women >88 cm (>35 in)
Polyunsaturated fat Up to 10% of total calories
Monounsaturated fat Up to 20% of total calories
TG 150 mg/dL
Total fat 25% to 35% of total calories HDL-C
Carbohydrates (esp. complex carbs) 50% to 60% of total calories Men <40 mg/dL
Fiber 20 30 grams/day Women <50 mg/dL
Protein ~ 15% of total calories Blood pressure 130 / 85 mmHg
Cholesterol <200 mg/day
Fasting glucose* 100 mg/dL
* Diagnosis is established when 3 of these risk factors are present.
Abdominal obesity is more highly correlated with metabolic risk factors than is BMI.
* Trans fatty acids also raise LDL-C and should be kept at a low intake. Some men develop metabolic risk factors when circumference is only marginally .

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

Treatment of the Metabolic


Syndrome
) Weight control
) Physical activity
) Rx of hypertension
) ASA for patients with CHD
) Rx of elevated TGs
) Rx of low HDL-C

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486-2497.
Relative Risk of Death in Patients With Metabolic
Syndrome Compared With Those Without Metabolic Step # 9 Treat Elevated Triglycerides
Syndrome
CHD mortality
4.0
CVD mortality Classification of Serum Triglycerides
3.5 All-cause mortality

* ) Normal <150 mg/dL


3.0
* * ) Borderline high 150199 mg/dL
*
Relative risk

2.5
* ) High 200499 mg/dL
2.0 *
1.5
) Very high 500 mg/dL
1.0
) Primary aim to lower LDL-C
0.5
) Intensify weight management, increase physical
0.0
NCEP NCEP WHO WHO activity, if LDL target is reached and TG still exceed
Waist >102 cm Waist >94 cm WHR >0.90 or Waist 94 cm 200mg/dL, then set secondary goal for non-HDL
BMI 30
*P<.05.

Subjects with metabolic syndrome (n=106-


(n=106-179) vs subjects without metabolic syndrome (n=1037-
(n=1037-1103).
) Fibrate or nicotinic acid if TG > 500mg/dL
Lakka H-M et al. JAMA.
JAMA. 2002;288:2709-
2002;288:2709-2716.

Elevated Triglycerides (200 mg/dL) NonHDL-Cholesterol

Risk category Non-HDL-C goal* NonHDL-C = total-C - HDL-C


(mg/dL)
)Strongly correlated with CHD events
CHD and CHD risk equivalent <130
)Strongly correlated with apo B levels
2 risk factors <160 )Takes into account all atherogenic lipoproteins
0 1 risk factors <190 )VLDL-C
)IDL-C
)remnant particles
* Non-HDL-C = Total Cholesterol HDL-C
)LDL-C
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486-2497.

Same LDL-C Levels, Different Cardiovascular Risk


Management of Low HDL-C
Large LDL Small, Dense LDL
LDL= ) Low HDL-C: <40 mg/dL (no specific goal defined
130 mg/dL for raising HDL-C)
Apo B More Apo B
) Targets of therapy
Cholesterol ) All persons with low HDL-C: achieve LDL-C goal; then
Ester set nonHDL-C goal decrease weight, increase
physical activity (if metabolic syndrome is present)

Fewer Particles More Particles ) Those with TG 200-499 mg/dL: achieve non-HDL-C
goal* as secondary priority
Correlates with: Correlates with:
TC 198 mg/dL TC 210 mg/dL ) Those with TG <200 mg/dL: consider drugs for raising
LDL-C 130 mg/dL LDL-C 130 mg/dL HDL-C (fibrates, niacin)
TG 90 mg/dL TG 250 mg/dL
HDL-C 50 mg/dL HDL-C 30 mg/dL
Non-HDL-C 148 mg/dL Non-HDL-C 180 mg/dL
* Non-HDL-C goal is set at 30 mg/dL higher than LDL-C goal.
Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486-2497.
Framingham Point Scale for Estimating 10-Year
Patient Case CHD Risk (Men/Women)
Age Total cholesterol HDL-C
20 34 = -9/-7 Age Age Age Age Age 60 = -1/-1
35 39 = -4/-3 2039 4049 5059 6069 7079 50 59 = 0/0
) 53 yo WM 61, 210 lbs (95.5Kg) waist 40 44 = 0/0 <160 0/0 0/0 0/0 0/0 0/0 40 49 = 1/1
circumference 40 with a BMI 27.7kg/sqm with a 45 49 =
50 54 =
3/3
6/6
160 199 4/4
200 239 7/8
3/3
5/6
2/2
3/4
1/1
1/2
0/1
0/1
<40 = 2/2

family history positive for CHD on both father and 55 59 =


60 64 =
8/8
10/10
240 279 9/11
280 11/13 8/10
6/8 4/5
5/7
2/3
3/4
1/2
1/2
mothers side is seen 12/02 by Family physician 65 69 =
70 74 =
11/12
12/14
Systolic blood pressure Smoker
If Untreated If Treated
secondary to a suggestion by a colleague 75 79 = 13/16
<120 0/0 0/0
Age Age Age Age Age
2039 4049 5059 6069 7079
120 129 0/1 1/3 No 0/0 0/0 0/0 0/0 0/0
) BP 153/98, smoker 1ppd (>20yrs) 130 139 1/2 2/4 Yes 8/9 5/7 3/4 1/2 1/1
140 159 1/3 2/5
160
) Lipid Panel: Tot. C 230mg/dL, LDL 187mg/dL, HDL- Total points: <0 0 1 2 3
2/4
4 5 6
3/6
7 8 9 10 11 12 13 14 15 16 >17
C 26mg/dL, TG 84 mg/dL 10-year CHD
risk (%) for men: <1 1 1 1 1 1 2 2 3 4 5 6 8 10 12 16 20 25 30
) Recommendations? Total points: <9 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
10-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;285:24862497.

Patient Risk Categories Based on Classification of LDL-C, HDL-C, TG, TC


the 10-year Risk Assessment
LDL-C (mg/dL) TG (mg/dL)
<100 Optimal <150 Normal
>20% High risk risk equivalent 100 129 Above, near optimal 150 199 Borderline high
130 159 Borderline high 200 499 High
160 189 High 500 Very high
10% 20% Moderate risk 190 Very high TC (mg/dL)
HDL-C (mg/dL) <200 Desirable
<40 Low 200 239 Borderline high
<10% Low risk
60 High 240 High

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:24862497. JAMA. 2001;285:2486-2497.

Formulas
Friedwalls Equation for calculating LDL-C:
( LDL ) = ( Total - HDL ) - ( TRG / 5 )
Note: not useful or accurate if Trigs exceed 400mg/dL
Eg: 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 / L
Conversion: (mg / dL) x 0.02586 = (mmol / L)
eg. 100mg/dL x 0.02586 = 2.59

(NEJM 312:20, 1300. 1985)