Editing Low-density lipoprotein (section)

==Testing==
[[Blood tests]] commonly report LDL-C: the amount of cholesterol that is estimated to be contained with LDL particles, on average, using a formula, the [[Friedewald equation]]. In a clinical context, mathematically calculated estimates of LDL-C are commonly used to estimate how much low-density lipoproteins drive the progression of atherosclerosis. The problem with this approach is that LDL-C values are commonly discordant with both direct measurements of LDL particles and actual rates of atherosclerosis progression.{{cn|date=November 2024}}

Direct LDL measurements are also available and better reveal individual issues but are less often promoted or done due to slightly higher costs and are available from only a couple of laboratories in the [[United States]]. In 2008, the [[American Diabetes Association|ADA]] and [[American College of Cardiology|ACC]] recognized direct LDL particle measurement by NMR as superior for assessing individual risk of cardiovascular events.<ref>{{cite journal |last1=Brunzell |first1=John D. |last2=Davidson |first2=Michael |last3=Furberg |first3=Curt D. |last4=Goldberg |first4=Ronald B. |last5=Howard |first5=Barbara V. |last6=Stein |first6=James H. |last7=Witztum |first7=Joseph L. |title=Lipoprotein Management in Patients With Cardiometabolic Risk |journal=Journal of the American College of Cardiology |date=April 2008 |volume=51 |issue=15 |pages=1512–1524 |doi=10.1016/j.jacc.2008.02.034 |pmid=18402913 }}</ref>

===Estimation of LDL particles via cholesterol content===
Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they have the best correlation with individual outcomes but because these lab methods are less expensive and more widely available.

The lipid profile does not measure LDL particles. It only estimates them using the Friedewald equation<ref name="Warnick">{{Cite journal |vauthors=Warnick GR, Knopp RH, Fitzpatrick V, Branson L |date=January 1990 |title=Estimating low-density lipoprotein cholesterol by the Friedewald equation is adequate for classifying patients on the basis of nationally recommended cutpoints |journal=Clinical Chemistry |volume=36 |issue=1 |pages=15–9 |doi=10.1093/clinchem/36.1.15 |pmid=2297909 |doi-access=free }}</ref><ref name="pmid4337382">{{Cite journal |vauthors=Friedewald WT, Levy RI, Fredrickson DS |date=June 1972 |title=Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge |journal=Clinical Chemistry |volume=18 |issue=6 |pages=499–502 |doi=10.1093/clinchem/18.6.499 |pmid=4337382 |doi-access=free }}</ref>
by subtracting the amount of cholesterol associated with other particles, such as [[High-density lipoprotein|HDL]] and VLDL, assuming a prolonged fasting state, etc.:
:<math>L \approx C - H - kT</math>
:where ''H'' is HDL cholesterol, ''L'' is LDL cholesterol, ''C'' is total cholesterol, ''T'' is triglycerides, and k is 0.20 if the quantities are measured in mg/dL and 0.45 in mmol/L.

There are limitations to this method, most notably that samples must be obtained after a 12 to 14 h fast and that LDL-C cannot be calculated if plasma triglyceride is >4.52&nbsp;mmol/L (400&nbsp;mg/dL). Even at triglyceride levels of 2.5 to 4.5 mmol/L, this formula is considered inaccurate.<ref name="Sniderman">{{Cite journal |vauthors=Sniderman AD, Blank D, Zakarian R, Bergeron J, Frohlich J |date=October 2003 |title=Triglycerides and small dense LDL: the twin Achilles heels of the Friedewald formula |journal=Clinical Biochemistry |volume=36 |issue=7 |pages=499–504 |doi=10.1016/S0009-9120(03)00117-6 |pmid=14563441}}</ref>  If both total cholesterol and triglyceride levels are elevated then a modified formula, with quantities in mg/dL, may be used
:<math>L = C - H - 0.16T</math>

This formula provides an approximation with fair accuracy for most people, assuming the blood was drawn after fasting for about 14 hours or longer, but does not reveal the actual LDL particle concentration because the percentage of fat molecules within the LDL particles, which are cholesterol, varies as much as 8:1 variation. There are several formulas published addressing the inaccuracy in LDL-C estimation.<ref>{{cite journal |last1=Anandaraja |first1=S. |last2=Narang |first2=R. |last3=Godeswar |first3=R. |last4=Laksmy |first4=R. |last5=Talwar |first5=K.K. |title=Low-density lipoprotein cholesterol estimation by a new formula in Indian population |journal=International Journal of Cardiology |date=June 2005 |volume=102 |issue=1 |pages=117–120 |doi=10.1016/j.ijcard.2004.05.009 |pmid=15939107 }}</ref><ref>{{Cite journal |last1=de Cordova |first1=Caio Mauricio Mendes |last2=de Cordova |first2=Mauricio Mendes |date=January 2013 |title=A new accurate, simple formula for LDL-cholesterol estimation based on directly measured blood lipids from a large cohort |journal=Annals of Clinical Biochemistry: International Journal of Laboratory Medicine |language=en |volume=50 |issue=1 |pages=13–19 |doi=10.1258/acb.2012.011259 |pmid=23108766 |doi-access=free}}</ref><ref>{{Cite journal |last1=Chen |first1=Yunqin |last2=Zhang |first2=Xiaojin |last3=Pan |first3=Baishen |last4=Jin |first4=Xuejuan |last5=Yao |first5=Haili |last6=Chen |first6=Bin |last7=Zou |first7=Yunzeng |last8=Ge |first8=Junbo |last9=Chen |first9=Haozhu |date=2010 |title=A modified formula for calculating low-density lipoprotein cholesterol values |journal=Lipids in Health and Disease |language=en |volume=9 |issue=1 |pages=52 |doi=10.1186/1476-511X-9-52 |pmc=2890624 |pmid=20487572 |doi-access=free}}</ref> The inaccuracy is based on the assumption that VLDL-C (Very low density lipoprotein cholesterol) is always one-fifth of the triglyceride concentration. Other formulae address this issue by using an adjustable factor<ref>{{cite journal |last1=Martin |first1=Seth S. |last2=Blaha |first2=Michael J. |last3=Elshazly |first3=Mohamed B. |last4=Toth |first4=Peter P. |last5=Kwiterovich |first5=Peter O. |last6=Blumenthal |first6=Roger S. |last7=Jones |first7=Steven R. |title=Comparison of a Novel Method vs. the Friedewald Equation for Estimating Low-Density Lipoprotein Cholesterol Levels From the Standard Lipid Profile |journal=JAMA |date=20 November 2013 |volume=310 |issue=19 |pages=2061–2068 |doi=10.1001/jama.2013.280532 |pmc=4226221 |pmid=24240933}}</ref> or using a regression equation.<ref>{{cite journal |last1=Sampson |first1=Maureen |last2=Ling |first2=Clarence |last3=Sun |first3=Qian |last4=Harb |first4=Roa |last5=Ashmaig |first5=Mohmed |last6=Warnick |first6=Russell |last7=Sethi |first7=Amar |last8=Fleming |first8=James K. |last9=Otvos |first9=James D. |last10=Meeusen |first10=Jeff W. |last11=Delaney |first11=Sarah R. |last12=Jaffe |first12=Allan S. |last13=Shamburek |first13=Robert |last14=Amar |first14=Marcelo |last15=Remaley |first15=Alan T. |title=A New Equation for Calculation of Low-Density Lipoprotein Cholesterol in Patients With Normolipidemia and/or Hypertriglyceridemia |journal=JAMA Cardiology |date=May 2020 |volume=5 |issue=5 |pages=540–548 |doi=10.1001/jamacardio.2020.0013 |pmc=7240357 |pmid=32101259}}</ref> There are few studies which have compared the LDL-C values derived from this formula and values obtained by direct enzymatic method.<ref name="Ramasamy 1486–1493">{{cite journal |last1=Ramasamy |first1=Jagadish |last2=Job |first2=Victoria |last3=Mani |first3=Thenmozhi |last4=Jacob |first4=Molly |title=Calculated values of serum LDL-cholesterol (LDL-C) – for better or worse? |journal=Nutrition, Metabolism and Cardiovascular Diseases |date=May 2021 |volume=31 |issue=5 |pages=1486–1493 |doi=10.1016/j.numecd.2021.01.016 |pmid=33744036 }}</ref> Direct enzymatic methods are found to be accurate and must be the test of choice in clinical situations. In resource-poor settings, the option to use the formula has to be considered.<ref name="Ramasamy 1486–1493" />

However, the concentration of LDL particles, and to a lesser extent, their size, has a stronger and consistent correlation with individual clinical outcomes than the amount of cholesterol within LDL particles, even if the LDL-C estimation is approximately correct. There is increasing evidence and recognition of the value of more targeted and accurate measurements of LDL particles. Specifically, LDL particle number (concentration) and, to a lesser extent, size have shown slightly stronger correlations with atherosclerotic progression and cardiovascular events than obtained using chemical measures of the amount of cholesterol carried by the LDL particles.<ref name=snid/> It is possible that the LDL cholesterol concentration can be low, yet LDL particle number high and cardiovascular events rates are high. Correspondingly, it is possible that LDL cholesterol concentration can be relatively high, yet LDL particle number is low, and cardiovascular events are also low.{{cn|date=November 2024}}

====Normal ranges====
In the US, the [[American Heart Association]], [[National Institutes of Health|NIH]], and [[National Cholesterol Education Program|NCEP]] provide a set of guidelines for fasting LDL-Cholesterol levels, estimated or measured, and risk for heart disease. As of about 2005, these guidelines were:<ref>{{Cite web |title=Cholesterol Levels |url=http://www.americanheart.org/presenter.jhtml?identifier=4500 |access-date=2009-11-14 |publisher=American Heart Association}}</ref><ref>{{Cite web |date=September 2007 |title=What Do My Cholesterol Levels Mean? |url=http://www.americanheart.org/downloadable/heart/119618151049911%20CholLevels%209_07.pdf |access-date=2009-11-14 |publisher=American Heart Association}}</ref><ref>{{Cite web |date=May 2001 |title=Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Executive Summary |url=http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf |website=National Heart, Lung, and Blood Institute (NHLBI) |publisher=National Institutes of Health}}</ref>

{| class="wikitable"
! Level [[kilogram|mg]]/[[litre|dL]]
! Level [[mole (unit)|mmol]]/L
! Interpretation
|-
| 25 to <50
| <1.3
| Optimal LDL cholesterol levels in healthy young children before onset of atherosclerotic plaque in heart artery walls
|-
| <70
| <1.8
| Optimal LDL cholesterol, corresponding to lower rates of progression, is promoted as a target option for those known to have advanced symptomatic cardiovascular disease clearly
|-
| <100
| <2.6
| Optimal LDL cholesterol, corresponding to lower, but not zero, rates for symptomatic cardiovascular disease events
|-
| 100 to 129
| 2.6 to 3.3
| Near-optimal LDL level, corresponding to higher rates of developing symptomatic cardiovascular disease events
|-
| 130 to 159
| 3.3 to 4.1
| Borderline high LDL level, corresponding to even higher rates for developing symptomatic cardiovascular disease events
|-
| 160 to 199
| 4.1 to 4.9
| High LDL level, corresponding to much higher rates for developing symptomatic cardiovascular disease events
|-
| >200
| >4.9
| Very high LDL level, corresponding to the highest increased rates of symptomatic cardiovascular disease events
|}

Over time, with more clinical research, these recommended levels keep being reduced because LDL reduction, including to abnormally low levels, was the most effective strategy for reducing cardiovascular death rates in one large [[double blind]], randomized clinical trial of men with [[hypercholesterolemia]];<ref name="pmid7566020 ">{{Cite journal |vauthors=Shepherd J, Cobbe SM, Ford I, et al |date=November 1995 |title=Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group |journal=The New England Journal of Medicine |volume=333 |issue=20 |pages=1301–7 |doi=10.1056/NEJM199511163332001 |pmid=7566020 |doi-access=free}}</ref> far more effective than coronary angioplasty/stenting or bypass surgery.<ref>{{Cite journal |last=William E. Boden |display-authors=etal |date=April 2007 |title=Optimal Medical Therapy with or without PCI for Stable Coronary Disease |journal=The New England Journal of Medicine |volume=356 |issue=15 |pages=1503–1516 |doi=10.1056/NEJMoa070829 |pmid=17387127 |doi-access=free}}</ref>

The 2004 updated American Heart Association, NIH, and NCEP recommendations for people with known atherosclerosis diseases are for lowering LDL levels to less than 70&nbsp;mg/dL. This low level of less than 70&nbsp;mg/dL was recommended for primary prevention of 'very-high risk patients' and secondary prevention as a 'reasonable further reduction'. This position was disputed.<ref>{{Cite journal |last=Hayward |first=Rodney A. |date=3 October 2006 |title=Narrative Review: Lack of Evidence for Recommended Low-Density Lipoprotein Treatment Targets: A Solvable Problem |journal=Ann Intern Med |volume=145 |issue=7 |pages=520–30 |doi=10.7326/0003-4819-145-7-200610030-00010 |pmid=17015870 }}</ref> Statin drugs involved in such clinical trials have [[Pleiotropy (drugs)|numerous physiological effects]] beyond simply the reduction of LDL levels.

From longitudinal population studies following the progression of atherosclerosis-related behaviors from early childhood into adulthood,<ref>{{cite journal |last1=Cybulska |first1=Barbara |last2=Kłosiewicz-Latoszek |first2=Longina |last3=Penson |first3=Peter E. |last4=Nabavi |first4=Seyed Mohammad |last5=Lavie |first5=Carl J. |last6=Banach |first6=Maciej |title=How much should LDL cholesterol be lowered in secondary prevention? Clinical efficacy and safety in the era of PCSK9 inhibitors |journal=Progress in Cardiovascular Diseases |date=July 2021 |volume=67 |pages=65–74 |doi=10.1016/j.pcad.2020.12.008 |pmid=33383060 |url=https://researchonline.ljmu.ac.uk/id/eprint/14560/1/How%20low%20should%20you%20go%20with%20LDL%20cholesterol%20lowering%20in%20secondary%20prevention.pdf }}</ref> the usual LDL in childhood, before the development of [[fatty streaks]], is about 35&nbsp;mg/dL. However, all the above values refer to chemical measures of lipid/cholesterol concentration within LDL, not measured low-density lipoprotein concentrations, which is the accurate approach.<ref name="snid">{{Cite journal |vauthors=Sniderman AD, Thanassoulis G, Glavinovic T, Navar AM, Pencina M, Catapano A, Ference BA |date=December 2019 |title=Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review |journal=JAMA Cardiology |volume=4 |issue=12 |pages=1287–1295 |doi=10.1001/jamacardio.2019.3780 |pmc=7369156 |pmid=31642874}}</ref>

A study was conducted measuring the effects of guideline changes on LDL cholesterol reporting and control for diabetes visits in the US from 1995 to 2004. It was found that although LDL cholesterol reporting and control for diabetes and coronary heart disease visits improved continuously between 1995 and 2004,<ref>{{Cite journal |last1=Wolska |first1=Anna |last2=Remaley |first2=Alan T. |year=2020 |title=Measuring LDL-cholesterol: what is the best way to do it? |journal=Current Opinion in Cardiology |volume=35 |issue=4 |pages=405–411 |doi=10.1097/HCO.0000000000000740 |pmc=7360339 |pmid=32412961}}</ref><ref>{{cite journal |last1=Howard |first1=Barbara V. |last2=Robbins |first2=David C. |last3=Sievers |first3=Maurice L. |last4=Lee |first4=Elisa T. |last5=Rhoades |first5=Dorothy |last6=Devereux |first6=Richard B. |last7=Cowan |first7=Linda D. |last8=Gray |first8=R. Stuart |last9=Welty |first9=Thomas K. |last10=Go |first10=Oscar T. |last11=Howard |first11=Wm. James |title=LDL Cholesterol as a Strong Predictor of Coronary Heart Disease in Diabetic Individuals With Insulin Resistance and Low LDL: The Strong Heart Study |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |date=March 2000 |volume=20 |issue=3 |pages=830–835 |doi=10.1161/01.atv.20.3.830 |pmid=10712410}}</ref> neither the 1998 ADA guidelines nor the 2001 ATP III guidelines increased LDL cholesterol control for diabetes relative to coronary heart disease.<ref name="wang">{{Cite journal |last1=Wang |first1=Y Richard |last2=G Caleb Alexander |last3=David O Meltzer |date=December 2005 |title=Lack of Effect of Guideline Changes on LDL Cholesterol Reporting and Control for Diabetes Visits in the U.S., 1995–2004 |journal=Diabetes Care |volume=28 |issue=12 |pages=2942–2944 |doi=10.2337/diacare.28.12.2942 |pmid=16306559 |doi-access=free}}</ref>

===Direct measurement of LDL particle concentrations===
There are several competing methods for measuring lipoprotein particle concentrations and size. The evidence is that the NMR methodology (developed, automated & significantly reduced in costs while improving accuracy as pioneered by [[Jim Otvos]] and associates) results in a 22-25% reduction in cardiovascular events within one year,<ref>{{Cite journal |last1=Peter P. Toth |last2=Michael Grabner |last3=Rajeshwari S. Punekar |last4=Ralph A. Quimbo |last5=Mark J. Cziraky |last6=Terry A. Jacobson |date=August 2014 |title=Cardiovascular risk in patients achieving low-density lipoprotein cholesterol and particle targets |journal=Atherosclerosis |volume=235 |issue=2 |pages=585–591 |doi=10.1016/j.atherosclerosis.2014.05.914 |pmid=24956532 |doi-access=free}}</ref> contrary to the longstanding claims by many in the medical industry that the superiority over existing methods was weak, even by statements of some proponents.<ref>{{Cite journal |last=Krauss RM |date=August 2010 |title=Lipoprotein subfractions and cardiovascular disease risk |journal=Current Opinion in Lipidology |volume=21 |issue=4 |pages=305–11 |doi=10.1097/MOL.0b013e32833b7756 |pmid=20531184 }}</ref>

Since the later 1990s, because of the development of NMR measurements, it has been possible to clinically measure lipoprotein particles at lower cost [under $80 US (including shipping) & is decreasing versus the previous costs of >$400 to >$5,000] and higher accuracy. There are two other assays for LDL particles; however, most estimate only LDL particle concentrations like LDL-C.{{cn|date=November 2024}}

The ADA and ACC mentioned direct LDL particle measurement by NMR in a 28 March 2008 joint consensus statement,<ref>{{Cite journal |last1=Brunzell |first1=John D. |last2=Davidson |first2=Michael |last3=Furberg |first3=Curt D. |last4=Goldberg |first4=Ronald B. |last5=Howard |first5=Barbara V. |last6=Stein |first6=James H. |last7=Witztum |first7=Joseph L. |date=15 April 2008 |title=Lipoprotein Management in Patients With Cardiometabolic Risk |journal=J Am Coll Cardiol |volume=51 |issue=15 |pages=1512–1524 |doi=10.1016/j.jacc.2008.02.034 |pmid=18402913}}</ref> as having advantages for predicting individual risk of atherosclerosis disease events, but the statement noted that the test is less widely available, is more expensive [about $13.00 US (2015 without insurance coverage) from some labs which use the Vantera Analyzer<ref>{{Cite web |title=Google |url=https://www.google.com/#q=Vantera+Analyzer |website=www.google.com}}</ref>]. Debate continues that it is "...unclear whether LDL particle size measurements add value to the measurement of LDL-particle concentration", though outcomes have continuously tracked LDL particle, not LDL-C, concentrations.

Using NMR, the total LDL particle concentrations in nmol/L plasma are typically subdivided by percentiles referenced to the 5,382 men and women participating in the MESA trial who are not on any lipid medications.<ref>{{Cite web |title=MESA - Multi-Ethnic Study of Atherosclerosis |url=https://www.mesa-nhlbi.org/ |website=www.mesa-nhlbi.org}}</ref>

LDL particle concentration can also be measured by measuring the concentration of the protein ApoB, based on the generally accepted principle that each LDL or VLDL particle carries one ApoB molecule.<ref>{{Cite journal |last1=Sniderman |first1=A. D. |last2=Thanassoulis |first2=G. |last3=Glavinovic |first3=T. |last4=Navar |first4=A. M. |last5=Pencina |first5=M. |last6=Catapano |first6=A. |last7=Ference |first7=B. A. |date=1 Dec 2019 |title=Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review |journal=JAMA Cardiology |volume=4 |issue=12 |pages=1287–1295 |doi=10.1001/jamacardio.2019.3780 |pmc=7369156 |pmid=31642874}}</ref>

====Optimal ranges====
The LDL particle concentrations are typically categorized by percentiles, <20%, 20–50%, 50th–80th%, 80th–95%, and >95% groups of the people participating and being tracked in the [[Multi-Ethnic Study of Atherosclerosis|MESA trial]], a medical research study sponsored by the United States National Heart, Lung, and Blood Institute.

{| class="wikitable"
! MESA Percentile
! LDL particles nmol/L
! Interpretation
|-
| 0–20%
| <1,000
| Those with the lowest rate of cardiovascular disease events & low (optimal) LDL particle concentration
|-
| 20–50%
| 1,000–1,299
| Those with a moderate rate of cardiovascular disease events & moderate LDL particle concentration
|-
| 50–80%
| 1,300–1,599
| Those with borderline-high rates of cardiovascular disease events & higher LDL particle concentration
|-
| 89–95%
| 1,600–2,000
| Those with a high rate of cardiovascular disease events and even higher LDL particle concentration
|-
| >95%
| >2,000
| Those with a very high rate of cardiovascular disease events and the highest LDL particle concentration
|-
|}

Over time, the lowest incidence of atherosclerotic events occurs within the <20% group, with increased rates for the higher groups. {{Citation needed |reason="by this table, a generally accepted health LDL concentration of 100 mg/dl would be in the 95th MESA percentile"|date=July 2024}} Multiple other measures, including particle sizes, small LDL particle concentrations, large total and HDL particle concentrations, along with estimations of [[insulin resistance]] pattern and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are also routinely provided.