The Solution? It

1
Identification and Management of the Patient with
Hyperlipidemia November 4, 2007 Joe Anderson,
PharmD, PhC, BCPS Office 272-3664 Email
janderson_at_salud.unm.edu College of
Pharmacy University of New Mexico Health
Sciences Center
2
Learning Objectives

1. Identify non-LDL cholesterol major risk factors
   for coronary heart disease (CHD)
2. Determine a patients 10-year risk of CHD and
   provide lipoprotein (LDL, HDL, and triglyceride)
   therapeutic goals
3. Describe the effect on the lipid profile (TC,
   LDL, HDL, and TGs) for the various classes of
   lipid-lowering medications
4. For a given patient with dyslipidemia, provide an
   appropriate pharmacotherapeutic plan (including
   drug regimen, monitoring parameters, and patient
   information

3
READINGS

• Executive summary of the third report of the
  National Cholesterol Education Program (NCEP)
  expert panel on detection, evaluation, and
  treatment of high blood cholesterol in adults
  (Adult Treatment Panel III). JAMA
  20012852486-97.
• Grundy SM, Cleeman JI, Merz CNB, et al.
  Implications of recent clinical trials for the
  National Cholesterol Education Program Treatment
  Panel III guidelines. Circulation 2004110227-39.

4
The Cardiovascular Continuum
Dzau V et al. Am Heart J. 19911211244-63.
5
Consequences of Hyperlipidemia

• Development of atherosclerosis leading to
  coronary heart disease (CHD) and cerebrovascular
  disease (CVD)
• 1.2 million people annually in the U.S.
  experience a cardiac event
• New or recurrent MI 865,000
• 565,000 new 300,000 recurrent
• Total CHD-related deaths 480,000
• 700,000 people suffer a stroke annually in the
  U.S.
• 500,000 new 200,000 recurrent
• Annual mortality 150,000
• 87 of all strokes are ischemic

Heart disease and stroke statistics2007 update
Rosamond W, et al. Circulation 200711569-171.
6
Cholesterol Homeostasis

• Cholesterol, TGs, and phospholipids are the major
  plasma lipids
• Cholesterol is a necessary component of cell
  membranes, steroid hormones, bile acid
• Plasma cholesterol is regulated by absorption
  (extrinsic), hepatic production (intrinsic), and
  hepatic bile acid excretion (intrinsic)
• ? Cholesterol LDL, ? HDL are known to
  contribute to development of CHD

7
Cholesterol Homeostasis

• Lipoproteins
• High MW water-soluble, responsible for
  cholesterol and TG transport
• Chylomicrons, VLDL, IDL, LDL, HDL, and Lp(a)
• LDL is the major cholesterol carrier
• CHD risk increases exponentially with increasing
  total and LDL cholesterol

8
Relation of LDL-C to CHD Risk Framingham Heart
Study
9
Cholesterol Homeostasis

• HDL particles sub-classified by size and lipid
  content
• HDL1, HDL2, HDL3, and HDL4
• Larger, more lipid-rich HDL2 and smaller denser
  HDL3 predominate in human plasma
• Subclasses may contribute differently to reverse
  cholesterol transport

10
Relation of HDL-C to CHD Risk
120
100
80
Incidence of CHD (per 1000 in 6 years)
60
40
20
0
lt35
35 - 55
gt55
HDL-cholesterol (mg/dL)
Assmann G, et al. Atherosclerosis
1996124(suppl)S11-S20.
11
(No Transcript)
12
Secondary causes of dyslipidemia
Drug/Drug Class TC TG HDL
Diabetes ? ? ? ? ?
Hypothyroidism ? ?
ETOH abuse ? ? ? ? ?
Nephrotic Syndrome ? ? ?
Smoking ? ? ? ?
Acute MI ? ? ?
Obesity ? ? ?
Physical activity ? ? ?
Pancreatitis ??
Menopause ? ? ? ?
?? large increase ? increase ? ? slight
increase ? decrease ? ? slight decrease
13
Potential drug-induced lipid changes
Drug/Drug Class TC TG HDL
Thiazide diuretics ? ? ?
Beta-blockers ? ? ?
Alpha1-antagonists ? ? ?
Estrogens (oral) ? ? ?
Estrogens (topical) ? ? ?
Glucocorticoids ? ? ??
Isotretinoin ? ?? ?
?? large increase ? increase ? ? slight
increase ? decrease ? no change.
14
Pathogenesis of Atherosclerosis

• Develops in response to altered endothelial
  integrity or injury.
• Injury can be from mechanical forces, or
  nonmechanical agents (exp. homocysteine, CO)
• Oxidation of LDL may be cytotoxic
• all cell types within vessel wall able to oxidize
• Oxidized LDL induces expression of adhesive
  cell-surface proteins (exp. VCAM)
• Monocytes adhere to vessel surface become
  macrophages.

15
Pathogenesis of Atherosclerosis

• Macrophages highly oxidize LDL and then take up
  the LDL creating foam cells
• Lipid accumulate in SMC, macrophages, and
  extracellular matrix
• Ultimately get build up of SMC, macrophages,
  fibrous tissue and lipid to form plaque.
• Platelets adhere to site of injury and secrete
  growth factors
• HDL promotes reverse cholesterol transport

16
(N Engl J Med 1997337408-16)
17
Lipid Lowering Agents
18
Bile acid-binding resins (BARs)

• Cholestyramine, colesevelam and colestipol
• MOA Block reabsorption of bile acids in the
  intestine which results in an increase in bile
  acid synthesis. Leading to an increase in LDL
  receptors
• 15-30 reduction in LDL 15-18 with colesevelam
  increase HDL 3-10 and increase TGs 0-12
• Reduce major coronary events and CHD deaths
  (NCEP ATP III Circulation 20021063143-3421)
• Adverse effects GI (bloating and constipation),
  ? TGs

19
Bile acid-binding resins (BARs)

• Drug interactions decrease absorption of anionic
  drugs (exp digoxin, thyroid hormone replacement,
  warfarin, thiazides)
• Dosing Cholestyramine 4-24 gm/d, Colestipol 5-30
  gm/d, Colesevelam (6 x 625 mg tablets) 3.8-4.2
  gm/d

20
Niacin or Nicotinic Acid

• MOA reduces hepatic VLDL synthesis, which
  reduces LDL and TGs
• Effect on Lipids decreases LDL 5-25, TGs
  20-50, and increases HDL 15-30 with
  crystalline, less with sustained release
• Reduces major coronary events and possibly
  mortality (NCEP ATP III Circulation
  20021063143-3421)
• Adverse effects
• Flushing, pruritus, and skin rash
• abdominal pain
• hepatotoxicity
• hyperglycemia
• Hyperuricemia

21
Niacin

• Monitoring
• glucose, uric acid at baseline and dose threshold
• LFTs (AST/ALT)
• Baseline
• monthly until dose stable for SR
• Q 3 months for first year on SR niacin
• Check once at dose threshold for IR and ER (4-8
  weeks)
• C/Is
• relative DM, gout, peptic ulcer
• absolute Liver disease
• Drug interactions Statins

22
Niacin

• Dose Start low and go slow!!!
• Immediate release
• 100 mg TID x 1 week, 250 mg TID x 1 wk, then 500
  mg TID x 1 week then assess response
• Can then increase to 750 mg TID and then to 1000
  mg TID if needed
• Extended release (Niaspan)
• 500mg QHS x 4 weeks, then 2 x 500mg QHS. May
  increase to 2000mg if needed
• Sustained release
• 250mg BID and increased weekly to 1.5-2gm

23
Niacin

• Patient Counseling to improve tolerability
• Slow titration
• Take with low-fat snack or meal
• IF no C/Is, administer 325mg ASA 30 minutes prior
  to first dose of niacin
• Take at bedtime
• Avoid other vasodilatory activities prior to
  niacin
• Alcohol use
• Hot beverages
• Spicy foods
• Hot showers or baths
• Vigorous physical activity

24
Fibric acid derivatives

• MOA inhibits lipolysis and increases lipoprotein
  lipase activity, decreasing serum VLDL and
  increasing HDL.
• Effects on lipoproteins Decreases TGs by 30-50
  and increases HDL by 10-20 may increase LDL
• Reduce major coronary events inconclusive data
  regarding increase CV, non-CV, total mortality
  (NCEP ATP III JAMA 20012852486-2497)
• Adverse effects
• GI
• hepatoxicity
• myopathy
• neutropenia

25
Fibric acid derivatives

• Monitoring
• LFTs at baseline, 6 and 12 weeks and then
  periodically (Q 3 months), Serum creatinine at
  baseline and periodically if impaired renal
  function, CBC at baseline and periodically,
  baseline creatine kinase (CK)
• C/Is Hepatic dysfunction and gallbladder
  disease
• Drug interactions warfarin (? PT/INR), statins
  (? myopathy), cyclosporine (? fibrate
  concentrations)
• Dosing
• Gemfibrozil 600 mg BID 30 minutes AC
• Fenofibrate 48 145 mg QD

26
HMG-CoA Reductase Inhibitors Statins

• MOA Inhibit HMG-CoA Reductase. Results in an
  increase in hepatic LDL receptors
• Effects on lipoproteins
• Decreases LDL 20-60
• Decreases TGs 10-30
• Increases HDL 5-10
• Proven efficacy to reduce
• Major coronary events and stroke
• CV-related and total mortality
• Coronary procedures (PCI/CABG)

(NCEP ATP III JAMA 20012852486-2497)
27
StatinsPleiotropic Effects

• Cardiovascular
• Stabilize atherosclerotic plaques
• Enhance vascular nitric oxide production
• Attenuate inflammation due to vascular injury
• Decrease oxidative stress
• Renal
• Modulate glomerular mesangial and interstitial
  inflammatory processes
• Endocrine
• Improve insulin sensitivity
• Skeletal
• Inhibit bone resorption

28
Dose Comparative Efficacy of Available Statins
Dose (mg) of agent Reduction
Atorvastatin Simvastatin Lovastatin Pravastatin F
luvastatin Rosuvastatin TC LDL-C 10 20 20 40 2
2 27 10 20 40 40 80 5 27 34 20 40 80 10 32 4
1 40 80 20 37 48 80 160 40 42 55
Not FDA approved. 45 52, 55 63
reduction in LDL-C.
Roberts WC. Am J Cardiol. 199780106-107. Stein
E et al. J Cardiovasc Pharmacol Therapeut.
199727-16. Crestor prescribing information
29
The Rule of 6sThe majority of LDL lowering
occurs at the lowest statin dose
LDL reduction
57
57
57
3-STEP TITRATION
Statin at starting dose
1st
2nd
3rd
Doubling
Based on results from STELLAR Trial.

Jones et al. Am J Cardiol 200392152-60.
30
HMG-CoA Reductase Inhibitors Statins

• Adverse effects headache, GI, elevated
  transaminase levels (AST/ALT), myopathy
• Drug interactions
• Cyp450 3A4 Inhibitors Cyclosporine, grapefruit
  juice, macrolides, triazole antifungals,
  fluoroquinolones, SSRIs, diltiazem, verapamil,
  amiodarone, omeprazole, protease inhibitors
• Pravastatin, fluvastatin (2C9) and rosuvastatin
  (2C9 minor) not metabolized by 3A4
• Monitoring AST/ALT before and 12 weeks after
  initiation of statin or after dosage increase
  then periodically (every 6 months), CK at
  baseline and if symptoms

31
Statin Advisory Definitions of Muscle Toxicity

• Myopathy a general term referring to any
  disease of muscles myopathies can be acquired
  or inherited and can occur at birth or later in
  life
• Myalgia muscle ache or weakness without
  creatine kinase (CK) elevation
• Myositis muscle symptoms with increased CK
  levels
• Rhabdomyolysis muscle symptoms with marked CK
  elevation (?10x the upper limit of normal ULN)
  and creatinine elevation (usually with brown
  urine and urinary myoglobin)

Pasternak RC et al. J Am Coll Cardiol.
200240568-573. Pasternak RC et al. Circulation.
20021061024-1028.
32
HMG-CoA Reductase Inhibitors Statins

• Hepatic monitoring
• If AST/ALT 1-3 x ULN, continue statin.
• If AST/ALT gt 3 x ULN, obtain additional hepatic
  function studies (exp. direct and indirect
  bilirubin).
• If evidence of liver damage, d/c statin. If no
  evidence of liver damage decrease statin dose and
  recheck AST/ALT.
• Myopathy Monitoring
• If symptoms, obtain CK (rule out other causes,
  obtain TSH)
• If symptoms tolerable and CK lt 10 x ULN, continue
  statin and monitor CK and symptoms frequently
• If symptoms intolerable with or without CK
  elevation, d/c statin
• If symptoms and CK gt 10 x ULN, d/c statin

McKenney JM, et al. Am J Cardiol
200697suppl89C-94C.
Pasternak RC, et al. Circulation 20021061024-28.
33
Statin Advisory Monitoring Parameters, Follow-Up
Schedule
Headache, dyspepsia Evaluate baseline symptoms, 68 wk after initiating therapy, then at each follow-up visit
Muscle soreness,tenderness, or pain Evaluate baseline muscle symptoms and CK levels muscle symptoms 612 wk after initiating therapy and at each follow-up visit CK measurement when muscle soreness, tenderness, or pain present
ALT, AST Evaluate baseline ALT/AST, 12 wk after initiating therapy, then annually or as indicated
ALTalanine transferase ASTaspartate
transferase CKcreatine kinase
Pasternak RC et al. J Am Coll Cardiol.
200240568-573.Pasternak RC et al. Circulation.
20021061024-1028.
34
Statin Advisory Clinical Precautions When
Prescribing Statin Therapy

• Myopathy more likely to occur at higher doses
• Doses should not exceed those required to attain
  ATP III goals
• Attention should be paid to factors that may
  increase risk for myopathy (see next slide)

Pasternak RC et al. J Am Coll Cardiol.
200240568-573.Pasternak RC et al. Circulation.
20021061024-1028.
35
Statin Advisory Risk Factors for
Statin-Associated Myopathy

• Other considerations
• Advanced age (especially ?80 yr women more than
  men)
• Small body frame, frailty
• Multisystem disease (eg, chronic renal
  insufficiency, especially due to diabetes)
• Multiple medications
• Perioperative periods

• Concomitant meds or consumption of
• Fibrates
• Nicotinic acid (rarely)
• Cyclosporine
• Azole antifungals
• Itraconazole, ketoconazole
• Macrolide antibiotics
• Erythromycin, clarithromycin
• HIV protease inhibitors
• Nefazodone (antidepressant)
• Verapamil
• Amiodarone
• Large quantities of grapefruit juice (?1 qt/d)
• Alcohol abuse

Pasternak RC et al. J Am Coll Cardiol.
200240568-573.Pasternak RC et al. Circulation.
20021061024-1028.
36
Safety Summary for HMG-CoA Reductase Inhibitors

• Excellent patient acceptance
• Few drug-drug interactions
• Few side effects
• most common are gastrointestinal mild to
  moderate
• at high doses, elevated ALT/AST in 1 to 2
• myopathy reported in 0.1 (CK gt10 x ULN)
• Only rare cases of toxicity
• No increases in total or non-CHD mortality

Lovastatin Study Groups I through IV. Arch Intern
Med. 19931531079-1087. Second Report of the
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults
(ATP II). September 1993 NIH Publication 93-3095.
37
Ezetimibe (Zetia)

• Selective intestinal cholesterol absorption
  inhibitor
• Dose 10mg QD
• Decreases LDL-C by 15-20, TGs by 5-10 and
  increases HDL by 4-9 in monotherapy and as
  add-on
• No data on CV morbidity or mortality
• No effect on blood levels of fat soluble vitamins
• May increase risk of AST/ALT elevation when used
  in combination with statins

38
Effect of Ezetimibe Statin Therapy on Lipids in
Patients With Primary Hypercholesterolemia
LDL-C
HDL-C
TG
5.0

2.7
1.0
0.0
-5.0
-2.9
-3.7
D from baseline
-10.0
-15.0
-14.0
-20.0
-25.0
Statin Placebo (n390)
-25.1
Statin Ezetimibe (n379)
-30.0
Plt0.001 vs placebo. Plt0.05 vs placebo.
Gagné C et al. Am J Cardiol. 2002901084-1091.
39
Simvastatin/Ezetimibe (Vytorin)
Simvastatin
Vytorin

• Combination of a statin with selective intestinal
  cholesterol absorption inhibitor
• Dose 10mg/10mg, 10mg/20mg, 10mg/40mg, 10mg/80mg QD

LDL-C Reduction at 12 weeks



plt0.001 vs monotherapy

Goldberg et al. Mayo Clin Proc 200479620-9.
40
Miscellaneous agents

• Fish Oil (Omega-3 Fatty Acids)
• Effective at lowering TGs (25-30) can increase
  LDL (5-10) esp at higher doses (gt 3 gm/day),
  minimal effects on HDL
• MOA Not understood, one possible mechanism is
  increased plasma lipoprotein lipase activity.
• Supplementation demonstrated to decrease CHD
  events (MI, death, nonfatal stroke)
• Lovaza (formally Omacor)
• 1 gram capsule 465 mg EPA 375 mg DHA
• Dose 4 gm/day
• Decrease TGs by 45 (baseline TGs gt 500 mg/dL)
• Max EPA (mixture of 180 mg EPA 120 mg DHA) 1
  gm/capsule
• Titrate to max of 4 gm/day (12 capsules)
• Side Effects Higher doses (gt 3 gm/day) can
  effect bleeding time and may impair insulin
  secretion, GI (nausea, diarrhea, eructation,
  taste disturbance)

41
Miscellaneous agents

• Fish Oil (Omega-3 Fatty Acids)

Summary of AHA Recommendations for Omega-3 Fatty
Acid Intake
Population Recommendation
Patients without CHD Eat a variety of (preferably oily) fish at least twice a week. Include oils and foods rich in alpha-linolenic acid. (flaxseed, canola, and soybean oils flaxseed and walnuts)
Patients with CHD Consume 1 g of EPA/DHA per day, preferably from oily fish. EPA/DHA supplements could be considered in consultation with the physician.
Patients needing triglyceride lowering 2 4 grams of EPA/DHA per day provided as capsules under a physicians care
Kris-Etherton PM, et al. Circulation
20021062747-57.
42
Miscellaneous agents

• Vitamins E, C, and beta-carotene
• Vit. E CHAOS study demonstrated reduction in NF
  MI, but not replicated in subsequent studies
  (HPS, HOPE, etc.)
• Vit C antioxidant, no evidence of benefit for
  reduction in events
• Beta-carotene CARET study
• 30mg beta-carotene and 25,000 IU retinol were
  associated with increased risk of CV mortality
  and total mortality as a result of increase in
  lung CA.

43
Miscellaneous agents

• Metamucil
• Good (? LDL 10-15)
• Garlic
• probably good (? TC 5-15)
• Olestra WOW
• Not so good (? TC 5-8)

44
Alcohol and The Heart

• Moderate alcohol consumption is associated with
  lower mortality
• Most evidence with red wine
• Moderate consumption (lt 2 drinks/day 20 gm/day
  alcohol) associated with
• 12 increase in HDL-C
• decreased LDL oxidation
• decreased platelet aggregation
• Higher consumption associated with increased
  mortality
• Increased BP, arrhythmia, TG, stroke, and MI

AHA Scientific Advisory Circulation
2001103472-475.
45
Wine Consumption and CHD
CHD -4.99W 652.4 r -0.580
Hegsted DM, Ausman LM. J Nutr. 19881181184-1189.
46
Relation Between CHD Events and LDL-C Outcomes in
Statin Trials
30
4S-PI
HPS-Pl
25
2 Prevention
4S-Rx
HPS-Rx
20
with CHD event
LIPID-Rx
15
LIPID-PI
CARE-Rx
CARE-PI
1 Prevention
HPS-Pl
10
w/revascstroke CHD only
AFCAPS-PI
HPS-Rx
WOSCOPS-PI
5
WOSCOPS-Rx
AFCAPS-Rx
0
PIplacebo Rxtreatment
90
110
130
150
170
190
210
70
Mean LDL-C level at follow-up (mg/dL)
HPS enrolled high-risk primary- and
secondary-prevention patients. HPS. Lancet.
20023607. Downs. JAMA. 19982791615. LIPID. N
Engl J Med. 19983391349. Sacks. N Engl J Med.
19963351001. 4S. Lancet. 19953451274.
Shepherd. N Engl J Med. 19953331301.
47
NCEP ATP IIIRelationship between changes in LDL
and HDL levels and CHD risk
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA 20012852486-2497.
48
Proposed Mechanisms of Event Reduction by
Lipid-Lowering Therapy

• Improved endothelium-dependent vasodilation
• Stabilization of atherosclerotic lesions
• especially nonobstructive, vulnerable plaques
• Reduction in inflammatory stimuli
• lipoproteins and modified lipoproteins
• Prevention, slowed progression, or regression of
  atherosclerotic lesions

Libby P. Circulation. 1995912844-2850.
49
Adult Treatment Panel III (ATP III)
GuidelinesExecutive Summary (JAMA
20012852486-97)Full Report Available online
at http//www.nhlbi.nih.gov/guidelines/cholestero
l/index.htm

• National Cholesterol Education Program

50
National Cholesterol Education Program Reports

• Adult Treatment Panel I (1988) Adult Treatment
  Panel II (1983) Adult Treatment Panel III (2001)
  Adult Treatment
  Panel III Update (2004)
  
• Recommendations for Improving Cholesterol
  Measurement (1990)Recommendations on Lipoprotein
  Measurement (1995)
• Population Strategies for Blood Cholesterol
  Reduction (1990)
• Blood Cholesterol Levels in Children and
  Adolescents (1991)

51
ATP III Cholesterol Screening

• Recommendation for Screening/Detection
• Complete lipoprotein profile preferred
• Fasting total cholesterol, LDL, HDL,
  triglycerides
• Secondary option
• Non-fasting total cholesterol and HDL
• Proceed to lipoprotein profile if TC ?200 mg/dL
  or HDL lt40 mg/dL

52
ATP III LDL-C, HDL-C, TC Classification
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
53
NCEP-ATP IIIClassification of Serum Triglycerides
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA 19932693015-3023. Expert Panel on
Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults. JAMA
20012852486-2497.
54
ATP III Major CHD Risk FactorsOther Than LDL-C

• Cigarette smoking
• Hypertension BP ?140/90 mm Hg or on
  antihypertensive medication
• Low HDL-C ?40 mg/dL
• Family history of premature CHD (1st-degree
  relative)
• male relative age ?55 years
• female relative age ?65 years
• Age
• male ?45 years
• female ?55 years

HDL-C ?60 mg/dL is a negative risk factorand
negates one other risk factor.
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
55
ATP III Additional CHD Risk Factors

• Life-habit risk factors targets for
  intervention not usedto set lower LDL-C goal
• obesity physical inactivity atherogenic
  diet
• Emerging risk factors can help guide intensity
  of risk-reduction therapy do not categorically
  alter LDL-C goals
• lipoprotein(a) homocysteine impaired
  fasting glucose prothrombotic and
  subclinical atherosclerotic proinflammatory
  factors disease

Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
56
ATP III The Metabolic Syndrome
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 increased.
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
57
CHD Risk Equivalents

• Myocardial infarction, unstable or stable angina,
  post-CABG, s/p angioplasty or other PCI
• Other clinical forms of atherosclerotic disease
  (peripheral arterial disease, abdominal aortic
  aneurysm, and symptomatic carotid artery disease)
• Diabetes
• Multiple risk factors that confer a 10-year risk
  for CHD gt20

58
ATP III Assessment of Risk

• For persons without known CHD, other forms of
• atherosclerotic disease, or diabetes
• Count the number of risk factors.
• Use Framingham scoring for persons with ?2 risk
  factors to determine the absolute 10-year CHD
  risk.
• Risk calculator available at http//hp2010.nhlbih
  in.net/atpiii/calculator.asp?usertypeprof

For persons with 01 risk factor, Framingham
calculations are not necessary.
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
59
Assessing CHD Risk in Men
ATP III Framingham Risk Scoring
Step 7 CHD Risk
Point Total 10-Year Risk Point Total 10-Year
Risk lt0 lt1 11 8 0 1 12 10 1 1 13 12 2 1
14 16 3 1 15 20 4 1 16 25 5 2 ³17 ³30
6 2 7 3 8 4 9 5 10 6
Step 2 Total Cholesterol
TC Points at Points at Points at Points
at Points at (mg/dL) Age 20-39 Age 40-49 Age
50-59 Age 60-69 Age 70-79 lt160 0 0 0 0 0 160-19
9 4 3 2 1 0 200-239 7 5 3 1 0 240-279 9 6 4 2 1
³280 11 8 5 3 1
Note Risk estimates were derived from the
experience of the Framingham Heart Study, a
predominantly Caucasian population in
Massachusetts, USA. Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA. 20012852486-2497.
60
Assessing CHD Risk in Women
ATP III Framingham Risk Scoring
Step 7 CHD Risk
Point Total 10-Year Risk Point Total 10-Year
Risk lt9 lt1 20 11 9 1 21 14 10 1 22 17 11
1 23 22 12 1 24 27 13 2 ³25
³30 14 2 15 3 16 4 17 5 18 6 19 8
Step 2 Total Cholesterol
TC Points at Points at Points at Points
at Points at (mg/dL) Age 20-39 Age 40-49 Age
50-59 Age 60-69 Age 70-79 lt160 0 0 0 0 0 160-19
9 4 3 2 1 1 200-239 8 6 4 2 1 240-279 11 8 5 3 2
³280 13 10 7 4 2
Note Risk estimates were derived from the
experience of the Framingham Heart Study, a
predominantly Caucasian population in
Massachusetts, USA. Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA. 20012852486-2497.
61
Risk assessment example

• 53 year-old man with BP 155/ 85 on HCTZ, TC
  235, TG 160, HDL 35, he does not smoke. His
  father died of an MI at age 54. (-) obesity, FBG
  89 mg/dL.
• How many risk factors does he have?
• 1 RF
• 2 RFs
• 3 RFs
• 4 RFs
• gt 4 RFs
• What is his 10-year risk of developing CHD?
• What is his LDL value?

62
Calculation of LDL Cholesterol The
Friedewald Equation

• LDL TC - (TG/5 HDL)
• Example LDL 235 - (160/5 35)
• LDL 235 - (32 35)
• LDL 235 - 67
• LDL 168

63
Calculation of LDL Cholesterol The
Friedewald Equation

• Limitations
• Equation is not valid for TGs gt 400 mg/dL
• Must obtain a direct LDL
• When compared, calculated LDL underestimates
  direct LDL by 20 mg/dL
• Exp. LDLdirect 110 mg/dL LDLcalc 90 mg/dL
• Underestimation is worse for each 100 mg/dL
  increase in TG above 200 mg/dL

(Pharmacotherapy 200424(2)167172.)
64
Step 1 Age
ATP III Framingham Risk Scoring
Expert Panel on Detection, Evaluation, and
Treatment of High BloodCholesterol in Adults.
JAMA. 20012852486-2497.
65
Step 2 Total Cholesterol
ATP III Framingham Risk Scoring
Men
TC Points at Points at Points at Points
at Points at (mg/dL) Age 20-39 Age 40-49 Age
50-59 Age 60-69 Age 70-79 lt160 0 0 0 0 0 160-19
9 4 3 2 1 0 200-239 7 5 3 1 0 240-279 9 6 4 2 1
³280 11 8 5 3 1
Note TC and HDL-C values should be the average
of at least two fasting lipoprotein
measurements. Expert Panel on Detection,
Evaluation, and Treatment of High
BloodCholesterol in Adults. JAMA.
20012852486-2497.
66
Step 3 HDL-Cholesterol
ATP III Framingham Risk Scoring
Men
Note HDL-C and TC values should be the average
of at least two fasting lipoprotein
measurements. Expert Panel on Detection,
Evaluation, and Treatment of High
BloodCholesterol in Adults. JAMA.
20012852486-2497.
67
Step 4 Systolic Blood Pressure
ATP III Framingham Risk Scoring
Note The average of several BP measurements is
needed for an accurate measurement of baseline
BP. If an individual is on antihypertensive
treatment, extra points are added. Expert Panel
on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults. JAMA.
20012852486-2497.
68
Step 5 Smoking Status
ATP III Framingham Risk Scoring
Note Any cigarette smoking in the past
month. Expert Panel on Detection, Evaluation,
and Treatment of High BloodCholesterol in
Adults. JAMA. 20012852486-2497.
69
Step 6 Adding Up the Points(Sum From Steps 15)
ATP III Framingham Risk Scoring
13
Expert Panel on Detection, Evaluation, and
Treatment of High BloodCholesterol in Adults.
JAMA. 20012852486-2497.
70
Step 7 CHD Risk for Men
ATP III Framingham Risk Scoring
Note Determine the 10-year absolute risk for
hard CHD (MI and coronary death) from point
total. Expert Panel on Detection, Evaluation,
and Treatment of High BloodCholesterol in
Adults. JAMA. 20012852486-2497.
71
Risk assessment example

• What is his 10-year risk of developing CHD?
• 12
• What is his LDL goal?

72
Update to ATP III Guidelines Rationale

• Results of 5 trials
• Confirm the benefit of cholesterol-lowering
  therapy in moderately high and high-risk patients
• Support the ATP III LDL-C goal of lt100 mg/dL
• Support the inclusion of patients with diabetes
  in the high-risk category and confirm the
  benefits of LDL-lowering therapy in these
  patients
• Confirm that older persons benefit from
  therapeutic lowering of LDL-C
• Provide new information on efficacy of risk
  reduction in high-risk patients with relatively
  low LDL-C levels

Grundy SM et al. Circulation. 2004110227-239.
73
Heart Protection Study (HPS)Major vascular
events by prior disease
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
(10269)
(10267)
STATIN better
PLACEBO better
999
1250
(23.5)
(29.4)
Previous MI
591
(18.9)
(24.2)
Other CHD (not MI)
460
No prior CHD
172
212
(18.7)
(23.6)
CVD
327
420
(24.7)
(30.5)
PVD
276
367
(13.8)
(18.6)
Diabetes
24 SE 3
2033
2585
(19.8)
(25.2)
ALL PATIENTS
reduction
(2Plt0.00001)
Lancet 2002 360 722.
0.4
0.6
0.8
1.0
1.2
1.4
74
Heart Protection Study (HPS)Major Vascular
Events by LDL Cholesterol
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
Lipid levels
at entry
(10269)
(10267)
STATIN better
PLACEBO better
LDL cholesterol (mg/dl)
282
358
(16.4)
(21.0)
lt 100
668
871
(18.9)
(24.7)
³
100 lt 130
1083
1356
(21.6)
(26.9)
³
130
24 SE 3
2033
2585
(19.8)
(25.2)
ALL PATIENTS
reduction
(2Plt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
Lancet 2002 360 722.
75
ATP III Updated LDL-C Goals, Treatment Cutpoints
LDL-C Goal
ConsiderDrug Therapy
Initiate TLC
Risk Category
lt100 mg/dL(optionallt70 mg/dL)
?100 mg/dL(lt100 mg/dL consider drug options)
?100 mg/dL
High riskCHD or CHD risk equivalents(10-year
risk gt20)
lt130 mg/dL(optionallt100 mg/dL)
?130 mg/dL(100129 mg/dL consider drug options)
?130 mg/dL
Moderatelyhigh risk?2 risk factors(10-year
risk 1020)
CHD risk equivalents clinical manifestations of
noncoronary forms of atherosclerotic disease
(cerebrovascular disease, peripheral vascular
disease), diabetes, and gt 2 major CHD risk
factors with 10-year risk gt20 for hard CHD. The
optional LDL-C goal of lt70 mg/dL is favored in
those at very high risk established CHD
multiple risk factors (esp DM), or severe and
poorly controlled risk factors (esp smoking),
metabolic syndrome (esp TGs gt 200 mg/dL and
non-HDL gt 130 mg/dL with HDL lt 40 mg/dL), acute
coronary syndromes. Any person at high or
moderately high risk with lifestyle-related risk
factors is a candidate for TLC to modify these
risk factors regardless of LDL-C level.
Grundy SM et al. Circulation. 2004110227-239.
76
ATP III Updated LDL-C Goals, Treatment Cutpoints
Not modified in update
LDL-C Goal
ConsiderDrug Therapy
Initiate TLC
Risk Category
lt130 mg/dL
?160 mg/dL
?130 mg/dL
Moderate risk ?2 risk factors(10-year risk
lt10)
lt160 mg/dL
?190 mg/dL(160189 mg/dLLDL-Clowering drug
optional)
?160 mg/dL
Lower risk01 risk factor
Grundy SM et al. Circulation. 2004110227-239.
77
Risk assessment example

• What is his 10-year risk of developing CHD?
• 12, moderately high risk
• What is his LDL-C goal?
• lt 70 mg/dL
• lt 100 mg/dL, optional lt 70 mg/dL
• lt 130 mg/dL, optional lt 100 mg/dL
• lt 130 mg/dL
• lt 160 mg/dL

78
Dietary Management
79
Diet Therapeutic Lifestyle Changes (TLC)

• Four Goals of TLC
• Reduced intake of saturated fat and cholesterol
• Dietary and therapeutic options for enhancing LDL
  lowering
• Weight reduction
• BMI between 18.5 24.9 kg/m2
• Waist circumference (males lt 40 in females lt 35
  in)
• Increased regular physical activity

NCEP ATP III. Circulation. 20021063143-3421.
80
ATP III Nutritional Components of the TLC Diet
Trans fatty acids also raise LDL-C and should be
kept at a low intake. Note Regarding total
calories, balance energy intake and expenditure
tomaintain desirable body weight.
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
81
Benefits of Lifestyle Changes
Jones PJ. Curr Atheroscler Rep. 19991230-235.
Lichtenstein AH. Curr Atheroscler Rep.
19991210-214. Rambjor GS, et al. Lipids.
199631S45-S49. Ripsin CM, et al. JAMA.
19922673317-3325. Jenkins DJA, et al. Curr Opin
Lipidol. 20001149-56.
82
Low-carbohydrate vs. low-fat diets
changes in cholesterol
Samaha et al. N Engl J Med 20033482074-81.
Foster et al. N Engl J Med 20033482082-90.
n 63
n 132

p lt 0.05
Low-fat diet

Low-fat diet
Low-carb diet
Low-carb diet
83
Management of specific dyslipidemias
84
ATP III Management of Elevated TG
Primary aim of therapy is to get to LDL-C
goal. Primary aim of therapy is to reduce risk
for pancreatitis through TG lowering first, then
focus on LDL-C. To achieve nonHDL-C goal (set
at 30 mg/dL higher than LDL-C goal), intensify
therapy with LDL-Clowering drug, or add
nicotinic acid or fibrate.
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
85
ATP III Management of Low HDL-C

• Low HDL-C lt40 mg/dL (no specific goal defined
  for raising HDL-C)
• Targets of therapy
• all persons with low HDL-C achieve LDL-C goal
  then ? weight, ? physical activity (if metabolic
  syndrome is present)
• those with TG 200499 mg/dL achieve nonHDL-C
  goal as secondary priority
• those with TG lt200 mg/dL consider drugs for
  raising HDL-C (fibrates, niacin)

NonHDL-C goal is set at 30 mg/dL higher than
LDL-C goal.
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
86
ATP III Management of Very High LDL-C

• LDL-C ?190 mg/dL usually traced to genetic
  formsof hypercholesterolemia
• Recommended actions
• early detection in young adults through
  cholesterol screening to prevent premature CHD
• family cholesterol testing to identify affected
  relatives
• combination drug therapy usually required to
  achieve target LDL-C levels

Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
87
ATP III Management of Diabetic Dyslipidemia

• Primary target of therapy identification of
  LDL-C goal for persons with diabetes lt100 mg/dL
  (optional lt 70 mg/dL)
• Therapeutic options
• LDL-C 100129 mg/dL increase intensity of TLC
  optionally, initiate statin or add drug to modify
  atherogenic dyslipidemia (fibrate or nicotinic
  acid) intensify risk factor control
• LDL-C ?130 mg/dL simultaneously initiate TLC and
  statin
• TG ?200 mg/dL nonHDL-C becomes secondary target

Note Diabetic dyslipidemia is essentially
atherogenic dyslipidemia in persons with type 2
diabetes.NonHDL-C goal is set at 30 mg/dL
higher than LDL-C goal.
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497 and Grundy SM et al.
Circulation. 2004110227-239.
88
Lipid Algorithm
Step 1. Obtain fasting lipid panel

• Step 2. Perform risk assessment
• CHD or CHD risk equivalent(s)
• Add major risk factors
• Determine metabolic factors
• If gt 2 major risk factors, determine 10-year
  risk CHD 10-year risk calculator
  available at http//hin.nhlbi.nih.gov/atpiii/calc
  ulator.asp?usertypepub

89
Lipid Algorithm
Step 3. Determine LDL goal
90
Lipid Algorithm

• Step 3. LDL Goal (continued)
• Very High Risk, optional goal lt 70 mg/dL
  Established CHD and multiple risk factors (esp
  DM) or severe and poorly controlled risk factors
  (esp smoking) or metabolic syndrome (esp TGs gt
  200 mg/dL and non-HDL gt 130 mg/dL with HDL lt 40
  mg/dL) or acute coronary syndromes.
• Moderately High Risk, optional goal lt 100 mg/dL
  gt 2 risk factors and severe risk factors
  (smoking and/or family hx), TGs gt200 mg/dL
  non-HDL gt 160 mg/dL HDL lt 40 mg/dL, metabolic
  syndrome, and/or high hsCRP (gt 3 mg/L).

91
Lipid Algorithm
Step 4. Determine the percent LDL reduction
required to reach goal reduction required
patients LDL Goal LDL x 100
patients LDL

• Step 5. Initiate therapeutic lifestyle changes
• Smoking cessation
• Diet, including plant stanols/sterols, fish
  oils, fiber
• Weight reduction, physical activity

92
Lipid Algorithm
Step 5 (cont). Initiate therapeutic lifestyle
changes
Visit N
6 wks
6 wks
Q 4-6 mo
MonitorAdherenceto TLC

• Emphasizereduction insaturated fat
  cholesterol
• Encouragemoderate physicalactivity
• Consider referral toa dietitian

• Reinforce reductionin saturated fat
  andcholesterol
• Consider addingplant stanols/sterols
• Increase fiber intake
• Consider referral toa dietitian

• Initiate Tx forMetabolicSyndrome
• Intensify weightmanagement physical activity
• Consider referral to a dietitian

93
Lipid Algorithm

• Step 6. Initiate appropriate drug therapy
• Very high risk If baseline LDL gt 70 mg/dL
• High risk If baseline LDL gt 100 mg/dL
• Moderately high risk If baseline LDL gt 130
  mg/dL or if either baseline or follow-up TLC
  treatment LDL is 100 129 mg/dL
• Moderate risk If baseline LDL gt 160 mg/dL or
  follow-up TLC treatment is gt 130 mg/dL
• Lower risk If baseline LDL gt 190 mg/dL or
  follow-up TLC treatment is gt 160 mg/dL

94
Lipid Algorithm

• Step 6 (cont). Initiate appropriate drug therapy
• Selection of agent
• If LDL-C gt 20 above goal or patient is high or
  moderately high risk, statins should be the
  initial drug choice
• If LDL-C lt 20 above goal, then a statin,
  niacin, ezetimibe, or BAR are good choices
• IF TGs gt 500, then initiate TG lowering therapy
  (fibrate or niacin) to reduce risk of
  pancreatitis
• NOTE When initiating drug therapy for patients
  at very high risk, high risk, or moderately high
  risk the intensity of therapy should be such to
  achieve a 30 40 LDL reduction

95
Lipid Algorithm
Step 6 (cont). Initiate appropriate drug therapy
Dose LDL Reduction LDL Reduction LDL Reduction LDL Reduction LDL Reduction
Dose ATORVASTATIN (Lipitor) LOVASTATIN (Mevacor) PRAVASTATIN (Pravachol) ROSUVASTATIN (Crestor) SIMVASTATIN (Zocor)
5mg -- -- -- 45 --
10mg 37 21 20 46 28
20mg 43 27 24 52 35
40mg 48 31 30 55 39
80mg 51 40 37 -- 46
Comments Administer with the evening meal Starting dose should not be gt 20mg/day Starting dose should not be gt 40 mg/day
Based on results from the STELLAR trial. Jones
et al. Am J Cardiol 200392152-60. Information
from the product prescribing information
96
Lipid Algorithm

• Step 7. Repeat fasting lipid profile in 4 6
  weeks
• If not at goal, intensify statin dose
• OR
• Add ezetimibe, BAR, or niacin

• Step 8. Once LDL goal achieved, assess TGs and
  HDL
• If TG gt 200 mg/dL, achieve non-HDL-C (TC
  HDL-C) goal (LDL goal 30 mg/dL)
• Intensify therapy with LDL-lowering drug
• OR
• Add niacin or fibrate
• If TG lt 200 mg/dL, HDL lt 40 mg/dL, CHD or
  equivalent, consider fibrate or niacin

97
Percent reduction required Example of the 53
y/o male patient

• reduction required patients LDL - Goal LDL
• patients LDL
• Example of the 53 year-old man
• LDL 168
• Goal LDL lt 130, optional lt 100
• reduction (168 - 130)/168 23, or
• (168 100)/168 40

98
Treatment recommendationsExample of the 53 y/o
male patient

• Initiate TLC diet
• Pt is moderately high risk and LDL gt 20 above
  goal, therefore initiate LDL lowering drug
  therapy with statin.
• Since moderately high risk, intensity of drug
  therapy should achieve a 30 40 reduction
• Choices are Atorvastatin 10mg, rosuvastatin 5mg,
  simvastatin 20mg, lovastatin 40mg, or pravastatin
  40mg

99
Treatment recommendationsExample of the 53 y/o
male

• Monitoring
• Baseline AST/ALT, CPK, inquire into muscle,
  headache, and dyspepsia symptoms
• Follow-up
• At 6 weeks fasting lipid profile, determine if
  any muscle, headache, or dyspepsia sxs
• At 12 weeks AST/ALT, inquiry into symptoms
• AST/ALT semiannually or 12 weeks post dose
  increase, symptoms each visit, CPK if muscle
  symptoms are present

100
Medication Adherence
Ive also been treating the high cholesterol and
then I stopped the medicine because I got my
cholesterol down low. And, I had in the past, a
little blood pressure problem, which I treated
and then I got it down (Former US President
Clinton, awaiting coronary bypass surgery, calls
into Larry King Live from his hospital bed
posted Friday, Sept 3, 2004, 2331 h EST).
TC 233 TG 52 HDL 46 LDL 177 January
12, 2001 Presidents Annual Medical Check-up
101
Medication Adherence

• Compliance with lipid lowering therapy
• (Am J Cardiol 199678377-8.)
• 50 discontinue after 1 year
• 75 discontinue after 3 years
• Reasons for Discontinuation of therapy
• Patient not convinced of need
• Adverse effects
• Poor efficacy

102
Duran Central Pharmacy Lipid Survey

Did Dr tell you your TC goal?
Did Dr tell you your LDL goal?
Do you know your LDL goal?
Do you know your TC goal?
103
Medication Adherence

• Data from large Rx claims database (n 233,588)
  show discontinuation rates for lipid-lowering
  therapy are very high

Cumulative Discontinuation Rate ()
Kamel-Bahl SJ, et al. 200799530-4.
104
ATP III Improving AdherenceFocus on the Patient

• For optimum effectiveness, physicians should
  employ ?2 of these approaches for each patient
• Keep medication regimens simple
• Make instructions very explicit
• Suggest use of prompts
• Utilize systems to maintain patient contact
• Encourage support from family, friends
• Reinforce, reward adherence
• Increase visits for those who cannot reach
  treatment goal
• Make care more convenient, accessible
• Encourage self-monitoring

Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
105
ATP III Improving AdherenceFocus on the
Physician, Delivery System

• For the physician, medical office
• Use prompts to highlight lipid management
• Identify an in-office patient advocate
• Involve patients to prompt preventive care
• Use feedback to modify future care
• For the health delivery system
• Provide lipid management through a lipid clinic
• Utilize case management by nurses
• Implement telemedicine (phone follow-up)
  procedures
• Involve pharmacists in collaborative care
• Develop in-hospital critical care pathways

Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
106
ATP III Adherence to Treatment Goals
Patients Not at LDL-C Target Goal
of patients
gt 2 RFs
CHD
NHANES III National Center for Health
Statistics. 1994
L-TAP Pearson et al.
Arch Intern Med 2000160459-67.
Straka et al.
Pharmacotherapy 200121-818-27.
107
Duran Central PharmacyPercentage of patients at
goal (n 82)

NCEP-ATP II Goal
108
Hyperlipidemia Patient Cases
109
Case 1 60 yo male s/p MI with HTN (controlled on
ACE I), CHF, and DM (HbA1c is 7), TC 255, TG
292, LDL 163, HDL 34

• What is goal LDL?
• lt 70 mg/dL
• lt 100 mg/dL
• lt 130 mg/dL
• lt 160 mg/dL

110

• Case 1 continued
• What therapy should be implemented?

1. TLC diet
2. Niacin
3. Gemfibrozil
4. atorvastatin
5. A and D

111

• Case 1 continued
• What monitoring parameters?

Baseline LFTs, CPK, and muscle symptoms Repeat
FLP in 4 to 6 weeks. Ask about muscle symptoms
at every visit. CPK if muscle pain, tenderness,
or soreness. LFTs at 12 weeks and then
periodically (semi-annually) or 12 weeks post any
dose increase