Dyslipidemia: What Every
Resident Should Know
Med Study
• Lipoproteins
– Chylomicrons, VLDL, IDL, LDL, & HDL
• Hyperlipoproteinemia
– Familial syndromes
• Evaluation of hyperlipidemia
• Treatment of hyperlipidemia
– Guidelines, diet, & drugs
MKSAP
• Physiology & metabolism
• Diagnosis
– Secondary causes
• Management
– Increased LDL
– Increased triglycerides
– Decreased HDL
Pathways of Lipid Transport
Knopp, R. H. N Engl J Med 1999;341:498-511
Primary Lipoprotein Disorders Amenable to Treatment with Diet and Drug Therapy
Knopp, R. H. N Engl J Med 1999;341:498-511
Pathophysiologic Events Culminating in the Clinical Syndrome of Unstable Angina
Yeghiazarians, Y. et al. N Engl J Med 2000;342:101-114
JAMA 2001; 285: 2486-2497
NCEP Reports
• ATP I (1988)
– Prevention of CHD among patients with high LDL
(160) or borderline high LDL (130-159) with multiple
(2) risk factors
• ATP II (1994)
– Intensive management of LDL (100) among patients
with established CHD
• ATP III (2001)
– Prevention of CHD among high-risk patients
• DM as a CHD risk equivalent
• Use of Framingham risk score
• Therapeutic lifestyle changes
NCEP - ATP III
JAMA 2001; 285: 2486-2497
Question #1
• How often should the average adult patient
have his or her lipids measured?
Routine Testing
• Adults ≥ 20 yo should have a fasting lipid
panel measured every 5 years
• If the specimen is non-fasting, then only the
TC and HDL values can be used
– Obtain a fasting lipid panel if…
• TC ≥ 200 mg/dl, or
• HDL ≤ 40 mg/dl
JAMA 2001; 285: 2486-2497
Question #2
• What is the formula for calculating LDL
from total cholestrol (TC), HDL, &
triglycerides (TG)?
Calculation of LDL
• LDL = TC – [HDL + (TG  5)]
– TC = HDL + LDL + VLDL
– (TG  5) is an estimate of VLDL
• Formula is not reliable if TG > 400 mg/dl
Question #3
• What are 5 potential causes of “secondary
dyslipidemia” that should be ruled out
before to initiating lipid-lowering therapy?
Secondary Dyslipidemia
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Diabetes mellitus
Hypothyroidism
Obstructive liver disease
Chronic renal failure
Drugs
– Anabolic steroids, corticosteroids, progestins,
thiazides, protease inhibitors, Cyclosporine,
Sertraline (Zoloft), Isotretinoin (Accutane)
JAMA 2001; 285: 2486-2497
Secondary Dyslipidemia
• Increased LDL
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Obesity
Hypothyroidism
Nephrotic syndrome
Biliary cirrhosis
Thiazide diuretics
Pregnancy
• Increased triglycerides
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Obesity
Diabetes
Hypothyroidism
Chronic kidney disease
Alcohol
Thiazide diuretics
Corticosteroids
Nonselective blockers
– Estrogen
– Pregnancy
MKSAP 13
Question #4
• According to ATP III, what are the 3
categories of risk that modify LDL goals?
Categories of Risk
• CHD and CHD risk equivalents
• Multiple (2+) risk factors
• Few (0-1) risk factors
Question #5
• According to ATP III, which conditions are
considered to be CHD risk equivalents?
CHD Risk Equivalents
• Other forms of atherosclerotic disease
– Peripheral arterial disease
– Abdominal aortic aneurysm
– Symptomatic carotid artery disease
• Diabetes mellitus
• Multiple risk factors that confer a 10-year
risk for CHD >20%
– Framingham point score
Question #6
• According to ATP III, what are the 5 major
CVD risk factors that modify LDL goals?
Major Risk Factors
• Age
– Men  45 yo
– Women  55 yo
• Family history of premature CHD
– Males < 55 yo
– Females < 65 yo
• Cigarette smoking
• Hypertension (>140/90 mmHg or on meds)
• Low HDL (< 40 mg/dl)
Question #7
• For which of the following patients should
you calculate a Framingham point score in
order guide your lipid-lowering therapy?
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A 50 yo man with CHD
A 60 yo woman with diabetes mellitus
A 50 yo man who smokes cigarettes
A 60 yo woman without any other risk factors
Multiple Risk Factors
• Patients with  2 risk factors
• Framingham point score
• Ten-year risk for CHD
– > 20%
– 10-20%
– < 10%
Question #8
• According to ATP III, what is the LDL goal
for each of the 3 categories of risk?
– CHD or CHD risk equivalent
– Multiple (2+) risk factors
– Few (0-1) risk factors
LDL Goals
JAMA 2001; 285: 2486-2497
LDL Goals
• Diabetes mellitus
– LDL < 100
– ADA Guidelines (2005)
• Chronic kidney disease
– LDL < 100
– KDOQI Guidelines (2003)
Question #8
• According to ATP III, what are the LDL
cutpoints for initiating therapeutic lifestyle
changes and drug therapy for each category
of risk?
– CHD or CHD risk equivalent
– Multiple (2+) risk factors
– Few (0-1) risk factors
LDL Cutpoints
JAMA 2001; 285: 2486-2497
Question #10
• According to ATP III, which therapeutic
lifestyle changes (TLC) should physicians
recommend to patients with dyslipidemia?
Therapeutic Lifestyle Changes
• Low-fat diet
– Refer to a nutritionist
– www.nutrition.gov
• Increased physical activity
– www.fitness.gov
• Weight reduction
– www.nhlbi.nih.gov/health/public/heart/obesity/l
ose_wt/index.htm
JAMA 2001; 285: 2486-2497
Model of Steps in Therapeutic Lifestyle Changes (TLC)
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, JAMA
2001;285:2486-2497.
Copyright restrictions may apply.
Question #11
• Which of the following classes of drugs can
lower LDL the most?
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Bile acid sequestrants
Fibric acids
Nicotinic acid
Statins (HMG CoA reductase inhibitors)
LDL Lowering-Drugs
• Statins
18-55%
– Atorvastatin (Lipitor) & Simvastatin (Zocor)
• Bile acid sequestrants
15-30%
– Cholestyramine (Questran) & Colestipol (Colestid)
• Nicotinic acid
5-25%
– Niacin ER (Niaspan)
• Fibic acid
5-20%
– Fenofibrate (Tricor) & Gemfibrozil (Lopid)
Characteristics of Statins
Knopp, R. H. N Engl J Med 1999;341:498-511
Circulation 2004; 110: 227-239
Progression of Drug Therapy in Primary Prevention
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, JAMA
2001;285:2486-2497.
Copyright restrictions may apply.
Circulation 2004; 110: 227-239
Recent Clinical Trials
• HPS
– Lancet 2002; 360: 7-22
• PROSPER
– Lancet 2002; 360: 1623-1630
• ALLHAT-LLT
– JAMA 2002; 288: 2998-3007
• ASCOT-LLA
– Lancet 2003; 361: 1149-1158
• PROVE IT – TIMI 22
– N Engl J Med 2004; 350: 1495-1504
Heart Protection Study
• 20,536 adults age 40-80 yo with CHD, PAD, or
diabetes mellitus
• Simvastatin (Zocor) 40 mg qd v placebo
• Follow-up = 5 years
• LDL  132.6 to 89.7 mg/dl
• Primary outcomes
– All-cause mortality
– Vascular mortality
– CHD mortality
RR  13% (12.9% v 14.7%)
RR  17% (7.6% v 9.1%)
RR  18% (5.7% v 6.9%)
Lancet 2002; 360: 7-22
Prospective Study of Pravastatin in
the Elderly at Risk
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5,804 adults age 70-82 yo with, or at risk of, CVD
Pravastatin (Pravachol) 40 mg qd v placebo
Follow-up = 3.2 years
LDL  148.2 to 97.8 mg/dl
Primary outcome
– Composite of CHD death, non-fatal MI, and fatal or
nonfatal stroke
– RR  15% (14.1% v 16.2%)
Lancet 2002; 360: 1623-1630
Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial –
Lipid-Lowering Trial
• 10,355 adults ≥ 55 yo with HTN and ≥ 1 other
CHD risk factor
• Pravastatin (Pravachol) 40mg qd v placebo
• Follow-up = 4.8 years
• LDL  145.6 to 104 mg/dl
• No difference in the primary outcomes
– All-cause mortality
– CVD death
• CHD events and stroke  9% (stat. nonsignif.)
JAMA 2002; 288: 2998-3007
Anglo-Scandinavian Cardiac Outcomes
Trial – Lipid-Lowering Arm
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10,305 adults aged 40-79 yo with HTN
Atorvastatin 10mg po qd v placebo
Follow-up = 3.3 years
LDL  132.6 to 90.5 mg/dl
Primary outcome
– Composite of fatal CHD and nonfatal MI
– RR  36% (6% v 9.4%)
Lancet 2003; 361: 1149-1158
Pravastatin or Atorvastatin
Evaluation and Infection Therapy
• 4,162 adults ≥ 18 yo hospitalized for ACS
• Atorvastatin (Lipitor) 80mg qd v Pravastatin
(Pravachol) 40 mg qd
• Follow-up = 2 years
• LDL values
– Atorvastatin
– Pravastatin
 106 to 62 mg/dl
 106 to 95 mg/dl
• Primary outcome
– Composite of all-cause mortality, MI, unstable angina,
revascularization, and stroke
– RR  16% (22.4% v 26.3%)
N Engl J Med 2004; 350: 1495-1504
Circulation 2004; 110: 227-239
Lancet 2005; 366: 1267-1278
CTT (2005)
• 14 RCTs of statins published 1994-2004
• 90,056 subjects
– 55% had HTN
– 47% had CHD
– 21% had DM
• Mean follow-up = 4.7 years
• Mean baseline LDL = 147.8 mg/dl
• Mean decrease in LDL after 1 yr = 42.5 mg/dl
Lancet 2005; 366: 1267-1278
CTT (2005)
CTT (2005)
• Risk reduction per 1 mmol/L (39 mg/dl) decrease
in LDL cholesterol:
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All-cause mortality
CHD death
Major coronary events
Coronary revascularization
Ischemic stroke
Major vascular events
12%
19%
23%
24%
19%
21%
• No significant increase in the risk of cancer or
rhabdomyolysis
Lancet 2005; 366: 1267-1278
Question #12
• What is the incidence of elevated liver
transaminase levels with statin use?
Hepatotoxicity
• PROSPER: ALT & AST > 3X ULN
– Pravastatin 0.0003% v placebo 0.0003%
• HPS: ALT > 2X ULN
– Simvastatin 1.8% v placebo 1.6%
• PROVE IT: ALT > 3X ULN
– Atorvastatin 3.3% v Pravastatin 1.1%
Question #13
• What is the incidence of skeletal muscle
toxicity with statin use?
– Myalgias
– Elevated creatinine kinase (CK)
– Rhabdomyolysis
Myotoxicity
• Myalgias
– PROSPER: Prava. 0.01% v placebo 0.01%
– PROVE IT: Atorva. 3.3% v Prava. 1.1%
• Elevated CK > 4X ULN
– HPS: Simva. 0.30% v placebo 0.19%
• Elevated CK > 10X ULN
– PROSPER: Prava. 0% v placebo 0%
• Rhabdomyolysis
– HPS: Simva. 0.05% v placebo 0.03%
– PROSPER: Prava. 0% v placebo 0%
– PROVE IT: Atorva. 0% v Prava. 0%
Question #14
• According to ATP III, what are the five
clinical features of the metabolic syndrome?
JAMA 2001; 285: 2486-2497
Question #13
• Which of the following classes of drugs can
lower triglycerides (TG) the most?
–
–
–
–
Bile acid sequestrants
Fibric acids
Nicotinic acid
Statins (HMG CoA reductase inhibitors)
TG-Lowering Drugs
• Fibic acid
20-50%
– Fenofibrate (Tricor) & Gemfibrozil (Lopid)
• Nicotinic acid
20-50%
– Niacin ER (Niaspan)
• Statins
7-30%
– Atorvastatin (Lipitor) & Simvastatin (Zocor)
• Bile acid sequestrants
No change
– Cholestyramine (Questran) & Colestipol (Colestid)
Question #14
• Which of the following classes of drugs can
raise HDL the most?
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–
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Bile acid sequestrants
Fibric acids
Nicotinic acid
Statins (HMG CoA reductase inhibitors)
HDL-Raising Drugs
• Nicotinic acid
15-35%
– Niacin ER (Niaspan)
• Fibic acid
10-20%
– Fenofibrate (Tricor) & Gemfibrozil (Lopid)
• Statins
5-15%
– Atorvastatin (Lipitor) & Simvastatin (Zocor)
• Bile acid sequestrants
3-5%
– Cholestyramine (Questran) & Colestipol (Colestid)
JAMA 2001; 285: 2486-2497
Lipid-Lowering Medications and Effects on HDL Cholesterol Levels
Ashen, M. D. et al. N Engl J Med 2005;353:1252-1260
Question #15
• What is the role of Ezetimibe (Zetia) in
lipid-lowering drug therapy?
Role of Ezetimibe
• Inhibits intestinal absorption of cholesterol
• Dose = 10 mg po qd
• Ezetimibe alone  LDL 18-20%, whereas
Ezetimibe + Simvastatin  LDL 44-61%
– J Am Coll Cardiol 2002; 40: 2125-2134
– Mayo Clin Prac 2004; 79: 620-629
• Ezetimibe added to statin therapy helped 71% of
patients achieve their target LDL
– Mayo Clin Prac 2005; 80: 587-595
• No RCTs with clinical outcomes
Question #14
• What is “intensive” statin therapy?
Intensive Statin Therapy
• PROVE IT – TIMI 22
– N Engl J Med 2004; 350: 1495-1504
• REVERSAL
– JAMA 2004; 291; 1071-1080
• A to Z
– JAMA 2004; 292: 1307-1316
• IDEAL
– JAMA 2005; 294: 2437-2445
• TNT
– N Engl J Med 2005; 352: 1425-1435
Treating to New Targets
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10,001 adults aged 35-75 yo with CHD
Atorvastatin (Lipitor) 10 mg qd v 80 mg qd
Follow-up = 4.9 years
LDL values
– 10 mg
– 80 mg
 98 to 101 mg/dl
 99 to 77 mg/dl
• Primary outcome  22%
– Composite of CHD death, nonfatal MI, resuscitation
from cardiac arrest, and fatal or nonfatal stroke
N Engl J Med 2005; 352: 1425-1435
References
• “Executive Summary of the Third Report of the National Cholesterol
Education Panel (NCEP) Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults (Adult Treatment
Panel III).” JAMA 2001; 2486-2497.
• http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm
• Grundy SM, et al. “Implications of Recent Clinical Trials for the
National Cholesterol Education Program Adult Treatment Panel III
Guidelines.” Circulation 2004; 110: 227-239.
• Cholesterol Treatment Trialists’ Collaborators. “Efficacy and Safety
of Cholesterol-Lowering Treatment: Prospective Meta-analysis of Data
from 90,056 Participants in 14 Randomized Trials of Statins.” Lancet
2005; 366: 1267-1278.
References
• Knopp RH. “Drug Treatment of Lipid Disorders.” N Engl J Med
1999; 341: 498-511.
• Ashen MD, Blumenthal RS. “Low HDL Cholesterol Levels.” N Engl
J Med 2005; 353: 1252-1260.