What are the guidelines for checking apolipoprotein B (ApoB) or lipoprotein(a) [Lp(a)] levels in patients at high risk of cardiovascular events?

Guidelines for Checking Apolipoprotein B and Lipoprotein(a)

When to Measure Lipoprotein(a)

Measure Lp(a) at least once in patients with premature CVD, familial hypercholesterolemia, family history of premature CVD or elevated Lp(a), recurrent CVD despite optimal lipid-lowering therapy, or ≥5% 10-year risk of fatal CVD. 1

The European Society of Cardiology/European Atherosclerosis Society provides a Class IIa recommendation (Level C evidence) for measuring Lp(a) in these specific clinical scenarios 1. The Canadian Cardiovascular Society Guidelines similarly recommend measurement in these patient subsets, using a cutoff of >30 mg/dL to define abnormal levels 1, 2. The National Lipid Association also endorses measurement in these same patient populations 1.

Specific Lp(a) Thresholds

• Traditional risk threshold: >30 mg/dL or >75 nmol/L (approximately the 75th percentile in white populations) 1
• European high-risk threshold: >50 mg/dL (~100-125 nmol/L), representing the 80th percentile 1
• Abnormal level per Canadian guidelines: >30 mg/dL 2

Critical Caveat for Lp(a) Measurement

Lp(a) comprises 30-45% cholesterol by mass, which is reported as part of the laboratory "LDL-C" measurement 1, 2. This means patients with elevated Lp(a) may have falsely elevated LDL-C readings and are less likely to achieve target LDL-C levels 1. Additionally, statins and ezetimibe tend to increase Lp(a) mass levels, further complicating interpretation 1.

When to Measure Apolipoprotein B

Measure ApoB when standard LDL-C may underestimate cardiovascular risk, particularly in patients with hypertriglyceridemia, metabolic syndrome, diabetes, or when LDL-C targets are achieved but residual risk remains. 1, 2

The 2012 European guidelines state that ApoB is a similar risk marker to LDL cholesterol and a better index of the adequacy of LDL-lowering therapy 1. There is less laboratory error in determining ApoB than LDL cholesterol, particularly in patients with hypertriglyceridemia 1.

ApoB Target Levels

• Very high CVD risk patients: <80 mg/dL 1, 2
• High CVD risk patients: <100 mg/dL 1, 2

When ApoB is Particularly Useful

ApoB measurement provides refined risk assessment in patients at high cardiometabolic risk, such as those with diabetes mellitus or metabolic syndrome, as these conditions are often associated with normal LDL-C values but increased numbers of small, dense LDL particles (indicating increased ApoB levels) 3. Each atherogenic lipoprotein particle contains exactly one ApoB molecule, making it a direct measure of atherogenic particle number 4, 5.

Important Limitation: No General Population Screening

There is no justification for screening the general population for Lp(a) at present. 1 The European guidelines explicitly state this, and the American College of Cardiology Foundation/American Heart Association does not recommend measurement of lipid parameters beyond standard fasting lipid profiles for cardiovascular risk assessment in asymptomatic adults 2.

Clinical Algorithm for Advanced Lipid Testing

1. Start with standard fasting lipid profile (total cholesterol, LDL-C, HDL-C, triglycerides) for all patients 2

2. Consider Lp(a) measurement if patient has:

   • Premature CVD (men <55 years, women <65 years) 1
   • Familial hypercholesterolemia 1
   • Family history of premature CVD or elevated Lp(a) 1
   • Recurrent CVD events despite optimal statin therapy 1
   • ≥5% 10-year risk of fatal CVD 1

3. Consider ApoB measurement if patient has:

   • Metabolic syndrome or diabetes with normal LDL-C 3
   • Hypertriglyceridemia (>4.5 mmol/L or 400 mg/dL makes calculated LDL-C unreliable) 1
   • Discordance between calculated cardiovascular risk and LDL-C level 5
   • Need to assess adequacy of lipid-lowering therapy 1

Critical Pitfall: ApoB Underestimates Risk in High Lp(a) Patients

In patients with elevated Lp(a), ApoB may considerably underestimate risk because Mendelian randomization studies show that the atherogenicity of Lp(a) is approximately 7-fold greater than that of LDL on a per ApoB particle basis 6. In subjects with increased Lp(a), the association between ApoB and incident coronary heart disease is diminished or even lost 6. This is why measuring both markers separately provides more complete risk assessment in high-risk patients 2.

Measurement Standardization Challenges

Standardization of Lp(a) measurement remains challenging due to size heterogeneity of apo(a) 2. Different assays express Lp(a) levels either in mg/dL (mass) or nmol/L (molar concentration), with no reliable conversion factor between units 2. Despite these challenges, ApoB measurement has better standardization, availability, scalability, and relatively low cost compared to other advanced lipid markers 5.