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Familial Hypercholesterolemia Workup

  • Author: Mose July, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
 
Updated: Jul 10, 2016
 

Laboratory Studies

The diagnosis of both homozygous and heterozygous FH is based primarily on the finding of severe LDLc elevations in the absence of secondary causes of hypercholesterolemia with triglyceride levels that are within the reference range or mildly elevated and HDL cholesterol (HDLc) levels that are within the reference range or slightly low. A probable diagnosis of heterozygous FH can be made if the LDLc level is greater than 330 mg/dL or if tendon xanthomas are present in a patient with an LDLc level above the 95th percentile. Definitive diagnosis can be made only with gene or receptor analysis.

A substantial increase in serum triglyceride levels should raise the possibility of another lipid disorder.

Lipid analysis

Cholesterol levels are severely elevated in children and adults with homozygous FH, with total cholesterol and LDLc levels greater than 600 mg/dL and triglyceride levels within the reference range.

In patients with heterozygous FH, LDLc levels are commonly higher than 250 mg/dL and usually increase with age. An LDLc level higher than 200 mg/dL in a patient younger than 20 years is highly suggestive of heterozygous FH or, possibly, familial ligand defective apoB-100 (see Pathophysiology). In adults, LDLc levels higher than 290-300 mg/dL suggest heterozygous FH.

Lipoprotein (a) may be measured because patients with both heterozygous FH and high levels of lipoprotein (a) (>30 mg/dL) have a worse prognosis than those with normal levels of lipoprotein (a). However, all patients with FH are at very high risk for CAD and because no data are available to suggest that lipoprotein (a) should be specifically targeted for treatment.

Tests to rule out secondary hypercholesterolemia

Other laboratory testing may be suggestive by findings discerned thorough history and physical examination.

In the absence of symptoms or signs suggestive of a particular disorder, a limited workup should be performed to rule out secondary hypercholesterolemia.

Basic tests to rule out diabetes, hypothyroidism, hepatic disease, and renal disease are usually sufficient.

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Imaging Studies

Patients with homozygous FH should receive Doppler echocardiographic evaluation of the heart and aorta annually and, if available, computed-tomography coronary angiography every 5 years or more frequently if clinically indicated, taking into account the radiation exposure and severity of subclinical disease.

Children with homozygous FH should be referred to a pediatric cardiologist for consideration of vascular imaging studies (Pet scan, determination of carotid intima medial thickness, coronary catheterization) that can direct treatment for hypercholesterolemia.

Radiographic imaging of the Achilles tendon helps accurately measure Achilles tendon xanthomas, but the findings do not change lipid management.

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Other Tests

Lipoprotein electrophoresis is expensive and is unnecessary for the diagnosis of FH. Moreover, in the absence of preparative ultracentrifugation, it has no place in the workup of any lipid disorder. If fasting lipid analysis reveals elevated triglyceride levels and the diagnosis of FH is in doubt, beta quantification (ultracentrifugation and electrophoresis) may be performed at a major lipid center or one of the few commercial sites in the United States and other countries that performs this procedure.

LDL receptor analysis can be used to identify the specific LDL receptor defect. However, this analysis can only be performed at certain research laboratories and is expensive; and the results have no impact on management. LDL receptor or apoB-100 studies can help distinguish heterozygous FH from the similar syndrome of familial defective apoB-100, but this finding would not alter treatment.

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Procedures

The presence of an unusually high LDLc level should make identifying a cutaneous lesion straightforward. Possible entities include xanthelasmas or xanthomas.

If identification of a cutaneous lesion is unclear and the diagnosis of heterozygous FH is uncertain, a biopsy can be performed. Both xanthelasmas and the xanthomas of FH contain accumulations of cholesterol. By contrast, eruptive xanthomas in patients with severe hypertriglyceridemia (levels >1000 mg/dL) contain triglycerides (fat).

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Contributor Information and Disclosures
Author

Mose July, MD Fellow in Endocrinology, Diabetes and Metabolism, Marshall University School of Medicine

Mose July, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society

Disclosure: Nothing to disclose.

Coauthor(s)

Omolola Bolaji Olajide, MD, FACE Associate Professor, Consultant, Department of Internal Medicine, Program Director, Fellowship Program, Section of Endocrinology, Joan C Edwards School of Medicine at Marshall University

Omolola Bolaji Olajide, MD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, Endocrine Society, International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Yoram Shenker, MD Chief of Endocrinology Section, Veterans Affairs Medical Center of Madison; Interim Chief, Associate Professor, Department of Internal Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Wisconsin at Madison

Yoram Shenker, MD is a member of the following medical societies: American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Additional Contributors

Gregory William Rutecki, MD Professor of Medicine, Fellow of The Center for Bioethics and Human Dignity, University of South Alabama College of Medicine

Gregory William Rutecki, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Nephrology, National Kidney Foundation, Society of General Internal Medicine

Disclosure: Nothing to disclose.

References
  1. Illingworth DR, Duell PB, Connor WE. Disorders of lipid metabolism. Felig P, Baxter JD, Frohmin LA, eds. Endocrinology and Metabolism. 1315-1403.

  2. Ueda M. Familial hypercholesterolemia. Mol Genet Metab. 2005 Dec. 86(4):423-6. [Medline].

  3. Marks D, Thorogood M, Neil HA, Humphries SE. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis. 2003 May. 168(1):1-14. [Medline].

  4. Wood S. New EAS Consensus Document Tackles Familial Hypercholesterolemia. Medscape Medical News. Available at http://www.medscape.com/viewarticle/805252. Accessed: September 5, 2013.

  5. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society. Eur Heart J. 2013 Aug 15. [Medline].

  6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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. 2001 May 16. 285(19):2486-97. [Medline].

  7. National Cholesterol Education Program Expert Panel. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. The Expert Panel. Arch Intern Med. 1988 Jan. 148(1):36-69. [Medline].

  8. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004 Jul 13. 110(2):227-39. [Medline].

  9. Connor WE, Connor SL. Dietary treatment of familial hypercholesterolemia. Arteriosclerosis. 1989 Jan-Feb. 9(1 Suppl):I91-105. [Medline].

  10. Illingworth DR. Management of hypercholesterolemia. Med Clin North Am. 2000 Jan. 84(1):23-42. [Medline].

  11. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001 Nov 29. 345(22):1583-92. [Medline].

  12. Toklu B, Amirian J, Giugliano RP. Current indications, cost, and clinical use of anti-PCSK9 monoclonal antibodies. American College of Cardiology. Available at http://www.acc.org/latest-in-cardiology/articles/2016/05/18/14/34/current-indications-cost-and-clinical-use-of-anti-pcsk9-monoclonal-antibodies. May 19, 2016; Accessed: July 10, 2016.

  13. Wiegman A et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015 Sep 21. 36 (36):2425-37. [Medline]. [Full Text].

  14. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Familial hypercholesterolemia and coronary heart disease: a HuGE association review. Am J Epidemiol. 2004 Sep 1. 160(5):421-9. [Medline].

  15. Sibley C, Stone NJ. Familial hypercholesterolemia: a challenge of diagnosis and therapy. Cleve Clin J Med. 2006 Jan. 73(1):57-64. [Medline].

  16. Bjorkhem I, Boberg KM. Inborn errors in bile acid biosynthesis and storage of sterols other than cholesterol. Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001. 2073-2099.

  17. Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science. 2001 May 18. 292(5520):1394-8. [Medline].

  18. Kane JP, Havel RJ. Disorders of the biogenesis and secretion of lipoproteins containing the B apolipoproteins. Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001. 2717-2752.

  19. Goldstein JL, Brown MS. Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis. Circulation. 1987 Sep. 76(3):504-7. [Medline].

  20. Goldstein JL, Brown MS. Molecular medicine. The cholesterol quartet. Science. 2001 May 18. 292(5520):1310-2. [Medline].

  21. Hammond E, Watts GF, Rubinstein Y, et al. Role of international registries in enhancing the care of familial hypercholesterolaemia. Int J Evid Based Healthc. 2013 Jun. 11(2):134-9. [Medline]. [Full Text].

  22. de Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK, Sheldrick RC. Prevalence of Familial Hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). Circulation. 2016 Mar 15. 133 (11):1067-72. [Medline].

  23. Khachadurian AK, Uthman SM. Experiences with the homozygous cases of familial hypercholesterolemia. A report of 52 patients. Nutr Metab. 1973. 15(1):132-40. [Medline].

  24. Pisciotta L, Priore Oliva C, Pes GM, Di Scala L, Bellocchio A, Fresa R, et al. Autosomal recessive hypercholesterolemia (ARH) and homozygous familial hypercholesterolemia (FH): a phenotypic comparison. Atherosclerosis. 2006 Oct. 188(2):398-405. [Medline].

  25. Williams RR, Hunt SC, Schumacher MC, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol. 1993 Jul 15. 72(2):171-6. [Medline].

  26. Patel MD, Thompson PD. Phytosterols and vascular disease. Atherosclerosis. 2006 May. 186(1):12-9.

  27. [Guideline] Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis. 2011 Jul. 217(1):3-46. [Medline].

  28. [Guideline] Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Jul 1. 63 (25 Pt B):2889-934. [Medline]. [Full Text].

  29. European Atherosclerosis Society. New EAS Consensus Panel Statement on Homozygous FH. Available at http://www.eas-society.org/02-2014---consensus-on-homozygous-fh.aspx. Accessed: August 8, 2014.

  30. FDA Approves Atorvastatin/Ezetimibe Combo Tablet. Medscape. May 3 2013. [Full Text].

  31. Richter WO, Donner MG, Hofling B, Schwandt P. Long-term effect of low-density lipoprotein apheresis on plasma lipoproteins and coronary heart disease in native vessels and coronary bypass in severe heterozygous familial hypercholesterolemia. Metabolism. 47(7):863-8. [Medline].

  32. Thompsen J, Thompson PD. A systematic review of LDL apheresis in the treatment of cardiovascular disease. Atherosclerosis. 2006 Mar 16. [Epub ahead of print].

  33. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16. 372 (16):1500-9. [Medline].

  34. Koren MJ, Giugliano RP, Raal FJ, Sullivan D, Bolognese M, Langslet G, et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation. 2014 Jan 14. 129 (2):234-43. [Medline]. [Full Text].

  35. Langslet G, Emery M, Wasserman SM. Evolocumab (AMG 145) for primary hypercholesterolemia. Expert Rev Cardiovasc Ther. 2015 May. 13 (5):477-88. [Medline].

  36. Cuchel M, Meagher EA, du Toit Theron H, Blom DJ, Marais AD, Hegele RA, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2012 Nov 1. [Medline].

  37. Nainggolan L. Mipomersen Approved in US for Homozygous FH. Available at http://www.medscape.com/viewarticle/778465. Accessed: February 12, 2013.

  38. Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010 Mar 20. 375(9719):998-1006. [Medline].

  39. Kane JP, Malloy MJ, Tun P, Phillips NR, Freedman DD, Williams ML, et al. Normalization of low-density-lipoprotein levels in heterozygous familial hypercholesterolemia with a combined drug regimen. N Engl J Med. 1981 Jan 29. 304(5):251-8. [Medline].

  40. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011 Jun 22. 305(24):2556-64. [Medline].

  41. ODYSSEY outcomes: Evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab SAR236553 (REGN727). ClinicalTrials.gov. NCT01663402. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT01663402. 2015 Jul 10; Accessed: July 27, 2015.

  42. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16. 372 (16):1489-99. [Medline].

  43. Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J. 2015 Jun. 169 (6):906-915.e13. [Medline]. [Full Text].

  44. O'Riordan M. Rosuvastatin slows atherosclerosis in FH kids. Heartwire. June 6, 2014. [Full Text].

  45. Braamskamp M, Langslet G, McCrindle BW, et al. Efficacy and safety of rosuvastatin in children aged 6–17 years with familial hypercholesterolemia: findings from the CHARON study (abstract M140). Presented at EAS 2014: The 82nd European Atherosclerosis Society Congress; June 2, 2014; Madrid, Spain.

  46. Braamskamp MJAM, Langslet G, McCrindle BW, et al. Effect of rosuvastatin therapy on carotid intima media thickness in children with familial hypercholesterolemia: findings from the CHARON study. Presented at EAS 2014: The 82nd European Atherosclerosis Society Congress; June 3, 2014; Madrid, Spain.

  47. Cohen DE, Anania FA, Chalasani N,. An assessment of statin safety by hepatologists. Am J Cardiol. 2006 Apr 17. 97(8A):77C-81C. [Medline].

  48. Scandinavian Simvastatin Survival Study. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994 Nov 19. 344(8934):1383-9. [Medline].

  49. Jones PH, Davidson MH, Stein EA. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol. 2003 Jul 15. 92(2):152-60. [Medline].

  50. Thompson PD, Clarkson PM, Rosenson RS, National Lipid Association Statin Safety Task Force Liver Exert Panel. An assessment of statin safety by muscle experts. Am J Cardiol. 2006 Apr 17. 97(8A):69C-76C.

  51. Bulbulia R, Bowman L, Wallendszus K, et al. Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial. Lancet. 2011 Dec 10. 378(9808):2013-20. [Medline]. [Full Text].

  52. Stein EA, Dufour R, Gagne C, Gaudet D, East C, Donovan JM, et al. Apolipoprotein B Synthesis Inhibition with Mipomersen in Heterozygous Familial Hypercholesterolemia: Results of a Randomized, Double-Blind, Placebo Controlled Trial to Assess Efficacy and Safety as Add-on Therapy in Patients with Coronary Artery Disease. Circulation. 2012 Oct 11. [Medline].

  53. McKenney JM, Davidson MH, Jacobson TA, Guyton JR, National Lipid Association Statin Safety Task Force Liver Expert Panel. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol. 2006 Apr 17. 97(8A):89C-94C.

  54. Wending P. FDA pulls approval of niacin, fibrate in combo with statins. Heartwire. 2016 Apr 15. Available at http://www.medscape.com/viewarticle/862022.

  55. Amundsen AL, Khoury J, Iversen PO, Bergei C, Ose L, Tonstad S. Marked changes in plasma lipids and lipoproteins during pregnancy in women with familial hypercholesterolemia. Atherosclerosis. 2006 Feb 6. [Epub ahead of print].

  56. Aegerion Pharmaceuticals. FDA approves Aegerion Pharmaceuticals' Juxtapid (lomitapide) capsules for homozygous familial hypercholesterolemia (HoFH) [press release]. December 24, 2012. Available at http://ir.aegerion.com/releasedetail.cfm?ReleaseID=728650. Accessed: January 10, 2013.

  57. Buchwald H, Matts JP, Fitch LL, Campos CT, Sanmarco ME, Amplatz K, et al. Changes in sequential coronary arteriograms and subsequent coronary events. Surgical Control of the Hyperlipidemias (POSCH) Group. JAMA. 1992 Sep 16. 268(11):1429-33. [Medline].

  58. Nainggolan L. Lomitapide approved for homozygous familial hypercholesterolemia. Medscape Medical News. December 24, 2012. Available at http://www.medscape.com/viewarticle/776699. Accessed: January 10, 2013.

  59. Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest. 2003. 111(12):1795-803. [Medline]. [Full Text].

  60. Zuliani G, Vigna GB, Corsini A, Maioli M, Romagnoni F, Fellin R. Severe hypercholesterolaemia: unusual inheritance in an Italian pedigree. Eur J Clin Invest. 1995 May. 25(5):322-31. [Medline].

 
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Metacarpophalangeal joint tendon xanthomas in a 45-year-old man with heterozygous familial hypercholesterolemia.
Table 1. LDLc Target levels and levels Indicating Therapeutic Lifestyle Changes (TLC) and Drug Therapy
 



Risk Category



 



LDLc Target level,



mg/dL



 



LDLc level Indicating TLC,



mg/dL



 



LDLc level for Considering Drug Therapy,



mg/dL*



High risk:



CHD or CHD risk equivalent



(10-y risk >20%)



<100



Optional goal <70



>100 >100
Moderately high risk:



More than 2 risk factors



(10-y risk 10-20%)



130



Optional goal <100



>130 >130



(100-129 may consider drug options)



Moderate risk:



More than 2 risk factors



(10-y risk 10%)



<130 >130 >160
Lower risk:



0-1 risk factor



<160 >160 >190



(160-189 LDL-lowering drug optional)



*The 2004 update recommended that when statin therapy is initiated in patients at high or moderately high risk, a dose and strength should be chosen that achieves at least a 30-40% LDLc reduction (see Table 3).
Table 2. Recommended Dietary Intake
 



Food Category



 



Typical US Diet



 



NCEP Diet



 



Diet for FH



Cholesterol, mg/d 500 < 200 100
Total fat, % energy (calories) 40 25-35 20
Saturated fat, % energy (calories) 14 < 7 < 6
Carbohydrate, % energy (calories) 45 50-60 65
Protein, % energy (calories) Approximately 15 15 N/A
Table 3. Statin and Statin Combination Approved Doses, Expected LDLc Decrease, and Dose Required for 30-40% LDLc Reduction
 



Statin



 



FDA-Approved Dose



 



Expected LDLc Decrease



 



Dose Required for 30-40% LDLc Reduction



Atorvastatin 10-80 mg daily 35-60% 10 mg
Fluvastatin 20-40 mg at bedtime 20-30% 40 mg qd/bid
40 mg bid 35% 40 mg bid
Extended-release fluvastatin



(Lescol XL)



80 mg at bedtime 35-38% 80 mg at bedtime
Lovastatin 20-80 mg at supper 25-48% 40 mg at dinner
Extended-release lovastatin



(Altoprev)



20-60 mg at bedtime 25-45% 60 mg at bedtime
Pravastatin 40-80 mg at bedtime 30-40% 40 mg at bedtime
Rosuvastatin 10-40 mg daily 40-60% 5 mg daily
Simvastatin 20-80 mg daily at bedtime 35-50% 20 mg at bedtime
Simvastatin + ezetimibe



(Vytorin)



10/20 mg



10/40 mg



10/80 mg



at bedtime



50-60% 10/20 mg at bedtime
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