1. Dyslipidemia: What Every Resident Should Know

2. Med Study Lipoproteins Hyperlipoproteinemia
Chylomicrons, VLDL, IDL, LDL, & HDL
Hyperlipoproteinemia
Familial syndromes
Evaluation of hyperlipidemia
Treatment of hyperlipidemia
Guidelines, diet, & drugs

3. MKSAP Physiology & metabolism Diagnosis Management Secondary causes
Increased LDL
Increased triglycerides
Decreased HDL

4. Pathways of Lipid Transport
Figure 1. Pathways of Lipid Transport. Cholesterol is absorbed from the intestine and transported to the liver by chylomicron remnants, which are taken up by the low-density lipoprotein (LDL)-receptor-related protein (LRP). Hepatic cholesterol enters the circulation as very-low-density lipoprotein (VLDL) and is metabolized to remnant lipoproteins after lipoprotein lipase removes triglyceride. The remnant lipoproteins are removed by LDL receptors (LDL-R) or further metabolized to LDL and then removed by these receptors. Cholesterol is transported from peripheral cells to the liver by high-density lipoprotein (HDL). Cholesterol is recycled to LDL and VLDL by cholesterol-ester transport protein (CETP) or is taken up in the liver by hepatic lipase. Cholesterol is excreted in bile. The points in the process that are affected by the five primary lipoprotein disorders -- familial hypertriglyceridemia (FHTG), familial combined hyperlipidemia (FCHL), remnant removal disease (RRD, also known as familial dysbetalipoproteinemia), familial hypercholesterolemia (FH), and hypoalphalipoproteinemia -- are shown. The effects of drug therapy can also be understood from these pathways. Statins decrease the synthesis of cholesterol and the secretion of VLDL and increase the activity of LDL receptors. Bile-acid-binding resins increase the secretion of bile acids. Nicotinic acid decreases the secretion of VLDL and the formation of LDL and increases the formation of HDL. Fibrates decrease the secretion of VLDL and increase the activity of lipoprotein lipase, thereby increasing the removal of triglycerides. Adapted from Knopp.12
Knopp, R. H. N Engl J Med 1999;341:

5. Primary Lipoprotein Disorders Amenable to Treatment with Diet and Drug Therapy
Table 1. Primary Lipoprotein Disorders Amenable to Treatment with Diet and Drug Therapy.
Knopp, R. H. N Engl J Med 1999;341:

6. Pathophysiologic Events Culminating in the Clinical Syndrome of Unstable Angina
Figure 1. Pathophysiologic Events Culminating in the Clinical Syndrome of Unstable Angina. Numerous physiologic triggers probably initiate the rupture of a vulnerable plaque. Rupture leads to the activation, adhesion, and aggregation of platelets and the activation of the clotting cascade, resulting in the formation of an occlusive thrombus. If this process leads to complete occlusion of the artery, then acute myocardial infarction with ST-segment elevation occurs. Alternatively, if the process leads to severe stenosis but the artery nonetheless remains patent, then unstable angina occurs.
Yeghiazarians, Y. et al. N Engl J Med 2000;342:

7. JAMA 2001; 285:

9. NCEP Reports ATP I (1988) ATP II (1994) ATP III (2001)
Prevention of CHD among patients with high LDL (160) or borderline high LDL ( ) 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

10. NCEP - ATP III
JAMA 2001; 285:

11. Question #1
How often should the average adult patient have his or her lipids measured?

12. 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:

13. Question #2
What is the formula for calculating LDL from total cholestrol (TC), HDL, & triglycerides (TG)?

14. 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

15. Question #3
What are 5 potential causes of “secondary dyslipidemia” that should be ruled out before to initiating lipid-lowering therapy?

16. Secondary Dyslipidemia
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:

17. Secondary Dyslipidemia
Increased LDL
Obesity
Hypothyroidism
Nephrotic syndrome
Biliary cirrhosis
Thiazide diuretics
Pregnancy
Increased triglycerides
Obesity
Diabetes
Hypothyroidism
Chronic kidney disease
Alcohol
Thiazide diuretics
Corticosteroids
Nonselective -blockers
Estrogen
Pregnancy
MKSAP 13

18. Question #4
According to ATP III, what are the 3 categories of risk that modify LDL goals?

19. Categories of Risk CHD and CHD risk equivalents
Multiple (2+) risk factors
Few (0-1) risk factors

20. Question #5
According to ATP III, which conditions are considered to be CHD risk equivalents?

21. 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

22. Question #6
According to ATP III, what are the 5 major CVD risk factors that modify LDL goals?

23. Major Risk Factors Age Family history of premature CHD
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)

24. Question #7
For which of the following patients should you calculate a Framingham point score in order guide your lipid-lowering therapy?
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

25. Multiple Risk Factors Patients with  2 risk factors
Framingham point score
Ten-year risk for CHD
> 20%
10-20%
< 10%

27. 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

28. LDL Goals
JAMA 2001; 285:

29. LDL Goals Diabetes mellitus Chronic kidney disease LDL < 100
ADA Guidelines (2005)
Chronic kidney disease
KDOQI Guidelines (2003)

30. 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

31. LDL Cutpoints
JAMA 2001; 285:

32. Question #10
According to ATP III, which therapeutic lifestyle changes (TLC) should physicians recommend to patients with dyslipidemia?

33. Therapeutic Lifestyle Changes
Low-fat diet
Refer to a nutritionist
Increased physical activity
Weight reduction
JAMA 2001; 285:

34. Model of Steps in Therapeutic Lifestyle Changes (TLC)
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, JAMA 2001;285:
Copyright restrictions may apply.

35. Question #11
Which of the following classes of drugs can lower LDL the most?
Bile acid sequestrants
Fibric acids
Nicotinic acid
Statins (HMG CoA reductase inhibitors)

36. LDL Lowering-Drugs Statins 18-55% Bile acid sequestrants 15-30%
Atorvastatin (Lipitor) & Simvastatin (Zocor)
Bile acid sequestrants %
Cholestyramine (Questran) & Colestipol (Colestid)
Nicotinic acid %
Niacin ER (Niaspan)
Fibic acid %
Fenofibrate (Tricor) & Gemfibrozil (Lopid)

37. Characteristics of Statins
Table 4. Characteristics of Statins.
Knopp, R. H. N Engl J Med 1999;341:

38. Circulation 2004; 110:

39. Progression of Drug Therapy in Primary Prevention
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, JAMA 2001;285:
Copyright restrictions may apply.

40. Circulation 2004; 110:

41. Recent Clinical Trials
HPS
Lancet 2002; 360: 7-22
PROSPER
Lancet 2002; 360:
ALLHAT-LLT
JAMA 2002; 288:
ASCOT-LLA
Lancet 2003; 361:
PROVE IT – TIMI 22
N Engl J Med 2004; 350:

42. Heart Protection Study
20,536 adults age yo with CHD, PAD, or diabetes mellitus
Simvastatin (Zocor) 40 mg qd v placebo
Follow-up = 5 years
LDL  to 89.7 mg/dl
Primary outcomes
All-cause mortality RR  13% (12.9% v 14.7%)
Vascular mortality RR  17% (7.6% v 9.1%)
CHD mortality RR  18% (5.7% v 6.9%)
Lancet 2002; 360: 7-22

43. Prospective Study of Pravastatin in the Elderly at Risk
5,804 adults age yo with, or at risk of, CVD
Pravastatin (Pravachol) 40 mg qd v placebo
Follow-up = 3.2 years
LDL  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:

44. 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  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:

45. Anglo-Scandinavian Cardiac Outcomes Trial – Lipid-Lowering Arm
10,305 adults aged yo with HTN
Atorvastatin 10mg po qd v placebo
Follow-up = 3.3 years
LDL  to 90.5 mg/dl
Primary outcome
Composite of fatal CHD and nonfatal MI
RR  36% (6% v 9.4%)
Lancet 2003; 361:

46. 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  106 to 62 mg/dl
Pravastatin  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:

47. Circulation 2004; 110:

48. Lancet 2005; 366:

49. 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 = mg/dl
Mean decrease in LDL after 1 yr = 42.5 mg/dl
Lancet 2005; 366:

50. CTT (2005)

51. CTT (2005)
Risk reduction per 1 mmol/L (39 mg/dl) decrease in LDL cholesterol:
All-cause mortality 12%
CHD death 19%
Major coronary events 23%
Coronary revascularization 24%
Ischemic stroke 19%
Major vascular events 21%
No significant increase in the risk of cancer or rhabdomyolysis
Lancet 2005; 366:

52. Question #12
What is the incidence of elevated liver transaminase levels with statin use?

53. Hepatotoxicity PROSPER: ALT & AST > 3X ULN HPS: ALT > 2X ULN
Pravastatin % v placebo %
HPS: ALT > 2X ULN
Simvastatin 1.8% v placebo 1.6%
PROVE IT: ALT > 3X ULN
Atorvastatin 3.3% v Pravastatin 1.1%

54. Question #13
What is the incidence of skeletal muscle toxicity with statin use?
Myalgias
Elevated creatinine kinase (CK)
Rhabdomyolysis

55. Myotoxicity Myalgias Elevated CK > 4X ULN Elevated CK > 10X ULN
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%
PROVE IT: Atorva. 0% v Prava. 0%

56. Question #14
According to ATP III, what are the five clinical features of the metabolic syndrome?

57. JAMA 2001; 285:

58. 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)

59. TG-Lowering Drugs Fibic acid 20-50% Nicotinic acid 20-50%
Fenofibrate (Tricor) & Gemfibrozil (Lopid)
Nicotinic acid %
Niacin ER (Niaspan)
Statins %
Atorvastatin (Lipitor) & Simvastatin (Zocor)
Bile acid sequestrants No change
Cholestyramine (Questran) & Colestipol (Colestid)

60. Question #14
Which of the following classes of drugs can raise HDL the most?
Bile acid sequestrants
Fibric acids
Nicotinic acid
Statins (HMG CoA reductase inhibitors)

61. HDL-Raising Drugs Nicotinic acid 15-35% Fibic acid 10-20%
Niacin ER (Niaspan)
Fibic acid %
Fenofibrate (Tricor) & Gemfibrozil (Lopid)
Statins %
Atorvastatin (Lipitor) & Simvastatin (Zocor)
Bile acid sequestrants 3-5%
Cholestyramine (Questran) & Colestipol (Colestid)

62. JAMA 2001; 285:

63. Lipid-Lowering Medications and Effects on HDL Cholesterol Levels
Table 1. Lipid-Lowering Medications and Effects on HDL Cholesterol Levels.
Ashen, M. D. et al. N Engl J Med 2005;353:

64. Question #15
What is the role of Ezetimibe (Zetia) in lipid-lowering drug therapy?

65. 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:
Mayo Clin Prac 2004; 79:
Ezetimibe added to statin therapy helped 71% of patients achieve their target LDL
Mayo Clin Prac 2005; 80:
No RCTs with clinical outcomes

66. Question #14
What is “intensive” statin therapy?

67. Intensive Statin Therapy
PROVE IT – TIMI 22
N Engl J Med 2004; 350:
REVERSAL
JAMA 2004; 291;
A to Z
JAMA 2004; 292:
IDEAL
JAMA 2005; 294:
TNT
N Engl J Med 2005; 352:

68. Treating to New Targets
10,001 adults aged yo with CHD
Atorvastatin (Lipitor) 10 mg qd v 80 mg qd
Follow-up = 4.9 years
LDL values
10 mg  98 to 101 mg/dl
80 mg  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:

69. 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;
Grundy SM, et al. “Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.” Circulation 2004; 110:
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:

70. References
Knopp RH. “Drug Treatment of Lipid Disorders.” N Engl J Med 1999; 341:
Ashen MD, Blumenthal RS. “Low HDL Cholesterol Levels.” N Engl J Med 2005; 353: