Editing Low-density lipoprotein (section)

==Lowering LDL-cholesterol==
{| class="wikitable" style="float:right; width:40em; border:solid 1px #999999; margin:0 0 1em 1em;"
|-
! colspan=5 style="background-color: #CCEEEE;" | Markers indicating a need for LDL-C Reduction
(Per 2004 United States Government Minimum Guidelines<ref>{{Cite web |title=Management of Blood Cholesterol in Adults: Systematic Evidence Review from the Cholesterol Expert Panel &#124; National Heart, Lung, and Blood Institute (NHLBI) |url=http://www.nhlbi.nih.gov/health-pro/guidelines/current/cholesterol-guidelines/ |url-status=dead |archive-url=https://web.archive.org/web/20141125175151/http://www.nhlbi.nih.gov/health-pro/guidelines/current/cholesterol-guidelines |archive-date=2014-11-25 |access-date=2014-11-16}}</ref><ref>{{Cite web |title=Archived copy |url=https://www.acli.com/Events/Documents/Tue22812%20-%20Lipidology%20-%20Pamela%20Morris.pdf |url-status=dead |archive-url=https://web.archive.org/web/20160303223001/https://www.acli.com/Events/Documents/Tue22812%20-%20Lipidology%20-%20Pamela%20Morris.pdf |archive-date=2016-03-03 |access-date=2014-11-16}}</ref>)
|-
! If the patient's cardiac risk is...
! then the patient should consider LDL-C reduction if the count in mg/dL is over...
! and LDL-C reduction is indicated if the count in mg/dL is over...
|-
| High, meaning a 20% or greater risk of heart attack within 10 years or an extreme risk factor
| 70<ref name="BBDstatins">{{Citation |author1 = Consumer Reports |author1-link = Consumer Reports |author2 = Drug Effectiveness Review Project |author2-link = Drug Effectiveness Review Project |date = March 2013 |title = Evaluating statin drugs to treat High Cholesterol and Heart Disease: Comparing Effectiveness, Safety, and Price |publisher = Consumer Reports |work = Best Buy Drugs |page = 9 |url = http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/StatinsUpdate-FINAL.pdf |access-date = 27 March 2013 }}, which cites
* {{Cite web |last1=United States Department of Health and Human Services |author-link1=United States Department of Health and Human Services |last2=National Heart, Lung, and Blood Institute |author-link2=National Heart, Lung, and Blood Institute |last3=National Institutes of Health |author-link3=National Institutes of Health |date=June 2005 |title=NHLBI, High Blood Cholesterol: What You Need to Know |url=http://www.nhlbi.nih.gov/health/public/heart/chol/wyntk.htm |url-status=dead |archive-url=https://web.archive.org/web/20130401072344/http://www.nhlbi.nih.gov/health/public/heart/chol/wyntk.htm |archive-date=2013-04-01 |access-date=27 March 2013 |website=nhlbi.nih.gov}}</ref>
| 100<ref name="BBDstatins" />
|-
| moderately high, meaning a 10-20% risk of heart attack within 10 years and more than 2 heart attack risk factors
| 100<ref name="BBDstatins" />
| 130<ref name="BBDstatins" />
|-
| moderate, meaning a 10% risk of heart attack within 10 years and more than 2 heart attack risk factors
| 130<ref name="BBDstatins" />
| 160<ref name="BBDstatins" />
|-
| low, meaning less than 10% risk of heart attack within 10 years and 1 or 0 heart attack risk factors
| 160<ref name="BBDstatins" />
| 190<ref name="BBDstatins" />
|-
|}

The [[mevalonate pathway]] serves as the basis for the biosynthesis of many molecules, including cholesterol. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase ([[HMG CoA reductase]]) is an essential component and performs the first of 37 steps within the cholesterol production pathway, and is present in every animal cell. Statins block this first step.<ref name="Endo1992">{{cite journal | vauthors = Endo A | title = The discovery and development of HMG-CoA reductase inhibitors | journal = Journal of Lipid Research | volume = 33 | issue = 11 | pages = 1569–1582 | date = November 1992 | pmid = 1464741 | doi = 10.1016/S0022-2275(20)41379-3 | doi-access = free | title-link = doi }}</ref>

LDL-C is not a count of actual LDL particles. LDL-C represents how much cholesterol is being transported by all LDL particles, which is either a smaller concentration of large particles or a high concentration of small particles. LDL-C itself can be estimated by subtraction (Friedewald's method)<ref name=h704>{{cite web |title=Laboratory Procedure Manual; Total Cholesterol, HDL-Cholesterol, Triglycerides, and LDL-Cholesterol; Serum; Hitachi 704 |url=https://www.cdc.gov/nchs/data/nhanes/nhanes_03_04/l13_c_met_lipids.pdf |website=cdc.gov}}</ref> or directly measured; see the section [[#Testing]] above to see how it's measured.<ref name=pmid34709388>{{cite journal |last1=Sajja |first1=A |last2=Park |first2=J |last3=Sathiyakumar |first3=V |last4=Varghese |first4=B |last5=Pallazola |first5=VA |last6=Marvel |first6=FA |last7=Kulkarni |first7=K |last8=Muthukumar |first8=A |last9=Joshi |first9=PH |last10=Gianos |first10=E |last11=Hirsh |first11=B |last12=Mintz |first12=G |last13=Goldberg |first13=A |last14=Morris |first14=PB |last15=Sharma |first15=G |last16=Blumenthal |first16=RS |last17=Michos |first17=ED |last18=Post |first18=WS |last19=Elshazly |first19=MB |last20=Jones |first20=SR |last21=Martin |first21=SS |title=Comparison of Methods to Estimate Low-Density Lipoprotein Cholesterol in Patients With High Triglyceride Levels. |journal=JAMA Network Open |date=1 October 2021 |volume=4 |issue=10 |pages=e2128817 |doi=10.1001/jamanetworkopen.2021.28817 |pmid=34709388|pmc=8554644 |doi-access=free }}</ref> LDL particles carry many lipid molecules (typically 3,000 to 6,000 lipid molecules per LDL particle); this includes cholesterol, triglycerides, phospholipids and others. An LDL-C measurement cannot account for differences in size and composition between types of LDL.<ref>{{cite journal |last1=McNamara |first1=JR |last2=Small |first2=DM |last3=Li |first3=Z |last4=Schaefer |first4=EJ |title=Differences in LDL subspecies involve alterations in lipid composition and conformational changes in apolipoprotein B. |journal=Journal of Lipid Research |date=September 1996 |volume=37 |issue=9 |pages=1924–35 |doi=10.1016/S0022-2275(20)37557-X |pmid=8895058|doi-access=free }}</ref>

=== Pharmaceutical ===
{{main|Lipid-lowering agent}}
* [[PCSK9 inhibitor]]s, in clinical trials, by several companies, are more effective for LDL reduction than the statins, including statins alone at high dose (though not necessarily the combination of statins plus ezetimibe).{{cn|date=February 2025}} They have been approved and are recommended in patients not receiving enough reduction from their maximally tolerated dose of statins + ezetimibe.<ref name="AlenghatDavis2019">{{cite journal | vauthors = Alenghat FJ, Davis AM | title = Management of Blood Cholesterol | journal = JAMA | volume = 321 | issue = 8 | pages = 800–801 | date = February 2019 | pmid = 30715135 | pmc = 6679800 | doi = 10.1001/jama.2019.0015 }}</ref>
* [[Statin]]s reduce high levels of LDL particles by inhibiting the enzyme HMG-CoA reductase in cells, the rate-limiting step of cholesterol synthesis. To compensate for the decreased cholesterol availability, synthesis of LDL receptors (including hepatic) is increased, resulting in an increased clearance of LDL particles from the extracellular water, including of the blood.<ref name="Endo1992"/>
* [[Ezetimibe]] reduces intestinal absorption of cholesterol, thus can reduce LDL particle concentrations when combined with statins.<ref>{{Cite web |last=Research |first=Center for Drug Evaluation and |title=Drug Safety Information for Healthcare<!-- "heathcare" in original --> Professionals - Follow-up to the January 25, 2008 Early Communication about an Ongoing Data Review for Ezetimibe/Simvastatin (marketed as Vytorin), Ezetimibe (marketed as Zetia), and Simvastatin (marketed as Zocor) |url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm079524.htm |website=[[Food and Drug Administration]]}}</ref>
* [[Niacin (substance)|Niacin]] (nicotinic acid), lowers LDL by selectively inhibiting hepatic diacylglycerol acyltransferase 2, reducing [[triglyceride]] synthesis and VLDL secretion through a receptor HM74<ref>{{Cite journal |vauthors=Meyers CD, Kamanna VS, Kashyap ML |date=December 2004 |title=Niacin therapy in atherosclerosis |journal=Current Opinion in Lipidology |volume=15 |issue=6 |pages=659–65 |doi=10.1097/00041433-200412000-00006 |pmid=15529025}}</ref> and HM74A or GPR109A.<ref name="pmid17238156">{{Cite journal |vauthors=Soudijn W, van Wijngaarden I, Ijzerman AP |date=May 2007 |title=Nicotinic acid receptor subtypes and their ligands |journal=Medicinal Research Reviews |volume=27 |issue=3 |pages=417–33 |doi=10.1002/med.20102 |pmid=17238156 }}</ref> Introduced in 1955.
* [[Clofibrate]] is effective at lowering cholesterol levels, but has been associated with significantly increased cancer and stroke mortality, despite lowered cholesterol levels.<ref>{{Cite journal |date=September 1984 |title=WHO cooperative trial on primary prevention of ischemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Report of the Committee of Principal Investigators |journal=Lancet |volume=2 |issue=8403 |pages=600–4 |doi=10.1016/s0140-6736(84)90595-6 |pmid=6147641 }}</ref> Other developed and tested [[fibrate]]s, e.g. [[fenofibric acid]]<ref>{{Cite web |title=TRILIPIX (fenofibric acid) |url=https://www.rxabbvie.com/pdf/trilipix_pi.pdf |access-date=7 July 2024}}</ref> have had a better track record and are primarily promoted for lowering VLDL particles (triglycerides), not LDL particles, yet can help some in combination with other strategies.
* [[Probucol]], introduced in the 1970s. Now known to work through, among other ways, changing the shape and size of the LDL particle so they can be taken up by the liver without involving the [[LDL receptor]].  It has been discontinued in the west due to HDL-C decreases that were not explainable at the time. It's now known that it enhances the [[reverse cholesterol transport]] and antioxidant functions of HDL despite decreasing HDL-C.<ref name="pmid26125504">{{cite journal |vauthors=Yamashita S, Masuda D, Matsuzawa Y |title=Did we abandon probucol too soon? |journal=Current Opinion in Lipidology |volume=26 |issue=4 |pages=304–16 |date=August 2015 |pmid=26125504 |doi=10.1097/MOL.0000000000000199}}</ref>

====Not approved as drugs ====
* Several [[CETP inhibitor]]s have been researched to improve HDL concentrations, but so far, despite dramatically increasing HDL-C, have not had a consistent track record in reducing atherosclerosis disease events. Some have increased mortality rates compared with placebo.
* Some [[tocotrienol]]s, especially delta- and gamma-tocotrienols, are being promoted as statin alternative non-prescription agents to treat high cholesterol, having been shown in vitro to have an effect. In particular, gamma-tocotrienol appears to be another HMG-CoA reductase inhibitor, and can reduce cholesterol production.<ref>{{Cite journal |last1=Song |first1=B.L. |last2=DeBose-Boyd, R.A. |year=2006 |title=Insig-Dependent Ubiquitination and Degradation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Stimulated by Delta- and Gamma-Tocotrienols |journal=J. Biol. Chem. |volume=281 |issue=35 |pages=25054–25601 |doi=10.1074/jbc.M605575200 |pmid=16831864 |doi-access=free}}</ref> As with statins, this decrease in intra-hepatic (liver) LDL levels may induce hepatic LDL receptor up-regulation, also decreasing plasma LDL levels. As always, a key issue is how benefits and complications of such agents compare with statins—molecular tools that have been analyzed in large numbers of human research and clinical trials since the mid-1970s.{{cn|date=February 2025}}
* [[Phytosterol]]s are widely recognized as having a proven LDL cholesterol lowering efficacy'<ref>{{Cite web |last=European Food Safety Authority, Journal |year=2010 |title=Scientific opinion on the substantiation of health claims related to plant sterols and plant stanols and maintenance of normal blood cholesterol concentrations |url=http://www.efsa.europa.eu/en/efsajournal/pub/1813}}</ref> A 2018 review found a dose-response relationship for phytosterols, with intakes of 1.5 to 3&nbsp;g/day lowering LDL-C by 7.5% to 12%,<ref>{{Cite journal |last1=Trautwein |first1=Elke |last2=Vermeer |first2=Mario |last3=Hiemstra |first3=Harry |last4=Ras |first4=Rouyanne |date=7 September 2018 |title=LDL-Cholesterol Lowering of Plant Sterols and Stanols—Which Factors Influence Their Efficacy? |journal=Nutrients |publisher=MDPI AG |volume=10 |issue=9 |page=1262 |doi=10.3390/nu10091262 |pmc=6163911 |pmid=30205492 |doi-access=free}}</ref> but reviews as of 2017 had found  no data indicating that the consumption of phytosterols may reduce the risk of CVD.<ref>{{Cite journal |last1=Cabral |first1=Carlos Eduardo |last2=Klein |first2=Márcia Regina Simas Torres |year=2017 |title=Phytosterols in the Treatment of Hypercholesterolemia and Prevention of Cardiovascular Diseases |journal=Arquivos Brasileiros de Cardiologia |publisher=Sociedade Brasileira de Cardiologia |volume=109 |issue=5 |pages=475–482 |doi=10.5935/abc.20170158 |pmc=5729784 |pmid=29267628}}</ref> Current supplemental guidelines for reducing LDL recommend doses of phytosterols in the 1.6-3.0&nbsp;grams per day range (Health Canada, EFSA, ATP III, FDA) with a 2009 meta-analysis demonstrating an 8.8% reduction in LDL-cholesterol at a mean dose of 2.15&nbsp;gram per day.<ref>{{Cite journal |last1=Demonty |first1=I. |last2=Ras |first2=R.T. |last3=van der Knaap |first3=H.C. |last4=Duchateau |first4=G.S. |last5=Meijer |first5=L. |last6=Zock |first6=P.L. |last7=Geleijnse |first7=J.M. |last8=Trautwein |first8=E.A. |date=Feb 2009 |title=Continuous dose-response relationship of the LDL-cholesterol-lowering effect of phytosterol intake. |journal=The Journal of Nutrition |volume=139 |issue=2 |pages=271–84 |doi=10.3945/jn.108.095125 |pmid=19091798 |doi-access=free}}</ref>

=== Lifestyle ===
LDL cholesterol can be lowered through dietary intervention by limiting foods with [[saturated fat]] and avoiding foods with [[trans fat]].<ref name=":0">{{Cite web |title=Cholesterol Diet: How Nutrition & Foods Impact Levels |url=https://my.clevelandclinic.org/health/articles/16867-cholesterol--nutrition-tlc |access-date=2024-02-16 |website=Cleveland Clinic |language=en}}</ref> Saturated fats are found in meat products (including poultry), full-fat dairy, eggs, and refined tropical oils like coconut and palm.<ref>{{Cite web |title=Saturated Fat |url=https://www.heart.org/en/healthy-living/healthy-eating/eat-smart/fats/saturated-fats |access-date=2024-02-16 |website=www.heart.org |language=en}}</ref> Added trans fat (in the form of partially hydrogenated oils) has been banned in the US since 2021.<ref>{{Cite journal |last=Nutrition |first=Center for Food Safety and Applied |date=2023-08-30 |title=Trans Fat |url=https://www.fda.gov/food/food-additives-petitions/trans-fat |journal=FDA |language=en}}</ref> However, trans fat can still be found in red meat and dairy products as it is produced in small amounts by ruminants such as sheep and cows.<ref>{{cite book |doi=10.1533/9780857092557.3.383 |quote=In addition to hydrogenated oils, dairy products are a dietary source of trans fatty acids. Ruminant fat contains on average 1–3% trans fatty acids, which originate from the action of ruminant bacteria on feed unsaturated fatty acids.  |chapter=Functional fats and spreads |title=Functional Foods |date=2011 |last1=Turpeinen |first1=A. |last2=Merimaa |first2=P. |pages=383–400 |isbn=978-1-84569-690-0 }}</ref><ref>{{cite book |doi=10.1016/B978-0-12-811297-7.00026-3 |quote=Milk, dairy products, and meat from ruminants contain ∼2%–10% trans fatty acids |chapter=Trans Fatty Acids and Mortality |title=The Molecular Nutrition of Fats |date=2019 |last1=Delgado |first1=Graciela E. |last2=Kleber |first2=Marcus E. |pages=335–345 |isbn=978-0-12-811297-7 }}</ref> LDL cholesterol can also be lowered by increasing consumption of soluble fiber and plant-based foods.<ref>{{cite journal |last1=Schoeneck |first1=Malin |last2=Iggman |first2=David |title=The effects of foods on LDL cholesterol levels: A systematic review of the accumulated evidence from systematic reviews and meta-analyses of randomized controlled trials |journal=Nutrition, Metabolism and Cardiovascular Diseases |date=May 2021 |volume=31 |issue=5 |pages=1325–1338 |doi=10.1016/j.numecd.2020.12.032 |pmid=33762150 }}</ref>

Another lifestyle approach to reduce LDL cholesterol has been minimizing total body fat, in particular fat stored inside the [[abdominal cavity]] ([[Adipose tissue|visceral body fat]]). Visceral fat, which is more metabolically active than subcutaneous fat, has been found to produce many enzymatic signals, e.g. [[resistin]], which increase [[insulin resistance]] and circulating VLDL particle concentrations, thus both increasing LDL particle concentrations and accelerating the development of diabetes mellitus.{{cn|date=February 2025}}