Transcript L3_Dyslipidemia2013...

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MANAGEMENT OF
DYSLIPIDEMIAS
Ghada A. Bawazeer. MSc, PharmD. BCPS
Assistant Professor-Clinical Pharmacy Dept.
King Saud University
College of Pharmacy
Sep 2013
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Learning Objectives
1. List the major modifiable and nonmodifiable risk
factors for coronary heart disease (CHD)
2. Determine a patient’s CHD risk and
corresponding treatment goals according to the
most recent clinical practice guidelines.
3. Outline the components of appropriate
therapeutic lifestyle changes.
4. List the amounts of macronutrients
recommended in the therapeutic lifestyle change
(TLC) diet.
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Learning Objectives
5. Compare and contrast the role of the different
antihyperlipidemic agents: mechanism of action,
effects on lipids and lipoproteins, side effect
profile drug interaction concerns, starting and
maintenance doses and relative costs.
6. Appropriately select pharmacologic therapy for
the specific lipid disorders and specific patient
factors.
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Learning Objectives
7.
Describe when combination pharmacotherapy for
hyperlipidemia is most appropriate.
8.
Develop a plan for evaluating therapeutic outcomes
and monitoring drug therapy in the management of
hyperlipidemia and in selected disease comorbidities
9.
List the major clinical trials of antihyperlipidemic
agents for the primary and secondary CV prevention
and describe the outcome for the major end point in
each.
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Required Reading Chapter
• Talbert RL. Chapter 28. Dyslipidemia. In: Talbert RL,
DiPiro JT, Matzke GR, Posey LM, Wells BG, Yee GC, eds.
Pharmacotherapy: A Pathophysiologic Approach. 8th ed.
New York: McGraw-Hill; 2011.
• Guidelines Recommendations from :
• 2012 American Association of Clinical Endocrinologists’ Guidelines
• 2012 Update of the Canadian Cardiovascular Society Guidelines
for the Diagnosis and Treatment of Dyslipidemia for the Prevention
of Cardiovascular Disease in the Adult
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Supporting Clinical Practice Guidelines
European Society of Cardiology Guideline 2011
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Other Clinical Practice Guidelines
• The National Cholesterol Education Program (NCEP)
Adult Treatment Panel III (ATP III) , 2002
 Recommendations for the
management of
hypercholesterolemia in
adults
Expected release date of the ATP IV is
2012, or Later !!!
http://www.nhlbi.nih.gov/guidelines/choles
terol/atp3_rpt.htm
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Introduction
• Cardiovascular diseases are a worldwide burden
• The most common manifestations of CVD
• High blood pressure (65 million)
• Coronary heart disease (CHD) (13 million)
• Stroke (5.4 million)
• Heart failure (4.9 million)
www.who.org
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Introduction
• Cholesterol and triglycerides, the major plasma lipids, are
essential substrates for cell membrane formation and
hormone synthesis, and provide a source of free fatty
acids
• Transported as complexes of lipids and proteins known as
lipoproteins.
• Total cholesterol and LDL-C increase throughout life in
men and women, representing an atherogenic pattern and
increased risk of CV diseases
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LDL-C levels is a major risk for CHD
Circulation 2004, 110:227-239
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Relationship between Total Cholesterol &
CHD risk
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Dyslipidemia
• Disorder of lipoprotein metabolism
• Including lipoprotein overproduction & deficiency
• May manifest as elevation of total cholesterol, elevation in
LDL cholesterol, elevation in triglycerides or low HDL
cholesterol concentration, or some combination of these
abnormalities.
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Etiology of Dyslipidemia
• Primary Causes
• Overproduction and/or impaired removal of
lipoproteins
• Genetic: Six categories based on
phenotype
•Frederickson phenotype
FYI
Genetic Causes of Dyslipidemia
• Type I – Familial Hyperchylomicronemia
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•
•
Fasting triglycerides > 1000 mg/dl
Defect in lipoprotein lipase or apo CII
Not necessarily at increased risk of CAD
• Type II - Familial Hypercholesterolemia (type II)
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•
•
•
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LDL-C > 95th percentile for age and gender
CAD in men by 3rd or 4th decade
Defect in LDL receptor
Autosomal dominant inheritance
Prevalence 1:500
• Familial Defective apo B 100
•
•
Defective apo B alters LDLr handling
Previously undetecable from FH
FYI
Genetic Causes of Dyslipidemia
• Type III – Hyperlipoproteinemia
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•
•
Increased TC, VLDL, decreased HDL; Increased VLDL:TG
Defect in apo E results in increased concentration of remnant particles
Rare
• Type IV – Familial Hypertriglyceridemia
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Increased TC (due to VLDL), TG, decreased LDL, HDL
Results from hepatic overproduction of VLDL
Prevalence 1:100 – 1:50; Association with CAD not as strong as FH
Heterogeneous inheritance
Very sensitive to diet and EtOH
• Type V
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•
Increase in chylomicrons and VLDL
Rare
FYI
Genetic Causes of Dyslipidemia
• Familial Combined Hyperlipidemia
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•
•
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Increased TC, LDL and/or triglycerides; decreased HDL
Most common genetic dyslipidemia: prevalence 1:50
Heterogenous inheritance
Accounts for 10-20% of patients with premature CAD
• Defects in HDL Metabolism
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•
•
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Most often low HDL is secondary to other dyslipidemia
Not all associated with increased CAD risk (e.g. apo AIMilano)
Tangier’s Disease
CETP defects result in increased HDL
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Secondary Causes of Dyslipidemia
Hypercholesterolemia
• Hypothyroidism; Obstructive liver
disease; Nephrotic syndrome; Drugs:
cyclosporine, thiazides, isotretinoin,
protease inhibitors
Hypertriglyceridemia
• Obesity, DM, Pregnancy, CRF, Alcohol,
Stress, Sepsis, Acute hepatitis, SLE,
Drugs: estrogen, β-blockers, steroids,
acid resins, thiazides
Low HDL
• Type-2 DM, Rheumatoid arthritis,
Malnutrition, Obesity, Cigarette
smoking, physical inactivity, some
drugs
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Rational for Treating Dyslipidemia
• Atherosclerosis is the primary etiology of CV diseases
• Results from epidemiological studies, primary and
secondary prevention trials demonestrated:
for every 1% reduction in LDL,
there is a 1% reduction in
CHD event rates
Elevations of HDL of 1% result in
approximately a 2% reduction
in CHD events
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Dyslipidemia & Atherosclerosis
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Dyslipidemia & Atherosclerosis
• Major complications resulting from atherosclerosis
include: myocardial infarction, stroke,
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SCREENING
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Who to screen for Dyslipidemia?
• If absence of CV risk factor:
• Young Adults (Men 20-45 yrs, Women 20-55 yrs)
• Evaluate all adults 20 years of age for dyslipidemia Every 5 years
as part of a global risk assessment
• Middle-Aged Adults (Men 45-65 yrs, Women 55-65 yrs)
• Evaluate every 1-2 years
• In presence of CV risk factors:
• Screen at any age
AACE Lipid and Atherosclerosis Guidelines, Endocr Pract. 2012;18(Suppl 1)
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CV Risk Factors
AACE Lipid and Atherosclerosis Guidelines, Endocr Pract. 2012;18(Suppl 1)
2012 CCS Dyslipidemia Guidelines Update
Anderson TJ, Gregoire J et al., Can J Cardiol 2013 Feb;29(2): 151-167
2016-08-07
Copyright © 2013, Canadian Cardiovascular Society
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What tests to use for screening?
• Fasting Lipid Profile:
• Total cholesterol, LDL-C, triglycerides, and HDL-C
• Fasting for 9-12 hrs
• If non-fasting state Only TC and HDL are usable
• Get a fast lipid panel if TC> 200 or HDL < 40 mg/dL
• If TC or HDL are abnormal obtain another lipid panel
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What tests to use for screening?
• Calculated LDL-C
• Friedewald equation
• Inexpensive method of estimating LDL-C
• Valid if in the fasting state
• Inaccurate if TG > 200 mg/dL, invalid if TG > 400 mg/dL
• Direct measurement recommended in certain cases
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Classification of TC, LDL, and HDL, and
TG in Adults
AACE Lipid and Atherosclerosis Guidelines, Endocr Pract. 2012;18(Suppl 1)
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Unit conversion
• to convert from mmol/L to mg/dL.
• multiply the total cholesterol, LDL cholesterol or HDL cholesterol
values by 39
• to convert from mg/dL to mmol/L
• Divide the total cholesterol, LDL cholesterol or HDL cholesterol
values by 39.
• Triglyceride values:
• multiplied by 89 to convert from mmol/L to mg/dL,
• divided by 89 to convert from mg/dL to mmol/L.
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CV Risk Assessment
• Determine the 10-year risk (high, intermediate, low) of a
coronary event using risk assessment tools.
• Framingham (recommended by NCEP, AACE)
• Modified Framingham RS (recommended by CCS)
• Reynolds Risk Score (recommended by AACE)
• SCORE (Systemic Coronary Risk Estimation). (Recommended
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•
•
•
by ESC)
ASSIGN (CV risk estimation model from the Scottish
Intercollegiate Guidelines Network)
QRISK
PROCAM (Prospective Cardiovascular Munster Study)
WHO (World Health Organization) risk score
2012 CCS Dyslipidemia Guidelines Update
Risk assessment
“We recommend that a cardiovascular risk assessment using the “10 Year
Risk” provided by the Framingham model be completed every 3 to 5 years for
men age 40 to 75, and women age 50 to 75. This should be modified (percent
risk doubled) when family history of premature CVD is positive (i.e. 10 relative
<55 years for men; <65 years for women). A risk assessment may also be
completed whenever a patient’s expected risk status changes. Younger
individuals with >1 risk factor for premature CVD may also benefit from a risk
assessment to motivate them to improve their lifestyle.
(Strong Recommendation, Moderate-quality Evidence)”
Anderson TJ, Gregoire J et al., Can J Cardiol 2013 Feb;29(2): 151-167
2016-08-07
Copyright © 2013, Canadian Cardiovascular Society
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2012 CCS Dyslipidemia Guidelines Update
Anderson TJ, Gregoire J et al., Can J Cardiol 2013 Feb;29(2): 151-167
2016-08-07
Copyright © 2013, Canadian Cardiovascular Society
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CVD − Cardiovascular Risk for Men
POINTS
RISK
POINTS
RISK
POINTS
RISK
-3 or less
<1%
5
3.9 %
13
15.6 %
-2
1.1 %
6
4.7 %
14
18.4 %
-1
1.4 %
7
5.6 %
15
21.6 %
0
1.6 %
8
6.7 %
16
25.3 %
1
1.9 %
9
7.9 %
17
29.4 %
2
2.3 %
10
9.4 %
18+
> 30 %
3
2.8 %
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11.2 %
4
3.3 %
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13.3 %
Multiplied by 2 when family history of premature
CVD is positive
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Risk Levels Stratification by FRS
Risk
Category
Risk Factors/10-Yr risk
High
• clinical evidence of atherosclerosis, previous
MI, or coronary revascularization by PCI or
CABG or cerebrovascular disease (TIA,
stroke), PAD, abdominal aortic aneurysm.
• DM
• CKD
• HTN + 3 risk factors
• FRS >20%
Moderate
• No high risk features
• FRS 10-19%
Low
• No high risk features
• FRS <10
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CKD as CV Risk Factor
• SHARP Study:
• benefit of lipid-lowering therapy with a combination of statin and
ezetemibe in this CKD patients,
• eGFR 45 mL/min/1.73 m or albumin:creatinine ratio
(ACR) of 30 mg/mmol (300 mg/day) is considered high
risk
• an eGFR 60 mL/min/1.73 m and an ACR of 3 mg/mmol
are also at higher risk.
2012 CCS Dyslipidemia Guidelines Update
Limitations of 10 year risk estimates
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•
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•
•
•
Sensitive to the patient’s age
Majority of individuals identified as being at low risk
More accurate among younger individuals
Competing risk increases with age (i.e cancer)
Risk categories (low, inter.,high) chosen arbitrary by consensus
Sub-optimal understanding and use
Despite the limitations assessing total CVD risk improves
management of blood pressure and blood lipids
Anderson TJ, Gregoire J et al., Can J Cardiol 2013 Feb;29(2): 151-167
2016-08-07
Copyright © 2013, Canadian Cardiovascular Society
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Limitations of 10 year risk estimates
Example:
• A 30 years old female, overweight, smoker, SBP
of 160 mmHg, TC 6.2, HDL 1 mmol/L
• Her 10 year risk is 6.5%
• Results: Screened as “low risk”, Potential for false
reassurance
• A 60 years old women will have a 9.4% CV risk
without accounting for any other risk factor
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“Cardiovascular Age”
• A 10-year risk does not fully account for risk in younger
individuals
• In these individuals, the calculation and discussion of a
Cardiovascular Age improve the likelihood that patients will
reach lipid targets and that poorly controlled hypertension will
be treated
• CV Age:
• the age of the vascular system of a patient with different
cardiovascular risk factors
• Calculated using the following scale:
Secondary Testing
•
Secondary Testing for further risk assessment
and guidance for therapy
1. Recommended for patients with “intermediate
risk” (10-19% FRS after adjustment for family
history)
2. Suggested for patients with “low to
intermediate risk” (5-9% FRS after adjustment
for family history)
3. Not recommend for high risk or very low risk
(FRS<5%)
Canadian Journal of Cardiology. 2013; 29: 151-167
2012 CCS Dyslipidemia Guidelines Update
Optional Biomarkers for Further Risk Assessment
Biomarker
Indications for testing
Frequency of testing
Normal Range
Lp(a)
• Further risk assessment
particularly in individuals with a
family history of premature CVD
• Genetically determined risk
factor
• Repeat testing not required
< 30 mg/dl
(< 300 mg/L)
hsCRP
• Men > 50y and women > 60y who
are not candidates for statin Rx
based on conventional risk factors
• q 3 y from age 50 y (M) 60 y (F)
• If > 2.0 mg/L, repeat in 2-4 wk,
use lower value for risk
assessment
< 1.0 lowest risk
> 2.0 increased risk
> 3.0 high risk
A1C
• Further risk assessment in selected
subjects with FPG >5.6 mmol/L
• q1-5y
• more frequently if weight gain
or incr FBG
< 5.5% low risk
5.5-6.0 % mid risk
6.0-6.5 % high risk
> 6.5 % diabetes
Urinary Alb/Cr
• T2DM
• poorly controlled HTN
• Selected patients who are not
candidates for statin Rx based on
conventional risk factors
• q 1 y for patients with T2DM or
poorly controlled HTN
< 3 mg/mmol
Anderson TJ, Gregoire J et al., Can J Cardiol 2013 Feb;29(2): 151-167
2016-08-07
Copyright © 2013, Canadian Cardiovascular Society
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TREATMENT
THRESHOLDS AND
TARGETS
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Goals of Therapy
• Patient oriented outcomes:
• reduce the risk first or recurrent events such
as MI, angina, heart failure, or ischemic
stroke or other forms of peripheral arterial
disease such as carotid stenosis or
abdominal aortic aneurysm.
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Treatment Thresholds and Targets
• LDL-C is the primary goal
If TG is > 500 mg/dL, TG is primary target.
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Treatment Thresholds and Targets
• Non-HDL and plasma apo B as alternate primary targets
• Better reflection of atheroma
• Alternate goal when TG >200 mg/dl (LDL is inaccurate)
• applicable in a nonfasting state
• Non-HDL= TC - HDL
• It estimate the total number of atherogenic particles
in plasma (VLDL + IDL+ LDL)
• Better predictor of CHD risk in groups with elevated
triglycerides >200 mg/dL (e.g. DM, MetS, CKD)
• non-HDL goal is 30 mg/dL higher than
established LDL-C risk levels
Treatment Thresholds and Targets
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Treatment Thresholds and Targets
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Treatment Thresholds and Targets
• AACE Guideline
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Zero
B. One
C. Two
D. Three
A.
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Zero
B. One
C. Two
D. Three
A.
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• What is MM 10-year risk of CHD?
a. <10%
b. Between 10-15%
c. >20%
d. No need to calculate her FRS she is low
risk
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Total= 9+3+2-1=13 points
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• Which of the following is the goal LDL (mg/dL) for M.M.?
a. < 70
b. <100
c. <130
d. < 160
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Management of Dyslipidemia
• Non-pharmacological therapy
• Lifestyle Modification
• Pharmacological Therapy
• Statins
• Fibrates
• Niacin
• Drug that affect cholesterol absorption: Bile acid
sequestrants, Ezetimibe
2012 CCS Dyslipidemia Guidelines Update
Lifestyle Modification
• Health behaviour interventions are the
cornerstone of cardiovascular disease
management and prevention
• Diet
• Exercise
• Alcohol intake
• Cigarette smoking
• Stress and mental health issues
Anderson TJ, Gregoire J et al., Can J Cardiol 2013 Feb;29(2): 151-167
2016-08-07
Copyright © 2013, Canadian Cardiovascular Society
55
2012 CCS Dyslipidemia Guidelines Update
Table 7. Expected Benefit of Health Behaviour Changes
Intervention (minimal dose for effect)
Dietary cholesterol intake98
< 300 mg/day (NCEP step I diet)
< 200 mg/day (NCEP step II diet)
Expected Outcome
↓ LDL-C
10-12%
12-16%
Saturated fats < 7% of daily caloric intake107
↓ LDL-C 5-10%; ↓ CVD mortality 14%
Phytosterols 1-2 g/day100
↓ LDL-C 5-8%
Soy proteins with isoflavones 25g/day101
↓ LDL-C 3-5%
Viscous fibre 10 g/day102
↓ LDL-C 3-5%
Nuts 30-67 g/day103
↓ LDL-C 5-7%, ↓ TG 5-10%
Portfolio type diet104
↓ LDL-C 8-14%
Mediterranean type diet105
↓ LDL-C 5-10%; ↓ CVD mortality
DASH (Dietary Approaches to Stop
Hypertension) diet106
↓ CVD mortality in those with hypertension
Anderson TJ, Gregoire J et al., Can J Cardiol 2013 Feb;29(2): 151-167
2016-08-07
Copyright © 2013, Canadian Cardiovascular Society
56
2012 CCS Dyslipidemia Guidelines Update
Table 7. Expected Benefit of Health Behaviour Changes
Intervention (minimal dose effect)
Expected Outcome
Moderated Alcohol intake 1-2 drinks/day
↑ HDL 5-10%, ↓ CVD events
Weight loss and reduction of abdominal obesity42
5-10% of body weight loss
↓ LDL-C, ↑ HDL, ↓ TG,
↓cardiometabolic risk
Omega -3 - 2-4 g of eicosapentaenoic acid (EPA) plus
docosahexaenoic acid (DHA)/day
with ↑ TG
↓ TG 25-30% in pts.
Exercise109,110
30-60 min/day moderate to vigorous intensity
↑ HDL 5-10%, ↓ CVD events
Smoking cessation
↑ HDL, ↓ CVD events
Anderson TJ, Gregoire J et al., Can J Cardiol 2013 Feb;29(2): 151-167
2016-08-07
Copyright © 2013, Canadian Cardiovascular Society
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Therapeutic lifestyle changes (TLC)
• Cornerstone treatment, recommended to ALL patients
• TLC Diet:
• reduced intakes of saturated fats and cholesterol
• dietary options to reduce LDL such as plant stanols
and sterols and increased soluble fiber intake
• Mediterranean diet associated with >70% in CV
endpoints compared to Western diet
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TLC: Diet
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“What fits your busy schedule better,
exercising one hour a day or being dead 24
hours a day?”
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Therapeutic lifestyle changes (TLC)
• If adhered to optimally TLC diet may result in 20-
30% reduction in LDL
• Allow 3 months therapy of TLC before advancing
to drug therapy unless patient is in the high risk
category
• Help patient overcome barriers related to TLC
implementation:
• Involve all family members
• Provide resources for the patient and his/her
family
• Reliable resources: e.g. AHA, NHLBI
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TLC Diet Resources
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Therapeutic lifestyle changes (TLC)
• Increased physical activity and
• accumulate at least 150 min. of moderate-to-vigorousintensity aerobic physical activity per week, in bouts of
10 min or more to reduce cardiovascular disease risk
• weight reduction
• Target: Normal weight: BMI 18.5 – 24.9
• Reasonable loss 10% within 6 months
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Therapeutic lifestyle changes (TLC)
• Smoking Cessation
• Can significantly increases HDL-C, with improvement
observed in as few as 30 days
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 Abundance of evidence that showed



Sudden CHD deaths and non-fatal MI
Revascularization procedures
Strokes
↓ 25% to 40%
↓ 25% to 50%
↓ 15% to 32%
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Effects of Drug Therapy on Lipids and
Lipoproteins
• Lipid lowering agents
• Decrease synthesis of VLDL and LDL
• Niacin, fibrate, statins
• Enhance VLDL clearance
• Fibrates
• Enhance LDL catabolism
• Statins, BAS
• Decrease cholesterol absorption
• ezetimibe
• Elevate HDL
• Fibrate, niacin
• Or some combination of the above
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Effects of Drug Therapy on Lipids and
Lipoproteins
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Lipoprotein Phenotype and Recommended Drug
Treatment
Chylomicrons
Restriction of dietary fat
LDL
LDL + VLDL
IDL (LDL1)
VLDL
VLDL+ Chylomicrons
+ Restriction of dietary fat
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HMG-CoA Reductase Inhibitors- Statins
• Efficacy
• Drugs of choice for high LDL-C and/or CHD or CHD risk
• Reduce LDL-C 24%–60%.
• When selecting a statin, consider the percentage of LDL
reduction needed.
• (current LDL-C−goal LDL-C)/currentLDL-C×100
• Select an initial dose to achieve an LDL-C
reduction of 30%–40% if possible.
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HMG-CoA Reductase Inhibitors- Statins
• "pleiotropic" effects of statins
• improvement in outcome as early as six months
• Plaque stabilization
• Reduced inflammation
• Reversal of endothelial dysfunction
• Decreased thrombogenicity
• Reduction in ventricular arrhythmias
• Evidence of such effects is not conclusive
Pedersen TR. Am J Cardio drugs; 10:10-17 (2010)
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HMG-CoA Reductase Inhibitors- Statins
• 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor
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HMG-CoA Reductase Inhibitors- Statins
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Ther Adv Cardiovasc Dis. 2008;2(3):157-166
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Statins
most
potent
• cerivastatin :
• withdrawn in 2001 because of serious rhabdomyolysis
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Statins
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Pravastatin 20 mg orally daily with an LDL-C goal of
less than 130 mg/dL.
B. Lovastatin 20 mg orally daily with an LDL-C goal of less
than 160 mg/dL.
C. Atorvastatin 20 mg/day with an LDL-C goal of less than
130 mg/dL.
D. Simvastatin 20 mg/day with an LDL-C goal of less than
160 mg/dL.
A.
77
Statins
• Used as monotherapy
• Or in combination:
• In high risk subjects or patients with very high
LDL-C levels need additional treatment.
• Patients who are statin intolerant or are not able
to tolerate higher statin doses.
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Combination Therapy
• Statin + bile sequestrants
• Achieves more reduction in LDL (10-20%)
• statin + ezetimibe
• Further reduction in LDL by 12% to 20%
• No mortality benefit
• SEAS Study: compared simvastatinezetimibe therapy to placebo in 1873
patients with mild-to-moderate
asymptomatic AS.
• Statin + fibrate
• Caution: increased risk of myopthy
N Engl J Med. 2008; 359: 1343–1356
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How much Statins to give?
• Start therapy with a statin dose that will achieve at
least a 30% to 40% reduction in LDL-C levels.
• If LDL is highly elevated aim for a dose that will give
at least 50% reduction
• Each doubling of dose further reduce LDL by 6-7%
(rule of 6)
• If further lowering is required adding another agent with different MOA is an
alternative.
• Rosuvastatin requires dosage adjustment in
severe renal impairment & hepatic disease
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Contraindications of Statins
• Absolute: Severe liver disease
• (AST/ALT more than 3 × ULN
• Relative: Use with certain medications
(strong cytochrome P450 [CYP] 3A4
inhibitors)
• Pregnancy category X
81
Statins Adverse effects
• Well tolerated
• Mild symptoms:
• headache, GI symptoms (dyspepsia, flatus,
constipation, abdominal pain)
• Lens opacity: Lovastatin
• In the studied age group this is common irrespective of drug
therapy. No statistical association exist.
• elevated serum transaminases: ALT, AST
• Muscle toxicity: myalgia, myopathy, rhabdomyolysis
• Lova- and rosuva: increase bleeding time (PT)
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Statins Adverse effects
• Risk of new diabetes
• Small risk of inducing diabetes (9%)
Lancet 2010;375:735–742.
• Risk of cancer
• highly significant inverse relationship between achieved LDL-C
levels and rates of newly diagnosed cancer.
• Memory Loss and Confusion
• Not serious and the patients’ symptoms were reversed by stopping
the statin.
83
Statins Adverse effects
 Elevated hepatic transaminases (ALT)
generally occur in 1%–1.5%
› clinically important elevation if ALT >3 times upper
limit of normal
› Higher intensity doses associated with increased risk
 Management:
 Reversal of transaminase elevation with dose
discontinuation.
 Re-challenge is possible with the same agent
or another statin
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Statins Adverse effects
 Myalgia:
› Muscle symptoms with normal CPK serum
 Myositis (mayopathy): occur in 0.1-1%
 Myalgia with increase in CPK > 10 times the upper limit of normal
 Rhabdomyolysis: rare SE
› CPK > 10,000-100,000 units/L
› CPK rises within 12 hours of onset of muscle injury, peaks in 1-3
days, declines 3-5 days after injury
› May case renal faliure or death
 rosuvastatin may be associated with higher risk than other statins
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Statins Adverse effects
• Factors increasing the risk of muscle toxicity:
• Patient factors
• age, gender, Renal or hepatic impairment, hypothyroidism, polypharmacy
• Statin factors:
• Dose, lipophyilicity, bioavailability,
• potential for drug-drug interaction (CYP 3A4)
• Antibiotics: erythromycin, clarithromycin
• Azole antifungals (itraconazole, ketoconazole, and miconazole)
• CCB (diltiazem and verapamil)
• Protease inhibitor
• Cyclosporine
• Grapefruit juice
• Concomitant use with gemfibrozile
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FDA Limit use of 80 mg Simvastatin
this dose should only
be used by patients who
have been taking it for
12 months or longer
without ill effect
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Statins Adverse effects
• Management of muscle complaints:
• Use clinical judgment
• Careful history to rule out other causes (i.e.,
trauma, hypothyroidism,high impact sport
physical activity).
• Test for CPK
• If high, stop the statin until CPK returns to
normal
• Advice drinking large quantities of fluids to
facilitate renal excretion of myoglobin.
• May restart statin using different agent with
careful monitoring
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Statins Adverse effects
• Manage drug interaction:
• Use different drug if possible
• Hold statins for the duration of treatment
• Use lowest effective dose
• Monitor therapy
• in patients on cyclosporine, gemfibrozil
• Use Pravastatin
• If fibrate-statin combination is required
• Use Fenofibrate
89
Statins Adverse effects
• CYP3A4 substrates: Simvastatin, lovastatin, atorvastatin
• Avoid, if possible, with strong CYP3A4 inhibitors
• (e.g., itraconazole, ketoconazole, erythromycin, clarithromycin, HIV
protease inhibitors, nefazodone, cyclosporine, telithromycin,
danazol, amiodarone, verapamil).
• Preferable to use pravastatin, rosuvastatin
• Maximal dose of simvastatin is 10 mg/day when
combined with verapamil or diltiazem.
• Maximal dose of simvastatin is 20 mg/day when
combined with amiodarone, amlodipine, or ranolazine.
90
Statins Adverse effects
• Alternate dose regimen had been
suggested to improve tolerability.
• CV benefit is not studied with such doses
Endocrinol Metab Clin North Am 2009;38:121-36
91
Non-Statin Lipid Lowering Agents in
HPERCHOLETEREMIA
92
Bile Acid Resins (BAR)
• Colestipol, cholestyramine,
colesevelam
Bile Acid Resins (BAR)
• Bind intestinal bile acid >> reduce
colesterol >> up-regulation of LDL-C
receptors
• Normally 2nd-line agents when statins not
sufficient or not tolerated
• May aggravate hypertriglyceridemia
• caution if TG > 200 mg/dL
• contraindicated if TG > 400 mg/dL
93
Bile Acid Resins (BAR)
• Low doses well-tolerated
• With proper counseling & dose titration; many
patients tolerate higher doses
• Tablet formulation may increase palatability;
however, tablets are large
• Mix powder with liquids or food such as orange
juice, oatmeal, applesauce
• Colestipol: odorless, tasteless
• Colesevelam (0.625gm): 6 tablets as once or twice
• Better tolerability than older resin
94
Bile Acid Resins (BAR)
• Adverse effects:
• The higher the dose the higher rate of SE >> better
used in combination
• GI distress (e.g. bloating, flatulence), constipation
• Management: titrate slowly, increase fluid intake,
increase dietary bulk, add stool softeners
• hypernatremia, hyperchloremia
• impair fat soluble vitamin absorption
• A, D, E, K
• Elevate TG
• Colesevelam has a better SE profile
95
96
Bile Acid Resins (BAR)
• Reduce bioavailability of acidic drugs:
• Coumarin anticoagulants,
• Nicotinic acid,
• Thyroxine
• Acetaminophen
• Hydrocortisone
Alternate time
administration:
Allow 6 hours
between the BAR
and other drugs
• Hydrochlorothiazide
• loperamide
• Iron
Colesevelam
binds less to
acidic anions
cholesterol Absorption Inhibitor
• Ezetimibe
• Inhibits cholesterol absorption across the gut by
50-70%
• Used as second-line therapy in association with
statins.
• Available as 10 mg tablet
• Dosed once daily without regard to meals
• ~18-22% LDL reduction
• Effect of ezetimibe on CV morbidity & mortality
is unknown
• SE: diarrhea, arthralgias, cough, fatigue
97
98
Nicotinic Acid Derivatives
• Place of therapy:
• used to treat hypercholesteremia in
combination (with BAR) or as monotherapy
• first-line agent or an alternative for the
treatment of hypertriglyceridemia and diabetic
dyslipidemia
• Second line therapy in heperlipidemia
• Evidence showed it can reduce CHD events.
• The only drug that lowers Lp(a)
99
Nicotinic Acid Derivatives
• Niacin
• Raise HDL-C in a dose-dependent manner by 25%
• Reduce both LDL-C by 15–18% and TG by 20–40% at the 2 g/day
dose.
• Lower Lp(a) levels by up to 30% at this dose.
100
Nicotinic Acid Derivatives
101
Niacin
Nicotinic Acid Derivatives
• OTC & Rx
• IR, SR, & ER formulations
• IR: Low cost, frequent dosing, SE
• SR: available as OTC (sold as food supplements) to
treat niacin deficiency, high risk of liver toxicity.
AVOID
• ER (Niaspan®): better SE profile than crystalline
niacin
• Different formulations >> different metabolism >> SE
profile is variable
• Don’t confuse nicotinamide with nicotinic acid
102
103
Nicotinic Acid Derivatives

Cutaneous flushing, itching
 Prostaglandn mediated >> vasodilation
› Management
› Take with meals, avoid giving with hot drinks
› slowly titrating the dose upward
› Don’t skip doses (flushing related to plasma peaks)
› aspirin 325 mg given shortly before niacin ingestion.
› Use ER Niacin once daily at bed time
› Laropiprant is
 a selective antagonist of the prostaglandin D2 receptor
subtype 1 (DP1),
 Decrease flushing with ER niacin by 50%
104
Nicotinic Acid Derivatives
• Laboratory abnormalities: elevated LFT, uric acid
and glucose.
• May exacerbate gout & DM
• monitor closely
• Use slow dose titration
• activation of peptic ulcer
• Dry eyes
• Hepatitis: common with SR niacin
105
Nicotinic Acid Derivatives
• Hepatotoxicity:
• Defined as an increase in LFT > 3x upper
normal range
• Reversible upon discontinuation
• High incidence with SR niacin
• Fatigue, anorexia, malaise, nausea
• Niaspan:
• Incidence ,1% when use doses exceeding 2
gm/d
106
Nicotinic Acid Derivatives
• Acanthosis nigricans
of the skin in skinfold areas and an
• Associated with high doses
• Ext Marker of insulin resistance
• Darkening
107
Nicotinic Acid Derivatives
• Contraindications:
• active liver disease, severe gout
• Combination with statin or gemfibrozil therapy
increases myopathy risk
Fibric Acids
• Gemfibrozil, fenofibrate, clofibrate
• Drugs of choice in hypertriglyceridemia
• Used in Mixed dylipidemia
• TC remains fairly unchanged
• May increase HDL > 10 to 15%
• May cause 20 to 25% LDL reduction in patients
with heterozygous familial hypercholesterolemia
• Efficacy depends on lipoprotein type, baseline TG
108
Fibric Acids
• MOA: activate peroxisome proliferator-
activated receptors alpha (PPARα):
• Increase LDL receptor synthesis >>>
VLDL, TG
• Increases fatty acid oxidation >>>
VLDL, TG
• Increase synthesis of apolipoprotein
A-1 >> HDL
109
110
Fibric Acids
• Gemfibrozil dosed BID 30 min before meals
• Fenofibrate can be taken without regards to
food
• Contraindicated in renal failure
• Combination therapy with niacin or statins
increases risk of muscle toxicity
• Gemfibrozil > fenofibrate
• Fenofibrate preferred for combination with
statin
• Why?
Fibric Acids
• Adverse effects:
• GI complaints, rash, myalgia, headache, fatigue
• transient increase in transaminase & alkaline phosphatase
• Avoid in active liver disease
• Enhance formation of gallstones
• enhanced hypoglycemic effects in patients on
sulfonylureas
• may potentiate effects of oral anticoagulants
• monitor PT/INR closely in patients on anticoagulants
• Phototoxicity (fenofibrate)
111
Omega 3 Fatty Acids (Fish Oil)
 Diets rich in omega 3 fatty acids from oily fish
decrease TC, TG, LDL, increase HDL &
decrease CV events
 Rx fish oil: Lovaza®
› lowers TG 14 to 30%
› raises HDL ~10%
 FDA approved as dietary adjunct for very high
TG levels (> 500 mg/dL)
 Thrombocytopenia, bleeding disorders: potential
complication of high doses
112
Omega 3 Fatty Acids
• < 3 g/day generally recognized as safe
• Until further research is done on nutraceuticals it is
recommended that patients get dietary EPA & DHA
• 2 to 4 g of EPA & DHA may be used for very high TG
• Adverse effects:
• GI disturbance
• fishy aftertaste
• increased bleeding risk
• worsening glycemic control
• increased LDL
• abnormal LFTs
113
CETP Inhibitors
 CETP (cholesterol ester transfer protein)




inhibition leads to elevation in HDL levels
The CETP inhibitor torcetrapib substantially
increased HDL & decreased LDL
Torcetrapib resulted in increased BP & CHD
events
Unknown whether lack of efficacy due to
mechanism of action or chemical specific events
Other means of raising HDL are being
researched & tested
114
115
Combination Therapy
• Start with monotherapy
• If LDL is still elevated, options:
• Increase statin dose
• Add another lipid lowering agent
• Statin+ezitimib
• Statin+fibrate
• Statin+niacin
116
MANAGEMENT OF
HYPERTRIGLYCERIDEMIA
Hypertriglyceridemia
• If TG is very high (> 500 mg/dL)
• Increased risk of pancreatitis
• TG > 500 mg/dL: genetic form of
hypertriglyceridemia often coexists with
other causes (e.g. DM)
• Non-HDL secondary outcome
117
Hypertriglyceridemia
 Management
• dietary fat restriction (10% to 20% of calories)
• weight loss
• alcohol restriction
• Smoking cessation
• treat coexisting disorders
118
119
Hypertriglyceridemia
 Medications for TG > 500 mg/dL
› niacin
› fibrate: preferred in diabetics
› higher-potency statins: atorvastatin,
rosuvastatin, simvastatin
› fenofibrate may be preferred in combination
with statins
› Fish oil
 Successful treatment: TG < 500 mg/dL
120
MANAGEMENT OF LOW
HDL-C
Low HDL-C
 Low HDL: strong independent CHD risk
predictor
 ATP III: low HDL-C < 40 mg/dL
 No specific goal for HDL-C raising
 Causes of low HDL
› insulin resistance
› physical inactivity
› type 2 diabetes mellitus
› cigarette smoking
› very high carbohydrate intake
› certain drugs
121
Low HDL-C
• Low HDL is a strong independent risk factor
• LDL remains ATP III 1˚ target
• ATP III recommendations:
• TLC: weight reduction, increased physical activity,
smoking cessation
• drug therapy
• fibric acid derivatives
• niacin
• potential for greatest HDL increase
• effect more pronounced with regular or IR forms than SR
122
123
DIABETIC
DYSLIPIDEMIA
Diabetic Dyslipidemia
• Characterized by
• Elevated TG, low HDL, & minimally elevated LDL (mixed
dyslipidemia)
• DM ATP III CHD risk equivalent
• 1˚target for therapy: LDL-C
• Goal of treatment:
• LDL-C < 100 mg/dL (unless patient had an overt CHD, goal <70)
• If LDL > 100 mg/dL: TLC + drug therapy
Diabetes Care 2010124
125
Diabetic Dyslipidemia
• Statins often considered initial drugs of
choice
• Meta-analysis:
• Statin therapy reduces the 5 year incidence
of major CVD events by 20% per mmol/L
reduction in LDL-C regardless of initial LDLC or other baseline characteristics
Lancet 2010;376:1670–1681
126
Diabetic Dyslipidemia
• ACCORD study
• The action to Control Cardiovascular Risk in Diabetes
• Combination of statin+fenofibrate didn’t reduce rate of fatal
and non-fatal CHD, non fatal stroke compared to statin alone
(simvastatin)
• BAR
• Avoid in diabetes: worsen constipation, may inc TG (which already
increased in this population)
• ADMIT and ADVENT trial
• IR niacin and ER are very effective in raising HDL,
lowering TG and LDL
127
METABOLIC
SYNDROME
128
Metabolic Syndrome
• People with MetS have a 2-fold increase in CV
outcomes and 1.5-fold increase in all-cause
mortality
• Treatment
• TLC in all people with MetS
• Drug therapy
• Statin is the drug of choice
• Target: LDL-C <100 mg/dL
• Statin combination with ezetimibe
• Niacin
• fibrate
129
Metabolic Syndrome
Parameters
NCEP ATP3 2005
Required Number of abnormalities is > 3 of:
Glucose
HDL
TG
Obesity
HTN
FBG >100 mg/dL or drug treatment for
elevated blood glucose
<40 mg/dL(men); < 50 mg/dL (women) or drug
treatment for low HDL-C
>150 mg/dL or drug treatment for elevated
triglycerides
Waist >102 cm (men) or > 88 cm (women)
>130/85 mmHg or drug treatment for
hypertension
130
SPECIAL
CONSIDERATIONS
Elderly
• Older patients potentially benefit to a greater
extent from cholesterol lowering than younger
populations.
• Evidence for treatment above the age of 80–85
years is limited. Use clinical judgment
131
132
Elderly
• Heart Protection Study (HPS)
• Included more elderly subjects (>70y.o) than any
other trial
• Simvastatin 40 mg
• Elderly subjects have the same CHD event rate
reduction as younger patients
• More susceptible to adverse effects of lipid-lowering
drug therapy
• Start with lower doses, titrate slowly to minimize
adverse effects
Women
• Cholesterol: important CHD determinant
• relationship not as strong as for women as men
• HDL may be more important predictor of disease in women
• No apparent difference between men & women in LDL/HDL
genetic regulation
• Obesity is an important determinant of CHD in women
• Combined estrogen plus progestin hormone therapy should not
be used to prevent CVD in postmenopausal women
133
Women
 TC & TG levels increase throughout pregnancy
› average cholesterol increase: 30 to 40 mg/dL around
weeks 36 to 39
› TGs may increase as much as 150 mg/dL
 Drug therapy typically not initiated nor




continued during pregnancy
TLC is the mainstay
BARs & absorption inhibitors may be
considered for use in high risk patients
Statins: category X
ezetimibe: category C
134
Children
• Drug therapy not recommended for age < 8 yrs
• Different guidelines gave different goals
• Bile acid sequestrants 1st-line in the past
• GI adverse effects limit use
• New evidence shows statins are safe & effective
in children
• greater lipid lowering than BAR
• severe forms may require more aggressive treatment
• e.g., familial hypercholesterolemia
135
136
Renal insufficiency
• RI without proteinuria >>> inc TG, LDL and
dec HDL
• Dialysis doesn't correct lipid abnormalities
but renal transplantation may
• transplantation-related medications (steroids,
cyclosporine)
• may aggravate lipid abnormalities
• Increase incidence of SE: muscle toxicity
137
Renal insufficiency
• Pravastatin and fluvastatin safer in this
group
• Lovastatin may accumulate
• simvastatin, lovastatin, atorvastatin, and
fibric acid derivatives may increase the risk
of severe myopathy
138
Transplantation patients
• Lipid abnormalities are common
• Immunosuppressive drug regimens also have
important adverse effects on lipid metabolism
• Glucocorticoids
• Cyclosporine
• Management:
• TLC
• Statins are first line agents
• Initiation should be at low doses with careful uptitration
139
Transplantation patients
• Manage potential drug interaction
• Statins + Cyclosporine >> increased risk of myopathy
• Fluvastatin, pravastatin, pitavastatin, and rosuvastatin have less
potential for this interaction
• Patient unable to take statin
• Ezetimibe
• nicotinic acid
• Fibrate: caution because of risk of myopathy
• Cholestyramine: ineffective, avoid because of drug interaction
140
HIV patients
• HIV patients have low TC and LDL-C as well as low HDL-
C and increased TG.
• Highly active antiretroviral treatment (HAART) causes an
increase of LDL-C and TG >> doubling their CAD risk
• HAART also increases blood pressure and insulin
resistance >>> increased CAD risk.
• Management:
• Dietary changes and regular physical activity
• May switch to another HAART regimen
• Statin can be used (tx of choice)
• Avoid simvastatin
• fibrates
141
HIV patients
• may be prescribed when HTG is predominant.
• European AIDS Clinical Society:
• Simvastatin is contraindicated in patients receiving ritonavirboosted protease inhibitor based antiretroviral treatment
• Combination of rosuvastatin with lopinavir/ritonavir should also be
used with caution.
• patients who cannot tolerate statin treatment, ezetimibe
could be an option.
• bile acid sequestrants is not recommended
• may increase TG and their effects on the absorption of antiretroviral
drugs have not been studied.
142
Hypertension
• Hypertensive patients have a great prevalence of high
cholesterol levels
• In patients with HTN and hyperLipidemia
• Avoid using drugs that
elevate cholesterol (diuretics
and BB)
• Careful when using bile acid sequestrants>>
drug interaction
• Niacin may magnify the hypotensive effects of
vasodilators
143
Role of pharmacist
• Lipid Specialty clinics
• Expensive but cost effective because more
patients achieve their targeted goals
• Project ImPACT
• Improved patient adherence and 2/3 of patient
achieved their goals
144
MONITORING OF LIPIDS AND
ENZYMES IN PATIENTS ON
LIPID-LOWERING DRUG
THERAPY
145
European Heart Journal (2011) 32, 1769–1818
146
European Heart Journal (2011) 32, 1769–1818
147
European Heart Journal (2011) 32, 1769–1818
148
European Heart Journal (2011) 32, 1769–1818