advanced lipoprotein analysis (printer friendly)

12/30/13 Advanced Lipoprotein Analysis (printer-friendly)

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This article is a CME certified activity. To earn credit for this activity visit:http://www.medscape.org/viewarticle/815311

CME Information

CME Released: 12/13/2013 ; Valid for credit through 12/13/2014

Target Audience

This activity was developed for practicing primary care physicians, nurse practitioners, physician assistants, andother healthcare professionals who manage patients with lipid disorders.

Goal

Lipoproteins are complex molecules containing proteins, cholesterol, and phospholipid. While standard lipid panelsprovide important clinical information, they may not fully characterize a patient's cardiovascular disease andcardiometabolic risk. In these cases, advanced lipid testing can often provide this additional information. Join us asKarol E. Watson, MD, PHD, FACC, discusses advanced lipid testing and its place in clinical practice.

Learning Objectives

Upon completion of this activity, participants should be able to:

1. Identify in their clinical practice patients who are at increased cardiometabolic risk even with adequatecholesterol lowering.

2. More confidently include advanced lipid testing in screening and treatment strategies for select patients atincreased cardiometabolic risk.

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Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

All other healthcare professionals completing continuing education credit for this activity will be issued a certificate ofparticipation.

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The Omnia-Prova Education Collaborative, Inc., designates this enduring material for a maximum of 0.25 AMA PRACategory 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in

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Faculty and Disclosures

Author

Karol E. Watson, MD, PHD, FACC

Professor of Medicine/Cardiology, University of California at Los Angeles, Los Angeles, California

the activity.

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Disclosure: Dr. Watson is a consultant for Aegerion and on the clinical trial adjudication committee for Merck.

Reviewer

Gregory Pokrywka, MD, FACP, FNLA, NCMP

Director, Baltimore Lipid Center, Fellow, National Lipid Association, Assistant Professor, Johns Hopkins University

School of Medicine, Baltimore, Maryland

Disclosure: Dr. Pokrywka is on the commercial Interest speakers bureau for Astra Zeneca, Daichii Sankyo

International, Genentech, Health Diagnostics Labs, Kowa Pharmaceuticals America, Inc., Lilly USA, LLC, and

LipoScience.

Planners

Barry A. Fiedel, PhD

Vice President, Clinical and Scientific Affairs, The Omnia-Prova Education Collaborative, Fort Washington, PA

Disclosure: No relationship to report.

Christine Finnegan

Clinical Education Director, Prova Education, Fort Washington, PA


Sean T. Saunders, CCMEP

VP, CME, Outcomes and Communications, The Omnia-Prova Education Collaborative, Fort Washington, PA


Erica Spengler

Activity Manager, The Omnia-Prova Education Collaborative, Fort Washington, PA


Karol E. Watson, MD, PHD, FACC

This CME activity is based on a lecture presented by Dr. Karol Watson at Prova Education's From Guideline to

Practice: Managing Challenging Cases in Primary Care program held on October 25, 2013, in Pasadena, California.

Lipoproteins allow lipids such as cholesterol to be transported in the blood stream.

Advanced Lipoprotein Analysis CME

CME Released: 12/13/2013 ; Valid for credit through 12/13/2014



Slide 1.

The most dense and largest of them, mostly triglyceride-carrying lipoproteins, are chylomicrons and the very low

density lipoproteins (VLDLs); also included are low- and high- density lipoproteins (LDLs and HDLs, respectively), the

latter the only anti-inflammatory, anti-atherosclerotic lipoprotein.



Slide 2.

Cholesterol carried in LDL (LDL-C) has the most direct relationship to atherosclerosis.

Based on 2004 Guidelines, the LDL-C target for high-risk patients is <100 mg/dL; for the very high-risk patient the

target LDL-C is <70 mg/dL. Low risk is <160 mg/dL while moderately high risk falls in between at <130 mg/dL.



Slide 3.

What exactly are lipoproteins, how are they constructed, and what is their structural relationship with cholesterol?

Lipoproteins are physiologically complex: a non-polar lipid core surrounded with a polar surface coat, plus

(apo)proteins. For such a complicated particle, it is surprising we reduce it down to just LDL-C in our Standard Lipid

Panel.

Is the typical standard lipid panel suboptimal?



Slide 4.

The standard lipid panel typically provides information on total cholesterol, HDL cholesterol, triglycerides, and

sometimes VLDL. What some physicians and many patients may not realize is that the LDL-C value received in the

report is in almost all cases a calculated LDL-C, and not directly measured. It is calculated by taking total cholesterol

and then subtracting the sum of HDL plus triglycerides divided by 5. For a measured LDL-C, the actual value of

cholesterol present in LDL, a direct LDL-C measurement may need to be ordered.

Moreover, certain lipid subanalyses are often absent in the lipid profile report. One that may have import is the LDL

particle (LDL-P) number.

A recent consensus statement from the American Diabetes Association (ADA) and the American College of

Cardiology (ACC) suggests that direct LDL-C measurements are better than calculated...and ...assessment of

LDL particles (LDL-P) is actually better than measuring the LDL cholesterol, as LDL-P number is a better

predictor of cardiovascular risk than LDL-C alone.



Slide 5.

Another important point is that among individuals who have the exact same LDL-C level, they may have very different

LDL-P numbers. For illustration's sake, say the LDL-C is100 mg/dL. There could be a few large particles with an

average amount of cholesterol per particle, or there could be many small particles with less cholesterol per particle;

in the end, exactly the same LDL-C but the total number of LDL-P is different.

Why might this be important?

The relationship between LDL-C level and LDL-P number has been known for many years. Fredricksen and

colleagues in 1967 said:

"LDL particles are the causal agents in atherosclerosis."

"The more LDL particles a person has, the higher the risk of plaque buildup that causes heart attacks,

regardless of how much cholesterol those particles carry."

That remains basically true. The American Diabetes Association in a consensus statement relates that:

"The mean concentration of LDL cholesterol in those [patients] with type 2 diabetes is not significantly

different from that in those individuals who [do] not have diabetes. However, qualitative changes in LDL

cholesterol may be present.

"Patients with diabetes tend to have higher proportions of smaller and denser LDL-P, which is more

susceptible to oxidation and may, therefore, increase the risk of cardiovascular events in



atherosclerosis."

Slide 6.

Clearly, assessing more than just the cholesterol content is important. This is true for LDL, and it is also true for

HDL. These are data from the VA-HIT Study. This study evaluated individuals at risk for cardiovascular disease, using

a fibrate to help target an increase in HDL level, the primary end point being a decrement in cardiovascular risk.

The result was not fully expected.

The amount of cholesterol carried in HDL turned out to be a weak predictor of fibrate benefit and decrement in risk. A

similar result was observed with Apo-A1, though a somewhat better (though not significantly significant) predictor of

benefit.

HDL particle number was by far the best predictor of protection in this study, an outcome that was also statistically

significant. Thus, as with LDL, where LDL particle number is the best predictor of negative events, HDL particle

number is the best predictor of protection against such events.

If we are to believe that when assessing LDL-P number along with LDL-C we are potentially identifying a level of extra

CVD risk for patients, exactly how much and how significant is that extra risk?

Data gleaned from three (3) clinical trials help answer that question: 1) Framingham Heart Study; 2) the Multi-Ethnic

Study of Atherosclerosis; and 3) the VA-HIT Study.



Slide 7.

The Framingham Heart Study demonstrated a discordant relationship between LDL-C and LDL-P in that patients with

high LDL-C (and low LDL-P) had relatively less risk for a poor outcome (measured as Event-Free Survival) when

compared with patients with a low LDL-C but high LDL-P.



Slide 8.

Data from the Multi-Ethnic Study of Atherosclerosis (or MESA), which evaluated carotid atherosclerosis,

demonstrated that while carotid atherosclerosis risk was lower in individuals whose LDL-C was normal (<100 mg/dL)

when coincident with a low LDL-P number (Q1), as LDL-P numbers became progressively higher (Q2 through Q4)

carotid atherosclerosis risk continued to climb in a statistically significant trend.



Slide 9.

This relationship between LDL-C and LDL-P was also illustrated the VA HIT Study. When a patient's LDL-C level was

high that alone represented an increased risk for a CHD event, though not statistically significant. Similar findings

were observed for for non-HDL and APO-B as markers for increased CHD event risk.

Conversely, when LDL-P was assessed, it was found to be a statistically significant marker for increased CHD event

risk.

There are a number of advanced lipid tests that can assist the clinician when assessing a patient's CVD or

cardiometabolic risk status despite what appears to be a favorable LDL-C. There are basically three technical

methods for measuring LDL-P.

They are:

1. The Berkeley Heart Advanced Lipid Profile. Berkeley uses a gradient gel electrophoresis technique.

2. The Vertical Automated Profile, also short-handed as VAP. VAP measures particle density by gradient

ultracentrifugation.

3. Nuclear Magnetic Resonance (NMR) spectroscopy to differentiate various LDL particle numbers.



Slide 10.

Berkeley utilizes gradient gel electrophoresis to sift/separate different lipoproteins based on their electrophoretic

characteristic sizes through a process called "mobility shifts." This technique does not give information about

cholesterol, but does offer information about size. Thus, it provides quantification of the number of particles of different

sizes and an estimate can be obtained with regard to particle number.

This is the type of profile obtained; it can provide information about LDL size, particle number, etc.



Slide 11.

The VAP technique employs ultracentrifugation to separate lipoprotein fractions. The technique permits resolution of

different lipoprotein subclasses based on their densities. A computerized system then provides the needed

information with regard to the different lipoprotein classes.



Slide 12.

With NMR spectroscopy, each lipoprotein subclass broadcasts a unique NMR "sound." These sounds can be

separated through NMR spectroscopy and the signals deconstructed. A computerized system provides the needed

information with regard to the different lipoprotein classes in the sample.

In closing, lipoproteins are very complex molecules containing proteins, cholesterol, and phospholipid. Standard lipid

panels provide important clinical information, no question, but they do not provide the complete picture. Additional

information beyond the standard lipid panel is sometimes needed to adequately assess risk, and advanced lipid

testing can provide additional information that may help you to better define your patient's risk.

NOTE ADDED IN PROOF

Impact of 2013 Updated ACC/AHA Guidelines on the Treatment of Blood Cholesterol

On November 12, 2013 new ACC/AHA guidelines on the treatment of blood cholesterol to reduce atherosclerotic

cardiovascular disease (ASCVD) risk in adults was published in Circulation (see:

http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.full.pdf).

A seminal component of the new guidelines is the absence of set LDL-C targets, replaced by four (4) categories of

patients (termed Major Statin Benefit Groups) with recommendation for consideration of different intensity statin

intervention based on use of a risk calculator assessing 10-year risk for developing ASCVD.

As described in this CME activity and based in part on three (3) critical clinical trials, advanced lipid testing, notably

http://www.medscape.org/px/trk.svr/815311?exturl=http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.full.pdf



measurement of LDL-P, has proven to be a better indicator of cardiovascular disease/cardiometabolic risk for many

patients than is LDL-C alone. The removal of set targets for LDL-C in the recently released Guidelines does not

diminish the potential benefit of advanced lipid testing within the four Major Statin Benefit Groups as part of an

ongoing assessment of therapeutic and lifestyle efficacy. As always, including advanced lipid testing is based on

physician assessment for each individual patient within their clinical practice.


References

1. Brunzell JD, et al. Diabetes Care. 2008;31:811-822.

2. Otvos JD, et al. Am J Cardiol. 2002;90(suppl):22i-29i.

3. Fredrickson DS, et al. NEJM. 1967;276:148-156.

4. American Diabetes Association. Diabetes Care. 2004;27:S68-S71.

5. Otvos JD, et al. Circulation. 2006;113:1556-1563.

6. Cromwell WC, et al. J Clin Lipidol. 2007;1:583–592.

7. Otvos J, et al. J Clin Lipidol. 2011;5: 105–113.

8. Otvos JD. Clin Lab. 2002;48:171-180.

9. Brunzell JD, et al. Diabetes Care. 2008;31:811-822.

Disclaimer

The educational activity presented above may involve simulated case-based scenarios. The patients depicted in thesescenarios are fictitious and no association with any actual patient is intended or should be inferred.

The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that supporteducational programming on medscape.org. These materials may discuss therapeutic products that have not beenapproved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcareprofessional should be consulted before using any therapeutic product discussed. Readers should verify allinformation and data before treating patients or employing any therapies described in this educational activity.

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