1. Assess CV risk and target modifiable risk factors.

2. Educate patients about therapeutic lifestyle interventions for reducing CV risk.

3. Implement management plans for primary and secondary prevention of CV disease (CVD).

4. Identify patients at very high risk for CVD and institute an evidence-based management plan.

5. Discuss the use of serum markers for risk-stratification among patients at intermediate risk for CVD.

Diagnosis and Treatment of Hyperlipidemia

Cardiovascular (CV) disease (CVD): number one cause of death in United States; ≈90% of risk attributed to known risk factors; risk factors—include positive family history, elevated blood pressure (BP), smoking, and dyslipidemia; of these, dyslipidemia management has most room for improvement (only 18%-30% of patients achieve recommended levels)

Management approaches: primary prevention—management to achieve target (eg, cholesterol level) in patients without history of event or evidence of established disease; new guidelines recommend primary prevention strategies to lower cholesterol in patients at moderate to high risk for CVD; secondary prevention—management to achieve target in patients with established disease; lowering cholesterol in these patients decreases rates of mortality and nonfatal events; general approach—calculate risk (with, eg, Framingham risk calculator); obtain fasting lipid profile; determine whether patient has existing CVD; design management plan based on risk

Calculating risk: Framingham risk calculator calculates 10-yr risk for coronary death or myocardial infarction (MI) based on age, sex, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels, smoking history, and BP; shortcomings—lifespan has increased since original Framingham study (no data from patients \>79 yr of age); calculator does not factor in family history (important consideration in risk assessment)

LDL targets: based on risk category; LDL <100 mg/dL considered optimal, because atherogenesis arrests at this level; in Americans, average LDL 136 mg/dL, but treatment not recommended for all patients with LDL \>100 mg/ dL (problems include cost and adverse effects); guidelines consider risk- and cost-benefit ratios; recommendation of LDL <100 mg/dL reserved for patients at high risk (ie, with established disease)

Therapeutic lifestyle changes: nutritional medicine consultation recommended (when possible) for thorough nutritional counseling; diet—increase soluble fiber (good sources include beans, pears, apples, and oats); reduce and maintain body mass index (BMI) <25 (further reduction in BMI not associated with additional reduction in LDL); exercise—increase physical activity to ≥2000 steps/day; encourage walking during normal daily activities; consider formal prescription for exercise

Medical therapy: recommended for secondary prevention; acceptable for primary prevention in some cases, but therapeutic lifestyle strategies should be attempted first; Medical Letter provides unbiased information (not supported by advertising) about medications; treatment guidelines for dyslipidemia published in February 2008; resins—effective at lowering LDL; associated with abdominal adverse effects; niacin—inexpensive; improves all aspects of lipid profile; may cause flushing and dyspepsia (most patients can tolerate dose of 500 mg); fibrates—fenofibrate and gemfibrozil; only fenofibrate should be combined with statin (gemfibrozil plus statin increases risk for rhabdomyolysis); combination therapies—ezetimibe may be combined with other therapies (eg, simvastatin); lovastatin plus niacin; fish oil—prescription formulation (Lovasa) available; patients report fewer adverse effects (eg, belching, odor), compared to over-the-counter (OTC) formulations

Statins: all have anti-inflammatory effects; potency increases when given at night because serum level peaks when cholesterol production peaks (1:00 to 3:00 AM); safety—adverse effects rare; simvastatin available OTC in United Kingdom since 2004; large meta-analysis found low risk overall; adverse effects include elevated transaminases (reversible), rhabdomyolysis (very rare), and myalgias (uncommon in clinical trials; may be more common in practice); options—atorvastatin; lovastatin (must take with food); pravastatin (dual pathways of elimination; lowest rate of adverse effects; only statin approved for aviators); simvastatin (most data); fluvastatin (least potent); rosuvastatin (high potency; may increase risk for reduced creatinine clearance in Asian subpopulations)

Lowering LDL targets: Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) showed that atorvastatin lowered LDL levels further than pravastatin (average, 62 mg/dL vs 95 mg/dL) and was associated with 16% fewer events and 28% fewer deaths among patients with established disease; reversing atherogenesis— although atherogenesis arrests at LDL <100 mg/dL, it reverses at LDL <80 mg/dL; updated guidelines—consider goal of LDL <70 mg/dL for patients at very high risk (note, basic research shows reversal of atherogenesis at LDL <80 mg/dL, but participants in clinical trials had levels <70 mg/dL); set goal of LDL <100 mg/dL for patients at high risk

Beyond LDL: Other Serum Markers for Risk Assessment

Traditional risk factors: 90% of risk for CVD determined by hypertension, smoking history, family history, and LDL; however, 50% of patients who have CV events have normal LDL levels; other markers may help predict events in patients at intermediate risk

Atherosclerosis: requires “raw materials” (excess lipids) and “machinery” (inflammation); serum markers must measure one of these

Candidate markers: HDL; triglycerides; apolipoprotein A-1 (apo A-1); apolipoprotein B (apo B); lipoprotein(a); high-sensitivity C-reactive protein (hs CRP); homocysteine; requirements—measurable (ie, assay available, accurate, and cost-effective); adds information beyond that obtained from traditional risk factors; available treatment improves clinical outcomes

HDL (“good cholesterol”): anti-inflammatory molecule, performs reverse cholesterol transport (transports lipids from LDL to liver); functional HDL—inversely associated with CV risk; nonfunctional HDL—some patients have very high levels of HDL (\>100 mg/dL) but have elevated CV risk; in trials, torcetrapib increased HDL levels by up to 150%, but mortality increased

Tests: assays available, accurate, and cost-effective

Added information: increasing HDL decreases mortality and CV events independently of LDL; decreasing HDL increases risk for death; raising HDL decreases risk, even among patients with optimized LDL levels

Treatment: aerobic exercise (≈30 min/day) raises HDL levels up to 5% and lowers triglycerides; tobacco cessation raises HDL levels up to 10%; each kilogram of weight loss (for patients with BMI \>25) increases HDL; moderate consistent use of alcohol (0-1 drinks/day for women; 1-2 drinks/day for men) raises HDL up to 12% (however, inconsistent or heavier drinking has multiple negative effects); medications—statins and thiazolidinediones (TZDs) modestly raise HDL; fibrates raise HDL 10% to 20%; niacin therapy results in most significant increases in HDL; most patients can tolerate 500 mg (especially when taken with food); new formulations may reduce adverse effects (eg, flushing, dyspepsia)

Case 1: man, 49 yr of age, with recent history of inferior wall MI and 2-vessel angioplasty; evidence of 20% to 40% stenosis in other vessels; previously told that his cholesterol “was fine”; patient reports “social” smoking and drinking; medication—baby aspirin; statin and β-blocker prescribed, but patient wants second opinion; family history—no male relative (going back 4 generations) lived to 55 yr of age without significant cardiac event; CV risk—very high (known disease; significant family history); treatment goals—lower LDL to <70 mg/dL; raise HDL to >50 mg/dL; management—optimize weight (to raise HDL and lower triglycerides); stop smoking completely; initiate statin (consider atorvastatin or rosuvastatin because these raise HDL levels somewhat); increase exercise (eg, daily walking); limit alcohol intake to 1 to 2 drinks/day (consistently); initiate niacin therapy

Apolipoprotein A-1: coats HDL molecules; critical for antioxidant and anti-inflammatory functions of HDL; promotes reverse cholesterol transport; test—available, accurate, and reproducible; added information—good measure of functional HDL; associated with superior prediction of CV risk, compared to LDL or non-HDL levels; effect on management—treatment available (same approaches as for increasing HDL); unknown whether raising apo A-1 will have effect on clinical outcome (clinical trial in progress); note—assay does not require fasting

Apolipoprotein B: coats all non-HDL lipoproteins; provides direct measure of concentration of all atherogenic particles (LDL, very low-density lipoprotein [VLDL] and intermediate-density lipoproteins [IDL]); test— available (may be performed without fasting), accurate, reproducible, and cost-effective; added information— more predictive of CV risk than LDL or non-LDL levels; useful for assessing VLDL and IDL levels in patients taking statins; effect on management—unknown; cutoff levels not established; significant variance among ethnic populations; no large outcome trials

Lipoprotein [Lp](a): coats phospholipids; resembles fibrinogen, so interferes with normal fibrinolysis; promotes atherogenesis; test—available and accurate; 90th percentiles established (39.0 mg/dL in men; 39.5 mg/dL in women); added information—independently associated with CV risk; associated with unstable angina and unstable plaque (promotes growth of new lesions); effect on management—no outcome studies available; limited medical therapies (primarily niacin, but also large [2-3 g] doses of neomycin); statins have no effect; test most useful for patients with known disease, or strong family history but normal lipid levels, and those with high LDL resistant to medical therapy

Triglycerides: elevations associated with increased CV risk (may not be independent of other factors); important to identify etiology of elevation (eg, hypothyroidism, medication use [eg, diuretics, estrogen agents, antiretroviral agents, atypical antipsychotics, resins]; alcohol abuse)

Tests: available, but measurements vary significantly from one day to next

Added information: clinical trials show limited benefit of lowering triglycerides once LDL levels controlled; levels \>200 mg/dL associated with increased risk in women; levels \>500 mg/dL increase risk for pancreatitis (\>1000 mg/dL requires immediate intervention)

Effect on management: study in women showed that nonfasting (but not fasting) levels associated with CV events, independently of other risk factors; 2- to 4-hr postprandial measurement most useful (indication of body’s ability to clear triglycerides after meal), but difficult to implement; approaches to lowering triglycerides—weight loss; aerobic exercise; reducing intake of simple sugars; supplementation with omega-3 fatty acids; medical therapy (niacin; fibrates; statins [modest effect])

High-sensitivity C-reactive protein: test—does not require fasting; widely available and accurate; added information—predicts risk independently of traditional risk factors; most useful in patients at intermediate risk; effect on management—small outcome study showed benefit of lowering CRP at all levels of LDL; larger outcome trial (in progress) looking at CRP reduction as primary prevention strategy in 15,000 patients with optimal LDL levels and intermediate to high CRP levels (randomized to placebo or rosuvastatin); approaches to lowering CRP—statin therapy; smoking cessation; aerobic exercise; BP control; achieving and maintaining optimal BMI

Case 2: woman, 45 yr of age; routine lipid panel shows total cholesterol 203 mg/dL, HDL 48 mg/dL, triglycerides 155 mg/dL, and LDL 124 mg/dL; current smoker (1.5 packs/day); positive family history (mother had MI at 64 yr of age); normal weight and heart rate; risk—intermediate, because of positive family history, low HDL (<50 mg/dL considered low in premenopausal women), and slightly elevated triglycerides (<150 mg/dL desirable in women); hs CRP—3.2 mg/L (\>3 mg/L signals high risk; \>10 mg/L may signal cancer or collagen vascular disease); management—aerobic exercise; smoking cessation (difficult); hs-CRP remained elevated, so low-dose statin added

Homocysteine: test—inaccurate; highly variable; added information—does not independently predict risk; effect on management—multiple outcome studies show that lowering homocysteine levels (through folic acid supplementation) does not reduce CV risk and may increase some events (eg, unstable angina)

Summary: HDL—important for risk assessment and management; apo A-1, apo B, and Lp(a)—potentially useful markers, but clinical outcome studies limited; triglycerides—postprandial measurements may provide important information; fasting measures have limited value; hs-CRP—likely valuable as marker of risk, but data from larger outcome trials not yet available; homocysteine—not useful