Dyslipidemia: Management Using Optimal Lipid-Lowering Therapy

Abstract

French

Objective:

To evaluate current approaches and explore emerging research related to dyslipidemia management.

Data Sources:

MEDLINE (2004-April 2012) was searched for randomized controlled trials using the terms dyslipidemia and lipid-lowering therapy or statin (>1000 hits). Separate searches (MEDLINE, Google) identified meta-analyses (2010–2011), disease prevalence statistics, and current consensus guidelines (2004–July 2011). Additional references were identified from the publications reviewed.

Study Selection and Data Extraction:

English-language articles on large multi-center trials were evaluated.

Data Synthesis:

National Cholesterol Education Program Adult Treatment Panel III guidelines for the reduction of cardiovascular risk recommend the attainment of specific low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol (non–HDL-C) target values, based on an individual's 10-year risk of coronary heart disease or global risk. For most patients unable to achieve recommended lipid level goals with therapeutic lifestyle changes, statins are the first option for treatment. Results of large, well-controlled clinical trials have demonstrated that statins are effective in primary and secondary prevention of cardiovascular disease in diverse populations, including patients with diabetes and the elderly, and that intensive statin therapy provides more effective lipid goal attainment and significantly greater risk reduction in patients with coronary artery disease. Stalin therapy is generally well tolerated but may increase the risk of myopathy. Statin use has been associated with increases in hepatic transaminases and an increased risk of diabetes, although the absolute risk of diabetes is low compared with the risk reduction benefit. Combination therapy including a statin may be appropriate for certain populations, but the risk reduction benefits of combination therapy remain unclear. Ezetimibe is an important treatment option for patients with hypercholesterolemia who do not tolerate intensive statin therapy. Although fibrates or niacin improves overall lipid profiles in patients with hypertriglyceridemia or dyslipidemia who are receiving statin therapy, their efficacy in reducing cardiovascular risk remains questionable and their use raises safety and tolerability concerns.

Conclusions:

Intensifying lifestyle changes and statin dose should be utilized first in patients not achieving their LDL-C and non-HDL-C goals.

Keywords

dyslipidemia therapy ezetlmibe-statin combination fibrates low-density lipoprotein cholesterol NCEP ATP III guidelines non–high-density lipoprotein cholesterol statins

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References

Roger

, Go

, Lloyd-Jones

. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation 2011; 123:e18–209.

Grundy

, Cleeman

, Merz

; Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004; 44:720–32.

Brunzell

, Davidson

, Furberg

. Lipoprotein management in patients with cardio-metabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care 2008; 31:811–22.

Toth

. An urgent matter—identifying your patients' cardiovascular risk and improving their outcomes. Atherosclerosis: the underlying disease. J Fam Pract 2009; 58:S19–25.

Paramsothy

, Katz

, Owens

, Burke

, Probstfield

, O'Brien

. Age-modification of lipoprotein, lipid, and lipoprotein ratio-associated risk for coronary artery calcium (from the Multi-Ethnic Study of Atherosclerosis [MESA]). Am J Cardiol 2010; 105:352–8.

Paramsothy

, Knopp

, Bertoni

. Association of combinations of lipid parameters with carotid intima-media thickness and coronary artery calcium in the MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2010; 56:1034–41.

Cohen

, Boerwinkle

, Mosley

Jr , Hobbs

. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354:1264–72.

Holla

, Cameron

, Berge

, Ranheim

, Leren

. Degradation of the LDL receptors by PCSK9 is not mediated by a secreted protein acted upon by PCSK9 extracellularly. BMC Cell Biol 2007; 8:9.

Maxwell

, Fisher

, Breslow

. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Pro Natl Acad Sci U S A 2005; 102:2069–74.

10.

MillionHearts. http://millionhearts.hhs.gov/index.shtml (accessed 2011 Dec 20).

11.

Smith

Jr , Benjamin

, Bonow

. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update. A guideline from the American Heart Association and American College of Cardiology Foundation. Circulation 2011; 124:2458–73.

12.

Goldberg

, Hopkins

, Toth

. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011; (3 suppl):S1–8.

13.

Hooper

, Summerbell

, Thompson

. Reduced or modified dietary fat for preventing cardiovascular disease. Cochrane Database Syst Rev 2011; 7:CD002137.

14.

Heran

, Chen

, Ebrahim

. Exercise-based cardiac rehabilitation for coronary heart disease. Cochrane Database Syst Rev 2011; 7:CD001800.

15.

Gr⊘ntved

, Hu

. Television viewing and risk of type 2 diabetes, cardiovascular disease, and all-cause mortality: a meta-analysis. JAMA 2011; 305:2448–55.

16.

Product information. Lipitor (atorvastatin calcium) tablets. Dublin, Ireland: Pfizer Ireland Pharmaceuticals, June 2009.

17.

Product information. Lescol (fluvastatin sodium). East Hanover, NJ: Novartis Pharmaceuticals Corporation, July 2011.

18.

Product information. Mevacor (lovastatin). Whitehouse Station, NJ: Merck & Co., Inc., May 2010.

19.

Product information. Livalo (pitavastatin). Montgomery, AL: Kowa Pharmaceuticals America, Inc., August 2011.

20.

Product information. Pravachol (pravastatin sodium). Princeton, NJ: Bristol-Myers Squibb Company, May 2011.

21.

Product information. Crestor (rosuvastatin calcium). Wilmington, DE: AstraZeneca Pharmaceuticals LP, May 2011.

22.

Product information. Zocor (simvastatin). Cramlington, UK: Merck Sharp & Dohme Ltd., October 2011.

23.

Product information. Welchol (colesevelam hydrochloride). Parsippany, NJ: Daiichi Sankyo, Inc., July 2011.

24.

Product information. Zetia (ezetimibe). North Wales, PA: Merck/Schering-Plough Pharmaceuticals, July 2011.

25.

Product information. Tricor (fenofibrate). Chicago, IL: Abbott Laboratories, September 2011.

26.

Product information. Lovaza (omega-3-acid ethyl esters). St. Petersburg, FL: GlaxoSmithKline, December 2010.

27.

Product information. Niaspan (niacin). Chicago, IL: Abbott Laboratories, December 2010.

28.

Mills

, Wu

, Chong

. Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials. Q J Med 2011; 104:109–24.

29.

Baigent

, Keech

, Kearney

; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366:1267–78.

30.

McKenney

, Davidson

, Jacobson

, Guyton

. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006; 97(suppl 8a):89C–94C.

31.

García Rodríguez

, Herings

, Johansson

. Use of multiple international healthcare databases for the detection of rate drug-associated outcomes: a pharmacoepidemiological programme comparing rosuvastatin with other marketed statins. Pnarmacoepidemiol Drag Saf 2010; 19:1218–24.

32.

Ridker

, Danielson

, Fonseca

; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359:2195–207.

33.

Mills

, Rachlis

, Wu

, Devereaux

, Arora

, Perri

. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J Am Coll Cardiol 2008; 52:1769–81.

34.

Brugts

, Yetgin

, Hoeks

. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009; 338:b2376.

35.

Taylor

, Ward

, Moore

. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2011; 1:CD004816.

36.

Hulten

, Jackson

, Douglas

, George

, Villines

. The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials. Arch Intern Med 2006; 166:1814–21.

37.

Cannon

, Steinberg

, Murphy

, Mega

, Braunwald

. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006; 48:438–45.

38.

Afilalo

, Duque

, Steele

, Jukema

, de Craen

, Eisenberg

. Statins for secondary prevention in elderly patients: a hierarchical bayesian meta-analysis. J Am Coll Cardiol 2008; 51:37–45.

39.

Colhoun

, Betteridge

, Durrington

. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364:685–96.

40.

Cholesterol Treatment Trialists' (CTT) Collaborators; Kearney

, Blackwell

, Collins

. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008; 371:117–25.

41.

Deedwania

, Stone

, Bairey Merz

. Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE). Circulation 2007; 115:700–7.

42.

Waters

, Brotons

, Chiang

; Lipid Treatment Assessment Project 2 Investigators. Lipid Treatment Assessment Project 2: a multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals. Circulation 2009; 120:28–34.

43.

Jukema

, Chiang

, Ferrières

. Lipid goals among patients with diabetes or metabolic syndrome: Lipid Treatment Assessment Project (L-TAP) 2. Curr Med Res Opin 2010; 26:2589–97.

44.

Javed

, Deedwania

, Bhatt

. Use of intensive lipid-lowering therapy in patients hospitalized with acute coronary syndrome: an analysis of 65,396 hospitalizations from 344 hospitals participating in Get With the Guidelines (GWTG). Am Heart J 2010; 160:1130–36, 1136.e1-3.

45.

Melloni

, Shah

, Ou

. Lipid-lowering intensification and low-density lipoprotein cholesterol achievement from hospital admission to 1-year follow-up after an acute coronary syndrome event: results from the Medications Applied aNd SusTAINed Over Time (MAINTAIN) registry. Am Heart J 2010; 160:1121–9, 1129.e1.

46.

Nicholls

, Brandrup-Wognsen

, Palmer

, Barter

. Meta-analysis of comparative efficacy of increasing dose of atorvastatin versus rosuvastatin versus simvastatin on lowering levels of atherogenic lipids (from VOYAGER). Am J Cardiol 2010; 105:69–76.

47.

Cholesterol Treatment Trialists' (CTT) Collaboration; Baigent

, Blackwell

, Emberson

. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376:1670–81.

48.

LaRosa

, Grundy

, Waters

; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352:1425–35.

49.

Pedersen

, Faergeman

, Kastelein

; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005; 294:2437–45.

50.

Cannon

, Braunwald

, McCabe

; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350:1495–504.

51.

de Lemos

, Blazing

, Wiviott

; A to Z Investigators. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004; 292:1307–16.

52.

Murphy

, Cannon

, Wiviott

, McCabe

, Braunwald

. Reduction in recurrent cardiovascular events with intensive lipid-lowering statin therapy compared with moderate lipid-lowering statin therapy after acute coronary syndromes from the PROVE IT-TIMI22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) trial. J Am Coll Cardiol 2009; 54:2358–62.

53.

Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group; Armitage J, Bowman L, Wallendszus K, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 2010; 376:1658–69.

54.

Baigent

, Landray

, Reith

; on behalf of the SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011; 377:2181–92.

55.

ACCORD Study Group; Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362:1563–74. Erratum: N Engl J Med 2010;362:1748.

56.

Rosseb⊘

, Pedersen

, Boman

; SEAS Investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008; 359:1343–56.

57.

Yokoyama

, Origasa

, Matsuzaki

. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007; 369:1090–8.

58.

AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365:2255–67.

59.

Ridker

, Danielson

, Fonseca

; JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373:1175–82.

60.

Hsia

, MacFadyen

, Monyak

, Ridker

. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. J Am Coll Cardiol 2011; 57:1666–75.

61.

Blaha

, Rivera

, Budoff

. Association between obesity, high-sensitivity C-reactive protein >=2 mg/L, and subclinical atherosclerosis: implications of JUPITER from the Multi-Ethnic Study of Atherosclerosis. Arterioscler Thromb Vase Biol 2011; 31:1430–8.

62.

Heart Protection Study Collaborative Group; Emberson

, Bennett

, Link

. C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20,536 patients in the Heart Protection Study. Lancet 2011; 377:469–76.

63.

Nissen

, Tuzcu

, Schoenhagen

; REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291:1071–80.

64.

Nicholls

, Ballantyne

, Barter

. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med 2011; 365:2078–87.

65.

Nissen

, Nicholls

, Sipahi

. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006; 295:1556–65.

66.

Takayama

, Hiro

, Yamagishi

; COSMOS Investigators. Effect of rosuvastatin on coronary atheroma in stable coronary artery disease: multi-center coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS). Circ J 2009; 73:2110–7.

67.

Liao

, Laufs

. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005; 45:89–118.

68.

The SEARCH Collaborative Group. SLC01B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med 2008; 359:789–99.

69.

U. S. Food and Drug Administration (FDA). FDA Safety Communication: Important safety label changes to cholesterol-lowering statin drugs [2-28-2012]. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm (accessed 19 Mar 2012).

70.

Sattar

, Preiss

, Murray

. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375:735–42.

71.

Preiss

, Seshasai

, Welsh

. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011; 305:2556–64.

72.

Mallinson

, Constantin-Teodosiu

, Sidaway

, Russell Westwood

, Greenhaff

. Blunted Akt/FOXO signalling and activation of genes controlling atrophy and fuel use in statin myopathy. J Physiol 2009; 587:219–30.

73.

Keech

, Simes

, Barter

; FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366:1849–61.

74.

Scott

, O'Brien

, Fulcher

; Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study Investigators. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care 2009; 32:493–8.

75.

Saha

, Arora

. Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus-a pooled meta-analysis of randomized placebo-controlled clinical trials. Int J Cardiol 2010; 141:157–66.

76.

Loomba

, Arora

. Prevention of cardiovascular disease utilizing fibrates-a pooled meta-analysis. Am J Ther 2010; 17:e182–8.

77.

Wanner

, Krane

, März

; German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353:238–48.

78.

Fellström

, Jardine

, Schmieder

; AURORA Study Group. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009; 360:1395–407.

79.

Holdaas

, Holme

, Schmieder

; on behalf of the AURORA study group. Rosuvastatin in diabetic hemodialysis patients. J Am Soc Nephrol 2011; 22:1335–41.

80.

Shepherd

, Kastelein

, Bittner

; Treating to New Targets Steering Committee and Investigators. Intensive lipid lowering with atorvastatin in patients with coronary artery disease, diabetes, and chronic kidney disease. Mayo Clin Proc 2008; 83:870–9.

81.

Cziraky

, Tan

, Bullano

, Yu

, Schiebinger

, Willey

. Impact of optimal lipid value achievement between 2005 and 2009 in patients with mixed dyslipidaemia on cardiovascular event rates. Int J Clin Pract 2011; 65:425–35.

82.

Ballantyne

, Jones

, Kelly

. Long-term efficacy of adding fenofibric acid to moderate-dose statin therapy in patients with persistent elevated triglycerides. Cardiovasc Drugs Ther 2011; 25:59–67.

83.

Roth

, McKenney

, Kelly

. Efficacy and safety of rosuvastatin and fenofibric acid combination therapy versus simvastatin monotherapy in patients with hypercholesterolemia and hypertriglyceridemia: a randomized, double-blind study. Am J Cardiovasc Drugs 2010; 10:175–86.

84.

Agouridis

, Tsimihodimos

, Filippatos

, Tselepis

, Elisaf

. High doses of rosuvastatin are superior to low doses of rosuvastatin plus fenofibrate or n-3 fatty acids in mixed dyslipidemia. Lipids 2011; 46:521–8.

85.

Jacobson

. Myopathy with statin-fibrate combination therapy: clinical considerations. Nat Rev Endocrinol 2009; 5:507–18.

86.

Prueksaritanont

, Zhao

, Ma

. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp Ther 2002; 301:1042–51.

87.

Cooper

, Martin

, Dane

, Warwick

, Raza

, Schneck

. Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects. Br J Clin Pharmacol 2003; 55:94–9.

88.

Jacobson

. A “hot” topic in dyslipidemia management-“how to beat a flush”: optimizing niacin tolerability to promote long-term treatment adherence and coronary disease prevention. Mayo Clin Proc 2010; 85:365–79.

89.

Kastelein

, Akdim

, Stroes

; ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008; 358:1431–43. Erratum: N Engl J Med 2008:358:1977.

90.

Villines

, Stanek

, Devine

. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol 2010; 55:2721–6.

91.

Avellone

, Di Garbo

, Guamotta

. Efficacy and safety of long-term ezetimibe/simvastatin treatment in patients with familial hypercholesterolemia. Int Angiol 2010; 29:514–24.

92.

Taylor

, Sullenberger

, Lee

, Grace

. 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 2004; 110:3512–7.

93.

AIM-HIGH Investigators. The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol: baseline characteristics of study participants. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: impact on Global Health outcomes (AIM-HIGH) trial. Am Heart J 2011; 161:538–43.

94.

Filion

KBH

, Khoury

, Bielinski

, Schiller

, Dendukuri

, Brophy

. Omega-3 fatty acids in high-risk cardiovascular patients: a meta-analysis of randomized controlled trials. BMC Cardiovasc Disord 2010; 10:24.

95.

Kromhout

, Giltay

, Geleijnse

; Alpha Omega Trial Group. n-3 Fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 2010; 363:2015–26.

96.

Rauch

, Schiele

, Schneider

; OMEGA Study Group. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation 2010; 122:2152–9.

97.

Ito

, McGowan

, Moriarty

. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011; 5(3 suppl):S38–45.

98.

Robinson

, Goldberg

. Treatment of adults with familial hypercholesterolemia and evidence for treatment: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011; 5(3 suppl):S18–29.

99.

Smilde

, van Wissen

, Awollersheim

, Trip

, Kaselein

JJP

, Stalenhoef

. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001; 357:577–81.

100.

Vuorio

, Kuoppala

, Kovanen

. Statins for children with familial hypercholesterolemia. Cochrane Database Syst Rev 2010; 7:CD006401.

101.

Daniels

, Gidding

, de Ferranti

; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Pediatric aspects of familial hypercholesterolemias: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011; 5(3 suppl):S30–7.

102.

Bays

, Davidson

, Massaad

. Safety and efficacy of ezetimibe added on to rosuvastatin 5 or 10 mg versus up-titration of rosuvastatin in patients with hypercholesterolemia (the ACTE Study). Am J Cardiol 2011; 108:523–30.

103.

Press release. NIH stops clinical trial on combination cholesterol treatment. NIH News; May 26, 2011. http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=2792 (accessed 2011 Dec 20).