Fatigued with Friedewald: Why Isn't Everyone Onboard Yet with the New LDL-C Equations?

Madhusudhanan Narasimhan ¹ Jing Cao ¹ Jeffrey Meeusen ² Alan Remaley ³ Seth Shay Martin ⁴ Alagarraju MUTHUKUMAR ^1*

• ¹ Department of Pathology, Medical School, University of Texas Southwestern Medical Center, Dallas, United States
• ² Mayo Clinic, Rochester, Minnesota, United States
• ³ National Institutes of Health (NIH), Bethesda, Maryland, United States
• ⁴ Johns Hopkins Medicine, Johns Hopkins University, Baltimore, Maryland, United States

Many laboratories utilize direct LDL-C assays as part of a reflex protocol at TG >400 mg/dL. Despite the cost associated with the direct LDL-C testing in place of freely available calculations, some laboratories still prefer direct LDL-C assay as part of lipid panel. This approach is followed regardless of the patient's LDL-C or TG levels. However, Miller et al. have shown biases with direct LDL-C assays, often leading to the overestimating of LDL-C in dyslipidemia patients (7). Importantly, their analytical performance in the current context of potent lipid-lowering therapies and stringent LDL-C target levels have remained insufficiently evaluated. It is notable that direct LDL-C assays are also susceptible to discrepancies due to different methodologies and inherent Although the newer LDL-C equations have been independently verified to calculate LDL-C up to TG 800 mg/dL with reasonable accuracy compared with direct LDL-C measurements in different populations (13)(14)(15), at TG levels >500 mg/dL, the clinical priority, in these cases, should be to first reduce the elevated TG level to prevent acute pancreatitis. Given this clinical need and the relatively better performance of the new calculations-based LDL-C estimations at even higher TG levels (Sampson-NIH, up to 800 mg/dL) and lower LDL-C levels (Martin/Hopkins equation, LDL-C <70 mg/dL), it is apparent that fewer patients will only require reflexive direct LDL-C measurements.However, it must be noted that no calculation method is perfect, and direct measurement may still be necessary in some cases, particularly when precise quantification of very low LDL-C levels is critical for clinical decision-making. Notably, in case of rare lipid disorders as in type III hyperlipidemia, the FW equation performs poorly due to inaccurate VLDL-C estimation. However, the Martin/Hopkins equation uses an adjustable factor for the TG:VLDL-C ratio, which may provide more accurate estimates in atypical lipid profiles. Nevertheless, they may still have limitations in accurately estimating LDL-C in type III hyperlipidemia due to the condition's unique lipid profile and an accumulation of remnant lipoproteins. Also, in case of post-prandial conditions, unlike the FW equation, which is limited to fasting samples, the newer equations perform equally well in both fasting and non-fasting samples. Thus, while these newer equations offer improvements over the FW equation and can largely curtail the need for reflexive direct LDL-C measurements, they may not eliminate it entirely, especially for very high TG levels (>800 mg/dL), extremely low levels of LDL-C (below 40 mg/dL), or rare lipid disorders. However, it is important to know that direct LDL-C measurements can also be discordant, particularly in patients with high cardiovascular risk and/or dyslipidemia (7). Table 1 summarizes different LDL-C estimation methods comparison.Given that ADLM and other associations have also acknowledged the strength of newer equations, it is important to address why are we still stuck in the old era and still using the FW equation? Recent informal surveys while indicating a slight increase in adoption of the newer equations, the uptake remains still lukewarm. This raises critical questions: What are the barriers to implementing the new LDL-C equations? Why does the reluctance to move on from the FW equation persist? Is it driven by convenience or perceived complications?We believe the primary reason lies in the convenience of sticking to routine practices and a strong reluctance to change, as the FW equation has been entrenched in clinical use for over 5 decades now. This indeed is also largely fueled by the absence of universal guidelines. Without a clear consensus about how new equations may benefit patients, practitioners and facilities may adopt "if it's not broken, don't fix it" approach and continue with established practices.One of the factors hindering the implementation of new equations, particularly, the MH equation is the prevalent misconception that it is copyrighted and would require a licensing fee for its commercial use. However, it has been recently clarified that the MH equation is royalty-free, addressing this concern. Additionally, some confusion may linger about the term "free" in "royalty-free", as it could be interpreted that it is free only from ongoing royalties but still require a significant one-time licensing fee or other specific licensing terms. Recently, Johns Hopkins University has abandoned the patent application to facilitate the use of their equation without intellectual property restrictions (16). Notably, this decision means that this formula is allowed for broader access and application and can be used freely or even modified without any licensing barriers. Thus, the previously misconstrued concern regarding the "no royalty-free" notion is no longer an issue for the transition to using MH equation. Furthermore, despite some concern about the complexity of implementing the MH equation, Johns Hopkins has made this equation more readily accessible in formats that can be seamlessly integrated into LIS and middleware systems like Data Innovations. Laboratories are encouraged to contact JHTT-Communications@jh.edu and smart100@jhmi.edu for assistance with this process (16). Indeed, they have gone a step further and willing to share line-by-line sample code with labs/health systems that are intending to implement their equation. This approach allows faster, more convenient implementation, with each step in the code visible and modifiable for adaptability across LIS platforms and lab protocols. Besides, it can foster collaboration and troubleshooting through peer-reviewed code snippets. Indeed, the MH equation's ease of implementation is exemplified by its increasing adoption in laboratories While these recent changes reflect the growing recognition of the value of the new LDL-C equations and there is now momentum to move towards these next-gen equations, the transition is still far from complete. Although it must be acknowledged that FW equation have served well for decades, its well-known negative bias contributes to the undertreatment of patients, which is a major issue with lipid-lowering therapy (22).Whatever the reason for its ongoing use, be it convenience, familiarity, and or the perceived complexity of change, it is becoming increasingly untenable to persist with the FW equation given the crucial role that LDL-C plays in the management of cardiovascular disease, a leading worldwide cause of death and morbidity. Indeed, in our view it is long past due to break "free" from the conservative mindset and adopt one of the newer "free" LDL-C equations, specifically the Martin/Hopkins or Sampson-NIH.