Dyslipidemia Diagnosis

• 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 (TC)
• High-density lipoprotein cholesterol (HDL-C)
• Non-HDL-C: TC - HDL-C
• Triglycerides (TG)
• Low-density lipoprotein cholesterol (LDL-C) is derived by Friedewald formula: LDL-C (mmol/L) = TC - HDL-C - (TG x 0.45) or LDL-C (mg/dL) = TC - HDL-C - (TG x 0.2)

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
  • TC and HDL-C can be measured accurately at any time of the day
  • TG levels are affected by food resulting to a higher plasma level of about 0.3 mmol/L (27 mg/dL), by alcohol intake within 24 hours prior to measurement and by smoking during the fasting state
  • Non-HDL cholesterol can be computed even from a non-fasting lipid profile
• Friedewald formula can only be used if TG <4.5 mmol/L (<400 mg/dL) but is only recommended for use during fasting states
• In patients with TG >4.5 mmol/L (>400 mg/dL), non-HDL-C >3.37 mmol/L (>130 mg/dL) should be the alternative primary target of treatment
• If TG 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)
• 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 TC, LDL-C, HDL-C and TG

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 TG level >2.9 mmol/L or >250 mg/dL) is recommended
  
  • Estimation by Friedewald equation is valid only for values obtained in the fasting state, and is largely inaccurate in TG levels >2.3 mmol/L (>200 mg/dL) and is invalid when TG levels are >4.5 mmol/L (>400 mg/dL)

HDL-C

• HDL-C >1.6 mmol/L (>60 mg/dL) is an independent negative risk factor for dyslipidemia in both sexes
  
• In women, very low HDL-C (<1.03 mmol/L or <40 mg/dL) is an independent risk factor for development of cardiovascular disease and mortality, even in the presence of normal LDL-C and/or TG levels or TC level <5.2 mmol/L (<200 mg/dL)
  
  • 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 (CKD)

Non-HDL-C (TC minus HDL-C)

• In patients with moderately increased TG (2.3-5.6 mmol/L or 200-500 mg/dL), 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 TG
• Shows the total atherogenic burden including particles contained within VLDL, intermediate-density lipoproteins (IDL), LDL, chylomicron remnants and lipoprotein(a) [Lp(a)]
• Can be considered as an additional therapeutic target for residual CV risk reduction after the LDL-C has been reached
  

Triglycerides

• TG levels >1.7 mmol/L (>150 mg/dL) may help identify those at risk for insulin resistance syndrome
  
• Persistent TG levels ≥175 mg/dL 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
• Can be considered as an additional therapeutic target to further reduce CV event in individuals on statin therapy who have achieved their LDL-C goal
• 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 TG ≥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
• Measurement of apo B-100 provides a more accurate evaluation of atherogenicity since all atherogenic particles (VLDL, IDL, LDL) contain 1 apo B-100 molecule

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 ≥430 nmol/L (≥180 mg/dL) 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

Other Diagnostic Tests

• A high-sensitivity C-reactive protein of ≥2 mg/dL and an ankle-brachial index of <0.9 are associated with increased risk of ASCVD 

Hypercholesterolemia

• Increased LDL, TC, and LDL-C

Hypertriglyceridemia

• A state where very-low-density lipoproteins (VLDL) and TG are significantly increased
  • Desirable level: TG <1.7 mmol/L (<150 mg/dL)
  • Moderate/high hypertriglyceridemia: TG 1.7-5.6 mmol/L (150-499 mg/dL)
  • Severe/very high hypertriglyceridemia: TG >5.6 mmol/L (≥500 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, TC, LDL-C, and TG

• Relative reduction of risk is proportional to the absolute LDL-C reduction and the absolute LDL-C reduction resulting from a particular drug regimen depends only on baseline LDL-C, at any given level of baseline risk the higher the initial LDL-C level the greater the absolute reduction in risk

• 2021 Canadian Cardiovascular Society (CCS) guideline recommends initiation of statin therapy for primary prevention based on the Framingham Risk Score (FRS):
  • High risk
  • Intermediate risk: FRS (10-19.9%) and any of the following:
    • LDL-C ≥3.5 mmol/L (≥135 mg/dL), non-HDL-C ≥4.2 mmol/L (≥162 mg/dL), ApoB ≥105 mg/dL, men ≥50 years and women ≥60 years with additional risk factors or with presence of other risk modifiers
  • Low risk: Not recommended for statin therapy except for individuals with any of the following:
    • LDL-C ≥5.0 mmol/L (≥193 mg/dL), non-HDL-C ≥5.8 mmol/L (≥225 mg/dL), ApoB ≥145 mg/dL or
    • Framingham Risk Score (FRS) is 5-9.9% with LDL-C ≥3.5 mmol/L (≥135 mg/dL), non-HDL-C ≥4.2 mmol/L (≥162 mg/dL), ApoB ≥105 mg/dL with other cardiovascular risk modifiers

Lipid Treatment Goals 

• Targeted approach to lipid management is primarily aimed at reducing atherosclerotic risk by substantially lowering LDL-C levels
• Currently, no specific treatment goals for HDL-C or TG levels have been established in clinical trials

• 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], Risk Factor Counting, 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
  • SCORE can be used in different populations when recalibrated by adjusting for secular changes in CVD mortality and risk factor prevalence
  • In the Philippines, Risk Factor Counting is used as the method of identifying the risk of the Filipino individual for CVD; statin therapy can be considered for primary prevention in individuals without diabetes aged ≥45 years old with LDL-C ≥130 mg/dL and at least ≥2 risk factors

• 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)
  • 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 and excess of small, dense LDL)
  • Chronic inflammatory conditions, eg HIV/AIDS, psoriasis, rheumatoid arthritis
  • 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

• 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 TG 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 hours 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