Dyslipidemia: Managing a Key

Cardiovascular Risk Factor

AIMGP Clinic Seminar
Updated by R. Cavalcanti
Sep 2007
Outline
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
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
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
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?
How should you manage his lipids?
Case 2
45 F
Healthy, BP 125/80
Non-smoker, EtOH: 3 standard drinks/week
No cardiovascular symptoms
Lipids measured at annual visit:
TC 6.5, LDL 4.1, HDL 1.4, TG normal (TC/HDL 4.6)
What is her estimated risk of a cardiovascular
event in the next 10 years?
How should you manage her lipids?
Case 3
55 F
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)
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
Aging Population
>20% Canadians will be >65 years old by 2011
1,900,000 Canadians >80 years old by 2026
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)
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 cardio-
vascular risk
Global CV risk should be used to assess
treatment goals and modalities
Cardiac endpoints:
non-fatal MI
death due to CAD
Global Risk Assessment
Risk assessment model adapted from the
Framingham Heart Study
This model only applies in:
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:
DM
History of CAD
Ischemic stroke
Peripheral arterial disease
CRF ( < 60 ml/min of GFR)
Global Risk Assessment
What are the risk factors in Framingham
risk calculator?

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)
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
Eruptive xanthomata on
the forearm of a patient
with severe TGs
Xanthelasmas
and tendon
xanthomata in
patients with
severe LDL
(the patient at
the bottom has
heterozygous
familial
hyperchol-
esterolemia)
Diagnosis of Asymptomatic
Atherosclerosis
To aid in risk stratification
Recommended:
Physical examination
Ankle-Brachial Index
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
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

Factors Influencing Risk
Assessment
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)
Presence of Abdominal Obesity: Risk
with waist circumference as a useful estimate
Factors Influencing Risk
Assessment
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
Lipoprotein(a) (lp(a))
Appears to be an independent risk factor for
premature atherosclerosis and CAD
Factors Influencing Risk
Assessment
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
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 10-
year risk of 11-19% (moderate risk)
More aggressive Rx?
Factors Influencing Risk
Assessment
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
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:
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
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
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
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
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
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 1
st
vs. 3
nd
tertile
OR 1.62 2
nd
vs. 3
rd
tertile
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
In low or moderate risk patients
Start with lifestyle, progress to Rx based on targets
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 cant 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
In high risk patients mounting evidence
supports lower LDL-C targets

Latest CCS guidelines (CJC 2006):
High risk patients: LDL-C < 2.0; TC:HDL <4.0
Revision NCEP (Circulation 2004):
Suggested targets for high risk patients
LDL-C <1.8
Treatment
If TC/HDL ratio is still high:
Lifestyle modification
Increasing Statin Dose (with LDL at target)
Combination Drug Therapy
Treatment
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
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
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
(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
If TGs:
Ideal target <1.7
1
st
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:
Fibrate
Niacin
Salmon oil
Follow-Up
Which blood work should be ordered
in follow-up? How frequently?
Follow-Up
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
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)
CK (< 0.5% incidence):
Get baseline
Check only if symptomatic with myalgias (ATP III
guideline)
Case 1 Revisited
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)
What is her estimated risk of a cardiovascular
event in the next 10 years?
Calculated to be 1%
How should you manage her lipids?
Case 3 Revisited
55 F
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%
How should you manage her lipids?