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Emerging Lipoprotein-Related Therapeutics for Patients with Diabetes

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Lipoproteins in Diabetes Mellitus

Part of the book series: Contemporary Diabetes ((CDI))

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Abstract

Dyslipidemia is a major risk factor for atherosclerosis in both diabetic and nondiabetic subjects, which is a common cause of morbidity and premature mortality. Based on and supported by favorable outcomes of clinical trials, drugs targeting lipoprotein metabolism are widely used, particularly in developed countries. Drugs to improve lipid levels, in particular to lower low-density lipoprotein (LDL) cholesterol (LDL-C), are commonly used for the primary and secondary prevention of cardiovascular disease. Of the LDL-C-lowering drugs, HMG-CoA reductase inhibitors (“statins”) are particularly effective at reducing cardiovascular disease, both in people with and without diabetes mellitus [1, 2], with more intensive LDL-C lowering being more effective than less intensive LDL-C lowering [3–12]. Statins are effective cardioprotective agents in both type 1 and type 2 diabetes patients [2].

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References

  1. Cholesterol Treatment Trialists’ (CTT) Collaboration; Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. 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(9753): 1670–1681.

    Google Scholar 

  2. Cholesterol Treatment Trialists’ Collaborators, Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C. 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.

    Article  CAS  PubMed  Google Scholar 

  3. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage J, Bowman L, Wallendszus K,Bulbulia R, Rahimi K, Haynes R, Parish S, Peto R, Collins R. 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(9753):1658–69.

    Google Scholar 

  4. Chan DK, O’Rourke F, Shen Q, Mak JC, Hung WT. Meta-analysis of the cardiovascular benefits of intensive lipid lowering with statins. Acta Neurol Scand. 2011;124(3):188–95.

    Article  CAS  PubMed  Google Scholar 

  5. Murphy SA, Cannon CP, Wiviott SD, McCabe CH, Braunwald E. 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-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) trial. J Am Coll Cardiol. 2009;54(25): 2358–62.

    Article  CAS  PubMed  Google Scholar 

  6. LaRosa JC, Deedwania PC, Shepherd J, Wenger NK, Greten H, DeMicco DA, Breazna A. TNT investigators. Comparison of 80 versus 10 mg of atorvastatin on occurrence of cardiovascular events after the first event (from the Treating to New Targets [TNT] trial). Am J Cardiol. 2010;105(3):283–7.

    Article  CAS  PubMed  Google Scholar 

  7. Tikkanen MJ, Szarek M, Fayyad R, Holme I, Cater NB, Faergeman O, Kastelein JJ, Olsson AG, Larsen ML, Lindahl C, Pedersen TR. IDEAL investigators. Total cardiovascular disease burden: comparing intensive with moderate statin therapy insights from the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial. J Am Coll Cardiol. 2009;54(25):2353–7.

    Article  CAS  PubMed  Google Scholar 

  8. Josan K, Majumdar SR, McAlister FA. The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials. CMAJ. 2008;178(5):576–84.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Deedwania P, Stone PH, Bairey Merz CN, Cosin-Aguilar J, Koylan N, Luo D, Ouyang P, Piotrowicz R, Schenck-Gustafsson K, Sellier P, Stein JH, Thompson PL, Tzivoni D. 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(6):700–7.

    Article  CAS  PubMed  Google Scholar 

  10. Rouleau J. Improved outcome after acute coronary syndromes with an intensive versus standard lipid-lowering regimen: results from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial. Am J Med. 2005;118(Suppl 12A): 28–35.

    Article  PubMed  CAS  Google Scholar 

  11. Nissen SE. Halting the progression of atherosclerosis with intensive lipid lowering: results from the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial. Am J Med. 2005;118(Suppl 12A):22–7.

    Article  PubMed  CAS  Google Scholar 

  12. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J. Wenger NK; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425–35.

    Article  CAS  PubMed  Google Scholar 

  13. Lee M, Saver JL, Towfighi A, Chow J, Ovbiagele B. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis. 2011;217(2):492–8.

    Article  CAS  PubMed  Google Scholar 

  14. Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, Grobbee DE, Cass A, Chalmers J, Perkovic V. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010;375(9729):1875–84.

    Article  CAS  PubMed  Google Scholar 

  15. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesaniemi YA, Sullivan D, Hunt D, Colman P, d’Emden M, Whiting M, Ehnholm C. Effects of long-term fenofibrate therapy on cardiovascular events in 9,795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366(9500):1849–61.

    Google Scholar 

  16. Scott R, O’'Brien R, Fulcher G, Pardy C, d’Emden M, Tse D, Taskinen MR, Ehnholm C, Keech A, on behalf of the FIELD Study Investigators. The effects of fenofibrate treatment on cardiovascular disease risk in 9,795 people with type 2 diabetes and various components of the metabolic syndrome: the FIELD study. Diabetes Care. 2009;32(3):493–8.

    Article  CAS  PubMed  Google Scholar 

  17. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, Crouse 3rd JR, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff Jr DC, Cushman WC, Simons-Morton DG, Byington RP. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563–74.

    Article  PubMed  Google Scholar 

  18. Rajamani K, Colman PG, Li LP, Best JD, Voysey M, D’Emden MC, Laakso M, Baker JR, Keech AC, on behalf of the FIELD Study Investigators. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet. 2009;373(9677):1780–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. ACCORD Study Group; ACCORD Eye Study Group, Chew EY, Ambrosius WT, Davis MD, Danis RP, Gangaputra S, Greven CM, Hubbard L, Esser BA, Lovato JF, Perdue LH, Goff Jr DC, Cushman WC, Ginsberg HN, Elam MB, Genuth S, Gerstein HC, Schubart U, Fine LJ. Effects of medical therapies on retinopathy progression in type 2diabetes. N Engl J Med. 2010;363(3):233–44.

    Article  PubMed  CAS  Google Scholar 

  20. Keech AC, Mitchell P, Summanen PA, O'Day J, Davis TM, Moffitt MS, Taskinen MR, Simes RJ, Tse D, Williamson E, Merrifield A, Laatikainen LT, d’Emden MC, Crimet DC, O’Connell RL, Colman PG. FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet. 2007;370(9600):1687–97.

    Article  CAS  PubMed  Google Scholar 

  21. Davis TM, Ting R, Best JD, Donoghoe MW, Drury PL, Sullivan DR, Jenkins AJ, O'Connell RL, Whiting MJ, Glasziou PP, Simes RJ, Kesäniemi YA, Gebski VJ, Scott RS, Keech AC, on behalf of the FIELD Study Investigators. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia. 2011;54(20): 280–90.

    Article  CAS  PubMed  Google Scholar 

  22. Ting RD, Keech AC, Drury PL, Donoghoe MW, Hedley J, Jenkins AJ, Davis TM, Lehto S, Celermajer D, Simes RJ, Rajamani K, Stanton K, FIELD Study Investigators. Benefits and safety of long-term fenofibrate therapy in people with type 2 diabetes and renal impairment: the FIELD Study. Diabetes Care. 2012;35(2):218–25.

    Article  CAS  PubMed  Google Scholar 

  23. Sandhu S, Al-Sarraf A, Taraboanta C, Frohlich J, Francis GA. Incidence of pancreatitis, secondary causes, and treatment of patients referred to a specialty lipid clinic with severe hypertriglyceridemia: a retrospective cohort study. Lipids Health Dis. 2011;10:157.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Viljoen A, Wierzbicki AS. Diagnosis and treatment of severe hypertriglyceridemia. Expert Rev Cardiovasc Ther. 2012;10(4):505–14.

    Article  CAS  PubMed  Google Scholar 

  25. American Diabetes Association Clinical Practice Guidelines. VI. Prevention, management of complications. Diabetes Care. 2011;34 Suppl 1:S29.

    Google Scholar 

  26. Mihos CG, Salas MJ, Santana O. The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in cardiovascular disease: a comprehensive review. Cardiol Rev. 2010;18(6):298–304.

    Article  PubMed  Google Scholar 

  27. Florentin M, Liberopoulos EN, Kei A, Mikhailidis DP, Elisaf MS. Pleiotropic effects of nicotinic acid: beyond high density lipoprotein cholesterol elevation. Curr Vasc Pharmacol. 2011;9(4):385–400.

    Article  CAS  PubMed  Google Scholar 

  28. Tsimihodimos V, Liberopoulos E, Elisaf M. Pleiotropic effects of fenofibrate. Curr Pharm Des. 2009;15(5):517–28.

    Article  CAS  PubMed  Google Scholar 

  29. D'Adamo E, Caprio S. Type 2 diabetes in youth: epidemiology and pathophysiology. Diabetes Care. 2011;34 Suppl 2:S161–5.

    Article  PubMed  Google Scholar 

  30. Azzopardi P, Brown AD, Zimmet P, Fahy RE, Dent GA, Kelly MJ, Kranzusch K, Maple-Brown LJ, Nossar V, Silink M, Sinha AK, Stone ML, Wren SJ. Type 2 diabetes in young Indigenous Australians in rural and remote areas: diagnosis, screening, management and prevention. Med J Aust. 2012;197(1):32–6.

    Article  PubMed  Google Scholar 

  31. Pavkov ME, Bennett PH, Knowler WC, Krakoff J, Sievers ML, Nelson RG. Effect of youth-onset type 2 diabetes mellitus on incidence of end-stage renal disease and mortality in young and middle-aged Pima Indians. JAMA. 2006;296(4):421–6.

    Article  CAS  PubMed  Google Scholar 

  32. Eppens MC, Craig ME, Cusumano J, Hing S, Chan AK, Howard NJ, Silink M, Donaghue KC. Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes. Diabetes Care. 2006;29(6):1300–6.

    Article  PubMed  Google Scholar 

  33. McGill Jr HC, McMahan CA, Herderick EE, Malcom GT, Tracy RE, Strong JP. Origin of atherosclerosis in childhood and adolescence. Am J Clin Nutr. 2000;72 Suppl 5:1307S–15S.

    CAS  PubMed  Google Scholar 

  34. Strong JP, Malcom GT, Newman 3rd WP, Oalmann MC. Early lesions of atherosclerosis in childhood and youth: natural history and risk factors. J Am Coll Nutr. 1992;11(Suppl):51S–4S.

    Article  PubMed  Google Scholar 

  35. Illingworth DR. Management of hypercholesterolemia. Med Clin North Am. 2000;84(1):23–42.

    Article  CAS  PubMed  Google Scholar 

  36. Chapman MJ. Pitavastatin: novel effects on lipid parameters. Atheroscler Suppl. 2011;12(3):277–84.

    Article  CAS  PubMed  Google Scholar 

  37. Betteridge J. Pitavastatin - results from phase III & IV. Atheroscler Suppl. 2010;11(3):8–14.

    Article  CAS  PubMed  Google Scholar 

  38. Teramoto T. The clinical impact of pitavastatin: comparative studies with other statins on LDL-C and HDL-C. Expert Opin Pharmacother. 2012;13(6): 859–65.

    Article  CAS  PubMed  Google Scholar 

  39. Yamashita S, Tsubakio-Yamamoto K, Ohama T, Nakagawa-Toyama Y, Nishida M. Molecular mechanisms of HDL-cholesterol elevation by statins and its effects on HDL functions. J Atheroscler Thromb. 2010;17(5):436–51.

    Article  CAS  PubMed  Google Scholar 

  40. Catapano AL. Statin-induced myotoxicity: pharmacokinetic differences among statins and the risk of rhabdomyolysis, with particular reference to pitavastatin. Curr Vasc Pharmacol. 2012;10(2):257–67.

    Article  CAS  PubMed  Google Scholar 

  41. Teramoto T. Pitavastatin: clinical effects from the LIVES Study. Atheroscler Suppl. 2011;12(3):285–8.

    Article  CAS  PubMed  Google Scholar 

  42. Yokote K, Shimano H, Urashima M, Teramoto T. Efficacy and safety of pitavastatin in Japanese patients with hypercholesterolemia: LIVES study and subanalysis. Expert Rev Cardiovasc Ther. 2011;9(5):555–62.

    Article  CAS  PubMed  Google Scholar 

  43. Suh SY, Rha SW, Ahn TH, Shin EK, Choi CU, Oh DJ, Bae JH, Hur SH, Yun KH, Oh SK, Kim JH, Kim SW, Chae IH, Kim KS, Hong YJ, Jeong MH, LAMIS investigators. Long-term safety and efficacy of Pitavastatin in patients with acute myocardial infarction (from the Livalo Acute Myocardial Infarction Study [LAMIS]). Am J Cardiol. 2011;108(11): 1530–5.

    Article  CAS  PubMed  Google Scholar 

  44. Matsubara T, Naruse K, Arakawa T, Nakao M, Yokoi K, Oguri M, Marui N, Amano T,Ichimiya S, Ohashi T, Imai K, Sakai S, Sugiyama S, Ishii H, Murohara T. Impact of pitavastatin on high-sensitivity C-reactive protein and adiponectin in hypercholesterolemic patients with the metabolic syndrome: The PREMIUM Study. J Cardiol. 2012. [Epub ahead of print] PubMed PMID: 22884685.

    Google Scholar 

  45. Hibi K, Kimura T, Kimura K, Morimoto T, Hiro T, Miyauchi K, Nakagawa Y, Yamagishi M, Ozaki Y, Saito S, Yamaguchi T, Daida H, Matsuzaki M, JAPAN-ACS Investigators. Clinically evident polyvascular disease and regression of coronary atherosclerosis after intensive statin therapy in patients with acute coronary syndrome: serial intravascular ultrasound from the Japanese assessment of pitavastatin and atorvastatin in acute coronary syndrome (JAPAN-ACS) trial. Atherosclerosis. 2011;219(2):743–9.

    Article  CAS  PubMed  Google Scholar 

  46. Nozue T, Yamamoto S, Tohyama S, Umezawa S, Kunishima T, Sato A, Miyake S, Takeyama Y, Morino Y, Yamauchi T, Muramatsu T, Hibi K, Sozu T, Terashima M, Michishita I. Statin treatment for coronary artery plaque composition based on intravascular ultrasound radiofrequency data analysis. Am Heart J 2012;163(2):191–9.e1.

    Google Scholar 

  47. Ikeda K, Takahashi T, Yamada H, Matsui K, Sawada T, Nakamura T, Matsubara H. Effect of intensive statin therapy on regression of carotid intima-media thickness in patients with subclinical carotid atherosclerosis (a prospective, randomized trial: PEACE (Pitavastatin Evaluation of Atherosclerosis Regression by Intensive Cholesterol-lowering Therapy) study). Eur J Prev Cardiol 2012. [Epub ahead of print] PubMed PMID: 22689416.

    Google Scholar 

  48. Hong YJ, Jeong MH, Ahn Y, Kim SW, Bae JH, Hur SH, Ahn TH, Rha SW, Kim KS,Chae IH, Kim JH, Yun KH, Oh SK; Other LAMIS investigators. Effect of pitavastatin treatment on changes of plaque volume and composition according to the reduction of high-sensitivity C-reactive protein levels. J Cardiol. 2012;60(4):277–82. doi:10.1016/j.jjcc.2012.04.003.

    Google Scholar 

  49. Mori Y, Hirano T. Ezetimibe alone or in combination with pitavastatin prevents kidney dysfunction in 5/6 nephrectomized rats fed high-cholesterol. Metabolism. 2012;61(3):379–88.

    Article  CAS  PubMed  Google Scholar 

  50. Tamura Y, Murayama T, Minami M, Yokode M, Arai H. Differential effect of statins on diabetic nephropathy in db/db mice. Int J Mol Med. 2011;28(5):683–7.

    CAS  PubMed  Google Scholar 

  51. Kakuda H, Kanasaki K, Koya D, Takekoshi N. The administration of pitavastatin augments creatinine clearance associated with reduction in oxidative stress parameters: acute and early effects. Clin Exp Nephrol. 2012 Sep 5. [Epub ahead of print] PubMed PMID: 22948417.

    Google Scholar 

  52. Kimura S, Inoguchi T, Yokomizo H, Maeda Y, Sonoda N, Takayanagi R. Randomized comparison of pitavastatin and pravastatin treatment on the reduction of urinary albumin in patients with type 2 diabetic nephropathy. Diabetes Obes Metab. 2012;14(7):666–9.

    Article  CAS  PubMed  Google Scholar 

  53. Dijan JP, Maucci R, Guilmin L, Ferreirira T, Prister P. NCS a6560, a novel nitric oxide donating atorvastatin with a promising safety and efficacy profile: a randomised double blind placebo and active control study. Circulation. 2010;122 Suppl 21:A14267.

    Google Scholar 

  54. Masha A, Dinatale S, Allasia S, Martina V. Role of the decreased nitric oxide bioavailability in the vascular complications of diabetes mellitus. Curr Pharm Biotechnol. 2011;12(9):1354–63.

    Article  CAS  PubMed  Google Scholar 

  55. Out C, Groen AK, Brufau G. Bile acid sequestrants: more than simple resins. Curr Opin Lipidol. 2012;23(1):43–55.

    Article  CAS  PubMed  Google Scholar 

  56. Prawitt J, Staels B. Bile acid sequestrants: glucose-lowering mechanisms. Metab Syndr Relat Disord 2010;8(Suppl 1):S3–8. Epub 2010 Oct 26.

    Google Scholar 

  57. Zema MJ. Colesevelam hydrochloride: evidence for its use in the treatment of hypercholesterolemia and type 2 diabetes mellitus with insights into mechanism of action. Core Evid. 2012;7:61–75.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Bays HE. Long-term (52–78 weeks) treatment with colesevelam HCl added to metformin therapy in type 2 diabetes mellitus patients. Diabetes Metab Syndr Obes. 2012;5:125–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Younk LM, Davis SN. Evaluation of colesevelam hydrochloride for the treatment of type 2 diabetes. Expert Opin Drug Metab Toxicol. 2012;8(4): 515–25.

    Article  CAS  PubMed  Google Scholar 

  60. Descamps OS, De Sutter J, Guillaume M, Missault L. Where does the interplay between cholesterol absorption and synthesis in the context of statin and/or ezetimibe treatment stand today? Atherosclerosis. 2011;217(2):308–21.

    Article  CAS  PubMed  Google Scholar 

  61. Gupta EK, Ito MK. Ezetimibe: the first in a novel class of selective cholesterol-absorption inhibitors. Heart Dis. 2002;4(6):399–409.

    Article  CAS  PubMed  Google Scholar 

  62. Bays H. Ezetimibe. Expert Opin Investig Drugs. 2002;11(11):1587–604.

    Article  CAS  PubMed  Google Scholar 

  63. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, Wanner C, Krane V, Cass A, Craig J, Neal B, Jiang L, Hooi LS, Levin A, Agodoa L, Gaziano M, Kasiske B, Walker R, Massy ZA, Feldt-Rasmussen B, Krairittichai U, Ophascharoensuk V, Fellström B, Holdaas H, Tesar V, Wiecek A, Grobbee D, de Zeeuw D, Grönhagen-Riska C, Dasgupta T, Lewis D, Herrington W, Mafham M, Majoni W, Wallendszus K, Grimm R, Pedersen T, Tobert J, Armitage J, Baxter A, Bray C, Chen Y, Chen Z, Hill M, Knott C, Parish S, Simpson D, Sleight P, Young A, Collins R, 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(9784):2181–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Davidson MH, Stein EA, Bays HE, Maki KC, Doyle RT, Shalwitz RA, Ballantyne CM, Ginsberg HN. COMBination of prescription Omega-3 with Simvastatin (COMBOS)Investigators. Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week,randomized, double-blind, placebo-controlled study. Clin Ther. 2007; 29(7):1354–67.

    Article  CAS  PubMed  Google Scholar 

  65. Maki KC, Dicklin MR, Davidson MH, Doyle RT, Ballantyne CM. COMBination of prescription Omega-3 with Simvastatin (COMBOS) Investigators. Baseline lipoprotein lipids and low-density lipoprotein cholesterol response to prescription omega-3 acid ethyl ester added to Simvastatin therapy. Am J Cardiol. 2010;105(10):1409–12.

    Article  CAS  PubMed  Google Scholar 

  66. Bays HE, Maki KC, McKenney J, Snipes R, Meadowcroft A, Schroyer R, Doyle RT, Stein E. Long-term up to 24-month efficacy and safety of concomitant prescription omega-3-acid ethyl esters and simvastatin in ypertriglyceridemic patients. Curr Med Res Opin. 2010;26(4):907–15.

    Article  CAS  PubMed  Google Scholar 

  67. Mousavi SA, Berge KE, Leren TP. The unique role of proprotein convertase subtilisin/kexin 9 in cholesterol homeostasis. J Intern Med. 2009;266(6):507–19.

    Article  CAS  PubMed  Google Scholar 

  68. Lambert G, Charlton F, Rye KA, Piper DE. Molecular basis of PCSK9 function. Atherosclerosis. 2009;203(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  69. Humphries SE, Neely RD, Whittall RA, Troutt JS, Konrad RJ, Scartezini M, Li KW, Cooper JA, Acharya J, Neil A. Healthy individuals carrying the PCSK9 p.R46L variant and familial hypercholesterolemia patients carrying PCSK9 p.D374Y exhibit lower plasma concentrations of PCSK9. Clin Chem. 2009;55(12):2153–61.

    Article  CAS  PubMed  Google Scholar 

  70. Abifadel M, Rabès JP, Devillers M, Munnich A, Erlich D, Junien C, Varret M, Boileau C. Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum Mutat. 2009;30(4):520–9.

    Article  CAS  PubMed  Google Scholar 

  71. Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, Cohen JC, Hobbs HH. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet. 2006;79(3):514–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Awan Z, Seidah NG, MacFadyen JG, Benjannet S, Chasman DI, Ridker PM, Genest J. Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial. Clin Chem. 2012;58(1):183–9.

    Article  CAS  PubMed  Google Scholar 

  73. Baass A, Dubuc G, Tremblay M, Delvin EE, O'Loughlin J, Levy E, Davignon J, Lambert M. Plasma PCSK9 is associated with age, sex, and multiple metabolic markers in a population-based sample of children and adolescents. Clin Chem. 2009;55(9):1637–45.

    Article  CAS  PubMed  Google Scholar 

  74. Lambert G, Ancellin N, Charlton F, Comas D, Pilot J, Keech A, Patel S, Sullivan DR, Cohn JS, Rye KA, Barter PJ. Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment. Clin Chem. 2008;54(6):1038–45.

    Article  CAS  PubMed  Google Scholar 

  75. Chan DC, Hamilton SJ, Rye KA, Chew GT, Jenkins AJ, Lambert G, Watts GF. Fenofibrate concomitantly decreases serum proprotein convertase subtilisin/kexin type 9 and very-low-density lipoprotein particle concentrations in statin-treated type 2 diabetic patients. Diabetes Obes Metab. 2010;12(9): 752–6.

    Article  CAS  PubMed  Google Scholar 

  76. Costet P, Hoffmann MM, Cariou B, Guyomarc'h Delasalle B, Konrad T, Winkler K. Plasma PCSK9 is increased by fenofibrate and atorvastatin in a non-additive fashion in diabetic patients. Atherosclerosis. 2010;212(1):246–51.

    Article  CAS  PubMed  Google Scholar 

  77. Davignon J, Dubuc G. Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels. Trans Am Clin Climatol Assoc. 2009;120:163–73.

    PubMed Central  PubMed  Google Scholar 

  78. Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, Lisbon E, Gutierrez M, Webb C, Wu R, Du Y, Kranz T, Gasparino E, Swergold GD. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366(12): 1108–18.

    Article  CAS  PubMed  Google Scholar 

  79. Stamler J. The coronary drug project-findings with regard to estrogen, dextrothyroxine, clofibrate and niacin. Adv Exp Med Biol. 1977;82:52–75.

    CAS  PubMed  Google Scholar 

  80. The coronary drug project. Findings leading to further modifications of its protocol with respect to dextrothyroxine. The coronary drug project research group. JAMA. 1972;220(7):996–1008.

    Google Scholar 

  81. Medici M, Rivadeneira F, van der Deure WM, Hofman A, van Meurs JB, Styrkársdottir U, van Duijn CM, Spector T, Kiel DP, GEFOS Consortium, Uitterlinden AG, Visser TJ, Peeters RP. A large-scale population-based analysis of common genetic variation in the thyroid hormone receptor alpha locus and bone. Thyroid. 2012, 22(2):223–4

    Google Scholar 

  82. Goumidi L, Gauthier K, Legry V, Mayi TH, Houzet A, Cottel D, Montaye M, Proust C, Kee F, Ferrières J, Arveiler D, Ducimetière P, Staels B, Dallongeville J, Chinetti G, Flamant F, Amouyel P, Meirhaeghe A. Association between a thyroid hormone receptor-α gene polymorphism and blood pressure but not with coronary heart disease risk. Am J Hypertens. 2011;24(9):1027–34.

    Article  CAS  PubMed  Google Scholar 

  83. Mazziotti G, Canalis E, Giustina A. Drug-induced osteoporosis: mechanisms and clinical implications. Am J Med. 2010;123(10):877–84.

    Article  CAS  PubMed  Google Scholar 

  84. Moriguchi M, Noso S, Kawabata Y, Yamauchi T, Harada T, Komaki K, Babaya N, Hiromine Y, Ito H, Yamagata S, Murata K, Higashimoto T, Park C, Yamamoto A, Ohno Y, Ikegami H. Clinical and genetic characteristics of patients with autoimmune thyroid disease with anti-islet autoimmunity. Metabolism. 2011;60(6):761–6.

    Article  CAS  PubMed  Google Scholar 

  85. Kowalik MA, Perra A, Pibiri M, Cocco MT, Samarut J, Plateroti M, Ledda-Columbano GM, Columbano A. TRbeta is the critical thyroid hormone receptor isoform in T3-induced proliferation of hepatocytes and pancreatic acinar cells. J Hepatol. 2010;53(4):686–92.

    Article  CAS  PubMed  Google Scholar 

  86. Tancevski I, Demetz E, Eller P. Sobetirome: a selective thyromimetic for the treatment of dyslipidemia. Recent Pat Cardiovasc Drug Discov. 2011;6(1):16–9.

    Article  CAS  PubMed  Google Scholar 

  87. Parhofer KG. Lipoprotein(a): medical treatment options for an elusive molecule. Curr Pharm Des. 2011;17(9):871–6.

    Article  CAS  PubMed  Google Scholar 

  88. Shiohara H, Nakamura T, Kikuchi N, Ozawa T, Nagano R, Matsuzawa A, Ohnota H, Miyamoto T, Ichikawa K, Hashizume K. Discovery of novel indane derivatives as liver-selective thyroid hormone receptor β (TRβ) agonists for the treatment of dyslipidemia. Bioorg Med Chem. 2012;20(11):3622–34.

    Article  CAS  PubMed  Google Scholar 

  89. Merki E, Graham MJ, Mullick AE, Miller ER, Crooke RM, Pitas RE, Witztum JL, Tsimikas S. Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice. Circulation. 2008;118(7):743–53.

    Google Scholar 

  90. Visser ME, Wagener G, Baker BF, Geary RS, Donovan JM, Beuers UH, Nederveen AJ, Verheij J, Trip MD, Basart DC, Kastelein JJ, Stroes ES. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. Eur Heart J. 2012;33(9):1142–9.

    Article  CAS  PubMed  Google Scholar 

  91. Stein EA, Bays H, O'Brien D, Pedicano J, Piper E, Spezzi A. Lapaquistat acetate: development of a squalene synthase inhibitor for the treatment of hypercholesterolemia. Circulation. 2011;123(18): 1974–85.

    Article  CAS  PubMed  Google Scholar 

  92. Wierzbicki AS, Hardman T, Prince WT. Future challenges for microsomal transport protein inhibitors. Curr Vasc Pharmacol. 2009;7(3):277–86.

    Article  CAS  PubMed  Google Scholar 

  93. Samaha FF, McKenney J, Bloedon LT, Sasiela WJ, Rader DJ. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat Clin Pract Cardiovasc. 2008;5(8):497–505.

    Article  CAS  Google Scholar 

  94. Tardif JC, Grégoire J, L'Allier PL, Anderson TJ, Bertrand O, Reeves F, Title LM, Alfonso F, Schampaert E, Hassan A, McLain R, Pressler ML, Ibrahim R, Lespérance J, Blue J, Heinonen T, Rodés-Cabau J, Avasimibe and Progression of Lesions on UltraSound (A-PLUS) Investigators. Effects of the acyl coenzyme A: cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions. Circulation. 2004;110(21):3372–7.

    Article  CAS  PubMed  Google Scholar 

  95. Nissen SE, Tuzcu EM, Brewer HB, Sipahi I, Nicholls SJ, Ganz P, Schoenhagen P, Waters DD, Pepine CJ, Crowe TD, Davidson MH, Deanfield JE, Wisniewski LM, Hanyok JJ, Kassalow LM, ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) Investigators. Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med. 2006;354(12):1253–63.

    Article  CAS  PubMed  Google Scholar 

  96. Meuwese MC, de Groot E, Duivenvoorden R, Trip MD, Ose L, Maritz FJ, Basart DC, Kastelein JJ, Habib R, Davidson MH, Zwinderman AH, Schwocho LR, Stein EA, CAPTIVATE Investigators. ACAT inhibition and progression of carotid atherosclerosis in patients with familial hypercholesterolemia: the CAPTIVATE randomized trial. JAMA. 2009;301(11):1131–9.

    Article  CAS  PubMed  Google Scholar 

  97. Arsenault BJ, Boekholdt SM, Kastelein JJ. Lipid parameters for measuring risk of cardiovascular disease. Nat Rev Cardiol. 2011;8(4):197–206.

    Article  CAS  PubMed  Google Scholar 

  98. Mangalmurti SS, Davidson MH. The incremental value of lipids and inflammatory biomarkers in determining residual cardiovascular risk. Curr Atheroscler Rep. 2011;13(5):373–80.

    Article  CAS  PubMed  Google Scholar 

  99. Jenkins AJ, Best JD, Klein RL, Lyons TJ. Lipoproteins, glycoxidation and diabetic angiopathy. Diabetes Metab Res Rev. 2004;20(5):349–68.

    Article  CAS  PubMed  Google Scholar 

  100. Mahley RW, Huang Y. Atherogenic remnant lipoproteins: role for proteoglycans in trapping, transferring, and internalizing. J Clin Invest. 2007;117(1): 94–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Mulder M, Lombardi P, Jansen H, van Berkel TJ, Frants RR, Havekes LM. Low density lipoprotein receptor internalizes low density and very low density lipoproteins that are bound to heparan sulfate proteoglycans via lipoprotein lipase. J Biol Chem. 1993;268(13):9369–75.

    CAS  PubMed  Google Scholar 

  102. de Beer F, Hendriks WL, van Vark LC, Kamerling SW, van Dijk KW, Hofker MH, Smelt AH, Havekes LM. Binding of beta-VLDL to heparan sulfate proteoglycans requires lipoprotein lipase, whereas ApoE only modulates binding affinity. Arterioscler Thromb Vasc Biol. 1999;19(3):633–7. PubMed PMID: 10073967.

    Article  PubMed  Google Scholar 

  103. Anber V, Millar JS, McConnell M, Shepherd J, Packard CJ. Interaction of very-low-density, intermediate-density, and low-density lipoproteins with human arterial wall proteoglycans. Arterioscler Thromb Vasc Biol. 1997;17(11):2507–14. PubMed PMID: 9409221.

    Article  CAS  PubMed  Google Scholar 

  104. Kohli P, Cannon CP. Triglycerides: how much credit do they deserve? Med Clin North Am. 2012;96(1): 39–55.

    Article  CAS  PubMed  Google Scholar 

  105. Wierzbicki AS, Clarke RE, Viljoen A, Mikhailidis DP. Triglycerides: a case for treatment? Curr Opin Cardiol. 2012;27(4):398–404. PubMed PMID: 22565137.

    Article  PubMed  Google Scholar 

  106. Talayero BG, Sacks FM. The role of triglycerides in atherosclerosis. Curr Cardiol Rep. 2011;13(6):544–52.

    Article  PubMed Central  PubMed  Google Scholar 

  107. Dallinga-Thie GM, Franssen R, Mooij HL, Visser ME, Hassing HC, Peelman F, Kastelein JJ, Péterfy M, Nieuwdorp M. The metabolism of triglyceride-rich lipoproteins revisited: new players, new insight. Atherosclerosis. 2010;211(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  108. Austin MA. Refining and expanding the role of small, dense low-density lipoproteins. Atherosclerosis. 2009;207(2):350–1.

    Article  CAS  PubMed  Google Scholar 

  109. Barter P. HDL-C: role as a risk modifier. Atheroscler Suppl. 2011;12(3):267–70.

    Article  CAS  PubMed  Google Scholar 

  110. Tabet F, Rye KA. High-density lipoproteins, inflammation and oxidative stress. Clin Sci (Lond). 2009;116(2):87–98.

    Article  CAS  PubMed  Google Scholar 

  111. Rye KA, Bursill CA, Lambert G, Tabet F, Barter PJ. The metabolism and anti-atherogenic properties of HDL. J Lipid Res. 2009;50(Suppl):S195–200.

    PubMed  Google Scholar 

  112. Barter PJ, Puranik R, Rye KA. New insights into the role of HDL as an anti-inflammatory agent in the prevention of cardiovascular disease. Curr Cardiol Rep. 2007;9(6):493–8.

    Article  PubMed  Google Scholar 

  113. Barter PJ, Baker PW, Rye KA. Effect of high-density lipoproteins on the expression of adhesion molecules in endothelial cells. Curr Opin Lipidol. 2002;13(3):285–8.

    Article  CAS  PubMed  Google Scholar 

  114. Jenkins AJ, Rowley KG, Lyons TJ, Best JD, Hill MA, Klein RL. Lipoproteins and diabetic microvascular complications. Curr Pharm Des. 2004;10(27): 3395–418.

    Article  CAS  PubMed  Google Scholar 

  115. Watts GF, Karpe F. Why, when and how should hypertriglyceridemia be treated in the high-risk cardiovascular patient? Expert Rev Cardiovasc Ther. 2011;9(8):987–97.

    Article  CAS  PubMed  Google Scholar 

  116. Mehra S, Movahed H, Movahed A. Emerging therapies for residual risk. Rev Cardiovasc Med. 2012;13(1):e24–31.

    PubMed  Google Scholar 

  117. Judge EP, Phelan D, O'Shea D. Beyond statin therapy: a review of the management of residual risk in diabetes mellitus. J R Soc Med. 2010;103(9): 357–62.

    Article  PubMed Central  PubMed  Google Scholar 

  118. Wanner C, Krane V. Recent advances in the treatment of atherogenic dyslipidemia in type 2 diabetes mellitus. Kidney Blood Press Res. 2011;34(4):209–17.

    Article  CAS  PubMed  Google Scholar 

  119. Kumar A, Singh V. Atherogenic dyslipidemia and diabetes mellitus: what's new in the management arena? Vasc Health Risk Manag. 2010;6:665–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  120. Bruckert E, Labreuche J, Deplanque D, Touboul PJ, Amarenco P. Fibrates effect on cardiovascular risk is greater in patients with high triglyceride levels or atherogenic dyslipidemia profile: a systematic review and meta-analysis. J Cardiovasc Pharmacol. 2011;57(2):267–72. Review. PubMed PMID: 21052016.

    Article  CAS  PubMed  Google Scholar 

  121. Stumvoll M, Häring HU. Glitazones: clinical effects and molecular mechanisms. Ann Med. 2002;34(3): 217–24.

    CAS  PubMed  Google Scholar 

  122. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA. 2007;298(10):1189–95.

    Article  CAS  PubMed  Google Scholar 

  123. Piccinni C, Motola D, Marchesini G, Poluzzi E. Assessing the association of pioglitazone use and bladder cancer through drug adverse event reporting. Diabetes Care. 2011;34(6):1369–71.

    Article  PubMed  Google Scholar 

  124. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005;294(20):2581–6.

    Article  CAS  PubMed  Google Scholar 

  125. Kendall DM, Rubin CJ, Mohideen P, Ledeine JM, Belder R, Gross J, Norwood P, O'Mahony M, Sall K, Sloan G, Roberts A, Fiedorek FT, DeFronzo RA. Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy: A double-blind, randomized, pioglitazone-comparative study. Diabetes Care. 2006;29(5):1016–23.

    Article  CAS  PubMed  Google Scholar 

  126. Henry RR, Lincoff AM, Mudaliar S, Rabbia M, Chognot C, Herz M. Effect of the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet. 2009;374(9684):126–35.

    Article  CAS  PubMed  Google Scholar 

  127. Herz M, Gaspari F, Perico N, Viberti G, Urbanowska T, Rabbia M, Wieczorek Kirk D. Effects of high dose aleglitazar on renal function in patients with type 2 diabetes. Int J Cardiol. 2011;151(2):136–42.

    Article  PubMed  Google Scholar 

  128. Wilding JP. PPAR agonists for the treatment of cardiovascular disease in patients with diabetes. Diabetes Obes Metab. 2012;14(11):973–82. doi:10.1111/j.1463-1326.2012.

    Google Scholar 

  129. Cariou B, Zaïr Y, Staels B, Bruckert E. Effects of the new dual PPAR α/δ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care. 2011;34(9):2008–14.

    Article  CAS  PubMed  Google Scholar 

  130. Crouse 3rd JR. New developments in the use of niacin for treatment of hyperlipidemia: new considerations in the use of an old drug. Coron Artery Dis. 1996;7(4):321–6.

    Article  PubMed  Google Scholar 

  131. Faergeman O. Hypertriglyceridemia and the fibrate trials. Curr Opin Lipidol. 2000;11(6):609–14.

    Article  CAS  PubMed  Google Scholar 

  132. Niacin, fenofibrates increase benefits for statin users. These HDL- raising, triglyceride-lowering drugs beat out the use of additional LDL-lowering drugs. Duke Med Health News. 2010;16(8):1–2.

    Google Scholar 

  133. Nichols GA, Koro CE, Chan W, Bowlin SJ, Sprecher DL. The association between fibrate use, change in high-density lipoprotein cholesterol, and the risk of cardiovascular disease: a retrospective chart review involving up to 8 years of follow-up. Clin Ther. 2006;28(2):243–50.

    Article  CAS  PubMed  Google Scholar 

  134. Helmbold AF, Slim JN, Morgan J, Castillo-Rojas LM, Shry EA, Slim AM. The effects of extended release niacin in combination with omega 3 fatty acid supplements in the treatment of elevated lipoprotein (a). Cholesterol. 2010;2010:306147.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  135. Canner PL, Halperin M. Implications of findings in the coronary drug project for secondary prevention trials in coronary heart disease. The coronary; drug project research group. Circulation. 1981;63(6):1342–50.

    Article  CAS  PubMed  Google Scholar 

  136. Schlant RC, Forman S, Stamler J, Canner PL. The natural history of coronary heart disease: prognostic factors after recovery from myocardial infarction in 2,789 men. The 5-year findings of the coronary drug project. Circulation. 1982;66(2):401–14.

    Article  CAS  PubMed  Google Scholar 

  137. Song WL, Stubbe J, Ricciotti E, Alamuddin N, Ibrahim S, Crichton I, Prempeh M, Lawson JA, Wilensky RL, Rasmussen LM, Puré E, FitzGerald GA. Niacin and biosynthesis of PGD2 by platelet COX-1 in mice and humans. J Clin Invest. 2012;122(4):1459–68.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  138. Stern RH. The role of nicotinic acid metabolites in flushing and hepatotoxicity. J Clin Lipidol. 2007;1(3):191–3.

    Article  PubMed  Google Scholar 

  139. Cooper-DeHoff RM, Pacanowski MA, Pepine CJ. Cardiovascular therapies and associated glucose homeostasis: implications across the dysglycemia continuum. J Am Coll Cardiol. 2009;53 Suppl 5:S28–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  140. Maccubbin DL, Chen F, Anderson JW, Sirah W, McCrary Sisk C, Kher U, Olsson AG, Bays HE, Mitchel YB. Effectiveness and safety of laropiprant on niacin-induced flushing. Am J Cardiol. 2012;110(6):817–22.

    Article  CAS  PubMed  Google Scholar 

  141. Guyton JR, Fazio S, Adewale AJ, Jensen E, Tomassini JE, Shah A, Tershakovec AM. Effect of extended-release niacin on new-onset diabetes among hyperlipidemic patients treated with ezetimibe/simvastatin in a randomized controlled trial. Diabetes Care. 2012;35(4):857–60.

    Article  CAS  PubMed  Google Scholar 

  142. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345(22):1583–92.

    Article  CAS  PubMed  Google Scholar 

  143. Michos ED, Sibley CT, Baer JT, Blaha MJ, Blumenthal RS. Niacin and statin combination therapy for atherosclerosis regression and prevention of cardiovascular disease events: reconciling the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial with previous surrogate endpoint trials. J Am Coll Cardiol. 2012;59(23):2058–64.

    Article  CAS  PubMed  Google Scholar 

  144. HPS2/THRIVE Clinical Trials.gov. http://www.thrivestudy.org/ (as accessed June 2013).

    Google Scholar 

  145. Johns DG, Duffy J, Fisher T, Hubbard BK, Forrest MJ. On- and off-target pharmacology of torcetrapib: current understanding and implications for the structure activity relationships (SAR), discovery and development of cholesteryl ester-transfer protein (CETP) inhibitors. Drugs. 2012;72(4):491–507.

    Article  CAS  PubMed  Google Scholar 

  146. Shear C, Beltangady M, Ports W, Duggan W, Barter P. Torcetrapib: predictors of increased clinical risk in the ILLUMINATE study. Circulation 2008;118:S_370–S_371. Abstract 1694

    Google Scholar 

  147. Yvan-Charvet L, Matsuura F, Wang N, Bamberger MJ, Nguyen T, Rinninger F, Jiang XC, Shear CL, Tall AR. Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arterioscler Thromb Vasc Biol. 2007;27:1132–8.

    Article  CAS  PubMed  Google Scholar 

  148. Brousseau ME, Diffenderfer MR, Millar JS, Nartsupha C, Asztalos BF, Welty FK, Wolfe ML, Rudling M, Björkhem I, Angelin B, Mancuso JP, Digenio AG, Rader DJ, Schaefer EJ. Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion. Arterioscler Thromb Vasc Biol. 2005;25(5):1057–64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  149. Hu X, Dietz JD, Xia C, Knight DR, Loging WT, Smith AH, Yuan H, Perry DA, Keiser J. Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition. Endocrinology. 2009;150:2211–9.

    Article  CAS  PubMed  Google Scholar 

  150. Forrest MJ, Bloomfield D, Briscoe RJ, Brown PN, Cumiskey AM, Ehrhart J, Hershey JC, Keller WJ, Ma X, McPherson HE, et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol. 2008;154:1465–73.

    Article  CAS  PubMed  Google Scholar 

  151. Stein EA, Roth EM, Rhyne JM, Burgess T, Kallend D, Robinson JG. Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial. Eur Heart J. 2010;31(4):480–8.

    Article  CAS  PubMed  Google Scholar 

  152. Lüscher TF, Taddei S, Kaski JC, Jukema JW, Kallend D, Münzel T, Kastelein JJ, Deanfield JE, dal-VESSEL Investigators. Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial. Eur Heart J. 2012;33(7):857–65.

    Article  PubMed  CAS  Google Scholar 

  153. Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet. 2011;378(9802):1547–59.

    Article  CAS  PubMed  Google Scholar 

  154. Cannon CP, Dansky HM, Davidson M, Gotto AM Jr, Brinton EA, Gould AL,Stepanavage M, Liu SX, Shah S, Rubino J, Gibbons P, Hermanowski-Vosatka A,Binkowitz B, Mitchel Y, Barter P, DEFINE Investigators. Design of the DEFINE trial: determining the EFficacy and tolerability of CETP INhibition with AnacEtrapib. Am Heart J 2009;158(4):513–519.e3.

    Google Scholar 

  155. REVEAL trial. Clinicaltrials.gov. http://clinicaltrials. gov/show/NCT01252953. (as accessed June 2013).

    Google Scholar 

  156. White CR, Datta G, Mochon P, Zhang Z, Kelly O, Curcio C, Parks D, Palgunachari M, Handattu S, Gupta H, Garber DW, Anantharamaiah GM. Vasculoprotective effects of apolipoprotein mimetic peptides: an evolving paradigm in Hdl therapy. Vasc Dis Prev. 2009;6:122–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  157. Bucci M, Cigliano L, Vellecco V, D'Andrea LD, Ziaco B, Rossi A, Sautebin L, Carlucci A, Abrescia P, Pedone C, Ianaro A, Cirino G. Apolipoprotein A-I (ApoA-I) mimetic peptide P2a by restoring cholesterol esterification unmasks ApoA-I anti-inflammatory endogenous activity in vivo. J Pharmacol Exp Ther. 2012;340(3):716–22.

    Article  CAS  PubMed  Google Scholar 

  158. Di Bartolo BA, Vanags LZ, Tan JT, Bao S, Rye KA, Barter PJ, Bursill CA. The apolipoprotein A-I mimetic peptide, ETC-642, reduces chronic vascular inflammation in the rabbit. Lipids Health Dis. 2011;10:224.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  159. Imaizumi S, Navab M, Morgantini C, Charles-Schoeman C, Su F, Gao F, Kwon M, Ganapathy E, Meriwether D, Farias-Eisner R, Fogelman AM, Reddy ST. Dysfunctional high-density lipoprotein and the potential of apolipoprotein A-1 mimetic peptides to normalize the composition and function of lipoproteins. Circ J. 2011;75(7):1533–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  160. Vecoli C, Cao J, Neglia D, Inoue K, Sodhi K, Vanella L, Gabrielson KK, Bedja D, Paolocci N, L’abbate A, Abraham NG. Apolipoprotein A-I mimetic peptide L-4F prevents myocardial and coronary dysfunction in diabetic mice. J Cell Biochem. 2011;112(9): 2616–26.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  161. Datta G, Epand RF, Epand RM, Chaddha M, Kirksey MA, Garber DW, Lund-Katz S, Phillips MC, Hama S, Navab M, Fogelman AM, Palgunachari MN, Segrest JP, Anantharamaiah GM. Aromatic residue position on the nonpolar face of class a amphipathic helical peptides determines biological activity. J Biol Chem. 2004;279(25):26509–17.

    Article  CAS  PubMed  Google Scholar 

  162. Carballo-Jane E, Chen Z, O’Neill E, Wang J, Burton C, Chang CH, Chen X, Eveland S, Frantz-Wattley B, Gagen K, Hubbard B, Ichetovkin M, Luell S, Meurer R, Song X, Strack A, Langella A, Cianetti S, Rech F, Capitò E, Bufali S, Veneziano M, Verdirame M, Bonelli F, Monteagudo E, Pessi A, Ingenito R, Bianchi E. ApoA-I mimetic peptides promote pre-β HDL formation in vivo causing remodeling of HDL and triglyceride accumulation at higher dose. Bioorg Med Chem. 2010;18(24):8669–78.

    Article  CAS  PubMed  Google Scholar 

  163. Thompson GR, HEART-UK LDL Apheresis Working Group. Recommendations for the use of LDL apheresis. Atherosclerosis. 2008;198(2):247–55.

    Article  CAS  PubMed  Google Scholar 

  164. Sacks FM, Rudel LL, Conner A, et al. Selective delipidation of plasma HDL enhances reverse cholesterol transport in vivo. J Lipid Res. 2009;50(5): 894–907.

    Article  CAS  PubMed  Google Scholar 

  165. Waksman R, Torguson R, Kent KM, et al. A first in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome. J Am Coll Cardiol. 2010;55(24):2727–35.

    Article  PubMed  Google Scholar 

  166. Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA. 2012;308(10):1024–33.

    Article  CAS  PubMed  Google Scholar 

  167. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSIPrevenzione trial. Lancet 1999;354(9177):447–55.

    Google Scholar 

  168. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K, Japan EPA. lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369(9567):1090–8.

    Article  CAS  PubMed  Google Scholar 

  169. ORIGIN Trial Investigators, Bosch J, Gerstein HC, Dagenais GR, Díaz R, Dyal L, Jung H, Maggiono AP, Probstfield J, Ramachandran A, Riddle MC, Rydén LE, Yusuf S. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367(4):309–18.

    Article  CAS  PubMed  Google Scholar 

  170. Ballantyne CM, Bays HE, Kastelein JJ, Stein E, Isaacsohn JL, Braeckman RA, Soni PN. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110(7):984–92.

    Article  CAS  PubMed  Google Scholar 

  171. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the multi-center, plAcebo-controlled, randomized, double-blINd, 12-week study with an open-label extension [MARINE] trial). Am J Cardiol. 2011;108(5):682–90.

    Article  CAS  PubMed  Google Scholar 

  172. Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ, Watkins SM, Olefsky JM. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 2010;142(5):687–98.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  173. Gerritsen G, Rensen PC, Kypreos KE, Zannis VI, Havekes LM, Willems van Dijk K. ApoC-III deficiency prevents hyperlipidemia induced by apoE overexpression. J Lipid Res. 2005;46(7):1466–73.

    Article  CAS  PubMed  Google Scholar 

  174. Yamamoto M, Morita SY, Kumon M, Kawabe M, Nishitsuji K, Saito H, Vertut-Doï A, Nakano M, Handa T. Effects of plasma apolipoproteins on lipoprotein lipase-mediated lipolysis of small and large lipid emulsions. Biochim Biophys Acta. 2003; 1632(1–3):31–9.

    Article  CAS  PubMed  Google Scholar 

  175. Pollin TI, Damcott CM, Shen H, Ott SH, Shelton J, Horenstein RB, Post W, McLenithan JC, Bielak LF, Peyser PA, Mitchell BD, Miller M, O’Connell JR, Shuldiner AR. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science. 2008;322(5908):1702–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  176. Glueck CJ, Budhani SB, Masineni SS, Abuchaibe C, Khan N, Wang P, Goldenberg N. Vitamin D deficiency, myositis-myalgia, and reversible statin intolerance. Curr Med Res Opin. 2011;27(9): 1683–90.

    Article  PubMed  Google Scholar 

  177. Mas E, Mori TA. Coenzyme Q(10) and statin myalgia: what is the evidence? Curr Atheroscler Rep. 2010;12(6):407–13.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, RMIT University, Plenty Road, 71, Bundoora, VIC, 3083, Australia

    Peter J. Little B.Pharm., Ph.D.

  2. Monash University, Melbourne, VIC, Australia

    Peter J. Little B.Pharm., Ph.D.

  3. Division of Metabolism, Endocrinology and Nutrition, University of Washington School of Medicine, Seattle, WA, USA

    Alan Chait

  4. Vascular Biology and Atherosclerosis, BakerIDI Heart and Diabetes Insitute, Melbourne, VIC, Australia

    Alex Bobik

  5. Department of Medicine, The University of Melbourne, St. Vincent’s Hospital, Melbourne, VIC, Australia

    Andrzej S. Januszewski

  6. NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia

    Andrzej S. Januszewski

  7. Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy, 3065, Melbourne, VIC, Australia

    David O’Neal

  8. Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, 941 Stanton L. Young Blvd., BSEB 302F, Oklahoma City, OK, USA

    Alicia J. Jenkins M.D., F.R.A.C.P.

  9. University of Sydney, NHMRC Clinical Trials Centre, Camperdown, Sydney, NSW, Australia

    Alicia J. Jenkins M.D., F.R.A.C.P.

Authors
  1. Peter J. Little B.Pharm., Ph.D.
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  2. Alan Chait
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  3. Andrzej S. Januszewski
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  4. Alex Bobik
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  5. David O’Neal
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  6. Alicia J. Jenkins M.D., F.R.A.C.P.
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Corresponding author

Correspondence to Peter J. Little B.Pharm., Ph.D. .

Editor information

Editors and Affiliations

  1. NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia

    Alicia J. Jenkins

  2. College of Medicine, University of Illinois, Peoria, Illinois, USA

    Peter P. Toth

  3. Section of Endocrinology and Diabetes Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

    Timothy J. Lyons

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© 2014 Springer Science+Business Media New York

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Little, P.J., Chait, A., Januszewski, A.S., Bobik, A., O’Neal, D., Jenkins, A.J. (2014). Emerging Lipoprotein-Related Therapeutics for Patients with Diabetes. In: Jenkins, A., Toth, P., Lyons, T. (eds) Lipoproteins in Diabetes Mellitus. Contemporary Diabetes. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-7554-5_23

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  • DOI: https://doi.org/10.1007/978-1-4614-7554-5_23

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4614-7553-8

  • Online ISBN: 978-1-4614-7554-5

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