““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
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
Step #1 Determine Fasting Lipid Levels of LDL-C, HDL-C, TG, TC
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
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
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
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
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497.
>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
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497.
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
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
* 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
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
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
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
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
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
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497.
>20%
Classification of LDL-C, HDL-C, TG, TC
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
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)