Transcript Dyslipidemia - Annals of Internal Medicine

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Ann Int Med. 153 (3): ITC2-1.
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© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
in the clinic
Dyslipidemia
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
What preventive lifestyle measures
should clinicians recommend to reduce
risk for dyslipidemia?
 Greatest risk reduction if:
• CAD
• CAD equivalents
CAD equivalents:
•Diabetes
•Aortic aneurysm
•Periph vasc disease
•Carotid disease w/sxs
•Framingham risk > 20%
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
Who should be screened for dyslipidemia?
USPSTF:
Men > 20 years & women > 35 if:
•Risks for CAD
•FH premature CAD, or lipid d/o
•PE suggests hyperlipidemia
NCEP- ATP III:
All adults > 20 years
•Promote healthy behavior
•Public awareness
•Identify those at risk
•Benefit unclear
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
Who should be screened for dyslipidemia?
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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
Who should be screened for dyslipidemia?
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%
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
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)
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
Screening
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
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%
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
How should clinicians measure and
interpret triglyceride levels?
 Elevated TGs:
 Increased CAD risk: Women > Men




Normal: <1.70 mmol/L (<150 mg/dL);
Borderline: 1.70–2.25 mmol/L (150–199 mg/dL)
High: 2.26–5.64 mmol/L (200–499 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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
How should clinicians measure and
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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
How should clinicians measure and
interpret HDL levels?
 HDL <1.0 mmol/L (<40 mg/dL)  ? Acquired:
 Tobacco
 Obesity
 Inactivity
 Hypertriglyceridemia
 Type 2 diabetes mellitus
 Carbohydrates
 Genetic mutations
 β-blockers, androgenic steroids
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
What should clinicians look for in the
history and physical examination of a
patient with dyslipidemia?
 Coronary risks
 Secondary causes: drugs
 BP
 BMI
 Peripheral, carotid pulses/bruits
Drugs & Dyslipidemia
• Corticosteroids
• Androgenic steroids
• Progestogens
• Thiazides
• β-blockers
• Retinoic acid derivatives
• Oral estrogens
 Secondary causes: liver, thyroid
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
What are the causes of secondary
dyslipidemia, and how should clinicians
diagnose them?
Drugs & Dyslipidemia
• Corticosteroids
• Androgenic steroids
• Progestogens
• Thiazides
• β-blockers
• Retinoic acid derivatives
• Oral estrogens
 Hypothyroidism
 Obstructive liver disease
 Nephrotic syndrome
 Renal failure
 Uncontrolled diabetes
 Tobacco or alcohol use
 Medications  consider stopping
 Address secondary causes before drug therapy 
 Dyslipidemia may resolve
 Rx may be ineffective
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
Diagnosis
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
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
fat)  Reduces LDL 5–15% (ATP III TLC diet)
 Aerobic exercise: Running, walking, cycling,
swimming enhance weight reduction
 Facilitates achieving optimum lipid levels
 Adopt lifestyle
changes
regardless
drug Tx
 Set goals, select strategies, risk factor ctrl 
Schedule periodic weight checks, counseling
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
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 4.14–4.89 mmol/L (160–189 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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
What options are available for drug therapy?
Statins
 Atorvastatin (10–80 mg/d)
 Fluvastatin (20–40 mg nightly or 80 mg XL nightly)
 Lovastatin (10–40 mg evening meal or 10–60 XL nightly)
 Pravastatin (10–80 mg at bedtime)
 Rosuvastatin (5–40 mg/d)
 Simvastatin (5–80 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): don’t give
rosuvastatin w/warfarin or gemfibrozil
 Don’t use in pregnant /nursing women
 Avoid: active liver disease
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
What options are available for drug therapy?
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
 Don’t use: triglyceride >3.39 mmol/L (>300 mg/dL) or GI dysmotility
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
What options are available for drug therapy?
Fibrates (reduce VLDL synthesis and lipoprotein lipase)
 Gemfibrozil (600 mg 2x/day)
 Fenofibrate (45–145 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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
What options are available for drug therapy?
Niacin (mechanism largely unknown)
 Niacin (500–750mg to 1–2g 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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
What options are available for drug therapy?
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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
What options are available for drug therapy?
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
 Don’t combine w/resins, fibrates, or cyclosporine
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
What options are available for drug therapy?
Ezetimibe and simvastatin (combo drug; selectively inhibit
intestinal absorption cholesterol & partially inhibit HMGCoA reductase)
 Ezetimibe, 10 mg nightly
 Simvastatin, 10–80 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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
What options are available for drug therapy?
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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
When is combination drug therapy for
dyslipidemia warranted?
When lipids severely elevated & unresponsive to monotherapy
 Lipid-lowering med combos:
Statins, bile acid-binding resins,
fibrates, nicotinic acid
 Specific agents more effective
in combo
 Nicotinic acid ( HDL-C
level,  triglycerides)
plus
statin ( LDL-C level)
 High-dose stain monotherapy 
may be superior combo Tx
Be vigilant for drug interxns
Fibrate-statin combo  meds
compete for metabolism via
cytochrome P450 system, may
induce rhabdomyolysis
Long-acting, nonflushing, OTC
niacin prep  can cause
hepatotoxicity
Ezetimibe-statin combo 
ezetimibe  LDL-C levels
(blocks absorption), but not
coronary events
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
What are the therapeutic goals of treatment?
Goals for Therapy Using LDL-C Levels
Risk group
High risk
CHD/CHD risk
equiv’ts, 10-y
risk >20%
Moderately
high ≥2 risk
LDL-C Goal
risk factor
Consider Drug
Therapy
mmol/L
mg/dL
mmol/L
mg/dL
mmol/L
mg/dL
<2.59
(optional
<1.81)
<100
(option’l
<70)
≥2.59
≥100
≥2.59
≥100
<3.35
<130
(optional
<100)
≥3.35
≥130
≥3.35
≥130
(consider
if 100–129)
<4.14
<160
≥4.14
≥160
≥4.92
≥190 (LDLC  drug
optional if
160-189)
factors, 10-y
risk <10%
Lower risk ≤1
Initiate Lifestyle
Changes
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
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/add’l 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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
What are the side effects of drug therapy?
 W/severe side effects...discontinue may be only option
 W/minor side effects…weigh risks & benefits of therapy
 May be reasonable to substitute one statin for another
when side effects occur (metabolism of various statins
differ)
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
Treatment
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
What should clinicians advise patients
about the use of complementaryalternative 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
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
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)
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.
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: NHLBI’s NCEP-ATP III:
www.nhlbi.nih.gov/guidelines/cholesterol/index.htm
 Comprehensive listing of guidelines at National Guideline
Clearinghouse  www.guidelines.gov
© Copyright Annals of Internal Medicine, 2010
Ann Int Med. 153 (3): ITC2-1.