Why Do Doctors Still Rely On LDL Instead Of Non-HDL Cholesterol?

–There’s broad agreement that non-HDL is a better measure than LDL.

For decades lipid experts have been saying that non-HDL is preferable to LDL cholesterol in the assessment of cardiovascular risk.

The subject is not controversial. Although they may disagree about its precise significance, every expert I contacted agreed that non-HDL is superior to LDL. Further, there is no downside to non-HDL, since obtaining a non-HDL level requires no additional cost or testing.

It is therefore surprising that the vast majority of clinicians, even most cardiologists, continue to rely on LDL. It’s a perfect example of how difficult it is to change medical practice without compelling incentives.

Non-HDL has been endorsed many times over the years by lipid experts, most recently by Robert Hegele (London, Ontario) in a New England Journal of Medicine editorial on the REVEAL trial. He noted that the trial “used non-HDL cholesterol levels, rather than LDL cholesterol levels, to gauge biochemical efficacy.” LDL cholesterol, he pointed out, “is usually not measured directly; rather, it is derived by means of an equation that incorporates total and HDL cholesterol levels and triglycerides. At ultra-low levels achieved with aggressive treatment, the calculated LDL cholesterol level is artifactually depressed. Solutions such as direct assays for LDL cholesterol or measuring apolipoprotein B to estimate the number of LDL particles are worth considering but would generate additional expense. In contrast, the non-HDL cholesterol level is calculated at no additional cost by subtracting the HDL cholesterol level from the total cholesterol level, and the value is stable and reliable at very low levels and regardless of whether patients are tested while fasting. Furthermore, the non-HDL cholesterol level integrates all atherogenic lipoproteins, correlates well with apolipoprotein B, and predicts cardiovascular risk better than the LDL cholesterol level.”

Although the issue is not new, one reason for greater urgency now is that the difference between non-HDL and LDL is more likely to be relevant today. This is because although non-HDL and LDL generally closely track each other, the divergence is found much more in rapidly growing patient populations like people with obesity, diabetes, and high triglycerides.

In some respects clinicians don’t need to pay attention to this issue because it is taken care of for them. In general, say the experts, the major risk factor calculators use non-HDL and not LDL to assess risk. Users of the tools— physicians or patients— enter the values of both total and HDL cholesterol, from which the non-HDL level is then calculated.

  Seth Martin (Johns Hopkins) pointed out that non-HDL-C is already in the European guidelines, NLA guidelines, and ACC consensus pathway. But, he asked, “I wonder how many are really using it in practice?” Martin said the lab at Johns Hopkins “finally added non-HDL-C to reports a few years ago” but, “my impression is that few clinicians pay attention to it. I gave a lunch talk on lipid management to the residents and polled the audience to see who was using non-HDL-C. One hand went up out of 50 or so residents. LDL-C is simply what clinicians know and use. It is deeply ingrained.” Martin said an alternative to using non-HDL is to provide “a more precise estimate” of LDL. His group has been working to improve the Friedewald equation currently used to estimate LDL.

Martin said “it’s truly a fascinating situation – the discordance between what has been written about for decades in the medical literature and what clinicians, not to mention insurers, the FDA, trialists, guideline writers, etc, are focused on.” He asked: “Is it partly a branding issue? ‘Non-HDL cholesterol’ – not so catchy…atherogenic cholesterol…better?”

Mohamed Elshazly (Cleveland Clinic) observed that while non-HDL “is not new for many cardiologists with expertise in this field, I believe that many cardiologists, the majority of non-cardiologists and medical students are still under the impression that LDL is the only measure of ‘bad cholesterol’.” He said that the FDA, trialists, and insurance companies “should incorporate non-HDL as a primary measure along with LDL in their trials, reviews and best practice measures.”

Rod Hayward (University of Michigan) said “focusing more on non-HDL-C has merit” and that “the evidence is overwhelming that it is better clinical tool. I’ve never done an analysis in which LDL measures outperformed non-HDL-C in helping to predict CVD risk or statin benefit.”

But Is It Worth The Trouble To Change?

While few would argue that non-HDL is superior to LDL, some believe that there’s no urgent need to address this issue.

Jennifer Robinson (University of Iowa) thinks that switching is not worth the bother. “It’s close enough,” said about LDL. “In terms of clinical practice, it’s not that important” to replace LDL with non-HDL. Lipidologists, she said, “are a minute fraction of doctors. We shouldn’t confuse our core physicians who don’t think about lipids all the time.” “Perfect shouldn’t be the enemy of the good,” she said.

James Stein (University of Wisconsin) said that the subject is “really important and we should be using it [non-HDL] more clinically, but it’s also a snooze because it’s old news and nothing new has come of it.”

Donald Lloyd-Jones (Northwestern) agreed that “non-HDL-C does provide some advantages over LDL-C in primary prevention, but in general they are fairly modest.” He said that “the bigger issue remains that it is risk, not solely LDL-C or non-HDL-C levels, that should be driving decision making about intensity of prevention efforts in primary prevention. One should never consider any lipid level outside of the context of the broader risk of the patient. The debate about which lipid measure to use can distract from that.”

Elshazly is not ready to abandon targets. “I think treatment targets will be necessary in secondary prevention especially that we now have an arsenal of medications that can lower LDL or non-HDL to very low levels.” On a broader scale, he said that improved risk stratification can also benefit   from additional information, including, besides non-HDL levels, family history, calcium scores, CRP, and others.

non-HDL-C captures cholesterol in all atherogenic lipoproteins; so, @cardiobrief, yes, ready for prime-time

non-HDL-C = TC – HDL-C pic.twitter.com/eY95crzey9

— Sek Kathiresan MD (@skathire) October 9, 2017