To fast or not to fast? Fat is the question

It’s also difficult to know how well patients comply with a fasting order, but Dr. Remaley suspects quite a few fail to do so. “Clinicians may not be aware of the current guidelines and may still tell their patients to fast, but laboratories often do not capture this information. When you look carefully, many people aren’t properly fasting.”

Although statistically, he notes, most lipids do not show a major change in the postprandial state, “there are some people, depending on what they ate last or maybe based on their metabolism, who will have a significant change in their HDL or LDL cholesterol. But they are the minority. For most people, the change, except for TG, is minor or clinically insignificant, when using this information for primary prevention or establishing what you should do to reduce cardiovascular risk.”

The biologic variability of most of the lipids is less than 10 percent, Dr. Remaley says. “But for triglycerides, it is very high—at least 20 percent, based on fasting studies. It could easily be larger than that in the postprandial state. That’s why if you’re using triglyceride, which is now the new recommendation as a risk-enhancer test, I think one should not use it based on the result of one sample. Previous recommendations stressed the importance of having multiple samples over a several-week period, maybe as many as five before making a decision on therapy. Ideally you should make a decision based on at least two or three samples, but even that, I think, most people don’t follow.”

Seldom are lipid results medical emergencies, Dr. Remaley notes, but laboratorians should flag some critical lipid values. “For example, when triglycerides are over 1,000 mg/dL, you start worrying about pancreatitis. I also study a lot of rare genetic disorders and I often see patients with very low HDL—many labs would say ‘undetectable.’ But you should probably consider flagging these results, too, so that these patients are referred to a lipidologist, because there are now new therapies for some of these rare genetic diseases.”

Abetalipoproteinemia is one of those rare genetic diseases. “They [patients] have undetectable LDL, and clinicians all the time say, ‘Oh, you’re going to live forever.’ But these patients may develop fat-soluble vitamin deficiencies and they can go blind and develop a neuropathy. Clinicians often just think of lipids in terms of cardiovascular disease, not in terms of the risk associated with pancreatitis or other conditions that can occur with rare genetic disease. Sometimes it takes 10 or 20 years until these patients get the correct diagnoses.” In his laboratory, he and colleagues have recommendations of their own as to what lipid values they should flag.

Dr. Remaley hopes to get the word out that the NIH equation, which is freely available, is a more accurate way to measure LDL. (To download it, go to https://doi.org/10.35092/yhjc.11903274.) “We evaluated it on over a quarter of a million people in our study, working with LabCorp and Mayo Clinic Laboratories. It can even save labs money from having to do direct LDL testing on high-triglyceride samples.” LabCorp has already made the switch to the new equation, and Mayo Clinic Laboratories is in the process of implementing it and plans to go live in December.

Mayo makes every effort to provide early morning phlebotomy appointments when patients are asked to fast before blood draws, says Jeffrey W. Meeusen, PhD, clinical chemist and co-director of cardiovascular laboratory medicine at Mayo. “Historically, fasting patients reported in the mornings and were accommodated regardless of their actual phlebotomy appointment time,” he says.

But during the pandemic, patients are asked to report at their scheduled time to reduce crowding in lobbies and waiting areas. “The ability to accurately assess LDL-C without a need for fasting is one of the strongest drivers for adoption of the new equation at Mayo Clinic,” Dr. Meeusen says.

When Dr. Otvos started a company called LipoScience in the late 1990s, the plan was that its nuclear magnetic resonance clinical analyzer could be introduced into the clinical laboratory workflow and used to produce an LDL particle number with minimal difficulty. The goal was to have a turnkey NMR analyzer on which a medical technologist could load 200 samples, push a button, and walk away, Dr. Otvos says.

LabCorp acquired LipoScience in 2014 and ended up keeping all the NMR analyzers for use at LabCorp, with the exception of one—the analyzer sitting in Dr. Remaley’s lab at NHLBI under a cooperative research agreement. “We are continuing to discover interesting things besides lipids and lipoproteins that can be extracted from the same NMR scan, such as glucose, different amino acids, and a biologically stable signal called GlycA that serves as a very good measure of systemic inflammation,” Dr. Otvos says. “So in essence, NMR is sort of analytic gravy; there’s no incremental analytic cost for measuring more than one thing.”

Specifically with lipids, an NMR scan that can give an LDL particle number also can give high-quality traditional lipid panel information as well as apoB. At LipoScience, Dr. Otvos says, “we had left it to other laboratories to measure the lipids. We were all about measuring what they couldn’t, which is the lipoprotein particles that contain the lipids. But we then came to the realization at LabCorp that it might be beneficial if the same measurement could serve many purposes—obtaining total cholesterol, HDL cholesterol, triglycerides, and apoB from the same spectrum with no reagents. And the analytic efficiencies associated with that could potentially allow it to be offered at lower cost, which has been the barrier to widespread adoption of apoB.” LabCorp received FDA clearance for this extended lipid panel assay in 2018, he says.

LDL particle number, like apoB, is unaffected by fasting and nonfasting, Dr. Otvos says. “It’s really only LDL cholesterol that suffers from the nonfasting calculation problem. So if we were using apoB or LDL particles as an alternative to LDL cholesterol for clinical decision-making about whether LDL-lowering is sufficient in a given patient, there would not be a worry about fasting versus nonfasting.”

In Dr. Otvos’ perfect world, apoB would be adopted as the alternative to LDL cholesterol for guiding LDL treatment decision-making, as European guidelines have recommended, he says. But a major impediment to doing so, he notes, “is that people have been doing things based on LDL cholesterol for 50 years. So you’d have to re-educate people to a certain extent. And then there’s the added analytic cost of apoB, which is typically measured using immunoassays.”

The Johns Hopkins researchers who introduced the Martin-Hopkins equation called attention to the Friedewald formula’s inaccuracy at low values, Dr. Otvos says. “It didn’t used to be the case that very many people had very low LDL cholesterol because there weren’t drugs to make that happen. Pharmacology has totally changed the landscape in the last five years.”

“It really is kind of a big deal because laboratories had to decide, for many years after the Martin equation was introduced, did they want to undergo the added cost of a royalty to Hopkins for the ability to report LDL-C calculated by an improved method. Most opted not to, and that was LabCorp’s decision.”

Now, however, the NIH equation has come along. “It is at least as good as the Hopkins equation and there is no need for a royalty to be paid,” Dr. Otvos says. He sees no real barrier to universal adoption of the NIH formula.

Dr. Otvos was never a fan of nonfasting lipid panels because, he says, “there is other information in a fasting sample that’s useful clinically.” He and others are interested in assessing diabetes risk concurrent with assessing cardiovascular risk, for example.

“Insulin resistance is something that leads to diabetes, and having a higher fasting triglyceride level is associated with insulin resistance. So if your triglyceride is 200 mg/dL fasting, there is something to be made of that clinically, if you choose to do so. If your focus is only on LDL cholesterol and LDL management, then fasting or nonfasting, it doesn’t matter.”

But fasting status should be indicated on laboratory reports, he believes. “So at least you will have a heads-up if the specimen was nonfasting and the triglyceride is 500 mg/dL. That would normally raise eyebrows because at a minimum the patient might be at risk for pancreatitis, and you’d worry about lowering the triglyceride therapeutically.” However, “If you had eaten a big fatty meal two hours before giving the specimen, your actual fasting triglyceride could well be 150 and not 500. The difference can be that big. So you don’t want to be inferring that a nonfasting triglyceride means anything clinically. You would want to order a fasting specimen for the clinical purpose of making something of the triglyceride information.”

Many clinicians may not have mixed purposes when they order a lipid panel. “But the fasting hypertriglyceridemia associated with pancreatitis risk is an independent clinical concern that’s well known to people. A lot of doctors are using the ratio of triglycerides to HDL cholesterol as an indirect measure of insulin resistance. It’s coming for free from the lipid panel, so you get a heads-up that here’s a patient for whom you might want to worry about diabetes risk.” As an aside, Dr. Otvos notes, LabCorp has biomarkers from the NMR scan that are much more effective than the triglyceride-to-HDL cholesterol ratio in assessing risk of diabetes—“one more fringe benefit of using an NMR machine to generate the lipid panel.”

Even before the new NIH formula became available, Dr. Otvos says, he found it fascinating that papers were being written about there being no need to fast. “That was without replacement of the Friedewald formula. So people were accepting the inaccuracy of LDL cholesterol that would occur with nonfasting samples from individual patients, because of the notion there wouldn’t be so many of those, and in the great majority of people there wouldn’t be a clinically significant difference. So the merits of convenience and the other drivers of nonfasting would take precedence over the accuracy of clinical decision-making on individual people.”

He found that bothersome. “No estimation is going to overcome completely a certain inaccuracy with a sample that is taken at a suboptimal time, when the fact that you just ate has caused a big change in what the lipoproteins look like.”

Dr. Otvos cautions against thinking that this better calculation of LDL cholesterol has eliminated all the downsides of LDL cholesterol as a marker of LDL-related risk. “The reality is, it absolutely does not. Even the most accurate direct measurement of LDL cholesterol is going to produce a value that will be discrepant with apoB in many, many patients, mostly when LDL cholesterol is low; then apoB will be higher. So this new NIH equation isn’t going to solve the world’s problems.”

“But now we have a calculation of LDL cholesterol that’s more robust and less sensitive to nonfasting. There is greater acceptance of nonfasting now that the Friedewald part of the reason for not going there is gone,” Dr. Otvos says. The national reference labs are offering it, “and there’s no reason,” he says, “why other laboratories should not be taking advantage of the added convenience to people.”

Anne Paxton is a writer and attorney in Seattle.