What is non-HDL (non-high-density lipoprotein) cholesterol?

What is Non-HDL Cholesterol?

Non-HDL cholesterol is calculated by subtracting HDL cholesterol from total cholesterol, and it represents the cholesterol content of all atherogenic apolipoprotein B-containing lipoproteins including LDL, VLDL, IDL, remnant lipoproteins, and Lp(a). 1

Definition and Calculation

• Non-HDL cholesterol = Total cholesterol - HDL cholesterol 1
• This simple calculation captures the sum of VLDL cholesterol, IDL cholesterol, and LDL cholesterol 1
• It quantifies the total pool of atherogenic lipoproteins in plasma 1

Why Non-HDL Cholesterol Matters

Superior to LDL Cholesterol in Several Clinical Contexts

• Non-HDL cholesterol predicts cardiovascular disease risk similarly to or even better than LDL cholesterol 1
• Multiple large epidemiological studies including the Health Professionals Follow-up Study, Framingham Heart Study, Framingham Offspring Study, and Women's Health Study have demonstrated the superiority of non-HDL cholesterol to LDL cholesterol in predicting coronary heart disease 1
• In clinical trials like Treating to New Targets (TNT) and Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL), on-treatment non-HDL cholesterol was a better predictor of reduced cardiovascular events than LDL cholesterol levels 1

Practical Advantages Over LDL Cholesterol

• Non-HDL cholesterol does not require fasting and can be measured in non-fasting samples, making it more convenient for patients 1
• Unlike calculated LDL cholesterol (using the Friedewald formula), non-HDL cholesterol remains accurate even when triglycerides are elevated above 4.5 mmol/L (400 mg/dL) 1
• It is a better measure than calculated LDL cholesterol, particularly for patients with high non-fasting triglyceride concentrations 1
• LDL cholesterol measurement is labor-intensive, incompletely validated when measured directly, and inaccurate when LDL levels are very low or triglycerides are high 1

Captures Residual Atherogenic Risk

• Non-HDL cholesterol includes remnant lipoproteins (partially degraded VLDL), which are atherogenic and contribute to cardiovascular risk 1
• It is highly correlated with apolipoprotein B levels (r>0.9), which directly measures the number of atherogenic particles 1
• Non-HDL cholesterol captures atherogenic particles that LDL cholesterol alone misses, particularly in patients with elevated triglycerides, diabetes, obesity, or metabolic syndrome 2, 3

Clinical Application and Treatment Targets

Guideline Recommendations

• The ACC/AHA identifies non-HDL cholesterol as a secondary target of therapy in persons with triglycerides greater than 200 mg/dL 1
• The goal for non-HDL cholesterol is 30 mg/dL higher than the corresponding LDL cholesterol goal because normal VLDL cholesterol is approximately 30 mg/dL 1
• For patients with established coronary disease and triglycerides ≥200 mg/dL, the non-HDL cholesterol goal is 130 mg/dL (corresponding to an LDL goal of <100 mg/dL) 1
• European guidelines recommend transferring LDL limits to non-HDL limits by adding 0.8 mmol/L (30 mg/dL) 1

When to Prioritize Non-HDL Cholesterol

• Use non-HDL cholesterol as the preferred marker in patients with elevated triglycerides (>200 mg/dL), diabetes, obesity, metabolic syndrome, or very low LDL cholesterol (<70 mg/dL) 2, 3
• Non-HDL cholesterol is particularly useful when LDL cholesterol cannot be accurately calculated due to high triglycerides 1
• Several guidelines recommend including non-HDL cholesterol measurements as adjuncts or alternatives to LDL cholesterol for risk assessment and monitoring treatment 1

Relationship to Apolipoprotein B

• Non-HDL cholesterol serves as an acceptable surrogate marker for total apolipoprotein B when apoB measurement is not available 1
• ApoB is the major apolipoprotein of all atherogenic lipoproteins (one apoB molecule per particle on chylomicrons, VLDL, IDL, LDL, and Lp(a)) 1
• While apoB directly measures particle number and may be slightly superior in some contexts, non-HDL cholesterol is more readily available and less expensive 1, 2
• In the Emerging Risk Factors Collaboration, non-HDL cholesterol and apoB had equivalent predictive value and were both superior to LDL cholesterol 1

Common Pitfalls to Avoid

• Do not ignore non-HDL cholesterol in patients with "controlled" LDL cholesterol but elevated triglycerides—these patients may have significant residual cardiovascular risk 4
• Non-HDL cholesterol should not be used as a treatment target in isolation; it is designated as a secondary target after LDL cholesterol goals are addressed 1
• Remember that non-HDL cholesterol includes Lp(a), which is independently atherogenic but not modifiable by most lipid-lowering therapies 4