Modern Therapies Call for an Update to the Friedewald Estimation

Seth S. Martin, MD, MHS
Johns Hopkins University School of Medicine

Martin SS. Modern therapies call for an update to the Friedewald estimation [published online February 25, 2019]. Cardiology Consultant.



While the gold standard for assessing low-density lipoprotein cholesterol (LDL-C) is ultracentrifugation, it is a method that is just not scalable or suitable for broad clinical practice. Ultracentrifugation requires much laboratory skill and is timely and expensive. Understanding there was a need for accurate estimation of LDL cholesterol levels, in the 1970s, Dr William Friedewald and colleagues developed what is now known as the Friedewald estimation—a technique that could be broadly applied in clinical practice.

When the Friedewald method was developed, it was highly accurate in that era of medicine, and it has served science very well over the years.

Friedewald and colleagues had recognized that although the estimated portion of the equation is not entirely accurate, it is a relatively small portion of the equation in people with higher levels of LDL cholesterol. And because it was a relatively small portion, they deemed the method’s assessment was reasonable.

However, the situation has changed, for in modern practice we drive LDL levels down to much lower levels, which has been achievable using modern therapies. And as such, the estimated portion of the equation is larger and, therefore, more important. This was fully predicted by Friedewald and colleagues that that would be the case, and we are now in need for a more precise assessment of the estimated portion of the equation.


A New Approach

The main benefit of our updated estimation technique is avoiding underestimation. We do this by going from the Friedewald estimation, which had a fixed factor conversion, to an adjustable factor, which is still based on the same data from the standard lipid profile. By using that adjustable factor, we avoid underestimation, unnecessary down-titration therapy, and the possibility of undertreatment based on these levels. That is the key advantage: getting a more accurate result for better informed clinical decisions that avoid undertreatment due to underestimation.

This avoidance of underestimation is going to be most helpful among high-risk patients, especially if they have obesity, diabetes, and higher triglyceride levels.

We found that about 20% to 25% of the time, patients who are classified by Friedewald as having LDL under 70, they are actually still above that 70 mark. And as you step down to lower LDL levels, the probability of large underestimation by the Friedewald method increases. 

Again, a high-risk patient, with heart disease and diabetes for example, undergoing treatment to lower LDLs is someone who will have the most benefit from an updated, more accurate assessment of LDLs. But the other situations where the method could be helpful as well is in more straightforward situations where you are assessing the baseline LDL levels of primary prevention patients and determining whether they qualify for a statin. In other words, not only can adjustments to current therapies be affected based on the on-treatment levels, but also the decision to even initiate therapy in the first place. 


Becoming Mainstream

As care becomes increasingly advanced and complicated, cardiologists have a lot to think about, so I hope cardiologists, as a field, do not have to spend too much time learning about and focusing on this challenge. The ideal situation is for labs to take ownership of delivering the most accurate results and providing those to frontline clinicians—who should be spending their time on making the best clinical decisions in partnership with patients. To make this all streamlined for clinicians would be the best outcome of our research.

At this time, until implementation at the lab level is more widespread, it is helpful to be aware whether your lab is using the Friedewald method and you get the result back—especially if LDL is low and triglycerides are high—that it could be a substantial underestimate. If you are getting results from a lab that does not use the updated method, know that there is an app out—the Hopkins LDL Calculator—that uses our method published in JAMA. While it is available, it is something I hope cardiologists and other frontline clinicians do not need to spend a lot of time on because I know every minute counts. 

Making such a change takes time. They say it takes 17 years for new evidence to be adopted in clinical practice; our paper was published in November 2013, so it hasn’t been that long on that 17-year timescale.

Quest Diagnostics labs throughout the country are using the estimation, so in a sense the updated method is already mainstream, but it is not as mainstream as we would like. It is going to take more time, more awareness, more guidelines to come out providing recommendations. Of note, the 2018 AHA/AHA Cholesterol Guidelines gave a thumbs up to our new system of estimating LDL cholesterol. These things take time in medical practice, especially when you are dealing with something as deeply engrained for decades like we have here, but I am hopeful that in the next few years it will become more consistently available to patients and clinicians.


Seth S. Martin, MD, MHS is an associate professor of medicine in the Division of Cardiology, Department of Medicine, at Johns Hopkins University School of Medicine. He is also the director of the Advanced Lipid Disorders Program at the Ciccarone Center for the Prevention of Cardiovascular Disease in Baltimore, Maryland.