© Copyright Annals of Internal Medicine, 2010Ann Int Med. 153 (3): ITC2-1.

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© Copyright Annals of Internal Medicine, 2010Ann Int Med. 153 (3): ITC2-1.

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© Copyright Annals of Internal Medicine, 2010Ann Int Med. 153 (3): ITC2-1.

in the clinic

Dyslipidemia

© Copyright Annals of Internal Medicine, 2010Ann 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, 2010Ann Int Med. 153 (3): ITC2-1.

What preventive lifestyle measures should clinicians recommend to reduce risk for dyslipidemia?

CAD equivalents:•Diabetes•Aortic aneurysm•Periph vasc disease•Carotid disease w/sxs•Framingham risk > 20%

Greatest risk reduction if:

• CAD

• CAD equivalents

© Copyright Annals of Internal Medicine, 2010Ann 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, 2010Ann Int Med. 153 (3): ITC2-1.

Who should be screened for dyslipidemia?

NCEP- ATP III:

All adults > 20 years

•Promote healthy behavior

•Public awareness

•Identify those at risk

•Benefit unclear

USPSTF:

Men > 20 years & women > 35 if:

•Risks for CAD

•FH premature CAD, or lipid d/o

•PE suggests hyperlipidemia

© Copyright Annals of Internal Medicine, 2010Ann Int Med. 153 (3): ITC2-1.

Who should be screened for dyslipidemia?

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

Children/Adolescents

© Copyright Annals of Internal Medicine, 2010Ann Int Med. 153 (3): ITC2-1.

Who should be screened for dyslipidemia?

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

Adults > 65 years

CAD Equivalents:•Diabetes•Aortic aneurysm•Periph vasc disease•Carotid disease w/sxs•Framingham risk > 20%

© Copyright Annals of Internal Medicine, 2010Ann 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, 2010Ann 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, 2010Ann Int Med. 153 (3): ITC2-1.

Screening

© Copyright Annals of Internal Medicine, 2010Ann 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, 2010Ann 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, 2010Ann 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, 2010Ann 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, 2010Ann 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, 2010Ann 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

Secondary causes: liver, thyroid

Drugs & Dyslipidemia• Corticosteroids• Androgenic steroids• Progestogens• Thiazides• β-blockers• Retinoic acid derivatives• Oral estrogens

© Copyright Annals of Internal Medicine, 2010Ann Int Med. 153 (3): ITC2-1.

What are the causes of secondary dyslipidemia, and how should clinicians diagnose them?

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

Drugs & Dyslipidemia• Corticosteroids• Androgenic steroids• Progestogens• Thiazides• β-blockers• Retinoic acid derivatives• Oral estrogens

© Copyright Annals of Internal Medicine, 2010Ann 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, 2010Ann Int Med. 153 (3): ITC2-1.

Diagnosis

© Copyright Annals of Internal Medicine, 2010Ann Int Med. 153 (3): ITC2-1.

What should clinicians advise patients about lifestyle changes?

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

Set goals, select strategies, risk factor ctrl Schedule periodic weight checks, counseling

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

Adopt lifestyle changes regardless drug Tx

Adopt lifestyle changes regardless drug Tx

© Copyright Annals of Internal Medicine, 2010Ann 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, 2010Ann 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, 2010Ann 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 womenAvoid: active liver disease

© Copyright Annals of Internal Medicine, 2010Ann 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, 2010Ann 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, 2010Ann 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, 2010Ann 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, 2010Ann 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, 2010Ann 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 HMG-CoA 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, 2010Ann 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, 2010Ann Int Med. 153 (3): ITC2-1.

When is combination drug therapy for dyslipidemia warranted?

Lipid-lowering med combos: Statins, bile acid-binding resins, fibrates, nicotinic acid

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

When lipids severely elevated & unresponsive to monotherapy

Specific agents more effective in combo

Nicotinic acid ( HDL-C level, triglycerides) plusstatin ( LDL-C level)

High-dose stain monotherapy may be superior combo Tx

© Copyright Annals of Internal Medicine, 2010Ann Int Med. 153 (3): ITC2-1.

What are the therapeutic goals of treatment?

Goals for Therapy Using LDL-C Levels

Risk group LDL-C Goal Initiate Lifestyle Changes

Consider Drug Therapy

mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL

High risk CHD/CHD risk equiv’ts, 10-y risk >20%

<2.59 (optional <1.81)

<100(option’l <70)

≥2.59 ≥100 ≥2.59 ≥100

Moderately high ≥2 risk factors, 10-y risk <10%

<3.35 <130 (optional <100)

≥3.35 ≥130 ≥3.35 ≥130 (consider if 100–129)

Lower risk ≤1 risk factor

<4.14 <160 ≥4.14 ≥160 ≥4.92 ≥190 (LDL-C drug optional if 160-189)

© Copyright Annals of Internal Medicine, 2010Ann 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, 2010Ann 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, 2010Ann 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, 2010Ann 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, 2010Ann Int Med. 153 (3): ITC2-1.

Treatment

© Copyright Annals of Internal Medicine, 2010Ann Int Med. 153 (3): ITC2-1.

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

© Copyright Annals of Internal Medicine, 2010Ann 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, 2010Ann 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