Transcript Hyperlipidemia - University of Toronto

Dyslipidemia: Managing a Key
Cardiovascular Risk Factor
AIMGP Clinic Seminar
Updated by R. Cavalcanti
Sep 2006
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 Recent Trials
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
– Full text of 2003 update is only online, at:
www.cmaj.ca/cgi/content/full/169/9/921/DC1
– “Recommendations for the management and
treatment of dyslipidemia” CMAJ
162(10):1441-7, 16 May 2000
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
– “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 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
Since hyperlipidemia is important as a risk
factor, it should be used to assess overall
cardiac risk, and that risk should in turn 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 is only:
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– For non-diabetic patients
– For patients without clinically evident
cardiovascular disease (including prior CAD,
ischemic stroke, and/or peripheral arterial
disease) or CRF
Global Risk Assessment
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Which patients are automatically considered
high risk (>20% 10-year risk)?
All adult patients with:
» DM
» History of CAD
» Ischemic stroke
» Peripheral arterial disease
» CRF
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:
– Men over age 40
– Women over age 50 (or post-menopausal)
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Other risk factors (at any age):
– DM, HTN, Smoking, Abdominal Obesity
– Family history of early cardiovascular disease
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Physical signs of hyperlipidemia (at any age):
– Xanthomata, xanthelasmas, arcus corneae, etc
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Evidence of existing atherosclerosis (at any age)
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
There is no longer a discrete triglyceride
goal in each category, but the optimal level
is set at TG <1.7
 If TG >10 it needs targeted treatment (diet
& lifestyle changes, fibrate or niacin, fish
oil) to prevent pancreatitis independent of
cardiovascular risk
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Factors Influencing Risk Assessment
Metabolic Syndrome
 Abdominal Obesity
 Apolipoprotein B (apoB)
 Lipoprotein(a)
 Homocysteine
 C-Reactive Protein (CRP)
 Genetic Risk
 Hormone Replacement Therapy (HRT)
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Factors Influencing Risk
Assessment
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Presence of the Metabolic Syndrome
– 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
– with waist circumference as a useful estimate
Factors Influencing Risk
Assessment
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Apolipoprotein B (apoB)
– There is 1 molecule of apoB in each atherogenic lipid
particle (VLDL, IDL, LDL, lp(a))’
– ↑apoB (for the same lipid levels) = smaller, denser,
more atherogenic LDL particles
– Better estimate than LDL of cardiovascular risk
– ApoB levels correlate better than LDL levels to
clinical outcomes in statin trials
– For ‘high risk’ patients, target apoB <0.9g/L
– Sample does not need to be fasting
Factors Influencing Risk
Assessment
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Lipoprotein(a) (lp(a))
– Appears to be an independent risk factor for premature
atherosclerosis and CAD
– Its atherogenicity seems to depend on the presence of
other factors, and its utility as a risk factor seems to
disappear if the LDL is markedly lowered
– Monogenic and not responsive to diet
– Lp(a) >30mg/dL in patients with TC/HDL ratio >5.5 or
other major risk factors may indicate need for earlier
and more intensive LDL-lowering therapy
Factors Influencing Risk
Assessment
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Homocysteine
– ↑homocysteine levels predict adverse outcomes in
patients with CAD
– Fixed-dose folate & B12 trials looking at
cardiovascular endpoints are ongoing
– No ‘treat-to-target’ trial (to homocysteine <9μmol/L)
– 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
Study data
– ↑CRP associated with abdominal obesity and the
metabolic syndrome
– May be clinically useful in identifying people who are
at higher risk than their Global Risk Assessment would
indicate (especially for people with a calculated 10-year
risk of 11-19%, so calculated to be at ‘moderate risk’)
Factors Influencing Risk
Assessment
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C-Reactive Protein (CRP)
– Do not measure during an acute illness or in patients
with chronic inflammatory disease
– Measure 2x, two weeks apart, and 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)
Factors Influencing Risk
Assessment
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Hormone Replacement Therapy (HRT):
– Should not be initiated for primary or secondary
prevention of CAD
– Unless otherwise necessary (e.g. for osteoporosis
treatment or for severe menopausal symptoms) try to
stop or taper HRT in women >55 years old who have
been on it for >5 years
– Consider stopping HRT in the setting of an acute
cardiovascular event
– Consider stopping HRT before an ACB, PCI, or other
surgical procedure
Selected Major Trials
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MRC/BHF Heart Protection Study:
– HPS: Lancet 360(9326):7-22, 6 July 2002
– 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%
» Decreased combined cardiovascular end points by 24%
– Benefits in all subgroups, including baseline LDL <2.6
– Very compelling, well done trial
– Ultimate LDL target still unclear, other studies now
looking at LDL targets of <1.8
Selected Major Trials
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Anglo-Scandinavian Cardiac Outcomes Trial
– ASCOT: Lancet 361(9364):1149-58, 5 April 2003
– 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
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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
Selected Major Trials
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The INTERHEART study
– Effect of potentially modifiable risk factors associated
with myocardial infarction in 52 countries: Lancet
364(9437):4999-5014, 4 Sept 2004
– Case Control: 15,152 cases & 14,820 controls in 52
countries on every inhabited continent
– Findings consistent between old/young, male/female,
different countries with different standards of living
– 9 risk factors accounted for >90% (in men) and >94%
(in women) of the population attributable risk (PAR) of
acute MI
Selected Major Trials
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The INTERHEART study:
– The 9 risk factors:
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Smoking (OR 2.87 current vs. never, p<0.0001)
↑ApoB/ApoA1 ratio (OR 3.25 1st vs. 5th quintile, p<0.0001)
History of HTN (OR 1.91, p<0.0001)
DM (OR 2.37, p<0.0001)
Abdominal Obesity (OR 1.12 1st vs. 3nd tertile & OR 1.62 2nd
vs. 3rd tertile, p<0.0001)
psychosocial factors (OR 2.67, p<0.0001)
eating fruits & vegetables daily (OR 0.70, p<0.0001)
≥3 units/week of alcohol (OR 0.91, p=0.03)
moderate/strenuous physical activity (OR 0.86 , p<0.0001)
Treatment
Treatment
Treatment
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In ‘high risk’ patients:
– Start drug treatment immediately, concurrently with
diet and lifestyle modification
– Priority is to get LDL <2.5 and TC/HDL <4
– Given HPS data:
» Treat with Simvastatin 40mg or equivalent statin
» LDL target of 2.5 at most
– If can’t reach LDL <2.5:
» Bile acid sequestrants (cholestyramine, colestipol)
» Cholesterol absorption inhibitors (ezetimibe) better tolerated
» Either can decrease LDL by another 10-20% compared with
statin alone
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:
– 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 (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 / CK:
– Get baseline
– Repeat whenever you test lipids:
» 6 weeks after a dose increase
» Every 6-12 months
– Check more frequently:
» If on maximum doses
» If on combination therapy (especially a statin plus a fibrate)
– Check if symptomatic
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)
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What is his estimated risk of a cardiovascular
event in the next 10 years?
– Assumed to be ≥20%
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How should you manage his lipids?
Case 2 Revisited
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45 F
– ‘Healthy’, BP 125/80
– Non-smoker, 3 units EtOH/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?
– 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)
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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?