From the Guidelines
When triglyceride levels exceed 400 mg/dL (4.5 mmol/L), the LDL cholesterol calculation using the Friedewald formula becomes unreliable and should not be used. At these high triglyceride levels, the formula significantly underestimates LDL cholesterol, as noted in the european guidelines on cardiovascular disease prevention in clinical practice 1. The calculation is valid only when the concentration of triglycerides is <4.5 mmol/L (400 mg/dL) because the triglyceride/cholesterol ratio in triglyceride-carrying lipoproteins (VLDL and chylomicrons) progressively increases as hypertriglyceridaemia increases in severity 1.
Key Points to Consider:
- The Friedewald formula assumes a fixed ratio between triglycerides and very low-density lipoprotein (VLDL) cholesterol, which becomes inaccurate with hypertriglyceridemia.
- Direct LDL measurement should be used instead of the calculated value when triglycerides are elevated above 400 mg/dL.
- Alternative formulas like the Martin-Hopkins equation may provide better estimates at moderately elevated triglyceride levels.
- Managing the underlying cause of hypertriglyceridemia through diet, exercise, and sometimes medication is important for accurate cholesterol assessment and cardiovascular risk reduction.
Clinical Implications:
- Healthcare providers should order a direct LDL test when triglycerides exceed 400 mg/dL.
- Accurate assessment of LDL cholesterol is crucial for determining cardiovascular risk and guiding treatment decisions.
- Elevated triglycerides are a significant risk factor for cardiovascular disease, and their management is essential for reducing this risk 1.
From the Research
When to Avoid Using LDL to Calculate Cholesterol
- Triglyceride levels play a significant role in determining the accuracy of LDL calculations.
- According to 2, when triglyceride (TG) levels are <150 mg/dl, differences between calculated and directly measured LDL-C values are minimal.
- However, when TG levels are >150 mg/dl, the accuracy of LDL calculations using the Friedewald equation decreases, and alternative methods such as the Martin-Hopkins or NIH equation 2 may be more accurate 2.
- Studies have shown that when TG levels are >250 mg/dl, inaccuracies are seen with all calculation methods, although the NIH equation 2 remains the most accurate 2.
- Another study found that when TG levels are ≥400 mg/dL, the Martin and Sampson equations demonstrate reduced bias compared to the Friedewald equation, but may still not be sufficiently accurate to report LDL-C 3.
- It is essential to consider the limitations of LDL calculations in patients with high triglyceride levels and to use alternative methods or direct measurement when possible, as supported by 4 and 5.
Alternative Methods for Estimating LDL-C
- The Martin-Hopkins equation and NIH equation 2 may be more accurate than the Friedewald equation for estimating LDL-C in patients with high triglyceride levels 2.
- A novel method using an adjustable factor for the TG:VLDL-C ratio has been shown to provide more accurate guideline risk classification than the Friedewald equation, especially in patients with high triglyceride levels 4.
- The Martin formula has been found to show a relatively better separation and strong correlation with directly measured LDL-C concentrations, although it may still have a negative bias 5.