Transcript Hyperlipidemia

Dyslipidemia: Managing a Key
Cardiovascular Risk Factor
AIMGP Clinic Seminar
Updated by R. Cavalcanti
Sep 2007
Outline
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Current Practice Guidelines
Cases
Global Risk Assessment
Whom to Screen for Dyslipidemia?
Risk Categories & Lipid Targets
Factors Influencing Risk Assessment
Selected Studies
Management
Cases Revisited
Current Practice Guidelines
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Canadian Guidelines
– “Recommendations for the management of
dyslipidemia and the prevention of cardiovascular
disease: summary of the 2003 update” CMAJ
169(9):921-4, 28 Oct 2003
– www.cmaj.ca/cgi/content/full/169/9/921/DC1
– CCS Position Statement on Dx and Rx
dyslipidemia. Canadian Journal of Cardiology
2006;22(11):913-927
Current Practice Guidelines
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American Guidelines
– “Implications of Recent Clinical Trials for the National
Cholesterol Education Program Adult Treatment Panel
III Guidelines”
» Circulation 110:227-39, 13 July 2004
– “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 285(19):2486-97, 16 May 2001
Case 1
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56 M
– Acute MI 4 months ago
– No current cardiovascular symptoms
– Tested for DM post-MI
» Negative
– Non-smoker, no HTN
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Lipids measured while in hospital post-MI:
– TC 4.2, LDL 2.5, HDL 1.3, TG normal (TC/HDL 3.2)
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What is his estimated risk of a cardiovascular
event in the next 10 years?
How should you manage his lipids?
Case 2
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45 F
– ‘Healthy’, BP 125/80
– Non-smoker, EtOH: 3 standard drinks/week
– No cardiovascular symptoms
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Lipids measured at annual visit:
– TC 6.5, LDL 4.1, HDL 1.4, TG normal (TC/HDL 4.6)
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What is her estimated risk of a cardiovascular
event in the next 10 years?
How should you manage her lipids?
Case 3
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55 F
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DM Type 2 x 10 years (HbA1c 9.7%), HTN
post menopausal, BMI 33
Non-smoker, EtOH: 4 standard drinks/day
No cardiovascular symptoms
Lipids measured at annual visit:
– TC 5.9, HDL 0.78, TG 9.8 (TC/HDL 7.6)
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What is her estimated risk of a cardiovascular
event in the next 10 years?
How should you manage her lipids?
Current Challenges in
Cardiovascular Risk Reduction
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Aging Population
– >20% Canadians will be >65 years old by 2011
– 1,900,000 Canadians >80 years old by 2026
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Obesity
– 31% of Canadians are obese
– Especially if abdominal adiposity, associated with
increased prevalence of metabolic syndrome features
(DM, HTN, ↑TGs, ↓HDL, insulin resistance)
– Associated with ↑inflammatory markers (CRP, IL-6)
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Diabetes
– 60,000 new cases per year in Canada
– 3,000,000 Canadians with DM by 2010
Global Risk Assessment
Hyperlipidemia is an important risk factor,
and should be used to assess overall cardiovascular risk
 Global CV risk should be used to assess
treatment goals and modalities
 Cardiac endpoints:
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– non-fatal MI
– death due to CAD
Global Risk Assessment
Risk assessment model adapted from the
Framingham Heart Study
 This model only applies in:
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– Patients without diabetes
– Patients without clinically evident
cardiovascular disease (prior CAD, ischemic
stroke, PAD) or CRF
Global Risk Assessment
Which patients are automatically considered
high risk (>20% 10-year risk)?
 All adult patients with:
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DM
History of CAD
Ischemic stroke
Peripheral arterial disease
CRF ( < 60 ml/min of GFR)
Global Risk Assessment
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What are the risk factors in Framingham
risk calculator?
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Age
Gender
Smoking history
Lipid profile (TC, HDL)
Systolic BP
If the calculated
10-year risk is:
≥20% - ‘High Risk’
11-19% - ‘Moderate
Risk’
≤10% - ‘Low Risk’
Whom to Screen for
Dyslipidemia?
Influenced by cardiac risk factors:
 By age alone (Canadian Guidelines):
– Men over age 40
– Women over age 50 (or post-menopausal)
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Adults at any age if:
– At least 2 risk factors
» DM, HTN, Smoking, Abdominal Obesity
» Family history of early cardiovascular disease
– Physical signs of hyperlipidemia
» Xanthomata, xanthelasmas, arcus corneae, etc
– Evidence of existing atherosclerosis
Manifestations of Dyslipidemia
Xanthelasmas
and tendon
xanthomata in
patients with
severe ↑LDL
(the patient at
the bottom has
heterozygous
familial
hypercholesterolemia)
Eruptive xanthomata on
the forearm of a patient
with severe ↑TGs
Diagnosis of Asymptomatic
Atherosclerosis
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To aid in risk stratification
Recommended:
– Physical examination
– Ankle-Brachial Index
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Possibly useful in patients already known to be at
‘moderate risk’:
– Carotid ultrasonography
– EKG
– Exercise stress testing in men >40 years old with
established cardiovascular risk factors
Risk Categories & Lipid Targets
More about LDL targets to come later – for high-risk patients,
these are minimum targets – they should be lower if at all
possible
Lipid Targets: Triglycerides
No discrete triglyceride goal in each
category, but the optimal level is TG <1.7
 TG >10 requires targeted treatment to
prevent pancreatitis independent of
cardiovascular risk
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– diet & lifestyle changes
– fibrate or niacin, fish oil
Factors Influencing Risk Assessment
Metabolic Syndrome
 Abdominal Obesity
 Apolipoprotein B (apoB)
 Lipoprotein(a)
 Homocysteine
 C-Reactive Protein (CRP)
 Genetic Risk
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Factors Influencing Risk
Assessment
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Presence of the Metabolic Syndrome: ↑ Risk
– A clustering of cardiovascular risk factors, including
abdominal obesity, insulin resistance, and hypertension,
as well as lipid abnormalities (↑TGs and ↓HDL)
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Presence of Abdominal Obesity: ↑ Risk
– with waist circumference as a useful estimate
Factors Influencing Risk
Assessment
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Apolipoprotein B (apoB)
– ↑ApoB (for the same lipid levels) = smaller,
denser, more atherogenic LDL particles
– ApoB levels correlate better than LDL levels
to clinical outcomes in statin trials
– For ‘high risk’ patients, target apoB <0.9g/L
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Lipoprotein(a) (lp(a))
– Appears to be an independent risk factor for
premature atherosclerosis and CAD
Factors Influencing Risk
Assessment
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Homocysteine
– ↑homocysteine levels predict adverse outcomes
in patients with CAD
– Fixed-dose folate & B12 supplementation trials
so far have been negative
– No evidence yet to screen for homocysteine
Factors Influencing Risk
Assessment
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C-Reactive Protein (CRP)
– ↑CRP may add prognostic information to
Framingham
– ↑CRP associated with abdominal obesity and
the metabolic syndrome
– May be useful in persons with a calculated 10year risk of 11-19% (‘moderate risk’)
» More aggressive Rx?
Factors Influencing Risk
Assessment
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C-Reactive Protein (CRP)
– Do not measure during acute illness or in
patients with chronic inflammatory disease
– Measure 2x, two weeks apart, use the lower
value
– Low risk <1 mg/ml & high risk 3-10mg/ml
– If >10mg/ml, look for infection/inflammation
Factors Influencing Risk
Assessment
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Genetic Risk
– A confirmed, unambiguous family history of early
onset CAD increases the risk for first-degree relatives
(parents, siblings, children)
» RRI 1.7-2.0
– Early onset is defined as <55 years old for men and <65
years old for women (this is the age of the index
relative who had the cardiac event)
Selected Major Studies
There are many, many, many trials of statins
 We will discuss:
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– MRC/HPS- largest trial of 2a. prevention (+ 1a.
prevention in high risk pt)
– ASCOT-LLA- largest trial of 1a. Prevention
– INTERHEART: largest study of risk factors
Selected Major Trials
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MRC/BHF Heart Protection Study:
– 20,556 men & women aged 40-80 with TC >3.5
– All at ‘high risk’ of CAD
» Known CAD/MI/PVD/CVS
» DM, HTN, or both
– RCT: Simvastatin 40mg vs. placebo
– Decreased death rate by 13% at 5 years
» Decreased combined cardiovascular end points by 24%
» Benefits in all subgroups, including baseline LDL <2.6
– Very compelling, well done trial
Lancet 360(9326):7-22, 6 July 2002
Selected Major Trials
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Anglo-Scandinavian Cardiac Outcomes Trial
– 9000 patients aged 40-79 with baseline TC <6.5
– All hypertensive
» Had at least 3 risk factors for CAD
» No pre-existing coronary disease
– RCT: Atorvastatin 10mg vs. placebo for 5 years
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↓ MI by 36%
↓ stroke rate by 27%
↓ all cardiovascular events and procedures by 21%
↓ total coronary events by 29%
– Study was stopped after 3 years because of significant
benefit in the treatment group
Lancet 361(9364):1149-58, 5 April 2003
Selected Major Studies
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The INTERHEART study
– Potentially modifiable risk factors associated
with MI in 52 countries:
– Case Control: 15,152 cases & 14,820 controls
in 52 countries on every inhabited continent
– Findings consistent between old/young,
male/female, different countries
– 9 risk factors accounted for
» >90% of the risk (in men)
» >94% of the risk (in women)
Lancet 364(9437):4999-5014, 4 Sept 2004
The INTERHEART study
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Increase risk
– ↑ApoB/ApoA1 ratio
» OR 3.25
– Smoking (current vs. never)
» OR 2.87
– Psychosocial factors
» OR 2.67
– DM
» OR 2.37
– History of HTN
» OR 1.91
– Abdominal Obesity
» OR 1.12 1st vs. 3nd tertile
» OR 1.62 2nd vs. 3rd tertile
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Protective:
– eating fruits &
vegetables daily
» OR 0.70
– ≥3 units/week of
alcohol
» OR 0.91
– moderate/strenuous
physical activity
» OR 0.86
Treatment
Treatment
Treatment
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In low or moderate risk patients
– Start with lifestyle, progress to Rx based on targets
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In ‘high risk’ patients:
– Start drug treatment immediately (statin), concurrently
with diet and lifestyle modification
– Priority is to get LDL <2.5 and TC/HDL <4
– If can’t reach LDL <2.5:
» Cholesterol absorption inhibitors (ezetimibe) better tolerated
» Bile acid sequestrants (cholestyramine, colestipol)
» Either can decrease LDL by another 10-20% compared with
statin alone
» Limited evidence for CV benefit
2004 ATP III Update
Lower LDL Targets
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In high risk patients mounting evidence
supports lower LDL-C targets
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Latest CCS guidelines (CJC 2006):
– High risk patients: LDL-C < 2.0; TC:HDL <4.0
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Revision NCEP (Circulation 2004):
– Suggested targets for high risk patients
– LDL-C <1.8
Treatment
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If TC/HDL ratio is still high:
– Lifestyle modification
– Increasing Statin Dose (with LDL at target)
– Combination Drug Therapy
Treatment
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Lifestyle modification:
– For ↑TGs:
» weight loss
» restriction of refined carbohydrates
» no alcohol, increased exercise
– For ↓HDL:
» weight loss
» increased monounsaturated fats
» moderate alcohol (if TGs normal)
» increased aerobic exercise
Treatment
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Increasing Statin Dose (with LDL at target):
– For ↓HDL and/or mild ↑TGs (TGs <5), may
achieve target TC/HDL ratio by increasing the
statin dose even if the target LDL has been
reached
Treatment
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Combination Drug Therapy (Limited if any evidence):
– Moderate ↑TGs -> add salmon oil (1-3g tid) to statin
– ↓HDL -> combine statin with niacin.
– Caution:
» 1) niacin can cause increased insulin resistance
» 2) niacin-statin combination increases risk of hepatotoxicity
– If intolerant to niacin:
» consider statin-fibrate combination
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(simvastatin or pravastatin with fenofibrate, NOT gemfibrozil)
» lowest possible doses of each
» very close follow-up watching for hepatotoxicity and myositis
» if no CRF
Treatment
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If ↑TGs:
– Ideal target <1.7
» 1st line: lifestyle modification
» Treatments aimed at lowering the TC/HDL ratio usually also
help lower TGs
– If TGs >6 despite lifestyle changes, need drug treatment
even if the TC/HDL ratio is acceptable
» Treatment is needed to avoid pancreatitis
» Options:
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Fibrate
Niacin
Salmon oil
Follow-Up
Which blood work should be ordered
in follow-up? How frequently?
Follow-Up
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Lipids:
– 6 weeks after start / change of dose (levels reach steady
state within 6 weeks of start/change of medication)
– Long-term follow-up every 6-12 months
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AST / ALT (0.5 –3% incidence):
– Get baseline
– Use with caution if AST/ALT > 3 x normal
– At 12 weeks after initiation or change in dose (FDA)
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CK (< 0.5% incidence):
– Get baseline
– Check only if symptomatic with myalgias (ATP III
guideline)
Case 1 Revisited
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56 M
– Acute MI 4 months ago
– No current cardiovascular symptoms
– Tested for DM post-MI
» Negative
– Non-smoker, no HTN

Lipids measured while in hospital post-MI:
– TC 4.2, LDL 2.5, HDL 1.3, TG normal (TC/HDL 3.2)

What is his estimated risk of a cardiovascular
event in the next 10 years?
– Assumed to be ≥20%

How should you manage his lipids?
Case 2 Revisited

45 F
– ‘Healthy’, BP 125/80
– Non-smoker, 3 units EtOH/week
– No cardiovascular symptoms

Lipids measured at annual visit:
– TC 6.5, LDL 4.1, HDL 1.4, TG normal (TC/HDL 4.6)
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What is her estimated risk of a cardiovascular
event in the next 10 years?
– Calculated to be 1%
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How should you manage her lipids?
Case 3 Revisited
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55 F
–
–
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DM Type 2 x 10 years (HbA1c 9.7%), HTN
post menopausal, BMI 33
Non-smoker, 4 units EtOH/day
No cardiovascular symptoms
Lipids measured at annual visit:
– TC 5.9, HDL 0.78, TG 9.8 (TC/HDL 7.6)

What is her estimated risk of a cardiovascular
event in the next 10 years?
– Assumed to be ≥20%
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How should you manage her lipids?