How LDL Cholesterol is Calculated
LDL cholesterol is most commonly calculated using the Friedewald formula: LDL-C = Total Cholesterol - HDL-C - (Triglycerides/5) when measured in mg/dL, or LDL-C = Total Cholesterol - HDL-C - (Triglycerides/2.2) when measured in mmol/L. 1
The Friedewald Formula
The standard calculation method endorsed by European and American guidelines uses the following equations 1, 2:
- In mg/dL: LDL-C = Total Cholesterol - HDL-C - (Triglycerides/5)
- In mmol/L: LDL-C = Total Cholesterol - HDL-C - (Triglycerides × 0.45)
This formula assumes that the ratio of triglycerides to cholesterol in VLDL particles is 5:1 when measured in mg/dL 3, 4.
Critical Limitations of the Friedewald Formula
The Friedewald calculation becomes invalid when triglycerides exceed 4.5 mmol/L (400 mg/dL), as the triglyceride-to-cholesterol ratio in VLDL particles progressively increases with worsening hypertriglyceridemia. 1, 3
Additional Accuracy Concerns
- The calculated LDL-C systematically underestimates true LDL-C by approximately 20 mg/dL on average compared to direct measurement, with this discrepancy increasing as triglycerides rise 5
- In patients with triglycerides 0.51-2.00 g/L, using a divisor of 4.5 instead of 5 provides better accuracy 4
- Female sex, elevated body mass index, and age in the fifth-sixth decades result in greater underestimation 5
When to Use Alternative Methods
For patients with triglycerides >4.5 mmol/L (400 mg/dL), or LDL-C <70 mg/dL, use direct LDL-C measurement or newer calculation methods like the Sampson-NIH2 equation (valid up to triglycerides of 9 mmol/L). 6, 2, 3
Newer Calculation Methods
- Sampson-NIH2 equation: Derived using beta-quantification and can be used with triglycerides up to 9 mmol/L 3
- Martin-Hopkins equation: Uses 180-cell stratification and can be used with triglycerides up to 4.5 mmol/L (extended version up to 9.04 mmol/L) 3
Clinical Impact on Treatment Decisions
Direct LDL-C measurements can differ by approximately 15% from calculated values, which is clinically significant for determining whether patients meet treatment goals. 1, 6
Treatment Goal Misclassification
- Approximately 50% of high-risk patients who appear to meet their LDL goal by calculated method actually fail to meet goal when measured directly 5
- When using the Friedewald formula with triglycerides ≤4.00 g/L, only 86% of patients are properly classified according to treatment cutpoints 4
Special Considerations in Treated Patients
Lipid-lowering medications alter the mathematical relationships between lipid components, making calculated LDL-C less accurate in patients on statin therapy. 6
- Statins specifically alter LDL particle composition and cholesterol content per particle 6
- Most LDL-C methods incorrectly count cholesterol in Lp(a) particles as "LDL-C," overestimating true LDL-C particularly in treated patients 6
- Patients with metabolic syndrome have discordant LDL-C and LDL particle numbers, with normal calculated LDL-C but higher particle numbers 6
Practical Algorithm for Clinical Use
For routine screening and most patients: Use the Friedewald formula if triglycerides <4.5 mmol/L (400 mg/dL) 1
For high triglycerides (>400 mg/dL): Use direct LDL-C measurement or calculate non-HDL-C (Total Cholesterol - HDL-C) as an alternative target 1
For very low LDL-C (<70 mg/dL) or treated high-risk patients: Consider direct measurement or Sampson-NIH2 equation for greater accuracy 6, 3
When direct measurement unavailable: Use non-HDL-C as the treatment target, which doesn't require triglyceride levels and may better predict cardiovascular risk 1