Coronary Artery Disease and Dyslipidemia

1
Coronary Artery Disease and Dyslipidemia

• Daniel S. Streetman, PharmD
• [phone]
• danstr_at_umich.edu

2
Overview

• Lipids and Lipoproteins
• CAD Pathophysiology
• Dyslipidemia Screening and Work-up
• Treatment
• Lifestyle Modification
• Pharmacologic
• Vitamins/Antioxidants/Natural Therapies
• Cases

3
Mortality CVD causes 10,500 more deaths per
year than the next six leading causes of death
combined
American Heart Association. 2001 Heart and Stroke
Statistical Update. Dallas, TX American Heart
Association, 2000.
4
Coronary Artery DiseaseStatistics and
Epidemiology

• Prevalence
• 12.4 million with CHD (6.3 million females)
• 7.3 million with history of a myocardial
  infarction
• 6.4 million with angina
• About 1/2 men 1/3 women gt 40 will develop CHD
• Mortality
• Average of 1 CVD death every 33 seconds
• gt 150,000 of those killed by CVD are lt 65 years
  old

American Heart Association. 2001 Heart and Stroke
Statistical Update. Dallas, TX American Heart
Association, 2000.
5
Coronary Artery DiseaseStatistics and
Epidemiology

• U.S. Rank (Death Rate)
• 1. Hawaii (110.7)
• 2. New Mexico (112.4)
• 3. Utah (124.7)
• 40. Michigan (197.6)
• 50. Oklahoma (219.7)
• 51. Missouri (220.4)
• 52. New York (253.1)

• International (Death Rate)
• Russian Federation (638)
• Hungary (420)
• Romania (361)
• United States (202)
• France (87)
• Japan (57)
• Korea (44)

American Heart Association. 2001 Heart and Stroke
Statistical Update. Dallas, TX American Heart
Association, 2000.
6
Lipids and Lipoproteins
7
Lipids

• Triglycerides
• Source sugars, alcohol
• Essential energy source
• Energy storage

• Cholesterol
• Source fats, dietary cholesterol
• Bile acid formation
• Hormone synthesis
• Cell membrane component

8
Lipids vs. Lipoproteins

• Lipids need to get to site of action for use
• Not water soluble ? not readily carried by
  bloodstream
• Special transport vehicle necessary for
  delivery of lipids to tissues for use
• Lipoprotein Proteins TG Cholesterol
  Phospholipids

9
Apolipoproteins

• Protein components of lipoproteins
• Several functions
• Structural
• Receptor binding
• Regulate enzyme activity
• Concentrations may related to CHD risk
• Possible site of genetic variation

10
Major Lipoproteins

• Chylomicrons
• Formed in intestines
• Metabolized via LPL into remnants which are
  taken-up by liver
• Primary function is transport of exogenous fatty
  acids and cholesterol

apoB-48
apoE
apoA-I, A-IV
apoC-I, C-II, C-III
11
Major Lipoproteins

• VLDL
• Formed in the liver
• Metabolized by LPL into IDL
• Primary function is TG and cholesterol transport

• IDL
• Formed via VLDL
• Metabolized by LPL into LDL
• Primary function is TG and cholesterol transport

apoB-100
12
Major Lipoproteins

• LDL
• Formed via IDL
• Metabolized by tissue and hepatic uptake
• Function is cholesterol transport

• HDL
• Formed primarily via metabolism of chylomicrons
  and VLDL
• Primary function is reverse cholesterol transport

13
Lipoprotein Metabolism
More Triglyceride
Less Triglyceride
- Apolipoproteins
LPL
LPL
- TGs
- TGs
Lower Cholesterol Concentration
Higher Cholesterol Concentration
14
Exogenous Pathway
Food particles
Liver
Bile Acids
Intestines
Chylomicrons
Chylomicron Remnants
Bloodstream
Breakdown of Triglyceride
Free Fatty Acids
15
Endogenous Pathway
LDL
HDL
Liver
Body Tissues
Bloodstream
IDL
VLDL
Breakdown of Triglyceride
Free Fatty Acids
16
CAD Pathophysiology
17
Fatty Streak

• Earliest manifestation of CAD
• Common in infants and children
• Endothelial dysfunction thought to be responsible

• Potential causes
• ? LDL
• Free radicals
• Smoking
• HTN
• Diabetes
• Genetics
• ? Homocysteine
• Herpes virus
• Chlamydia pneumoniae

18
Lumen
Necrosis
Lipid Core
19
Endothelial Function

• Mediate vascular tone
• NO release
• Inhibit coagulation
• Limit access to sub-endothelial space
• Regulate local response to insult

Endothelial Cells
Vascular Smooth Muscle Cells
20
Endothelial Dysfunction

• Loss of endothelium-dependent vasodilation
• Expression of cellular adhesion molecules
• Increased permeability
• Formation of cytokines, growth factors, and
  vasoactive molecules

Hyperinsulinemia
Lp(a)
HCY
Free Radicals
Chlamydia pneumoniae
ox-LDL
CMV
21
Endothelial Dysfunction

• Recruitment of monocytes and T-lymphocytes and
  migration into sub-endothelial space
• Lipid deposition precedes inflammatory cell
  migration
• Foam Cell formation

22
Foam Cell Formation
Macrophage
LDL
Oxidized LDL

Oxidative Stress
Foam Cell
23
LUMEN
Proteolytic Enzymes
Cytokines
Smooth Muscle Cells
Elastin
Foam Cell
Collagen
T-cell
24
Plaque Size and StabilityRelative size of
fibrous cap and lipid core
75 Stenosis
25 Stenosis
25
Culprit LesionsSeverity of stenoses prior to
myocardial infarction
Patients ()
Diameter Stenosis ()
Am J Cardio 199780(9A)2I-10I
26
Dyslipidemia Screening and Work-up
27
Cholesterol Screening

• NCEP-ATPIII
• All adults gt20yrs of age
• Fasting Lipid Profile
• At least every five years

• ACP
• Men 35-65 yrs of age
• Women 45-65 yrs of age
• TC only

Third Report of the Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults, NHLBI May 2001.
28
Classification of Cholesterol

• Total Cholesterol
• lt 200 mg/dL Desirable
• 200-239 mg/dL Borderline
• ? 240 mg/dL High
• LDL Cholesterol
• lt 100 mg/dL Optimal
• 100-129 mg/dL Near or above optimal
• 130-159 mg/dL Borderline high
• 160-189 mg/dL High
• ? 190 mg/dL Very high
• HDL Cholesterol
• lt 40 mg/dL Low
• ? 60 mg/dL High

Third Report of the Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults, NHLBI May 2001.
29
Major Risk Factors

• Positive Risk Factors
• Age (M ? 45, F ? 55 not on ERT or premature
  menopause without ERT)
• Family History
• Current Smoking
• Low HDL (lt 40 mg/dL)
• Hypertension (or on antihypertensive medication)
• Negative Risk Factor
• High HDL (? 60 mg/dL)

Third Report of the Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults, NHLBI May 2001.
30
Life Habit Risk Factors

• Obesity
• Not an independent risk factor
• Does increase CHD risk through effects on other
  risk factors (DM, ? LDL, ? HDL, ? TG, HTN)
• Physical inactivity
• Contributes to obesity and low HDL
• Atherogenic diet
• Contributes to poor lipid profile
• Deficiency of protective compounds

Third Report of the Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults, NHLBI May 2001.
31
Emerging Risk Factors

• Elevated Lp(a)
• Hyperhomocysteinemia
• Elevated fibrinogen
• Elevated PAI-1
• Elevated CRP

• Impaired fasting glucose
• Subclinical atherosclerosis
• Hypertriglyceridemia
• LDL phenotype B

Third Report of the Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults, NHLBI May 2001.
32
Metabolic Syndrome

• Constellation of various Major, Life Habit, and
  Emerging risk factors
• Characterized by the presence of ? 3 of the
  following
• Abdominal obesity
• Atherogenic lipid profile (high TG, low HDL,
  small LDL)
• Hypertension
• Insulin resistance
• Prothrombotic and/or proinflammatory states
• Secondary target of therapy

Third Report of the Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults, NHLBI May 2001.
33
Hypertriglyceridemia

• Hypertriglyceridemia (TG gt 800-1000mg/dL) is a
  known risk factor for pancreatitis
• Most epidemiologic studies suggest a positive
  relationship between TG concentration and CHD
• High TG frequently coexists with ?HDL and high
  concentrations of more atherogenic forms of LDL
• Once adjustment for HDL is made, the contribution
  of TG concentration to CHD risk is diminished

34
Lipoprotein(a)
LDL
Lp(a)
apoB-100
S
S
Plasminogen-like domain
35
Lipoprotein(a)

• Proposed mechanisms
• Competition with plasminogen ? ? plasmin
  synthesis and fibrinolysis
• Enhanced cholesterol deposition and foam cell
  formation
• Generation of O2 free radicals
• Induction of monocyte chemotactic activity
• ? Lp(a) in pts with TC gt 200 mg/dL normal TG
• ? Lp(a) in pts with TG gt 200 mg/dL normal TC
• ?? Lp(a) in pts with mixed hyperlipidemia

Circulation 1996942351-4.
36
Lipoprotein(a)

• Most prospective studies in men have found a link
  between ? Lp(a) and CHD
• However, several studies have also found no
  relationship between Lp(a) and CHD
• Of available lipid-lowering medications, only
  niacin and estrogen have demonstrated consistent
  Lp(a)-lowering effects

Circulation 1996942351-4.
37
Elevated Homocysteine

• Proposed effects of elevated homocysteine
• endothelial dysfunction
• promotion of LDL oxidation
• vascular smooth muscle proliferation
• coagulation abnormalities

Age (years)
Ann Intern Med 1999131363-75. Arch Intern Med
2000160422-34.
38
Homocysteine and Risk of CHDResults from
cross-sectional studies
Relative Risk (95 CI)
Ann Intern Med 1999131363-75. Arch Intern Med
2000160422-34.
39
Homocysteine and Risk of CHDResults from
case-control studies
Relative Risk/Odds Ratio (95 CI)
Eikelboom et al. Ann Intern Med 1999131363-75.
40
Homocysteine and Risk of CHDResults from
prospective studies
Relative Risk (95 CI)
Ann Intern Med 1999131363-75. Arch Intern Med
2000160422-34.
41
LDL Phenotype

• 15 distinct LDL subclasses
• Two primary LDL phenotypes (A B)
• Pattern A is predominantly larger, more buoyant
  LDL
• Pattern B is primarily smaller, more dense LDL

Larger More Buoyant
Smaller More Dense
Eur Heart J 199819(Suppl A)A24-A30.
Circulation 1996942351-4.
42
LDL Phenotype

• LDL pattern B is also associated with multiple
  other metabolic abnormalities
• ? HDL
• ? post-prandial lipemia
• ? susceptibility of LDL to oxidation
• ? arterial wall uptake
• Insulin resistance
• Some lipid-lowering agents may be most effective
  in patients with predominance of small, dense LDL

Eur Heart J 199819(Suppl A)A24-A30.
Circulation 1996942351-4.
43
Fibrinogen

• Finbrinogen ? Fibrin is the final step of the
  coagulation cascade
• Stimulates smooth-muscle-cell migration and
  proliferation
• Promotes platelet aggregation
• Increases plasma viscosity
• Binds lipoproteins in the vascular wall
• May enhance accumulation of cholesterol in plaques

Eur Heart J 199819(Suppl H)H11-7. Ann Intern
Med 1999130933-7. Blood Coagul Fibrinolysis
199910(Suppl 1)s29-s33.
44
C-Reactive Protein

• C-reactive protein (CRP) is an acute phase
  reactant produced in the liver and a marker of
  inflammation
• Association between ?CRP and CHD outcomes
• RR for any CVD death 1.8 (0.9-3.6) 74 elderly
  men
• RR for MI 2.9 (1.8-4.6) 1,086 men
• RR for any CVD event 4.4 (2.2-8.9) 366 women
• ASA ? incidence of MI significantly more in those
  individuals with highest CRP
• ? 56 p lt 0.02 vs. ? 14 p 0.77

Relative risk for highest vs. lowest quartile
of CRP
Am J Med 1999106506-12. NEJM 1997336973-9.
NEJM 2000342836-43.
45
Plasminogen Activator Inhibitor-1

• Endogenous inhibitor of bodys plasminogen
  activator
• Activated plasmin essential for clot lysis
• Elevated concentrations of PAI-1 associated with
  insulin resistance and type II DM

46
Lipid Profile

• Directly measures Total Cholesterol (TC),
  High-density Lipoproteins (HDL), and
  Triglycerides (TG)
• Low-density Lipoprotein (LDL) concentration
  estimated by calculation

LDL TC - HDL - (TG/5)
47
Lipid Profile

• LDL TC - HDL - (TG/5)
• Not valid when TG gt 400mg/dL
• It is possible to directly measure LDL
• Beta-quantification
• Ultracentrifugation

48
Lipid Profile

• Must fast for 9-12 hours prior to test
• Non-fasting ? TG
• No ? in TC or HDL
• Acute illness or infection
• Recent Trauma
• Diet change

• Recent weight loss
• Pregnancy
• Methodologic factors
• Patient position
• Assay variability
• Type of tube used
• Units
• mg/dL vs. mmol/L

49
Possible Causes of Secondary Dyslipidemia

• Diseases
• Diabetes
• Hypothyroidism
• Nephrotic Syndrome
• Obstructive Liver Disease

• Drugs
• Progestins
• Corticosteroids
• Anabolic steroids
• ?-blockers
• Thiazide diuretics
• Cyclosporin
• Sulfonylureas
• Isotretinoin
• Alcohol

50
Cholesterol - Thyroid ConnectionImportance of
Detecting and Treating Secondary Causes of
Dyslipidemia

• Hypothyroidism is 1cause of secondary
  dyslipidemia
• Nearly 90 of those with hypothyroidism have
  elevated cholesterol
• Up to 10 of individuals have ? TSH
• Only 60 of those on thyroid hormone have normal
  TSH

Arch Intern Med 2000160526-534. AACE Website
www.aace.com
51
Effect of Thyroid Disease on Cholesterol
Concentrations
mg/dL
Arch Intern Med 2000160526-534.
52
History and Physical Exam

• Past Medical History
• Cardiovascular disease
• Hepatic disease
• Renal disease
• PUD/GERD
• Gout/Hyperuricemia
• Gall bladder disease
• Diabetes
• Pancreatitis
• Thyroid disease
• Family History

• Social History
• Smoking
• Alcohol
• Other drugs
• Labs
• BUN/SCr
• AST/ALT
• Glucose
• Uric acid
• TSH
• Medications

53
When to Initiate Treatment

• NCEP Guidelines
• Diet Lifestyle if over goals
• Drug therapy if over goals by ? 30mg/dL
• Immediate drug therapy for some at higher risk
• Framingham Risk score
• Clinical Judgement
• Risk factors
• Degree of dyslipidemia

54
Framingham Risk Score

• Predicts 10-year risk of developing myocardial
  infarction and/or CHD death
• Assigns point values based on presence and
  severity of particular risk factors
• Age, TC, Smoking, HDL, SBP
• Separate scales for men and women
• 10-year risk gt20 considered CAD equivalent
• 10-year risk of 10-20 considered reason to start
  immediate drug therapy for LDL ? 130 mg/dL

55
Benefits of Therapy

• Primary Prevention
• Fewer coronary events
• Fewer angiographies, PTCAs, and CABGs

• Secondary Prevention
• Less lesion progression, fewer new lesions
• Increased lesion regression
• Fewer coronary events
• Less cardiac-related mortality
• Less overall mortality

56
Risks of Therapy

• Possible increase in non-cardiac mortality
• Adverse effects and toxicity
• Cost

57
Compliance

• Historically poor with all forms of therapy
• Evaluate possible barriers to compliance
• Fear, cost, necessity, etc.
• Try to match recommendations to patients
  lifestyle and capabilities

58
End Points

• What you expect to get from therapy
• Degree of LDL/TG lowering
• Amount of time until goals are met
• Diet therapies lower LDL 10
• Gradual reduction in risk
• Drug therapy can lower LDL gt 50
• Benefits on outcomes observed in months

59
Special Populations

• Children
• Lack of knowledge about efficacy/safety of drug
  therapy
• Diet and lifestyle modification preferred in
  nearly all cases (at least initially)
• Primarily used in nephrotic syndrome/familial
  dyslipidemia
• Elderly
• Few clinical studies address safety and efficacy
  of drugs in patients gt 65-75 years of age
• Cost-effectiveness

60
Special Populations Women

• Develop rapidly progressive CAD after menopause
• Initial CHD event more likely to be fatal
• Women receive less counseling and reach LDL goal
  less often (lt 10)

61
Therapeutic Lifestyle Changes (TLC) Diet

• Saturated fat lt 7 calories
• Polyunsaturated fat ? 10 calories
• Monounsaturated fat ? 20 calories
• Total fat 25-35 calories
• Carbohydrate 50-60 calories
• Fiber 20-30 g/day
• Protein 15 calories
• Cholesterol lt 200 mg/day

62
Monounsaturated Fatty Acids

• As replacement for saturated fats and/or
  carbohydrates
• Lower risk of CHD with Mediterranean diet
• MUFAs may ? platelet adhesiveness, maintain or
  increase HDL, ? elimination of cholesterol
• MUFA sources olive, canola, and peanut oils
• PUFA sources safflower, sesame, and sunflower
  oils

63
Complex Carbohydrates

• Carbohydrates (CHO) should be at least 50-60 of
  total calories
• Simple carbohydrates can cause surges of
  hyperglycemia and triglycerides
• Sources of complex carbohydrates often add fiber
  to the diet

64
Carbohydrate Sources

• Complex
• Starches
• flour, bread, corn, rice, oats, fruit, vegetables
• Insoluble Fiber
• whole wheat breads, cabbage, beets, carrots
• Soluble Fiber
• oat bran, psyllium, citrus fruits, barley

• Simple
• Sucrose
• table sugar, brown sugar, raw sugar
• Glucose
• dextrose, corn syrup
• Fructose
• fruits, vegetables, honey

65
Other Dietary Considerations

• Limit trans fatty acids
• Proven dietary components to lower cholesterol
• Plant stanols/sterols (2 g/day)
• Soluble fiber (10-25 g/day)
• Questionable role of alcohol

66
Trans Fatty Acids

• Most unsaturated fats are naturally cis fatty
  acids
• R-CCCC-R
• Trans fatty acids are formed during the
  hydrogenation of vegetable or fish oils
• Trans fatty acids may raise LDL and lower HDL
  more than cis fatty acids or natural oils
• Major sources margarine beef, pork, or lamb
  cookies/biscuits and white bread

H
H
67
Alcohol

• French Paradox
• Inversely related to CHD risk (J or U shaped
  relationship)
• Related at least in part to ethanol-induced ? HDL
• Wine phenolics may confer additional benefits

68
Alcohol
69
Education

• Role of cholesterol in heart disease
• Development and outcomes of CAD
• Available treatments
• Benefits and risks of treatment
• Role of patient

70
Exercise

• Safety
• Aerobic exercise
• gt 20 minutes per activity
• At least 3 days per week
• Promotes weight loss and ? HDL

71
Smoking Cessation

• Can lower oxidative stress
• Reversal of endothelial dysfunction
• ? HDL

72
Weight Loss

• Increases HDL
• Improves glycemic control
• Reduces blood pressure

73
Monitoring TLC Regimen

• Check adherence to regimen and lipid profile
  within 4-6 weeks and at 3 months
• After goals met, monitor every 3 months for one
  year, then every 6 months
• If goals not achieved, consider drug therapy or
  more aggressive TLC regimen

74
Ultra-Low-Fat Diets

• Very low fat diet
• ? 15 of calories from fat
• 15 of calories from protein
• 70 of calories from carbohydrates
• Difficult to evaluate epidemiologic data because
  often associated with other confounding lifestyle
  changes

75
Heidelberg Trial

• Reduce fat to lt 20 and cholesterol to lt 200 mg
  and to exercise at home for 30 min per day and in
  a group for 2 hrs per week
• Serial angiographic evaluations over 6 year period

BMI
LDL
Stenosis Diameter
HDL
Niebauer et al. Circulation 1997962534-41.
76
Lifestyle Heart Trial

• 7 of calories from fat, plus vigorous exercise,
  stress reduction, and weight loss
• Mean reduction in LDL of 16, and mean weight
  loss of 11 kg
• No significant change in HDL
• Coronary lesions regressed 82 in in intervention
  group

Ornish et al. Lancet 1990336129-33.
77
Pritikin Longevity Study

• Regimen
• lt 10 calories from fat
• lt 3 from saturated fat
• 35-40g/day/1000kcal dietary fiber
• 25mg cholesterol per day
• Vigorous physical exercise
• Cholesterol-lowering medication

• Outcomes
• Further 19 reduction in LDL within 3 weeks
• No data on weight loss or long-term compliance

Barnard et al. Am J Cardiol 1997791112-4.
78
Dietary Alternatives Study

• Compared 1 year of the following diets
• 30 fat lt300mg chol
• 26 fat 200mg chol
• 22 fat 100mg chol
• 18 fat 100mg chol
• 444 men enrolled

Weight
LDL
TG
JAMA 19972781509-15.
79
Cholesterol-Lowering Drug Therapy

• Fibrates
• Gemfibrozil
• Micronized Fenofibrate
• Clofibrate
• Bile Acid Sequestrants
• Cholestyramine
• Colestipol
• Colesevelam
• Niacin

• HMG CoA Reductase Inhibitors
• Lovastatin
• Pravastatin
• Simvastatin
• Fluvastatin
• Atorvastatin
• Rosuvastatin

80
HMG CoA Reductase Inhibitors
2.) Synthesis
1.) LDL Uptake
HMG CoA
HMG CoA
Cholesterol
Cholesterol
Bile Acids
Bile Acids
81
Possible Non-Lipid-Lowering Effects of the Statins

• Improvement of endothelial-dependent vasodilation
  (L,P,S,F,R)
• ? vascular smooth muscle proliferation (L,S,F,A
  P??)
• ? platelet-thrombus formation (P not S)
• ? fibrinogen concentration (P not S L,A??)

• ? PAI-1 concentrations (P not A L,S ??)
• Immune modulation (P)
• ? cholesterol accumulation in macrophages (L,P,S)
• ? LDL oxidation (L,P,S)
• ? leukocyte and monocyte adherence (P,R)
• ? blood viscosity (P not S L?)

J Clin Pharmacol 199939111-8. JAMA
19982791643-50. Br J Pharmacol 2001133406-12.
82
Statins - Dosing

• Start with lower dose and increase as needed
  (according to LDL)
• Pick dose appropriate to LDL-lowering needed
• Doses should be given in the evening or at
  bedtime
• May need to decrease dose occasionally
• Adding potentially interacting drug
• Profound drop in LDL

83
Statin Dose-Response Curve
CURVES Study. Am J Cardiol 199881582-7.
84
Statin Adverse Effects

• Major toxicities
• ? Hepatic transaminases
• Myalgias
• Rhabdomyolysis
• Selected minor adverse effects
• Dyspepsia/heartburn
• Headache
• Taste disturbances

85
Definitions

• Myalgia muscular pain, tenderness, and/or
  weakness. CK may be normal or slightly elevated
• Myositis muscular inflammation characterized by
  muscle weakness with or without elevated CK
• Myopathy muscle pain, tenderness, and weakness
  accompanied by CK elevations (gt10x ULN)

86
Definitions

• Rhabdomyolysis acute, potentially fatal
  skeletal muscle condition characterized by
  skeletal muscle destruction as evidenced by
  myoglobinemia, myoglobinuria, and CK elevations
  at least 10x ULN.
• Complications may include
• Hyperkalemia, hyperuricemia
• DIC
• Metabolic acidosis
• Cardiomyopathy
• Respiratory and/or renal failure

87
Statin-Related Myotoxicity

• Incidence of myalgia according to product
  labeling is 0.6-5.6
• Incidence of myopathy reported to be 0.5
• Rhabdomyolysis reported in 0.1-0.5

88
Mechanism of Myotoxicity

• Creatine kinase (CK) is responsible for
  generation of ATP from ADP in skeletal muscle and
  myocardium
• Muscle necrosis may be related to failure of
  energy production and ATP depletion
• Statins interfere with production of several key
  compounds that may be involved
• Ubiquinone
• Dolichols
• Mevalonate
• Farnesol
• Geranylgeraniol

89
Risk Factors for Myotoxicity

• Defective lipid metabolism
• Seizures
• Hypothermia
• Metabolic acidosis
• Hypoxia
• Viral infections
• Diabetes
• Hypothyroidism
• Heavy exercise

• Use with other potentially myotoxic medications
• Drug interactions
• Higher statin doses
• Electrolyte disturbances
• Major trauma
• Drugs of abuse
• Increasing age
• Female gender
• Renal/Hepatic disease

90
Myotoxicity Dose-Dependency
Davidson et al. Am J Cardiol 19977938-42.
91
Monitoring of Lipid Lowering Therapy

• Lipid Profiles
• Before initiation and at 6-12 weeks until stable
• Every 6 months thereafter
• Hepatic Transaminases
• Baseline and every 6-12 weeks until stable
• Every 6 months thereafter
• Creatine Kinase (CK)
• Only as needed
• Glucose, Uric Acid

92
Signs and Symptoms of Myotoxicity

• Symptoms consist primarily of gradually decreased
  muscle strength and localized or generalized
  muscle weakness.
• Symptoms can occur within days or may not occur
  for years after starting therapy.
• Symptoms involving other organ systems (such as
  fatigue, shortness of breath, decreased urine
  output, dark-colored/turbid urine).

93
Special High Risk Populations

• Post-transplant patients
• Considerable debate regarding best statin
• Pravastatin and fluvastatin may be preferred
• Low dose of other statins also used
• HIV patients
• Pravastatin, fluvastatin, or low-dose other
  statin
• Patients with neuromuscular disorders
• Low-dose statin

94
How do you Choose a Statin?Differences among the
HMG-CoA Reductase Inhibitors

• Potency (LDL, HDL, TG)
• Clinical efficacy
• Hydrophilic vs Lipophilic
• Pharmacokinetics
• Cost
• Drug Interactions
• Non-lipid effects

95
Comparative LDL Effects
Pravastatin
Lovastatin
Simvastatin
Fluvastatin
Rosuvastatin
Atorvastatin
20
10
40
20
10
20
40
40
1
20
80
10
40
5
20
80
80
40
80
20
80
Am J Cardiol 199881582-7. Am J Cardiol
200188504-8. J Int Med Res 20002847-68.
Clin Cardiol 20002339-46.
96
Comparative HDL Effects
10
40
80
20
10
40
10
20
20
40
40
20
20
80
40
Atorva
Prava
Simva
Lova
Fluva
CURVES Study. Am J Cardiol 199881582-7.
97
Comparative Lipid EffectsSimvastatin vs.
Atorvastatin
846 patients with baseline LDL 213, HDL 46, TG
186. Treated ? 12 wks.
LDL
TG
HDL
ApoA-I
Crouse III et al. Am J Cardiol 1999831476-7.
98
Comparative Lipid EffectsSimvastatin vs.
Atorvastatin
846 patients with baseline LDL 213, HDL 46, TG
186. Treated ? 12 wks.
HDL
ApoA-I
Crouse III et al. Am J Cardiol 1999831476-7.
99
Comparative TG Effects
Atorvastatin
Simvastatin
Pravastatin
Lovastatin
Fluvastatin
10
40
20
40
10
20
40
80
10
20
40
20
20
80
40
CURVES Study. Am J Cardiol 199881582-7.
100
Hydrophilicity

• More hydrophilic (pravastatin) agents thought to
  penetrate tissues less well than lipophilic
  agents
• Less efficacy (?)
• Less toxicity (?)
• Protein binding
• Renal and hepatic elimination

101
Statin-Related MyotoxicityIs there a difference
among the statins?

• Not surprisingly, all statins have been reported
  to cause myalgia, myopathy, and rhabdomyolysis
• Potential differences in risk according to each
  agents chemical properties
• Biggest difference related to potential to
  interact with other medications

More Lipophilic
More Hydrophilic
Simvastatin, Lovastatin
Atorvastatin, Fluvastatin
Rosuvastatin
Pravastatin
102
Statin Pharmacokinetics

• Distribution
• Hepatic vs Skeletal muscle vs other tissues
• Protein binding
• P (50) ltltlt S L F A C (95 to gt99)
• Metabolism
• Hepatic via CYP3A (S,L,P,A,C), CYP2C8 (C), or
  CYP2C9 (F)

103
Statin Pharmacokinetics

• Half-life
• Indirectly related to HDL-raising effects (?)
• S ltlt A
• Elimination
• Bile (primarily)
• Urine P (20) gt R (10) gt C F gt A S L

104
Drug Interactions

• Pharmacodynamic
• Risk of hepatotoxicity and/or myalgias or
  myopathy when combined with fibrates or niacin
• Pharmacokinetic
• ? absorption with bile acid sequestrants
• Inhibition or induction of CYP-based metabolism
• Inhibition of CYP activity

105
Statin Metabolism
Lovastatin, Simvastatin, Atorvastatin
CYP3A
Active and inactive metabolites, which are
excreted in urine and/or bile
CYP2C9
Fluvastatin
Rosuvastatin
Other enzymes/ renal
Pravastatin
106
CYP3A Interactions

• ALL statins (except fluvastatin and rosuvastatin)
  are metabolized at least in part by CYP3A
• CYP3A inhibitors may ? statin concentrations
• Verapamil, diltiazem, Azole antifungals,
  erythromycin, nefazodone, fluoxetine, Protease
  inhibitors
• CYP3A inducers may ? statin concentrations
• Rifampin, phenytoin, phenobarbital, troglitazone
• Statins may also interact with other CYP3A
  substrates (i.e., cyclosporine)

107
CYP2C9 Interactions

• Fluvastatin is metabolized by CYP2C9 and inhibits
  CYP2C9 activity
• CYP2C9 inducers (e.g., rifampin) and inhibitors
  (e.g., amiodarone) may ? or ? fluvastatin
  concentrations, respectively
• Fluvastatin can inhibit CYP2C9 activity,
  increasing the concentration and effect(s) of
  other CYP2C9 substrates (e.g., S-warfarin)

108
Bile Acid Sequestrants
2.) Synthesis
1.) LDL Uptake
HMG CoA
HMG CoA
Cholesterol
Cholesterol
Bile Acids
Bile Acids
Intestines
Intestines
109
Efficacy and Dosing

• ? TC, ? LDL, ? HDL, ?? TG
• Start with lower dose and increase as tolerated
  and as needed
• Lipid Research Clinics Coronary Primary
  Prevention Trial (LRC-CPPT)
• Cholestyramine vs. Placebo (n 3,800)
• 12.6 more LDL reduction 19 reduction in CAD
• Used doses of 16-24g/day

110
Precautions

• Adverse effects
• Constipation, bloating, abdominal pain,
  unpleasant taste and texture
• Drug interactions
• May interfere with absorption of other medications

111
Colesevelam (WelChol?)

• Non-absorbed polymer (water-absorbing hydrogel)
• Engineered to specifically bind to bile acids
• High affinity for trihydroxy and dihydroxy bile
  acids
• Gel-forming properties minimize GI irritation
• Specificity for bile acids minimizes interactions
• Dose 6-7 625mg tablets per day (3.75-4.375 g/d)
• Sankyo Pharma Inc. (AWP 142/month)

112
Colesevelam Efficacy and Safety

• Positive dose-response
• Relatively well tolerated
• Most Common AEs
• Constipation (0-10)
• Diarrhea (0-10)
• Flatulence (0-10)

TC
LDL
HDL
TG
Davison et al. Arch Intern Med 19991591893-1900.
113
Niacin

• Mechanism of action
• Inhibition of free fatty acid release from
  adipose tissue
• Inhibition of cAMP accumulation
• Inhibition of VLDL and LDL synthesis
• Increased LPL activity
• Effects on lipids
• ?? TC, ??? LDL, ?? HDL, ??? TG
• Conversion of LDL phenotypic pattern B into
  pattern A
• Lowers Lp(a)

114
Niacin - Efficacy

• Several studies have evaluated clinical efficacy
  of niacin
• Stockholm Ischemic Heart Disease Study
• Coronary Drug Project
• Cholesterol Lowering Atherosclerosis Study
• ? IHD-related mortality ? All-cause mortality ?
  risk of recurrent, non-fatal MI ? lesion
  progression ? lesion formation

115
Niacin - Dosing

• Immediate release
• 100mg TID ? by 100mg TID every week as tolerated
• Goal 500-1000mg TID
• Sustained release
• 375mg QD ? gradually as needed
• Goal 500-2000mg QD

116
Niacin - Precautions

• Adverse effects
• Flushing, pruritis, headache, fatigue
  (PG-mediated? -- ASA)
• Gastritis, abdominal pain, aggravation of PUD,
  hepatotoxicity
• Impaired glucose control, ? uric acid
  concentrations
• Drug interactions
• Alcohol ? risk of hepatotoxicity
• Statins, fibrates ? risk of hepatotoxicity
  and/or myalgias

117
IR vs SR Niacin - Tolerability
Vasodilatory Symptoms
GI Tract Symptoms
Fatigue
McKenney JM, et al. JAMA 1994271672-7.
118
IR vs SR Niacin - Safety
Mean Alkaline Phosphatase
Mean AST
Mean ALT
McKenney JM, et al. JAMA 1994271672-7.
119
IR vs SR Niacin - Toxicity

• At least 14 published case reports of severe
  hepatotoxicity associated with SR niacin
• Most reports in patients who were changed from IR
  to SR niacin
• Risk also seems to ? with SR doses gt 2000 mg
• As a result
• When changing from IR to SR, ? dose by 50
• Maximum SR dose 2000 mg

120
Fibrates

• Mechanism of action
• Inhibition of cholesterol synthesis
• Decreased TG synthesis
• Inhibition of lipolysis in adipose tissue
• Decreased production of VLDL/? clearance
• Increased plasma and hepatic LPL activity
• Effect on lipids
• ? TC, ? LDL, ?? HDL, ??? TG

121
Fibrates - Clinical Efficacy

• Effectiveness of the fibric acid derivatives has
  been investigated in several studies
• World Health Organization (clofibrate)
• Stockholm Ischemic Heart Disease Study
  (clofibrate)
• Helsinki Heart Study (gemfibrozil)
• Coronary Drug Project (clofibrate)
• Clinical Findings
• Questionable findings with clofibrate
• Progressive reduction in CAD and related
  endpoints with gemfibrozil

122
Fibrates - Dosing and Precautions

• Dosing
• Gemfibrozil 600mg BID
• Micronized Fenofibrate 67mg QD ? to 67-201mg QD
• Clofibrate 2g daily in divided doses
• Adverse effects
• Nausea, diarrhea, cholelithiasis, phototoxicity
• Drug interactions
• Increased risk of hepatotoxicity and/or myalgias
  with concurrent statins and/or niacin
• Protein binding displacement (e.g., warfarin)

123
Lipid Lowering Therapy - Monitoring Parameters

• Lipid Profiles
• Before initiation and at 6-12 weeks until stable
• Every 6 months thereafter
• Hepatic Transaminases
• Baseline and every 6-12 weeks until stable
• Every 6 months thereafter
• Creatine Phosphokinase (CPK)
• Only as needed
• Glucose, Uric Acid

124
Combination Therapy

• Superior LDL-lowering ability
• Combinations with a resin may provide benefit
  with little risk of additive toxicity
• Some concern about risk of rhabdomyolysis with
  statin-niacin or statin-fibrate combinations
• Others have found these combinations to be safe

Studied Combinations Statin Resin Statin
Resin Niacin Statin Niacin Statin
Fibrate Niacin Resin
125
Vitamins/Antioxidants

• Several proposed beneficial effects
• ? LDL oxidation
• ? cytotoxicity of LDL
• Restoration of normal endothelial function
• ? leukocyte adhesion
• ? platelet activation
• ? smooth muscle proliferation

126
Vitamins/Antioxidants

• Vitamin E
• Vitamin A
• ?-carotene
• Vitamin C
• Selenium
• Folic Acid

• Used rather frequently.
• Conflicting data exist regarding their reported
  benefits.
• Most convincing data from epidemiologic studies
• Relatively safe, but not innocuous (and not cheap
  - )

127
Vitamin E

• Inverse relationship between diets rich in
  vitamin E
• Observational studies indicate consumption of
  gt100 IU vitamin E per day for gt 2yrs had lower
  rates of CHD progression
• Have only been four randomized controlled studies
  of vitamin E
• Doses 50 to ? 400 IU n 2,002 - 52,000
  length 1.3 - 5yrs

128
Vitamin E
ATBC
CHAOS
GISSI
HOPE
Combined
Relative Risk (95 CI)
HOPE Investigators. N Engl J Med 2000342154-60.
129
Beta Carotene

• Alpha-Tocopheral Beta Carotene Cancer Prevention
  Study (ATBC)
• 20mg QD ?-carotene to gt 29,000 male smokers
• ? risk lung cancer and ? risk of IHD
• Beta Carotene and Retinol Efficacy Trial (CARET)
• 30mg QD ?-carotene and retinyl palmitate to
  18,000 men and women with history of smoking or
  asbestos exposure
• ? risk lung cancer and ? CVD mortality

130
Beta Carotene

• Physicians Health Study
• 50mg QOD ?-carotene for 12 years
• 22,071 US male physicians
• No significant differences
• Possibly slight increase in risk smokers

131
Vitamin C

• Water-soluble antioxidant
• Limited data from randomized controlled trials
• Proposed benefits
• Increased fibrinolytic activity
• Decreased platelet adhesiveness
• Decreased total cholesterol

132
Selenium

• Antioxidant
• Limited clinical evidence
• RDA 70 mcg/d (men), 55 mcg/d (women)
• Doses used for CHD 100 mcg/d
• Toxicity
• Nausea, abdominal pain, diarrhea, hair and nail
  changes, peripheral neuropathy, fatigue,
  irritability

133
Folic Acid

• Proposed benefit reduction in plasma
  homocysteine concentrations
• Must rule-out subactue B12 deficiency prior to
  starting folic acid
• Dose 0.4mg per day (higher in renal failure)
• May need to also take B6 (25-50mg/day) and B12
  (400-1000?g/day)

134
Homocysteine Metabolism
Methionine
SAM
Folate cycle
S
THF
DMG
Methyl-transferase
B12 MS
Methionine Cycle
CH2THF
SCH3
CH3THF
Betaine
Homocysteine
SAH
Transsulfuration Pathway
CBS
B6
Cystathionine
Cysteine
B6
135
the most prudent and scientifically
supportable recommendation for the general
population is to consume a balanced diet with
emphasis on antioxidant-rich fruits and
vegetables and whole-grains.
AHA Scientific Advisory. Circulation
199999591-5.
136
Herbs/Natural Products

• Garlic
• Fish Oils
• Red Yeast Rice
• Dietary Fiber
• Oat Bran
• Plant Sterols
• Guggul
• CoEnzyme Q10

137
Garlic (Allium sativum)

• Supposed to lower cholesterol
• Meta-analysis reported 9 reduction in TC
• Controversial (several studies found no benefit)
• Active ingredient allicin and related compounds
• Dose 1/2 - 1 clove per day (?)
• Onions (Allium cepa) may have similar benefits

138
Fish Oils

• Rich in omega-3 fatty acids
• Docosahexaenoic acid (DHA)
• Eicosapentaenoic acid (EPA)
• Effects on cholesterol (6g per day)
• ? LDL (5-10), ? HDL (1-3), ? TG (30)
• Found naturally in
• Salmon, mackerel, sardines, bluefish, tuna

139
Red Rice Yeast

• Active ingredient is mevinolin
• (a.k.a. lovastatin)
• ? TC, ? LDL, ? HDL, ? TG

140
Soluble Fiber

• Psyllium, oat bran, oatmeal, etc.
• Psyllium is probably the most effective dietary
  ingredient for lowering serum cholesterol.
  Nutrition News Focus - 2/3/00
• Doses
• Oat products 3-4 servings per day (320-450 kCal)
• Psyllium 10-12g per day
• Products with ? 51 whole grains can claim to be
  heart healthy

141
Plant Sterols

• Campesterol, stigmasterol, beta sitosterol, etc.
• Take Control ? contains plant sterols from
  soybeans
• Benecol? contains stanol esters from pine bark
• Proposed MOA
• Inhibition of cholesterol absorption
• Increased hepatic cholesterol secretion
• Decreased hepatic cholesterol synthesis
• Possible adverse effects on reproductive system
• Rare genetic disorder (sitosterolism) is
  associated with elevated plasma concentrations of
  plant sterols

142
Guggul

• ? TC (12-20), ? HDL (16), ? TG (16-22)
• Doses standardized to gugulipids or gugulsterones
• Gugulipids 1200-1500mg per day in 2-3 doses
• Gugulsterones (25mg per tablet) 75mg per day in
  2-3 doses
• Proposed MOA
• Bile acid sequestrant
• ? platelet adhesiveness, ? thyroid activity, ?
  fibrinolysis
• Adverse Effects
• GI (mild), headache
• Drug Interactions
• warfarin, decreased absorption of fat-soluble
  vitamins

143
CoEnzyme Q10

• AKA ubiquinone
• Normally present in mitochondria
• Antioxidant
• May be decreased by therapy with the statins
• May increase bleeding with warfarin

144
Other Natural Therapies

• Calcium carbonate
• Vitamin C (beyond antioxidant effects)
• Ho Shou Wu (Chinese herb)
• Hawthorn Berries
• Cayenne
• Lecithin
• Grapefruit pectin

145
Other Natural Therapies

• Pantethine
• Used by key enzymes in the transport and
  breakdown of triglycerides and cholesterol
• Clearesterol
• Special vitamin E - tocotrienol complex from rice
  bran
• Flaxseed oil
• alpha-linoleic acid (DHA precursor)