dyslipidemia
DYSLIPIDEMIA
Dyslipidemia is having an abnormal amount of lipids or fats in the blood.
Lipid profile is obtained from an individual with diabetes mellitus, coronary heart disease, cerebrovascular disease, peripheral arterial disease or other coronary heart disease risk factors or from an individual with family history or clinical evidence of familial hypercholesterolemia.
Plasma lipids are total cholesterol, high-density lipoprotein cholesterol, trigylcerides, and low-density lipoprotein cholesterol.
Evaluation of lipid profile must be performed in parallel with the risk assessment of coronary heart disease.
  • Lipid profile is obtained from an individual with diabetes mellitus, cardiovascular disease, cerebrovascular disease, or other cardiovascular disease risk factor(s) or from an individual with family history or clinical evidence of familial hypercholesterolemia
    • Cardiovascular diseases include coronary heart disease (CHD), myocardial infarction (MI), coronary insufficiency, angina, ischemic stroke, hemorrhagic stroke, transient ischemic attack, peripheral artery disease (PAD), and heart failure

Measure Plasma Lipids

  • Total cholesterol
  • High-density lipoprotein cholesterol (HDL-C)
  • Triglycerides (TG)
  • Low-density lipoprotein cholesterol (LDL-C) is derived by Friedewald formula: LDL-C (mmol/L) = total cholesterol - HDL-C - [triglycerides/2.2] or LDL-C (mg/dL) = total cholesterol - HDL-C - [triglycerides/5 ]

Considerations

  • Fasting or a non-fasting plasma lipid profile can be used in screening and in risk estimation
    • Non-fasting samples can be used to document baseline lipid levels before initiation of statin therapy in patients with clinical atherosclerotic cardiovascular disease (ASCVD)
    • Fasting lipid profile is recommended for initial evaluation in patients with a family history of premature ASCVD, genetic hyperlipidemia or for follow-up of patients with hypertriglyceridemia
    • Total cholesterol and HDL-C can be measured accurately at any time of the day
    • Triglycerides levels are affected by food resulting to a higher plasma level of about 27 mg/dL (0.3 mmol/L), by alcohol intake within 24 hours prior to measurement and by smoking during the fasting state
  • Friedewald formula can only be used if triglycerides <4.5 mmol/L (<400 mg/dL) but is only recommended for use during fasting states
  • In patients with triglycerides >4.5 mmol/L (400 mg/dL), non HDL-C should be the alternative primary target of treatment
  • If triglycerides is >2.3 mmol/L (200 mg/dL), non HDL-C is a better indicator of total atherogenic burden
  • Plasma measurement of cholesterol is 3% lower than serum measurements
  • Levels will be affected by recent acute illness (eg fever, surgery, stroke) and drugs (eg beta-blockers, steroids, thiazides)
  • Cholesterol level is low 24 hours-3 months after myocardial infarction
    • If possible, measure lipids within 24 hours of myocardial infarction
  • ≥1 measurement is needed to make hyperlipidemic diagnosis because of biological variability

Dyslipidemia Screening

  • The U.S. Preventive Services Task Force recommends that if risk of coronary heart disease (CHD) is increased, screen men 20-35 years old and women 20-45 years old 
  • More frequent assessments are needed for all patients with cardiovascular disease (CVD) risk factors and those with a family history of premature CVD (definite myocardial infarction or sudden death prior to age 55 years in father or other male 1st-degree relative, or before age 65 years in mother or other female 1st-degree relative)
  • Women should be screened in the same way as men

Young Adults (Men 20-45 Years of Age; Women 20-55 Years of Age)

  • The U.S. Preventive Services Task Force recommends screening for lipid disorders in men ≥35 years old and women ≥45 years old if the latter is at increased risk of CHD 
  • Evaluate for dyslipidemia every 5 years

Middle-aged Adults (Men 45-65 Years of Age; Women 55-65 Years of Age)

  • Evaluate at least every 1-2 years in the absence of CVD risk factors
  • Evaluate more frequently in the presence of multiple global CVD risk factors

Adults >65 Years of Age

  • Evaluate annually those with 0-1 cardiovascular disease risk factor

Adult with Diabetes Mellitus (DM)

  • All adult patients with diabetes mellitus should be screened annually for dyslipidemia

Pediatric Screening

  • Children >2 years of age should be screened every 3-5 years if they have CVD risk factors, family history of dyslipidemia or premature cardiovascular disease, obese or overweight, have other elements of insulin resistance syndrome, or have no available family history
  • Adolescents >16 years of age should be screened every 5 years
  • If with cardiovascular disease risk factors, with family history of dyslipidemia or premature cardiovascular disease, obese or overweight, or with other elements of insulin resistance syndrome, screen patient more frequently

Dyslipidemia Screening Tests

Fasting Lipid Profile

  • Used to ensure that the most accurate lipid assessment is achieved
    • For lipid screening, both fasting and non-fasting specimens may be utilized
  • Includes plasma or serum total cholesterol, LDL-C, HDL-C and triglycerides

LDL-C

  • Recommended as the primary lipid analysis method for screening, diagnosis and management of dyslipidemia 
  • Direct measurement of LDL-C in certain high-risk patients (eg patients with diabetes mellitus, vascular disease, fasting triglycerides level >250 mg/dL or >2.9 mmol/L) is recommended
    • Estimation by Friedewald equation is valid only for values obtained in the fasting state, and is largely inaccurate in triglycerides levels >200 mg/dL (>2.3 mmol/L) and is invalid when triglycerides levels are >400 mg/dL (4.5 mmol/L)

HDL-C

  • HDL-C >60 mg/dL (>1.6 mmol/L) is an independent negative risk factor for dyslipidemia in both sexes
  • In women, very low HDL-C (<40 mg/dL or 1.03 mmol/L) is an independent risk factor for development of cardiovascular disease and mortality, even in the presence of normal LDL-C and/or triglyceride levels or total cholesterol level <200 mg/dL (<5.2 mmol/L)
    • Women with low HDL-C have a cardiovascular disease risk elevated to almost 3-fold (as compared with women with high HDL-C)
  • Considered as an alternative risk marker, especially in combined hyperlipidemias, diabetes, metabolic syndrome or chronic kidney disease

Non-HDL-C (total cholesterol minus HDL-C)

  • In patients with moderately increased triglycerides (200-500 mg/dL or 2.3-5.6 mmol/L), diabetes mellitus and/or established cardiovascular disease, or if insulin resistance is suspected, measure non-HDL-C
  • Provides a better risk assessment than LDL-C alone in patients with moderately elevated triglycerides

Triglycerides

  • Triglycerides levels ≥150 mg/dL (>1.7 mmol/L) may help identify those at risk for insulin resistance syndrome
  • Triglycerides levels ≥200 mg/dL (≥2.3 mmol/L) may point to a significant increase in the risk for cardiovascular disease
  • Very high trigylceride level is associated with increased risk of pancreatitis

Apolipoprotein B

  • Target apo B level to <90 mg/dL (<0.9 g/L) for those at risk of cardiovascular disease (including those with diabetes mellitus)
  • Target apo B level to <80 mg/dL (<0.8 g/L) for those with established cardiovascular disease or those with diabetes mellitus who have ≥1 additional risk factors
  • May help evaluate the success of LDL-C lowering therapy
  • Recommended for risk assessment in patients with high TG levels, DM, obesity, metabolic syndrome or very low LDL-C levels
    • Considered as an alternative risk marker, especially in combined hyperlipidemias, diabetes, metabolic syndrome or chronic kidney disease
  • Apo B and/or Apo B/Apo A1 ratio calculation and evaluation in patients with (triglycerides ≥150, HDL-C <40, prior atherosclerotic cardiovascular disease (ASCVD) event, type 2 diabetes mellitus, and/or insulin resistance syndrome may help in determining the best treatment strategy
  • Apo B reflects LDL particle number and is considered a more potent measure of cardiovascular disease risk as compared with LDL-C and LDL particle size

Lipoprotein(a) [Lp(a)]

  • A LDL particle with an Apo(a) moeity that has pro-atherogenic effects attributed to its pro-coagulant and pro-inflammatory effects
  • Should be measured at least once in a person's lifetime to identify people who have inherited an elevated Lp(a) level of  ≥180 mg/dL (≥430 nmol/L) and have a very high lifetime risk of ASCVD
  • Should be considered in patients with an estimated 10-year risk of ASCVD that is near the threshold between high and moderate risk

Classification

Hypercholesterolemia

  • Increased LDL, total cholesterol, and LDL-C

Hypertriglyceridemia

  • A state where VLDL and triglycerides are significantly increased
    • Mild hypertriglyceridemia: Triglycerides >1.7 mmol/L (>150 mg/dL)
    • Moderate hypertriglyceridemia: Triglycerides <10 mmol/L (<880 mg/dL)
    • Severe hypertriglyceridemia: Triglycerides >10 mmol/L (>900 mg/dL)
  • Etiologic factors include heredity, obesity, type 2 diabetes mellitus, high carbohydrate diet, renal disease, medications (eg corticosteroids, Tamoxifen, Ciclosporin, estrogens, protease inhibitors, Isotretinoin)

Combined Dyslipidemia

  • Increased LDL, VLDL, total cholesterol, LDL-C, and triglycerides

Lipid Profile Evaluation

 

IDEAL LIPID LEVELS
  Optimal/Near-Optimal Serum Concentration Borderline High Serum Concentration High-Risk/Very High-Risk Serum Concentration
LDL-C Optimal: <100 mg/dL (<2.6 mmol/L)
Near-optimal: 100-129 mg/dL (2.6-3.3 mmol/L)
130-159 mg/dL (3.4-4.1 mmol/L) 160-189 mg/dL (4.1-4.9 mmol/L) (high)
≥190 mg/dL (4.9 mmol/L) (very high)
Triglycerides <150 mg/dL (<1.7 mmol/L) 150-199 mg/dL (1.7-2.3 mmol/L) 200-499 mg/dL (2.3-5.6 mmol/L) (high)*
≥500 mg/dL (>5.6 mmol/L) (very high)*
HDL-C ≥60 mg/dL (1.6 mmol/L) Male: 40-59 mg/dL (1-1.3 mmol/L)
Female: 50-59 mg/dL (1.3-1.5 mmol/L)
Male: <40 mg/dL (<1 mmol/L)
Female: <50 mg/dL (<1.3 mmol/L)
Non-HDL-C  30 mg/dL above LDL-C goal 30 mg/dL above LDL-C goal 25 mg/dL above LDL-C goal (extreme risk patients)
Total Cholesterol <200 mg/dL (5.2 mmol/L) 200-239 mg/dL (5.2-6.1 mmol/L) >240 mg/dL (6.2 mmol/L)
Apo B Not recommended <90 mg/dL (patients at risk of coronary heart disease) <80 mg/dL (patients with coronary heart disease or diabetes mellitus plus ≥1 risk factor)
<70 mg/dL (patients at extreme risk)
Modified from: Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of atherosclerosis. Endocr Pract. 2017.
*The Endocrine Society (2010) classifies triglyceride levels of >200 mg/dL as moderate hypertriglyceridemia (200-999 mg/dL), severe hypertriglyceridemia (1000-1999 mg/dL) and very severe hypertriglyceridemia (>2000 mg/dL); the levels corresponding to risk levels for premature cardiovascular disease and pancreatitis

 

Lipid Treatment Goals Based on Cardiovascular Disease Risk
 Risk Categories LDL-C Non-HDL-C Apolipoprotein B
Extreme Risk <55 mg/dL   <80 mg/dL <70 mg/dL 
Very High Risk  <70 mg/dL  <100 mg/dL <80 mg/dL
High Risk <100 mg/dL  <130 mg/dL  <90 mg/dL 
Moderate Risk <100 mg/dL1   <130 mg/dL  <90 mg/dL
Low Risk  <130 mg/dL1  <160 mg/dL --
1LDL-C levels for low to moderate risk patients average 115 mg/dL as per the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
Modified from: Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of atherosclerosis. Endocr Pract. 2017.

Risk Stratification

  • Evaluation of lipid profile must be performed in parallel with risk assessment for cardiovascular disease
    • LDL-C is used as primary lipid analysis for screening and risk estimation
  • Risk assessment tools [eg Framingham risk score, Reynold’s risk score, Systemic Coronary Risk Estimation (SCORE), Multi-Ethnic Study of Atherosclerosis (MESA) 10-year ASCVD risk with coronary artery calcification calculator, United Kingdom Prospective Diabetes Study (UKPDS) risk engine in individuals with type 2 diabetes mellitus, etc] are commonly used to assess a patient’s risk for cardiovascular disease
    • Point system for cardiovascular disease risk differs by gender
    • Framingham risk score:
      • Predictors include age, sex, smoker/non-smoker, total cholesterol and HDL cholesterol levels, systolic blood pressure and if the patient is being treated with antihypertensive drugs
      • High systolic blood pressure, age, total cholesterol and smoking are more significant in women
      • 130-139 mmHg systolic blood pressure has more points in women (untreated - 2; treated - 4) than in men (untreated - 1; treated - 2) but overall points have lower threshold for men than in women (10 total points = 6% 10-year risk in men vs 1% in women)
    • ASCVD risk assessment is not necessary in secondary prevention, in individuals with LDL-C ≥190 mg/dL, or in those 40-75 years old with diabetes mellitus
  • Identify patients with established cardiovascular disease or with cardiovascular disease risk equivalents: Diabetes mellitus, peripheral artery disease (PAD) or abdominal aortic aneurysm
  • Major independent risk factors for cardiovascular disease
    • Cigarette smoking
    • Hypertension (elevated blood pressure or on antihypertensive medication)
      • History of preeclampsia or pregnancy-induced hypertension in women
    • Low HDL cholesterol (<40 mg/dL)
    • Increased total serum cholesterol level
    • Increased non-HDL-cholesterol levels
    • Increased LDL-cholesterol levels (≥190 mg/dL)
    • Family history of premature atherosclerotic cardiovascular disease (male 1st-degree relative <55 years; female 1st-degree relative <65 years)
    • Age (men ≥45 years; women ≥55 years)
    • Chronic kidney disease (CKD) stage 3/4
    • Diabetes mellitus
      • For individuals with high HDL cholesterol (>60 mg/dL), subtract 1 risk factor from the total
      • History of gestational diabetes in women
  • Additional risk factors
    • Dyslipidemic triad (hypertriglyceridemia, low HDL-C, small dense LDL-C)
    • Obesity, abdominal obesity
    • Elevated apo B
    • Elevated LDL particle number
    • Fasting/postprandial hypertriglyceridemia
    • Family history of hyperlipidemia
    • Polycystic ovarian syndrome (PCOS) in women
    • Elevated small dense LDL-C
    • Microalbuminuria/proteinuria
    • History of premature menopause
    • South Asian ancestry
  • Nontraditional risk factors
    • Elevated lipoprotein (a)
    • Elevated clotting factors
    • Elevated inflammation markers
    • Elevated triglyceride-rich remnants
    • Elevated homocysteine levels
    • Apo E4 isoform
    • Elevated uric acid

Cardiovascular Disease Risk Categories

    Risk Category Risk Factors/10-year Risk
    Extreme Risk Progressive atherosclerotic cardiovascular disease including unstable angina after reduction of LDL-C to <70 mg/dL or
    Established clinical cardiovascular disease in patients with diabetes mellitus, chronic kidney disease, or heterozygous familial hypercholesterolemia or
    History of premature atherosclerotic cardiovascular disease at <55 years of age in males; <65 years of age in females
    Very High Risk History of recent hospitalization for acute coronary syndrome (ACS), coronary, carotid, or peripheral vascular disease and 10-year risk >20% or diabetes or CKD ¾ plus ≥1 additional risk factor(s) or heterozygous familial hypercholesterolemia
    High Risk ≥2 risk factors and 10-year risk 10-20% or CHD risk equivalents, including diabetes or moderate chronic kidney disease with no other risk factors
    Moderate Risk ≤2 risk factors and <10% 10-year cardiovascular disease risk 
    Low Risk 0 risk factor (<1% 10-year cardiovascular disease risk)

Metabolic Syndrome

  • Non-HDL-C is secondary target of therapy (LDL-C lowering is primary)

Clinical Identification

  • Any 3 or more of the following (including those on treatment):
    • Increased waist circumference (Asian cut off: ≥80 cm for females; ≥90 cm for males)
    • Raised triglycerides level ≥1.7 mmol/L (150 mg/dL) or specific treatment for this lipid abnormality
    • Reduced HDL cholesterol <1 mmol/L (40 mg/dL) in males and <1.3 mmol/L (50 mg/dL) in females or specific treatment for this lipid abnormality
    • Raised blood pressure (systolic blood pressure (SBP) ≥130 mmHg or diastolic blood pressure (DBP) ≥85 mmHg) or treatment of previously diagnosed hypertension
    • Disorders of glycemia:
      • Type 2 diabetes mellitus, or
      • Impaired glucose tolerance (IGT): Fasting plasma sugar <7 mmol/L (<125 mg/dL) and 2 hrs post-75 g glucose load 7.8-11.1 mmol/L (140-200 mg/dL), or
      • Impaired fasting glucose (IFG): Fasting plasma sugar 6.1-7.0 mmol/L (110-125 mg/dL)

Manage the Underlying Causes

  • Obesity and physical activity
    • Weight loss and increased physical activity will reduce all of the above risk factors
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