Hypercholesterolemia

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Hypercholesterolemia is "a condition with abnormally high levels of cholesterol in the blood. It is defined as a cholesterol value exceeding the 95th percentile for the population."[1] It should be differentiated from dyslipidemia, where the total cholesterol may not be abnormally high, but the ratios of lipid components are in an unhealthy range.

Prognostication

Non-HDL cholesterol and apolipoprotein B levels may better predict subsequent vascular disease thatn LDL-C levels.[2]According to the Friedewald formula, non-HDL cholesterol is LDL-cholesterol LDL-C and VLDL-C.[3] If LDL-C levels are used as goals of therapy:[4]

"A 'normal' VLDL cholesterol can be defined as that present when triglycerides are <150 mg/dL; this value typically is ≤30 mg/dL. Conversely, when triglyceride levels are >150 mg/dL, VLDL cholesterol usually is >30 mg/dL. Thus, a reasonable goal for non-HDL cholesterol is one that is 30 mg/dL higher than the LDL-cholesterol goal."

Accordingly, the U.S. Preventive Services Task Force states:[5].

  • "The preferred screening tests for dyslipidemia are total cholesterol and HDL-C on non-fasting or fasting samples. There is currently insufficient evidence of the benefit of including TG as a part of the initial tests used to screen routinely for dyslipidemia. Abnormal screening test results should be confirmed by a repeated sample on a separate occasion, and the average of both results should be used for risk assessment."
  • "Measuring total cholesterol alone is acceptable for screening if available laboratory services cannot provide reliable measurements of HDL-C; measuring both total cholesterol and HDL-C is more sensitive and specific for assessing coronary heart disease risk than measuring total cholesterol alone. In conjunction with HDL-C, the addition of either LDL-C or total cholesterol would provide comparable information, but measuring LDL-C requires a fasting sample and is more expensive. Direct LDL-C testing, which does not require a fasting sample measurement, is now available; however, calculated LDL (total cholesterol minus HDL minus TG/5) is the validated measurement used in trials for risk assessment and treatment decisions. In patients with dyslipidemia identified by screening, complete lipoprotein analysis is useful."

A more recent study confirms that non-fasting samples may be accurate.[6]

Regarding when to repeat evaluation of risk, "Repeat risk estimation before 8-10 years is not warranted for most people initially not requiring treatment. However, remeasurement within a year seems warranted in those with an initial 15-<20% risk [of cardiovascular disease within ten years]".[7]

Treatment

Antilipemic agents such include:

Studies of drugs other than statins show other drugs can lower the cholesterol, but without definite benefit on clinical events.[8] Examples include randomized controlled trials of:

It is not clear whether to treat to LDL targets. Studies are currently evaluating this.[25][26]

Clinical practice guidelines

Various clinical practice guidelines have addressed the treatment of hypercholesterolemia.

U.S. Preventive Services Task Force published in 2012 guidelines about screening. [5].

Clinical practice guidelines by the National Institute for Health and Clinical Excellence in 2008 recommend treatment if the estimated 10 year risk of cardiovascular disease is at least 20%.[27][28]

The American College of Physicians in 2004 addressed hypercholesterolemia in patients with diabetes [29]. Their recommendations are:

  • Recommendation 1: Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all patients (both men and women) with known coronary artery disease and type 2 diabetes.
  • Recommendation 2: Statins should be used for primary prevention against macrovascular complications in patients (both men and women) with type 2 diabetes and other cardiovascular risk factors.
  • Recommendation 3: Once lipid-lowering therapy is initiated, patients with type 2 diabetes mellitus should be taking at least moderate doses of a statin (the accompanying evidence report states "simvastatin, 40 mg/d; pravastatin, 40 mg/d; lovastatin, 40 mg/d; atorvastatin, 20 mg/d; or an equivalent dose of another statin")[30].
  • Recommendation 4: For those patients with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances.

The National Cholesterol Education Program revised their 2001 guidelines[31] in 2004 to include goal LDL values.[32]; however, their 2004 revisions have been criticized for use of nonrandomized, observational data.[33] A decision analysis found that treating to targets is not efficient.[34] However, in this analysis, an older version of the Framingham was used which incorporated EKG findings and included diabetics.[35]

Meta-analyses and trials

In 2012, a meta-analysis of 27 randomized controlled trials of patients, including some at low risk of vascular disease and some with prior vascular disease, reported reduced vascular events, "statins reduced the risks of vascular (RR per 1.0 mmol/L LDL cholesterol reduction 0.85, 95% CI 0.77—0.95) and all-cause mortality (RR 0.91, 95% CI 0.85—0.97)".[36]

Primary prevention

Several meta-analyses, summarizing the randomized controlled trials, have been published.

Older meta-analyses report similar results:

  • In 2001, a meta-analysis estimated that after 5 to 7 years of treatment with statins, the relative risk reduction of coronary heart disease events is decreased by approximately 30%[42]
  • In 2000, a meta-analysis concluded "treatment with lipid lowering drugs lasting five to seven years reduces coronary heart disease events but not all cause mortality in people with no known cardiovascular disease."[43]

Treating based on risk factors is probably better than treating to a specific target LDL cholesterol.[34] Using a calculator such as the NIH calculator:

Important randomized controlled trials included in the meta-analyses are:

  • AFCAPS/TexCAPS.[44] The 10 year risk of coronary heart disease among an average patient in this study ((age 57, male, non-smoker, total and HDL cholesterol values of 221 mg/dL and 36 mg/dL, respectively, SBP 138 mm/Hg with medications for hypertension) was 12%.
  • JUPITER which found that yreating patients with normal cholesterol level may benefit patients if their high sensitivity c-reactive protein is elevated according to the Jupiter randomized controlled trial.[45] However, the Jupiter trial was stopped early, the subjects had a projected 6.3% risk of coronary events over 5 years and only 17% of patients were taking aspirin.[45]
  • Excel studied low risk patients.[46]
  • Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study). These subjects had a 3% risk of coronary events in 5 years.[47]
Combination treatment

It is not clear that combination therapy is better than high dose hydroxymethylglutaryl-coenzyme A reductase inhibitors.[48]

If treatment with a hydroxymethylglutaryl-coenzyme A reductase inhibitor does not achieve a desirable cholesterol, other drugs that have been studied include eicosapentaenoic acid which is a metabolite of fish oil.[24] Ezetimibe, a cholesterol-absorption inhibitor, was not clearly beneficial in a study of diabetes mellitus type 2[12] and a study of mixed primary prevention and secondary prevention[14]. Niacin has been studied with improvements in the LDL and HDL[17] with uncertain[19] effects on carotid intima-media thickness.

Secondary prevention

Clinical practice guidelines by the National Institute for Health and Clinical Excellence recommend a treatment goal of <4 mmol/l (154 mg/dl) for total cholesterol or a low density lipoprotein cholesterol concentration of <2 mmol/l (77 mg/dl).[27][28] A systematic review summarized randomized controlled trials in secondary prevention.[49]

Combination treatment

If treatment with a hydroxymethylglutaryl-coenzyme A reductase inhibitor does not achieve a desirable cholesterol, other drugs that may be added for additional benefit include niacin[13][18][19] and fish oil. Ezetimibe, a cholesterol-absorption inhibitor, was not clearly beneficial in a study of diabetes mellitus type 2[12] and a study of mixed primary prevention and secondary prevention[14].

Diabetic patients

For more information, see: Diabetes_mellitus_type_2#Hypercholesterolemia.


Whether diabetes is an equivalent risk factor to having an existing myocardial infarction is debated.[50]

Statin therapy prevents major vascular events in about 1 of every 24 patients with diabetes who use the treatment for 5 years if they are similar to the patients in the meta-analysis by Kearney et al (Number needed to treat is 24).[51]

Treating to a goal of LDL-C < 70 mg/dl and systolic blood pressure to < 115 mm Hg may cause regression of carotid intima-media thickness in a randomized controlled trial.[52]

Complementary and alternative medicine

Preliminary research suggests possible benefit from artichoke leaf.[53]

References

  1. ↑ Anonymous. Hypercholesterolemia. National Library of Medicine. Retrieved on 2008-01-18.
  2. ↑ Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel PJ et al. (2012). "Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.". JAMA 307 (12): 1302-9. DOI:10.1001/jama.2012.366. PMID 22453571. Research Blogging.
  3. ↑ Friedewald WT, Levy RI, Fredrickson DS (1972). "Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.". Clin Chem 18 (6): 499-502. PMID 4337382. [e]
  4. ↑ National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2002). "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) final report.". Circulation 106 (25): 3143-421. PMID 12485966. [e]
  5. ↑ 5.0 5.1 Screening for Lipid Disorders: Recommendations and Rationale. Retrieved on 2012-01-05.
  6. ↑ Sidhu D, Naugler C (2012). "Fasting Time and Lipid Levels in a Community-Based Population: A Cross-sectional Study.". Arch Intern Med: 1-4. DOI:10.1001/archinternmed.2012.3708. PMID 23147400. Research Blogging.
  7. ↑ Bell KJ, Hayen A, Irwig L, Takahashi O, Ohde S, Glasziou P (2013). "When to remeasure cardiovascular risk in untreated people at low and intermediate risk: observational study.". BMJ 346: f1895. DOI:10.1136/bmj.f1895. PMID 23553971. Research Blogging.
  8. ↑ Keene D, Price C, Shun-Shin MJ, Francis DP (2014). "Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117 411 patients.". BMJ 349: g4379. DOI:10.1136/bmj.g4379. PMID 25038074. Research Blogging.
  9. ↑ Abourbih S, Filion KB, Joseph L, Schiffrin EL, Rinfret S, Poirier P et al. (2009). "Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review.". Am J Med 122 (10): 962.e1-8. DOI:10.1016/j.amjmed.2009.03.030. PMID 19698935. Research Blogging.
  10. ↑ 10.0 10.1 ACCORD Study Group. Ginsberg HN, Elam MB, Lovato LC, Crouse JR, Leiter LA et al. (2010). "Effects of combination lipid therapy in type 2 diabetes mellitus.". N Engl J Med 362 (17): 1563-74. DOI:10.1056/NEJMoa1001282. PMID 20228404. PMC PMC2879499. Research Blogging. Review in: J Fam Pract. 2010 Oct;59(10):582-4 Review in: Ann Intern Med. 2010 Jul 20;153(2):JC1-5
  11. ↑ Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR et al. (2005). "Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.". Lancet 366 (9500): 1849-61. DOI:10.1016/S0140-6736(05)67667-2. PMID 16310551. Research Blogging. Review in: Evid Based Med. 2006 Jun;11(3):86 Review in: ACP J Club. 2006 May-Jun;144(3):65
  12. ↑ 12.0 12.1 12.2 Howard BV, Roman MJ, Devereux RB, et al (April 2008). "Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: the SANDS randomized trial". JAMA 299 (14): 1678–89. DOI:10.1001/jama.299.14.1678. PMID 18398080. Research Blogging.
  13. ↑ 13.0 13.1 13.2 Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M et al. (2009). "Extended-release niacin or ezetimibe and carotid intima-media thickness.". N Engl J Med 361 (22): 2113-22. DOI:10.1056/NEJMoa0907569. PMID 19915217. Research Blogging.
  14. ↑ 14.0 14.1 14.2 Kastelein JJ, Akdim F, Stroes ES, et al (April 2008). "Simvastatin with or without ezetimibe in familial hypercholesterolemia". N. Engl. J. Med. 358 (14): 1431–43. DOI:10.1056/NEJMoa0800742. PMID 18376000. Research Blogging. Cite error: Invalid <ref> tag; name "pmid18376000" defined multiple times with different content Cite error: Invalid <ref> tag; name "pmid18376000" defined multiple times with different content
  15. ↑ Rossebø AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K et al. (2008). "Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.". N Engl J Med 359 (13): 1343-56. DOI:10.1056/NEJMoa0804602. PMID 18765433. Research Blogging.
  16. ↑ AIM-HIGH Investigators. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P et al. (2011). "Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.". N Engl J Med 365 (24): 2255-67. DOI:10.1056/NEJMoa1107579. PMID 22085343. Research Blogging.
  17. ↑ 17.0 17.1 McKenney JM, Jones PH, Bays HE, et al (June 2007). "Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study)". Atherosclerosis 192 (2): 432–7. DOI:10.1016/j.atherosclerosis.2006.11.037. PMID 17239888. Research Blogging. Cite error: Invalid <ref> tag; name "pmid17239888" defined multiple times with different content
  18. ↑ 18.0 18.1 Brown BG, Zhao XQ, Chait A, et al. (November 2001). "Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease". N. Engl. J. Med. 345 (22): 1583–92. PMID 11757504. [e] Cite error: Invalid <ref> tag; name "pmid11757504" defined multiple times with different content
  19. ↑ 19.0 19.1 19.2 Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA (December 2004). "Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins". Circulation 110 (23): 3512–7. DOI:10.1161/01.CIR.0000148955.19792.8D. PMID 15537681. Research Blogging. Cite error: Invalid <ref> tag; name "pmid15537681" defined multiple times with different content
  20. ↑ Phan BA, Muñoz L, Shadzi P, Isquith D, Triller M, Brown BG et al. (2012). "Effects of Niacin on Glucose Levels, Coronary Stenosis Progression, and Clinical Events in Subjects With Normal Baseline Glucose Levels (<100 mg/dl): A Combined Analysis of the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), and Carotid Plaque Composition by MRI During Lipid-lowering (CPC) Study.". Am J Cardiol. DOI:10.1016/j.amjcard.2012.09.034. PMID 23168285. Research Blogging.
  21. ↑ Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M et al. (2007). "Effects of torcetrapib in patients at high risk for coronary events.". N Engl J Med 357 (21): 2109-22. DOI:10.1056/NEJMoa0706628. PMID 17984165. Research Blogging.
  22. ↑ Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J et al. (2012). "Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome.". N Engl J Med. DOI:10.1056/NEJMoa1206797. PMID 23126252. Research Blogging.
  23. ↑ Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R et al. (2015). "Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial.". Eur Heart J. DOI:10.1093/eurheartj/ehv028. PMID 25687353. Research Blogging.
  24. ↑ 24.0 24.1 Yokoyama M, Origasa H, Matsuzaki M, et al (March 2007). "Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis". Lancet 369 (9567): 1090–8. DOI:10.1016/S0140-6736(07)60527-3. PMID 17398308. Research Blogging.
  25. ↑ IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (Study P04103AM3) Clinical Trials.gov
  26. ↑ Treat Stroke to Target (TST) ClinicalTrials.gov
  27. ↑ 27.0 27.1 Cooper A, O'Flynn N (2008). "Risk assessment and lipid modification for primary and secondary prevention of cardiovascular disease: summary of NICE guidance". BMJ. PMID 18511800. PMC 2405875. [e]
  28. ↑ 28.0 28.1 Anonymous (2008). Lipid modification. National Institute for Health and Clinical Excellence. Retrieved on 2008-08-26. Cite error: Invalid <ref> tag; name "urlNICE guidance by type" defined multiple times with different content
  29. ↑ Snow V, Aronson M, Hornbake E, Mottur-Pilson C, Weiss K (2004). "Lipid control in the management of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians". Ann Intern Med 140 (8): 644-9. PMID 15096336.
  30. ↑ Vijan S, Hayward RA (2004). "Pharmacologic lipid-lowering therapy in type 2 diabetes mellitus: background paper for the American College of Physicians". Ann. Intern. Med. 140 (8): 650-8. PMID 15096337. [e]
  31. ↑ Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001). "Executive Summary of The 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).". JAMA 285 (19): 2486-97. PMID 11368702.
  32. ↑ Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Stone NJ (2004). "Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines". J. Am. Coll. Cardiol. 44 (3): 720-32. DOI:10.1016/j.jacc.2004.07.001. PMID 15358046. Research Blogging.
  33. ↑ Hayward RA, Hofer TP, Vijan S (2006). "Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem". Ann. Intern. Med. 145 (7): 520-30. PMID 17015870. [e]
  34. ↑ 34.0 34.1 Hayward RA, Krumholz HM, Zulman DM, Timbie JW, Vijan S (2010). "Optimizing statin treatment for primary prevention of coronary artery disease.". Ann Intern Med 152 (2): 69-77. DOI:10.1059/0003-4819-152-2-201001190-00004. PMID 20083825. Research Blogging. Cite error: Invalid <ref> tag; name "pmid20083825" defined multiple times with different content
  35. ↑ Matheny M, McPheeters ML, Glasser A, Mercaldo N, Weaver RB, Jerome RN, Walden R, McKoy JN, Pritchett J, Tsai C. Systematic Review of Cardiovascular Disease Risk Assessment Tools [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 May. Available from http://www.ncbi.nlm.nih.gov/books/NBK56166/ PubMed PMID: http://pubmedogv/21796824.
  36. ↑ (2012) "The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.". Lancet. DOI:10.1016/S0140-6736(12)60367-5. PMID 22607822. Research Blogging.
  37. ↑ Tonelli M, Lloyd A, Clement F, Conly J, Husereau D, Hemmelgarn B et al. (2011). "Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis.". CMAJ 183 (16): E1189-202. DOI:10.1503/cmaj.101280. PMID 21989464. PMC PMC3216447. Research Blogging.
  38. ↑ Ray KK, Seshasai SR, Erqou S, Sever P, Jukema JW, Ford I et al. (2010). "Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants.". Arch Intern Med 170 (12): 1024-31. DOI:10.1001/archinternmed.2010.182. PMID 20585067. Research Blogging.
  39. ↑ Thavendiranathan P, Bagai A, Brookhart M, Choudhry N (2006). "Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials". Arch Intern Med 166 (21): 2307-13. DOI:10.1001/archinte.166.21.2307. PMID 17130382. Research Blogging.
  40. ↑ Brugts JJ, Yetgin T, Hoeks SE, et al. (2009). "The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials". BMJ 338: b2376. PMID 19567909. [e]
  41. ↑ Baigent C, Keech A, Kearney PM, et al (2005). "Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins". Lancet 366 (9493): 1267-78. DOI:10.1016/S0140-6736(05)67394-1. PMID 16214597. Research Blogging.
  42. ↑ Pignone MP, Phillips CJ, Atkins D, Teutsch SM, Mulrow CD, Lohr KN (2001). "Screening and treating adults for lipid disorders". American Journal of Preventive Medicine 20 (3 Suppl): 77–89. PMID 11306236. [e]
  43. ↑ Pignone M, Phillips C, Mulrow C (2000). "Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials.". BMJ 321 (7267): 983-6. PMID 11039962. PMC PMC27504. [e]
  44. ↑ Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA et al. (1998). "Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.". JAMA 279 (20): 1615-22. DOI:10.1001/jama.279.20.1615. PMID 9613910. Research Blogging.
  45. ↑ 45.0 45.1 Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ et al. (2008). "Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.". N Engl J Med 359 (21): 2195-207. DOI:10.1056/NEJMoa0807646. PMID 18997196. Research Blogging. Review in: Ann Intern Med. 2009 Jan 20;150(2):JC1-4 Review in: Evid Based Med. 2009 Apr;14(2):48
  46. ↑ Bradford RH, Shear CL, Chremos AN, Dujovne C, Downton M, Franklin FA et al. (1991). "Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia.". Arch Intern Med 151 (1): 43-9. PMID 1985608. [e]
  47. ↑ Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T et al. (2006). "Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial.". Lancet 368 (9542): 1155-63. DOI:10.1016/S0140-6736(06)69472-5. PMID 17011942. Research Blogging.
  48. ↑ Sharma M, Ansari MT, Abou-Setta AM, Soares-Weiser K, Ooi TC, Sears M et al. (2009). "Systematic review: comparative effectiveness and harms of combination therapy and monotherapy for dyslipidemia.". Ann Intern Med 151 (9): 622-30. DOI:10.1059/0003-4819-151-9-200911030-00144. PMID 19884623. Research Blogging.
  49. ↑ Cholesterol Treatment Trialists’ (CTT) Collaboration. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C et al. (2010). "Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.". Lancet 376 (9753): 1670-81. DOI:10.1016/S0140-6736(10)61350-5. PMID 21067804. Research Blogging.
  50. ↑ Bulugahapitiya U, Siyambalapitiya S, Sithole J, Idris I (February 2009). "Is diabetes a coronary risk equivalent? Systematic review and meta-analysis". Diabet. Med. 26 (2): 142–8. DOI:10.1111/j.1464-5491.2008.02640.x. PMID 19236616. Research Blogging.
  51. ↑ Kearney PM, Blackwell L, Collins R, et al (2008). "Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis". Lancet 371 (9607): 117–25. DOI:10.1016/S0140-6736(08)60104-X. PMID 18191683. Research Blogging.
  52. ↑ Howard, B. V., Roman, M. J., Devereux, R. B., Fleg, J. L., Galloway, J. M., Henderson, J. A., et al. (2008). Effect of Lower Targets for Blood Pressure and LDL Cholesterol on Atherosclerosis in Diabetes: The SANDS Randomized Trial. JAMA, 299(14), 1678-1689. DOI:10.1001/jama.299.14.1678.
  53. ↑ Wider B, Pittler MH, Thompson-Coon J, Ernst E (2009). "Artichoke leaf extract for treating hypercholesterolaemia.". Cochrane Database Syst Rev (4): CD003335. DOI:10.1002/14651858.CD003335.pub2. PMID 19821306. Research Blogging.

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