Dyslipidemia resident survival guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Classification

There are several ways in which lipoprotein abnormalities are classified. Lipoprotein disorders can be classified according to:

• The pattern of change in the lipoprotein levels, described as hyperlipidemia (increase in lipid levels) and hypolipidemia (decrease in lipid levels): However, this classification is problematic because the lipids and lipoproteins levels in some situation can be elevated in some types of lipoproteins and lipids and decreased in others.

• Phenotype, or the specific type of lipid that is increased, as classified by Fredrickson: This classification is problematic because it does not include abnormalities in the level of HDL.

• Etiology, as primary (genetic) or secondary to another condition: This classification can be problematic, because most conditions involve the intersection of genetics and lifestyle issues. However, there are a few well defined genetic conditions that are usually easy to identify.

• Levels of measured lipids (cholesterol and triglycerides), described as hypercholesterolemia and hypocholesterolemia or hypertriglyceridimia and hypotriglyceridemia: This distinction is not specific because it does not reflect the specific lipoprotein(s) that are abnormally high or low.

Fredrickson Classification of Hyperlipoproteinemia

Hyperlipoproteinemia

Type I: Familial hyperchylomicronemia

Type II

Type III: Dysbetalipoproteinemia

Type IV: Primary hypertriglyceridemia

Type V: Mixed hyperlipoproteinemia

Type A: Familial hypercholesterolemia

Type B: Familial combined hyperlipidemia

Type A

Type B

Type C

Fredrickson classification of Hyperlipidemias

Hyperlipoproteinemia	Synonyms	Problems	Labs description	Treatment
Type I	Buerger-Gruetz syndrome, primary hyperlipoproteinaemia, or familial hyperchylomicronemia	Decreased lipoprotein lipase (LPL) or altered ApoC2	Elevated chylomicrons	Diet control
Type IIa	Polygenic hypercholesterolaemia or familial hypercholesterolemia	LDL receptor deficiency	Elevated LDL only	Bile acid sequestrants, statins, niacin
Type IIb	Combined hyperlipidemia	Decreased LDL receptor and increased ApoB	Elevated LDL, VLDL and triglycerides	Statins, niacin, gemfibrozil
Type III	Familial Dysbetalipoproteinemia	Defect in ApoE synthesis	Increased IDL	Drug of choice: Gemfibrozil
Type IV	Endogenous Hyperlipemia	Increased VLDL production and decreased elimination	Increased VLDL	Drug of choice: Niacin
Type V	Familial Hypertriglyceridemia	Increased VLDL production and decreased LPL	Increased VLDL and chylomicrons	Niacin, gemfibrozil

Unclassified forms

Non-classified forms are extremely rare:

• Hypo-alpha lipoproteinemia
• Hypo-beta lipoproteinemia (prevalence 0.01-0.1%)

Classification According to Etiology

Lipoprotein Disorders

Primary (Genetic)

Secondary

LDL

Chylomicron Remnants

Lipoproteins Rich in Triglyceride (Chylomicrons, VLDL, IDL)

HDL

Multiple lipoproteins

Alcohol Diabetes Drugs Liver disease Obesity Renal disease Smoking Thyroid

High LDL: -Familial hypercholesterolemia -Familial defective apo B 100 -Autosomal dominant hypercholesterolemia (PCSK9) -Autosomal recessive hypercholesterolemia -Familial sistosterolemia -Familial lipoprotein a lipoproteinemia Low LDL: -Abetalipoproteinemia -Hypobetalipoproteinemia -PCSK 9 deficiency

-Deficiency in hepatic lipase -Type III dysbetalipoproteinemia

-Deficiency in lipoprotein lipase -Deficiency in Apo C-II -Deficiency in Apo A-V -Familial combined hyperlipidemia -Familial hypertriglyceridemia - Chylomicron retention disease

High LDL: -Cholesteryl ester transferase protein deficiency Low HDL: -Deficiency in Apo A-I -Deficiency in lecithin cholesterol acyltransferase (LCAT) -Familial hypoalphalipoproteinemia -Nieman-Pick disease -Tangier disease

- Familial combined hypolipidemia (ANGPTL3)

Classification According to Laboratory Results

Lipid Laboratory Tests

Total cholesterol

LDL-C

HDL-C

Triglycerides

High total cholesterol

Low total cholesterol

High LDL

Low LDL

High HDL

Low HDL

High triglyceride

Low triglyceride

Causes

Secondary causes of dyslipidemia may cause either an increase in total-cholesterol & low density lipoprotein-cholesterol (LDL-C) or an increase in total triglycerides & very low density lipoprotein cholesterol (VLDL-C). Common causes are listed below.

Increase in Total Cholesterol and LDL-C

• Hypothyroidism
• Nephrosis
• Dysgammaglobulinemia (systemic lupus erythematosus, multiple myeloma)
• Cholestatic hepatic diseases due to abnormal lipoproteins (e.g. primary biliary cirrhosis)
• Administration of protease inhibitors (treatment for HIV infection)
• Administration of progestin or anabolic steroids

Increase in Total Triglycerides and VLDL-C

• Chronic kidney disease
• Type 2 diabetes mellitus
• Obesity
• Excessive alcohol intake
• Hypothyroidism
• Administration of anti-hypertensive therapy (thiazide diuretics or B-blockers)
• Administration of corticosteroids
• Severe stress that increases endogenous corticosteroid concentration
• Elevated concentrations of estrogen (administration of oral (not transdermal) estrogen therapy, oral contraceptives, or pregnancy)
• Administration of protease inhibitors (treatment for HIV infection)

To view a comprehensive list of dyslipidemia causes, click here

Screening

Abbreviations: ASA: American society of anesthesiologists; BP: Blood Pressure; CCS: Canadian cardiovascular society; CrCl: Creatinine clearance; CXR: Chest X-ray; DNI: Do not intubate; DNR: Do not resuscitate; ECG: Electrocardiogram; eGFR: estimated glomerular filtration rate; HR:Heart rate; INR: International normalized ratio; LMWH: Low molecular weight heparin; LV: Left ventricle; LVED: Left ventricular ejection fraction; NOAC: Novel oral anticoagulant; NPO: Nothing per os; PMI: Point of maximal impulse; PT: Prothrombin time; RR: Respiratory rate; SpO2: Oxygen saturation; T: Temperature; VT: Ventricular tachycardia

Identify risk factors for CAD Major risk factors: ❑ Advanced age ❑ ↑ total serum cholesterol ❑ ↑ non-HDL-C (calculated by: total cholesterol minus HDL-C) ❑ ↑ LDL-C (either measured or calculated by: total cholesterol minus HDL-c minus (total triglycerides/5)) ❑ ↓ HDL-C ❑ Diabetes mellitus ❑ Hypertension ❑ Cigarette smoking ❑ Family history of CAD Additional risk factors: ❑ Obesity, especially abdominal ❑ Family history of hyperlipidemia ❑ Small, dense LDL-C ❑ ↑ Apo-B ❑ ↑ LDL particle number (measured by ApoB) ❑ Fasting/postprandial hypertriglyceridemia ❑ Polycystic ovarian syndrome ❑ Dyslipidemic triad Non-traditional risk factors: ❑ ↑ lipoprotein ❑ ↑ clotting factors ❑ Inflamamtory markers (e.g. hsCRP or Lipoprotein-associated phospholipase A2 (Lp-PLA2) ❑ Hyperhomocysteinemia ❑ ApoE4 isoform ❑ ↑ uric acid

Determine the 10-year risk of coronary event using ANY of the following assessment tools: ❑ Framingham Risk Assessment Tool (To be redirected to Framingham Risk Assessment Tool, click here) ❑ Reynolds Risk Score (To be redirected to Reynolds Risk Score website, click here)

High (Framingham 10-year global risk > 20%)

Intermediate (Framingham 10-year global risk between 10% and 20%)

Lower (Framingham 10-year global risk < 10%)

Optimal (Framingham 10-year global risk < 10% with optimal levels or risk factors and heart-healthy lifestyle)

Does the patient have type 2 diabetes mellitus?

Yes

No

Does the patient have ALL the following criteria for low-risk dyslipidemia during previous work-up? ❑ Low LDL-C < 100 mg/dL, AND ❑ HDL-C > 50 mg/dL, AND ❑ Triglycerides < 150 mg/dL

Adult patient

Pediatric patient (age at least 2 years)

Yes. The patient has ALL of the criteria for low-risk dyslipidemia

Either unknown history of lipid profile or No, the patient does not have ALL of the criteria for low-risk dyslipidemia (at least 1 criterion is not met)

Does that patient have risk factors for CAD (listed above)?

Does the patient have risk factors for CAD (listed above)?

Screen every 2 years

Screen annually

No

Yes

Yes

No

Screen patient more frequently than patients with no risk factors based on clinical judgement (unknown optimal interval)

Male patient

Female patient

Screen every 3 to 5 years

Do not screen patient for dyslipidemia

Age between 20 and 45 years

Age > 45 years to 65 years

Age > 65 years

Age between 20 years and 55 years

Age > 55 years to 65 years

Age > 65 years

Screen every 5 years More frequent screening is recommended for patients with risk factors for CAD (shown above)

Screen every 1 to 2 years More frequent screening is recommended for patients with risk factors for CAD (shown above)

Screen annually

Screen every 5 years More frequent screening is recommended for patients with risk factors for CAD (shown above)

Screen every 1 to 2 years More frequent screening is recommended for patients with risk factors for CAD (shown above)

Screen annually

Complete Diagnostic Approach

Boxes in red signify that an urgent management is needed.

Abbreviations: ASA: American society of anesthesiologists; BP: Blood Pressure; CCS: Canadian cardiovascular society; CrCl: Creatinine clearance; CXR: Chest X-ray; DNI: Do not intubate; DNR: Do not resuscitate; ECG: Electrocardiogram; eGFR: estimated glomerular filtration rate; HR:Heart rate; INR: International normalized ratio; LMWH: Low molecular weight heparin; LV: Left ventricle; LVED: Left ventricular ejection fraction; NOAC: Novel oral anticoagulant; NPO: Nothing per os; PMI: Point of maximal impulse; PT: Prothrombin time; RR: Respiratory rate; SpO2: Oxygen saturation; T: Temperature; VT: Ventricular tachycardia

Obtain a Detailed History History of present illness ❑ Address specific patient symptoms and complaints ❑ Obtain review of systems relevant to dyslipidemia and diseases associated with dyslipidemia ❑ Headache ❑ Dizziness ❑ Syncope/presyncope ❑ Blurry vision / double vision / reduced visual acquity ❑ Dysphagia ❑ Slurred speech ❑ Facial drooping ❑ Chest pain / Angina ❑ Palpitations ❑ Dyspnea ❑ Cough ❑ Abdominal pain ❑ Change in bowel movements ❑ Lower extremity pain, weakness, or tingling ❑ Peripheral edema ❑ Muscle pain ❑ Intake of dietary fat, saturated fat, fiber, and cholesterol intake ❑ Exercise patterns ❑ History of alcohol use ❑ History of smoking Past Medical History ❑ History of previous medical diagnoses / past medical complaints / hospitalizations and surgeries ❑ History of CAD or myocardial infarction ❑ History of diabetes mellitus ❑ History of hypertension ❑ History of renal disease ❑ History of hepatic disease ❑ History of stroke (ischemic or hemorrhagic) or transient ischemic attack (TIA) ❑ History of hypothyroidism Medications ❑ Current prescribed medications ❑ List of over-the-counter drugs ❑ Previous intake of medications and reason for discontinuation ❑ History of drug adverse effects ❑ History of herbs and supplement use ❑ Compliance to medications Allergies ❑ Known drug allergies ❑ Known environmental/food allergies Family history ❑ Family history of dyslipidemia ❑ Family history of premature CAD (i.e. Established CAD in father or 1st degree male relative before the age of 55 years OR established CAD in mother or 1st degree female relative before the age of 65 years) ❑ Family history of hypothyroidism ❑ Family history of stroke/TIA ❑ Family history of peripheral vascular disease Social History ❑ Overall living situation ❑ Occupation ❑ Exercise ❑ Diet (general) ❑ Smoking history ❑ Alcohol use ❑ Recreational drug use ❑ Stress ❑ Sexual lifestyle & contraceptive methods

Assess for CAD Risk Factors Major risk factors: ❑ Advanced age ❑ ↑ total serum cholesterol ❑ ↑ non-HDL-C (calculated by: total cholesterol minus HDL-C) ❑ ↑ LDL-C (either measured or calculated by: total cholesterol minus HDL-c minus (total triglycerides/5)) ❑ ↓ HDL-C ❑ Diabetes mellitus ❑ Hypertension ❑ Cigarette smoking ❑ Family history of CAD Additional risk factors: ❑ Obesity, especially abdominal ❑ Family history of hyperlipidemia ❑ Small, dense LDL-C ❑ ↑ Apo-B ❑ ↑ LDL particle number (measured by ApoB) ❑ Fasting/postprandial hypertriglyceridemia ❑ Polycystic ovarian syndrome ❑ Dyslipidemic triad Non-traditional risk factors: ❑ ↑ lipoprotein ❑ ↑ clotting factors ❑ Inflamamtory markers (e.g. hsCRP or Lipoprotein-associated phospholipase A2 (Lp-PLA2) ❑ Hyperhomocysteinemia ❑ ApoE4 isoform ❑ ↑ uric acid

Evaluate possible causes of secondary dyslipidemia if suggested by findings during history-taking and physical examination To view a complete list of dyslipidemia causes, click here

Determine the 10-year risk of coronary event using ANY of the following assessment tools: ❑ Framingham Risk Assessment Tool (To be redirected to Framingham Risk Assessment Tool, click here) ❑ Reynolds Risk Score (To be redirected to Reynolds Risk Score website, click here)

Examine the patient Vital signs ❑ High blood pressure Skin ❑ Xanthomas (eruptive, tuberous, tendinous) ❑ Xanthelesma ❑ Cool hairless extremities (suggestive of peripheral vascular disease) ❑ Other skin rashes that may be suggestive of secondary causes (e.g. systemic lupus erythematosus, drug eruptions, pregnancy rash) HEENT ❑ Arcus senilis (corneal arcus) Neck ❑ Carotid bruits ❑ Thyromegaly (when dyslipidemia is caused by thyroid disease) Peripheral ❑ Diminished distal pulses ❑ Femoral bruits

Order tests to rule out secondary causes of dyslipidemia Common causes include: ❑ Hypothyroidism ❑ Order TSH, FT4, and FT3 ❑ Nephrosis ❑ Order serum creatinine and urinalysis with either spot urine for proteins or 24-hour urinary collection for proteins, urinary protein to creatinine ratio ❑ Dysgammaglobulinemia ❑ Order ANA, anti-dsDNA antibodies, plasma and urine electrophoresis ❑ Cholestatic hepatic diseases ❑ Order GGT, ALP, and bilirubins ❑ Chronic kidney disease ❑ Order serum creatinine, BUN, urinalysis, and renal ultrasound ❑ Type 2 diabetes mellitus ❑ Order glycemia and HbA1c ❑ Excessive alcohol intake ❑ Drugs ❑ Any of the following: estrogen, progestin, protease inhibitors, beta-blockers, corticosteroids, anabolic steroids, protease inhibitors

Order fasting lipid profile

Total cholesterol ❑ Optimal: < 200 mg/dL ❑ Borderline: 200-239 mg/dL ❑ High/very high risk: ≥ 240 mg/dL

LDL-C May be either calculated or measured. Measured LDL-C is preferable, especially among certain high-risk populations (elevated triglycerides > 250 mg/dL, diabetes mellitus, peripheral vascular disease). To calculate LDL-C, use the following equation: LDL-C=(total cholesterol-HDL-C)/(triglycerides/5). Do NOT calculate LDL-C when triglycerides > 200 mg/dL (low to no validity of the equation). Instead, use measured LDL-C. ❑ Optimal: < 100 mg/dL ❑ Borderline: 130-160 mg/dL ❑ High risk: 160-189 mg/dL ❑ Very high risk: ≥ 190 mg/dL

HDL-C An optimal HDL-C concentration is a negative CAD risk factor in both genders (subtract 1 risk factor for CAD) ❑ Optimal: ≥ 60 mg/dL ❑ Borderline: 40-50 mg/dL (men) OR 50-59 mg/dL (women) ❑ High/very high risk: < 40 mg/dL (men) OR < 50 mg/dL (women)

Triglycerides ❑ Optimal: < 150 mg/dL ❑ Borderline: 150-199 mg/dL ❑ High risk: 200-499 mg/dL ❑ Very high risk: ≥ 500 mg/dL

Additional tests ❑ Non-HDL non-HDL is calculated by the following equation: non-HDL=total cholesterol - HDL-C non-HDL-C provides additional risk assessment information compared with LDL-C alone. Calculate non-HDL-C only in the following cases: Either moderate elevation of triglyceride (between 200 to 500 mg/dL), diabetes mellitus, insulin resistance syndrome, or established CAD ❑ ApoB ApoB reflects LDL-C particle number, which may be a more potent measure of CVD risk than either LDL-C or LDL-C particle size Optimal: < 90 mg/dL for patients with at risk of CAD (including diabetes mellitus) OR < 80 mg/dL for patients with established CAD or diabetes mellitus plus at least 1 additional risk factor ❑ Ratio of ApoB/ApoAI May be useful in evaluating residual risk (independent of LDL-C) in patients at high risk of CAD or patients with either established CAD, diabetes mellitus, or insulin resistance ❑ hsCRP Order hsCRP for patients with borderline risk or patients with LDL-C < 130 mg/dL hsCRP helps further stratify patient risk for CVD ❑ LP-PLA2 May provide more specificity than hsCRP and may be ordered for further stratification of CVD risk

Treatment

Confirmed Dyslipidemia

Set lipid goals ❑ Total cholesterol target: < 200 mg/dL ❑ LDL-C target: < 70 mg/dL for very high risk patients OR < 100 mg/dL for all other patients ❑ HDL-C target: As high as possible. At least > 40 mg/dL in both genders ❑ Non-HDL-C target: 30 mg/dL above LDL-C goal (target < 100 mg/dL for very high risk patients OR < 130 mg/dL for all other patients) ❑ Triglycerides target: < 150 mg/dL ❑ ApoB target: < 90 mg/dL for patients at risk of CAD (including patients with diabetes) or < 80 mg/dL for patients with established CAD or diabetes plus at least one additional CAD risk factor

Control modifiable CAD risk factors ❑ Hypertension ❑ Diabetes mellitus ❑ Obesity ❑ Cigarette smoking

Recommend lifestyle modification ❑ Recommend physical activity ❑ At least 30 minutes of moderate-intensity physical activity 4 to 6 times weekly ❑ Examples include brisk walking, riding stationary bicycle, water aerobics, cleaning/scrubbing/ mowing lawn, and sporting activities ❑ Recommend medical nutrition therapy (reduced calorie intake) ❑ Advise patients to have at least 5 servings/day of vegetables and fruits ❑ Advise patients to have more than 6 servings/day of grains, at least 1/3 of which are whole grain ❑ Advise patients to limit intake of saturated fat, trans-fats, and cholesterol ❑ Smoking cessation

Lipid goal achieved with lifestyle modification alone?

Yes

No

Administer pharmacological monotherapy Table of available classes, generic names, recommended daily doses, and dose ranges also available below algorithm. Click here. Statins Administration of any of the following statins is recommended to manage dyslipidemia ❑ Lovastatin: Recommended starting daily dose 20 mg PO once daily at bedtime. Dose range: 10-80 mg ❑ Pravastatin: Recommended starting daily dose 40 mg PO once daily at bedtime. Dose range: 10-80 mg ❑ Simvastatin: Recommended starting daily dose 20-40 mg PO once daily at bedtime. Dose range: 5-80 mg (80 mg not approved for therapy unless patient has been on treatment for more than 1 year without myopathy) ❑ Fluvastatin: Recommended starting daily dose 40 mg PO once daily at bedtime. Dose range: 20-80 mg ❑ Atorvastatin: Recommended starting daily dose 10-20 mg PO once daily at bedtime. Dose range: 10-80 mg ❑ Rosuvastatin: Recommended starting daily dose 10 mg PO once daily at bedtime. Dose range: 5-40 mg ❑ Pitavastatin: Recommended starting daily dose 2 mg PO once daily at bedtime. Dose range: 2-4 mg Fibrates Administration of any of the following fibrates is recommended to manage dyslipidemia ❑ Fenofibrate: Recommended starting daily dose 48-145 mg PO once daily. Dose range: 48-145 mg ❑ Gemfibrozil: Recommended starting daily dose 1200 mg PO once daily. Dose range: 1200 mg ❑ Fenofibric acid: Recommended starting daily dose 45-135 mg PO once daily. Dose range: 45-135 mg Nacin ❑ Immediate release: Recommended starting daily dose 250 mg PO once daily at bedtime. Dose range: 250-3000 mg ❑ Extended release: Recommended starting daily dose 500 mg PO once daily at bedtime. Dose range: 50-2000 mg Bile acid sequestrants Administration of any of the following bile acid sequestrants is recommended to manage dyslipidemia ❑ Cholestyramine: Recommended starting daily dose 8-16 mg PO once daily at bedtime. Dose range: 4-24 mg ❑ Colestipol: Recommended starting daily dose 2 mg PO once daily at bedtime. Dose range: 2-16 mg ❑ Colesevelam: Recommended starting daily dose 3.8 mg PO once daily at bedtime. Dose range: 3.8-4.5 mg Cholesterol absorption inhibitors ❑ Ezetimibe: Recommended starting daily dose 10 mg PO once daily at bedtime. Dose range: 10 mg

Aim to reduce LDL ❑ Statin monotherapy at recommended initial daily dose (LDL reduction: 21% to 55%) ❑ Fibrate monotherapy at recommended initial daily dose (LDL reduction: 20% to 25%) ❑ Niacin monotherapy at recommended initial daily dose (LDL reduction: 10% to 25%) ❑ Bile acid sequestrant monotherapy at recommended initial daily dose (LDL reduction: 10% to 25%) ❑ Ezetimibe monotherapy at recommended initial daily dose (LDL reduction: 10% to 18%)

Aim to reduce triglycerides ❑ Fibrates monotherapy at recommended initial daily dose with or without omega-3 fish oil (triglyceride reduction: 20% to 35%) ❑ Niacin monotherapy at recommended initial daily dose with or without omega-3 fish oil (triglyceride reduction: 20% to 30%)

Aim to increase HDL ❑ Niacin monotherapy at recommended initial daily dose (HDL increase: 10% to 35%) ❑ Fibrates monotherapy at recommended initial daily dose (HDL increase: 6% to 18%) ❑ Statin monotherapy at recommended initial daily dose (HDL increase: 2% to 10%)

Lipid goal achieved with optimal administration of antilipidemic monotherapy?

Yes

No

Does the patient have ANY of the following criteria to initiate combination pharmacotherapy? ❑ Markedly elevated cholesterol concentration, OR ❑ Mixed dyslipidemia (e.g. Hypertriglyceridemia and reduced HDL-C), OR ❑ Patient developed or at high risk of developing drug-associated, dose-dependent adverse effects

No

Yes

❑ Consider changing drug class

❑ Consider increasing dose of antilipidemic agent within dose range for each drug

Lipid goal achieved with optimal administration of antilipidemic monotherapy?

Yes

No

Admnister combination therapy ❑ Ezetimibe/simvastatin (1 pill): Recommended starting daily dose 10/20 mg PO once daily at bedtime. Dose range: 10/10 to 10/80 mg ❑ Extended-release niacin/simvastatin (1 pill): Recommended starting daily dose 500/20 mg PO once daily at bedtime. Dose range: 500/20 to 1000/20 mg

Follow-up

Do's

• Treat pediatric patients who are older than 8 years of age with either LDL-C > 190 mg/dL or LDL > 160 mg/dL plus any of the following conditions: either ≥ 2 CV risk factors even after lifestyle intervention, family history of premature CAD, or overweight/obese/insulin resistance.

Don'ts

• Do not routinely order homocysteine, uric acid, plasminogen activator inhibitor 1, or other inflammatory markers.
• Do not routinely perform non-invasive measures of atherosclerosis (e.g. carotid intima media thickness).
• Do not treat dyslipidemia among post-menopausal women with hormonal replacement therapy.