Are Low-Density Lipoprotein Cholesterol (LDL-C) and calculated Low-Density Lipoprotein (LDL) the same?

LDL-C and Calculated LDL: Understanding the Terminology and Clinical Differences

LDL-C (Low-Density Lipoprotein Cholesterol) is the term used to describe the cholesterol content within LDL particles, and it can be obtained through two different methods: calculation using the Friedewald formula or direct measurement—these are NOT clinically equivalent despite measuring the same biological entity. 1, 2

The Two Methods of Obtaining LDL-C

Calculated LDL-C (Friedewald Formula)

• The Friedewald equation calculates LDL-C as: Total Cholesterol - HDL-C - (Triglycerides/5) in mg/dL, or Total Cholesterol - HDL-C - (Triglycerides/2.2) in mmol/L. 1, 2
• This is the standard method used in most clinical trials and forms the evidence base for cholesterol management guidelines. 1
• The calculation assumes a constant cholesterol-to-triglyceride ratio in VLDL particles and requires three separate measurements (total cholesterol, HDL-C, and triglycerides), allowing methodological errors to accumulate. 1

Direct LDL-C Measurement

• Direct measurement uses immunochemical or enzymatic methods to measure LDL-C without calculation. 1
• This method can be used in non-fasting samples and when triglycerides are elevated. 1

Critical Clinical Differences Between Methods

Direct and calculated LDL-C values can differ by approximately 15%, which is clinically significant for treatment decisions. 1, 3

When the Friedewald Formula Becomes Invalid

• The Friedewald calculation cannot be used when triglycerides exceed 400 mg/dL (4.5 mmol/L) because the triglyceride-to-cholesterol ratio in VLDL progressively increases with worsening hypertriglyceridemia. 1, 2
• The formula should not be used in non-fasting samples. 1
• Research suggests the formula may also be inaccurate with very low triglyceride levels (<50 mg/dL) combined with high cholesterol. 4

Clinical Concordance Issues

• In one study, clinical concordance between direct and calculated LDL-C was present in only 40% of patients, with clinical discordance noted in 25%. 5
• Approximately 60% of subjects showed differences greater than 5 mg/dL and 6% between the two methods. 5
• One-third of patients had differences exceeding 15 mg/dL, and 25% had differences greater than 20 mg/dL. 5

Impact of Treatment on LDL-C Measurement

Lipid-lowering medications alter the mathematical relationships between lipid components, making calculated LDL-C less accurate in patients on statin therapy. 3

• Statin therapy specifically changes LDL particle composition, affecting cholesterol content per particle and particle size distribution. 3
• Patients with metabolic syndrome or hypertriglyceridemia have discordant LDL-C and LDL particle numbers, with normal LDL-C but larger particle numbers and lower cholesterol mass per particle. 3

Clinical Algorithm for Practice

Use the Friedewald formula for routine screening when triglycerides are <400 mg/dL (4.5 mmol/L) in fasting samples. 1, 2

Switch to direct LDL-C measurement or use non-HDL-C (Total Cholesterol - HDL-C) as an alternative target when: 1, 2

• Triglycerides ≥400 mg/dL (4.5 mmol/L)
• Non-fasting samples are obtained
• LDL-C <70 mg/dL (for improved accuracy) 3
• Patients are on lipid-lowering therapy and precise monitoring is needed 3

Common Pitfalls to Avoid

• Do not assume direct and calculated LDL-C are interchangeable for treatment decisions, especially near treatment thresholds (70,100,190 mg/dL). 1, 5
• Most LDL-C methods incorrectly count cholesterol in Lp(a) particles as "LDL-C," overestimating true LDL-C levels, particularly in treated patients. 3
• The disagreement between methods depends on the analytical system used and is associated with individual laboratory variations. 6
• Both methods show similar intraindividual variability (CV ~7%), requiring at least two measurements to reduce total variability to ≤5%. 7