AITC 1008 Dyslipidemia

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Copyright Annals of Internal Medicine, 2010

Ann Int Med. 153 (3): ITC2-1.
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in the clinic
Dyslipidemia

What preventive lifestyle measures
should clinicians recommend to reduce
risk for dyslipidemia?
Healthy diet
Regular exercise
Tobacco avoidance
Improved lipid profiles
Reduced CAD risk for all
Unlikely to achieve marked change Many require drugs

What preventive lifestyle measures
should clinicians recommend to reduce
risk for dyslipidemia?
Greatest risk reduction if: CAD equivalents:
Diabetes
CAD
Aortic aneurysm
CAD equivalents Periph vasc disease
Carotid disease w/sxs
Framingham risk > 20%

Who should be screened for dyslipidemia?
No direct evidence:
Screening & treatment reduced CVD or stroke
Indirect evidence to screen:
Men > 35 years
Women > 45 years

USPSTF: NCEP- ATP III:
Men > 20 years & women > 35 if: All adults > 20 years
Risks for CAD Promote healthy behavior
FH premature CAD, or lipid d/o Public awareness
PE suggests hyperlipidemia Identify those at risk
Benefit unclear

Children/Adolescents
American Association of Pediatrics:
> 2 years: Screen if FH or other CVD risks

Untreated hyperlipidemia increases adult risk
Lifestyle counseling if:
CVD risk factor
High LDL cholesterol
Overweight/obese with low HDL or high triglycerides
Consider meds if high LDL after counseling

Adults > 65 years
Moderate evidence for screening
Higher baseline risk of CHD
Total cholesterol predicts CHD
As in younger pts, screen all with CHD, or CAD risk equivalents
CAD Equivalents:
Diabetes
Aortic aneurysm
Periph vasc disease
Carotid disease w/sxs
Framingham risk > 20%

How and how often should clinicians
screen for dyslipidemia?
AHA & NCEP: Fasting lipid profile
Every 5 years for adults >20 years
Initial to include triglycerides & indirect LDL calculation
USPSTF: Fasting or nonfasting profile
Men >35 years, women >45 years with CHD risk
Total cholesterol and HDL only
LDL and triglycerides only to guide Rx

How and how often should clinicians
screen for dyslipidemia?
LDL is primary treatment target
Triglycerides are secondary target
LDL = Total cholesterol Triglycerides - HDL

5
Best after > 8 hours fasting
Measure LDL directly if TG > 4.52 mmol/L (400 mg/dL)

Screening

How should clinicians interpret lipid
screening results in relation to overall
cardiovascular risk?
Use equations to estimate CV risk
More accurate than lipid levels alone or counting risk factors
NHLBI (Framingham risk equation)

http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof
10-yr risk of CV event:

Low <10%
Moderate 10%20%
High >20%

What tests should clinicians obtain before
starting therapy for dyslipidemia?
Prospective studies:
Elevated LDL w/>2 CAD risk factors
10-yr risk >20% for MI or CAD death

Rx to reduce LDL decreases risk for CHD death
Focus on identifying & treating elevated LDL cholesterol levels
Identify causes of elevated LDL
Set targets of diet & drug therapy

How should clinicians measure and
interpret triglyceride levels?
Elevated TGs:
Increased CAD risk: Women > Men
Normal: <1.70 mmol/L (<150 mg/dL);

Borderline: 1.702.25 mmol/L (150199 mg/dL)
High: 2.265.64 mmol/L (200499 mg/dL)
Very high: >5.65 mmol/L (>500 mg/dL)
ATP III: TGs secondary Rx goal
Borderline familial abnormalities
High ? Other issues (DM, EtOH, renal failure, nephrosis)
Very high pancreatitis risk; warrants Rx

interpret HDL levels?
HDL: inverse association with coronary events
2% decrease coronary events/1% increase in HDL
HDL >1.6 mmol/L (>60 mg/dL) decreased risk
HDL <1.0 mmol/L (<40 mg/dL) increased risk

interpret HDL levels?
HDL <1.0 mmol/L (<40 mg/dL) ? Acquired:
Tobacco
Obesity
Inactivity
Hypertriglyceridemia
Type 2 diabetes mellitus
Carbohydrates
Genetic mutations
-blockers, androgenic steroids

What should clinicians look for in the
history and physical examination of a
patient with dyslipidemia?
Coronary risks Drugs & Dyslipidemia
Corticosteroids
Secondary causes: drugs
Androgenic steroids
BP Progestogens
Thiazides
BMI -blockers
Retinoic acid derivatives
Peripheral, carotid pulses/bruits Oral estrogens
Secondary causes: liver, thyroid

What are the causes of secondary
dyslipidemia, and how should clinicians
diagnose them?
Drugs & Dyslipidemia
Hypothyroidism Corticosteroids
Obstructive liver disease Androgenic steroids
Progestogens
Nephrotic syndrome
Thiazides
Renal failure -blockers
Uncontrolled diabetes Retinoic acid derivatives
Tobacco or alcohol use Oral estrogens
Medications consider stopping
Address secondary causes before drug therapy
Dyslipidemia may resolve
Rx may be ineffective

When should clinicians consider specialized
lipid tests or referral to a specialist?
Suspicion of familial hypercholesterolemia
Apolipoprotein measurements (e.g., apo A and B)
More accurate than lipids when values very high
May suggest cause
Guide choice of therapy
Assess risk of atherothrombosis
Strongly consider screening first-degree relatives

Diagnosis

What should clinicians advise patients
about lifestyle changes?
Normal-weight pts w/dyslipidemia (BMI 18.5-24.9 kg/m2):
Focus on healthy eating

Regular exercise
Overweight and obese pts (BMI 25 kg/m2):
Reduce caloric intake from fats, simple carbohydrates
30 mins physical activity most days
Diet (rich fruits, veg, nuts, whole grains,
monounsaturated oils; low red meat, animal
Adopt lifestyle
fat) Reduces LDL 515% (ATP III TLC diet)
changes
Aerobic exercise: Running, walking, cycling, regardless
swimming enhance weight reduction drug Tx
Facilitates achieving optimum lipid levels
Set goals, select strategies, risk factor ctrl
Schedule periodic weight checks, counseling
When should drug therapy be recommended?
Implementation of Interventions Based on NCEP-ATP III Goals
Patients 1 cardiac risk factor

LDL-C 4.14 mmol/L (160 mg/dL lifestyle changes
LDL-C 4.9 mmol/L (190 mg/dL), add drug Tx
LDL-C 4.144.89 mmol/L (160189 mg/dL), consider drug
Tx/pt preference
Patients w/ 2 risk factors and 10-y risk <10%

LDL-C 3.35 mmol/L (130 mg/dL lifestyle changes
LDL-C 4.14 mmol/L (160 mg/dL), consider drug Tx

When should drug therapy be recommended?
Implementation of Interventions Based on NCEP-ATP III Goals
Patients w/ 10-y risk 10% to 20%

LDL-C 3.35 mmol/L (130 mg/dL), strongly consider drug
Tx w/lifestyle changes
LDL-C 2.59-3.34 mmol/L (100-129 mg/dL), consider drug
Tx w/ lifestyle changes based on pt pref
Patients w/ 10-y risk >20%, CAD, or CAD risk equivalents

LDL-C 2.59 mmol/L (100 mg/dL), drug Tx & lifestyle
changes
LDL-C 1.81-2.59 mmol/L (70-100 mg/dL), lifestyle
changes and consider drug Tx

What options are available for drug therapy?
Statins
Atorvastatin (1080 mg/d)
Fluvastatin (2040 mg nightly or 80 mg XL nightly)
Lovastatin (1040 mg evening meal or 1060 XL nightly)
Pravastatin (1080 mg at bedtime)
Rosuvastatin (540 mg/d)
Simvastatin (580 mg at evening meal)
LDL-C lowering 22-63%, varies with drug; differing metabolism
allows substitution if AEs
Adverse effects:
Abnormal LFTs (relatively uncommon)
Myositis/myalgias (increased w/ fibrates): dont give
rosuvastatin w/warfarin or gemfibrozil
Dont use in pregnant /nursing women

Avoid: active liver disease
Bile acid sequestrants
Colestipol (2 scoops BID or TID)
Colsevelam hydrochloride (three 625-mg tabs BID)
Nonabsorbed; long-term safety established; lowers LDL-C 10-15%
1st-line: children and women w/child-bearing potential
2nd-line: w/ statins for synergy by inducing LDL-C receptors
Adverse effects:
Unpleasant taste/texture, bloating, heartburn, constipation

Drug interactions (avoid by administering 1 h before or 4 h after
meals)
Increased triglycerides
Dont use: triglyceride >3.39 mmol/L (>300 mg/dL) or GI dysmotility

Fibrates (reduce VLDL synthesis and lipoprotein lipase)
Gemfibrozil (600 mg 2x/day)
Fenofibrate (45145 mg/day depending on brand)
Best triglyceride level-reducing drugs, lowers 50% in many

patients; increases HDL-C level by 15%
Adverse effects: Nausea, skin rash
Unreliable reduction (and can increase) LDL-C
Caution:
W/statins myositis/myalgia
W/repaglinide severe hypoglycemia
Renal insufficiency or gallbladder disease

Niacin (mechanism largely unknown)
Niacin (500750mg to 12g nightly XR niacin)
Lowers LDL-C and triglycerides 10-30%; most effective drug

to raise HDL-C level (25-35%)
Drug of choice for combined hyperlipidemia and w/ low HDL-
C level
Adverse effects: Flushing, nausea, gout; may increase
glucose, LFTs uric acid, homocysteine
XR preparations limit flushing & LFT abnormal
Do not use in pregnancy or nursing
Long-acting OTC niacin prep not recommended: increased

hepatotoxicity

Omega-3 (polyunsaturated fatty acids inhibit hepatic
triglyceride synthesis, augment chylomicron triglyceride
clearance secondary to increased lipoprotein lipase activity)
4-6 g/day (higher dosing for OTC formulations)
Controls triglycerides up to 45%; raises HDL-C 13%
Adverse effects: Dyspepsia, nausea; may increase bleeding

time; use cautiously with anticoagulants
Can increase LDL-C in some w/increased triglycerides

Ezetimibe (selectively inhibits intestinal absorption of
cholesterol & related phytosterols)
10 mg 1x/day
Well-tolerated; reduces LDL-C 18%, triglycerides 8%, and

apolipoprotein B 16%
Can use w/statins for further LDL-C and triglyceride level
reduction and to increase HDL-C level
Adverse effects: Contraindicated w/liver disease or
elevated LFTs
Dont combine w/resins, fibrates, or cyclosporine

Ezetimibe and simvastatin (combo drug; selectively inhibit
intestinal absorption cholesterol & partially inhibit HMG-
CoA reductase)
Ezetimibe, 10 mg nightly
Simvastatin, 1080 mg nightly
Combination therapy may improve patient adherence;

synergistic benefits
Adverse effects: Abnormal LFTs; myositis, myalgia
Avoid with fibrates, >1g; niacin; amiodarone; or verapamil

due to increased risk for myopathy
Contraindicated: liver disease & pregnant/nursing women

Selection of the agent depends on type of dyslipidemia
For high LDL-C level only:
Consider statins first, resins or intestinal absorption blocker
second, niacin third
For high LDL-C and low HDL-C levels:

Consider statins first, niacin second
For high LDL-C, low HDL-C, and high triglyceride levels:

Consider niacin and statins first, fibrates second
For high triglyceride levels, w/ or w/o low HDL-C levels:

Consider fibrates first, niacin second
For low HDL-C levels only:

Consider niacin first, fibrates second

When is combination drug therapy for
dyslipidemia warranted?
When lipids severely elevated & unresponsive to monotherapy
Lipid-lowering med combos: Be vigilant for drug interxns
Statins, bile acid-binding resins,
Fibrate-statin combo meds
fibrates, nicotinic acid
compete for metabolism via
cytochrome P450 system, may
Specific agents more effective
induce rhabdomyolysis
in combo
Long-acting, nonflushing, OTC
Nicotinic acid ( HDL-C niacin prep can cause
level, triglycerides) hepatotoxicity
plus
Ezetimibe-statin combo
statin ( LDL-C level)
ezetimibe LDL-C levels
High-dose stain monotherapy (blocks absorption), but not
may be superior combo Tx coronary events

What are the therapeutic goals of treatment?
Goals for Therapy Using LDL-C Levels
Risk group LDL-C Goal Initiate Lifestyle Consider Drug
Changes Therapy
mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL
High risk <2.59 <100 2.59 100 2.59 100
CHD/CHD risk (optional (optionl
equivts, 10-y <1.81) <70)
risk >20%
Moderately <3.35 <130 3.35 130 3.35 130

high 2 risk (optional (consider
factors, 10-y <100) if 100129)
risk <10%
Lower risk 1 <4.14 <160 4.14 160 4.92 190 (LDL-

risk factor C drug
optional if
160-189)

What are the goals of treatment?
After LDL goals attained
Reduce triglyceride levels to <1.7 mmol/L

(<150 mg/dL)
Then attempt to increase HDL to >1.0
mmol/L (>40 mg/dL)
By selection/combo of drugs w/ effects
on multiple lipoproteins

How should therapy be monitored?
6 weeks after adding new lipid-lowering agent: Check fasting

lipid profile, discuss adherence, side effects
If LDL-C goal not achieved consider intensification of
therapy (reevaluate in 6 weeks)
Add new/addl drugs 1 at a time to help assess adverse
effects if they occur
Routine LFTs not recommended for patients on statins
Behavioral lifestyle changes may require more frequent

visits to foster adherence
Only 39% of patients receiving drug tx

and only 34% of patients receiving
dietary tx reach their NCEP goal

What are the side effects of drug therapy?
Statins
Elevated liver enzyme levels (relatively uncommon)
Myositis/myalgias (use w/fibrates increases risk)
Low frequency serious events; rhabdomyolysis rare
Fibrates
Nausea, skin rash
W/statins: increased incidence myositis, myalgias
Niacin
Flushing, nausea, headache, glucose intolerance, gout
Minimize flushing w/nonenteric-coated aspirin 1 hour
before evening dose w/low-fat snack; avoid hot
beverages, baths/showers around time of niacin dose

What are the side effects of drug therapy?
W/severe side effects...discontinue may be only option
W/minor side effectsweigh risks & benefits of therapy
May be reasonable to substitute one statin for another

when side effects occur (metabolism of various statins
differ)

Treatment

What should clinicians advise patients
about the use of complementary-
alternative therapies for dyslipidemia?
Do not substitute for drug therapy in high-risk pts
Plant-based diets have shown some effectiveness
Stanol ester-containing margarines or foods
Oat bran
Nuts in moderation
Dietary changes might affect serum lipid levels by

replacing fatty foods w/healthier choices

When should clinicians consult a lipid
specialist for help in managing dyslipidemia?
Management of rare or treatment-resistant lipid disorders
Special monitoring or complex regimens difficult to initiate

in routine practice
Familial hypercholesterolemia or type III dyslipoproteinemia
Very low HDL-C syndromes (HDL-C <0.5 mmol/L [<20 mg/dL])
Resistant hypertriglyceridemia (triglycerides >11.3 mmol/L

[>1000 mg/dL])
Management of pts at high risk for vascular event
Pts <45 years w/vascular disease
Pts w/evidence disease progression despite Rx (may need

multiple interventions; examine secondary causes, such as
unusual lipid/lipoprotein disorders, poor med adherence)
What do professional organizations
recommend regarding the care of
patients with dyslipidemia?
Recommendations on dyslipidemia screening differ
Age screening should be started
Which screening tests should be used
Most widely used lipid guideline: NHLBIs NCEP-ATP III:

www.nhlbi.nih.gov/guidelines/cholesterol/index.htm
Comprehensive listing of guidelines at National Guideline
Clearinghouse www.guidelines.gov


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Copyright Annals of Internal Medicine, 2010

Open in Slide Show mode

From the View menu, select the

Copyright Annals of Internal Medicine, 2010

Copyright Annals of Internal Medicine, 2010

Improved lipid profiles

Reduced CAD risk for all

Unlikely to achieve marked change Many require drugs

Copyright Annals of Internal Medicine, 2010

Copyright Annals of Internal Medicine, 2010

Screening & treatment reduced CVD or stroke

Indirect evidence to screen:

Men > 35 years

Women > 45 years

Copyright Annals of Internal Medicine, 2010

Copyright Annals of Internal Medicine, 2010

> 2 years: Screen if FH or other CVD risks

Lifestyle counseling if:

CVD risk factor

High LDL cholesterol

Overweight/obese with low HDL or high triglycerides

Consider meds if high LDL after counseling

Copyright Annals of Internal Medicine, 2010

Moderate evidence for screening

Higher baseline risk of CHD

Total cholesterol predicts CHD

As in younger pts, screen all with CHD, or CAD risk equivalents

Copyright Annals of Internal Medicine, 2010

Every 5 years for adults >20 years

Initial to include triglycerides & indirect LDL calculation

USPSTF: Fasting or nonfasting profile

Men >35 years, women >45 years with CHD risk

Total cholesterol and HDL only

LDL and triglycerides only to guide Rx

Copyright Annals of Internal Medicine, 2010

Triglycerides are secondary target

LDL = Total cholesterol Triglycerides - HDL

Best after > 8 hours fasting

Measure LDL directly if TG > 4.52 mmol/L (400 mg/dL)

Copyright Annals of Internal Medicine, 2010

Copyright Annals of Internal Medicine, 2010

NHLBI (Framingham risk equation)

10-yr risk of CV event:

Copyright Annals of Internal Medicine, 2010

Elevated LDL w/>2 CAD risk factors

10-yr risk >20% for MI or CAD death

Focus on identifying & treating elevated LDL cholesterol levels

Identify causes of elevated LDL

Set targets of diet & drug therapy

Copyright Annals of Internal Medicine, 2010

Increased CAD risk: Women > Men

Normal: <1.70 mmol/L (<150 mg/dL);

ATP III: TGs secondary Rx goal

Borderline familial abnormalities

High ? Other issues (DM, EtOH, renal failure, nephrosis)

Very high pancreatitis risk; warrants Rx

Copyright Annals of Internal Medicine, 2010

Copyright Annals of Internal Medicine, 2010

Copyright Annals of Internal Medicine, 2010

Copyright Annals of Internal Medicine, 2010

Apolipoprotein measurements (e.g., apo A and B)

More accurate than lipids when values very high