Advertisement

Role for Combination Therapy in Diabetic Dyslipidemia

  • Haider J. Warraich
  • Nathan D. Wong
  • Jamal S. RanaEmail author
Diabetes and Cardiovascular Disease (S Malik, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Diabetes and Cardiovascular Disease

Abstract

Individuals with type 2 diabetes mellitus have a high residual risk of cardiovascular disease (CVD) despite maximal statin therapy and lifestyle interventions. In addition, adults with diabetes frequently exhibit the pattern of elevated triglycerides, small dense LDL, and reduced levels of high density lipoprotein cholesterol (HDL), also known as diabetic dyslipidemia. The role of combination therapy with an additional agent such as niacin, ezetimibe, fenofibrate, and n-3 fatty acids have been extensively studied with disappointing results. Review of key trials assessing benefit of combination therapy to reduce CVD risk from dyslipidemia is performed. While combination therapy frequently results in an improvement in lipid profile, to date, no consistent improvement in clinical outcomes has been observed. Therefore, current guidelines do not recommend combination therapy in individuals with diabetes, highlighting the role of intensifying statin therapy and lifestyle interventions. The recently released The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE IT) demonstrated a small but significant improvement in clinical endpoints with addition of ezetimibe to statins in high-risk patients. Although this trial was not specifically targeted towards patients with diabetes, the results may influence the future role of a combination therapy in such a population.

Keywords

Type 2 diabetes mellitus Dyslipidemia Statins Fibrates Ezetimibe Fish oil 

Notes

Compliance with Ethics Guidelines

Conflict of Interest

Haider J. Warraich and Jamal S. Rana declare that they have no conflict of interest. Nathan D. Wong reports grants and personal fees from Amgen, Regeneron, and Bristol-Myers Squibb.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047–53.CrossRefPubMedGoogle Scholar
  2. 2.
    Fox CS, Pencina MJ, Wilson PW, Paynter NP, Vasan RS, D’Agostino Sr RB. Lifetime risk of cardiovascular disease among individuals with and without diabetes stratified by obesity status in the Framingham heart study. Diabetes Care. 2008;31(8):1582–4.CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241(19):2035–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Fox CS, Coady S, Sorlie PD, D’Agostino Sr RB, Pencina MJ, Vasan RS, et al. Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study. Circulation. 2007;115(12):1544–50.CrossRefPubMedGoogle Scholar
  5. 5.
    Geiss LS, Wang J, Cheng YJ, Thompson TJ, Barker L, Li Y, et al. Prevalence and incidence trends for diagnosed diabetes among adults aged 20 to 79 years, United States, 1980–2012. JAMA. 2014;312(12):1218–26.CrossRefPubMedGoogle Scholar
  6. 6.
    Mooradian AD. Cardiovascular disease in type 2 diabetes mellitus: current management guidelines. Arch Intern Med. 2003;163(1):33–40.CrossRefPubMedGoogle Scholar
  7. 7.
    Waters DD, Guyton JR, Herrington DM, McGowan MP, Wenger NK, Shear C, et al. Treating to New Targets (TNT) Study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit? Am J Cardiol. 2004;93(2):154–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Fitchett DH, Leiter LA, Goodman SG, Langer A. Lower is better: implications of the Treating to New Targets (TNT) study for Canadian patients. Can J Cardiol. 2006;22(10):835–9.CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Saely CH, Drexel H. Is type 2 diabetes really a coronary heart disease risk equivalent? Vasc Pharmacol. 2013;59(1–2):11–8.CrossRefGoogle Scholar
  10. 10.
    Whiteley L, Padmanabhan S, Hole D, Isles C. Should diabetes be considered a coronary heart disease risk equivalent?: results from 25 years of follow-up in the Renfrew and Paisley survey. Diabetes Care. 2005;28(7):1588–93.CrossRefPubMedGoogle Scholar
  11. 11.
    Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986;256(20):2823–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Prospective Diabetes UK. Study 27. Plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes Care. 1997;20(11):1683–7.CrossRefGoogle Scholar
  13. 13.
    Kannel WB. Lipids, diabetes, and coronary heart disease: insights from the Framingham Study. Am Heart J. 1985;110(5):1100–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Almdal T, Scharling H, Jensen JS, Vestergaard H. The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Arch Intern Med. 2004;164(13):1422–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2009;5(3):150–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Hirano T, Naito H, Kurokawa M, Ebara T, Nagano S, Adachi M, et al. High prevalence of small LDL particles in non-insulin-dependent diabetic patients with nephropathy. Atherosclerosis. 1996;123(1–2):57–72.CrossRefPubMedGoogle Scholar
  17. 17.
    Parish S, Offer A, Clarke R, Hopewell JC, Hill MR, Otvos JD, et al. Lipids and lipoproteins and risk of different vascular events in the MRC/BHF Heart Protection Study. Circulation. 2012;125(20):2469–78.CrossRefPubMedGoogle Scholar
  18. 18.
    Brunzell JD, Hokanson JE. Dyslipidemia of central obesity and insulin resistance. Diabetes Care. 1999;22 Suppl 3:C10–3.PubMedGoogle Scholar
  19. 19.
    Adiels M, Boren J, Caslake MJ, Stewart P, Soro A, Westerbacka J, et al. Overproduction of VLDL1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia. Arterioscler Thromb Vasc Biol. 2005;25(8):1697–703.CrossRefPubMedGoogle Scholar
  20. 20.
    Cummings MH, Watts GF, Umpleby AM, Hennessy TR, Kelly JM, Jackson NC, et al. Acute hyperinsulinemia decreases the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in NIDDM. Diabetes. 1995;44(9):1059–65.CrossRefPubMedGoogle Scholar
  21. 21.
    Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia. 2003;46(6):733–49.CrossRefPubMedGoogle Scholar
  22. 22.
    Haffner SM. The metabolic syndrome: inflammation, diabetes mellitus, and cardiovascular disease. Am J Cardiol. 2006;97(2A):3A–11.CrossRefPubMedGoogle Scholar
  23. 23.
    Watts GF, Playford DA. Dyslipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin dependent diabetes mellitus: an hypothesis. Atherosclerosis. 1998;141(1):17–30.CrossRefPubMedGoogle Scholar
  24. 24.
    Rana JS, Visser ME, Arsenault BJ, Despres JP, Stroes ES, Kastelein JJ, et al. Metabolic dyslipidemia and risk of future coronary heart disease in apparently healthy men and women: the EPIC-Norfolk prospective population study. Int J Cardiol. 2010;143(3):399–404.CrossRefPubMedGoogle Scholar
  25. 25.
    Rock CL, Flatt SW, Pakiz B, Taylor KS, Leone AF, Brelje K, et al. Weight loss, glycemic control, and cardiovascular disease risk factors in response to differential diet composition in a weight loss program in type 2 diabetes: a randomized controlled trial. Diabetes Care. 2014;37(6):1573–80.CrossRefPubMedGoogle Scholar
  26. 26.
    American Diabetes A. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37 Suppl 1:S14–80.CrossRefGoogle Scholar
  27. 27.
    Safeer RS, Ugalat PS. Cholesterol treatment guidelines update. Am Fam Physician. 2002;65(5):871–80.PubMedGoogle Scholar
  28. 28.
    Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368(14):1279–90.CrossRefPubMedGoogle Scholar
  29. 29.
    Salas-Salvado J, Bullo M, Estruch R, Ros E, Covas MI, Ibarrola-Jurado N, et al. Prevention of diabetes with Mediterranean diets: a subgroup analysis of a randomized trial. Ann Intern Med. 2014;160(1):1–10.CrossRefPubMedGoogle Scholar
  30. 30.
    Look ARG, Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(2):145–54.CrossRefGoogle Scholar
  31. 31.
    Sigal RJ, Kenny GP, Boule NG, Wells GA, Prud’homme D, Fortier M, et al. Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial. Ann Intern Med. 2007;147(6):357–69.CrossRefPubMedGoogle Scholar
  32. 32.
    Halverstadt A, Phares DA, Ferrell RE, Wilund KR, Goldberg AP, Hagberg JM. High-density lipoprotein-cholesterol, its subfractions, and responses to exercise training are dependent on endothelial lipase genotype. Metab Clin Exp. 2003;52(11):1505–11.CrossRefPubMedGoogle Scholar
  33. 33.
    Ruano G, Seip RL, Windemuth A, Zollner S, Tsongalis GJ, Ordovas J, et al. Apolipoprotein A1 genotype affects the change in high density lipoprotein cholesterol subfractions with exercise training. Atherosclerosis. 2006;185(1):65–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Wilund KR, Ferrell RE, Phares DA, Goldberg AP, Hagberg JM. Changes in high-density lipoprotein-cholesterol subfractions with exercise training may be dependent on cholesteryl ester transfer protein (CETP) genotype. Metab Clin Exp. 2002;51(6):774–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Cholesterol Treatment Trialists C, Kearney PM, Blackwell L, Collins R, Keech A, Simes J, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371(9607):117–25.CrossRefGoogle Scholar
  36. 36.
    Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011;305(24):2556–64.CrossRefPubMedGoogle Scholar
  37. 37.
    Cholesterol Treatment Trialists C, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. 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):1670–81.CrossRefGoogle Scholar
  38. 38.
    Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;1:CD004816.PubMedGoogle Scholar
  39. 39.
    Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care. 2009;32(10):1924–9.CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380(9841):565–71.CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735–42.CrossRefPubMedGoogle Scholar
  42. 42.
    Fruchart JC, Sacks F, Hermans MP, Assmann G, Brown WV, Ceska R, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102(10 Suppl):1K–34.CrossRefPubMedGoogle Scholar
  43. 43.
    Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5):383–93.CrossRefPubMedGoogle Scholar
  44. 44.
    Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6):580–91.CrossRefPubMedGoogle Scholar
  45. 45.
    Hamilton SJ, Watts GF. Atherogenic dyslipidemia and combination pharmacotherapy in diabetes: recent clinical trials. Rev Diabet Stud RDS. 2013;10(2–3):191–203.CrossRefGoogle Scholar
  46. 46.
    Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010;375(9729):1875–84.CrossRefPubMedGoogle Scholar
  47. 47.
    Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323(19):1289–98.CrossRefPubMedGoogle Scholar
  48. 48.
    Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345(22):1583–92.CrossRefPubMedGoogle Scholar
  49. 49.
    Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. 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(23):3512–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3. Curr Med Res Opin. 2006;22(11):2243–50.CrossRefPubMedGoogle Scholar
  51. 51.
    Lee JM, Robson MD, Yu LM, Shirodaria CC, Cunnington C, Kylintireas I, et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol. 2009;54(19):1787–94.CrossRefPubMedGoogle Scholar
  52. 52.
    Investigators A-H, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–67.CrossRefGoogle Scholar
  53. 53.
    Group HTC, Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203–12.CrossRefGoogle Scholar
  54. 54.
    Perry CM. Extended-release niacin (nicotinic acid)/laropiprant. Drugs. 2009;69(12):1665–79.CrossRefPubMedGoogle Scholar
  55. 55.
    Albers JJ, Slee A, O’Brien KD, Robinson JG, Kashyap ML, Kwiterovich Jr PO, et al. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes). J Am Coll Cardiol. 2013;62(17):1575–9.CrossRefPubMedCentralPubMedGoogle Scholar
  56. 56.
    Gervois P, Fruchart JC, Staels B. Drug Insight: mechanisms of action and therapeutic applications for agonists of peroxisome proliferator-activated receptors. Nat Clin Pract Endocrinol Metab. 2007;3(2):145–56.CrossRefPubMedGoogle Scholar
  57. 57.
    Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, et al. 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(9500):1849–61.CrossRefPubMedGoogle Scholar
  58. 58.
    Scott R, O’Brien R, Fulcher G, Pardy C, D’Emden M, Tse D, et al. 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(3):493–8.CrossRefPubMedCentralPubMedGoogle Scholar
  59. 59.••
    Group AS, Ginsberg HN, Elam MB, Lovato LC, Crouse 3rd JR, Leiter LA, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563–74. The ACCORD study showed that niacin actually caused harm in diabetics when combined with statins and led to the withdrawal of its use in clinical practice in these patients.CrossRefGoogle Scholar
  60. 60.
    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.CrossRefPubMedGoogle Scholar
  61. 61.
    Pearson TA, Denke MA, McBride PE, Battisti WP, Brady WE, Palmisano J. A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial. Mayo Clin Proc. 2005;80(5):587–95.CrossRefPubMedGoogle Scholar
  62. 62.
    Goldberg RB, Guyton JR, Mazzone T, Weinstock RS, Polis A, Edwards P, et al. Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia: the VYTAL study. Mayo Clin Proc. 2006;81(12):1579–88.CrossRefPubMedGoogle Scholar
  63. 63.
    Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358(14):1431–43.CrossRefPubMedGoogle Scholar
  64. 64.
    Fleg JL, Mete M, Howard BV, Umans JG, Roman MJ, Ratner RE, et al. Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial. J Am Coll Cardiol. 2008;52(25):2198–205.CrossRefPubMedCentralPubMedGoogle Scholar
  65. 65.
    Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009;361(22):2113–22.CrossRefPubMedGoogle Scholar
  66. 66.••
    Cannon CP, IMPROVE IT Investigators. IMPROVE-IT trial: a comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes after acute coronary syndromes. Chicago: American Heart Association Scientific Sessions; 2014. The results of IMPROVE IT were presented after significant delays but showed a benefit of adding ezetemibe to statin therapy in patients after acute coronary syndromes. The results for diabetic patients have as yet not been released.Google Scholar
  67. 67.
    Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, et al. 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.CrossRefPubMedGoogle Scholar
  68. 68.
    Bays HE, Maki KC, McKenney J, Snipes R, Meadowcroft A, Schroyer R, et al. Long-term up to 24-month efficacy and safety of concomitant prescription omega-3-acid ethyl esters and simvastatin in hypertriglyceridemic patients. Curr Med Res Opin. 2010;26(4):907–15.CrossRefPubMedGoogle Scholar
  69. 69.••
    Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, 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. Circulation. 2014;129(25 Suppl 2):S1–45. The most recent AHA/ACC guidelines suggest statins for all diabetics who are 40 years old or greater. These recommendations have also been echoed by the most recent guidelines of the American Diabetes Association.CrossRefPubMedGoogle Scholar
  70. 70.
    European Association for Cardiovascular P, Rehabilitation, Reiner Z, Catapano AL, De Backer G, Graham I, 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). Eur Heart J. 2011;32(14):1769–818.CrossRefGoogle Scholar
  71. 71.
    Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109–22.CrossRefPubMedGoogle Scholar
  72. 72.
    Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089–99.CrossRefPubMedGoogle Scholar
  73. 73.
    Nicholls SJ, Kastelein JJ, Schwartz GG, Bash D, Rosenson RS, Cavender MA, et al. Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial. JAMA. 2014;311(3):252–62.CrossRefPubMedGoogle Scholar
  74. 74.
    Seidah NG. Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors in the treatment of hypercholesterolemia and other pathologies. Curr Pharm Des. 2013;19(17):3161–72.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Haider J. Warraich
    • 1
  • Nathan D. Wong
    • 2
  • Jamal S. Rana
    • 3
    • 4
    Email author
  1. 1.Department of Medicine, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA
  2. 2.Division of Cardiology, Department of MedicineUniversity of California IrvineIrvineUSA
  3. 3.Division of CardiologyKaiser Permanente Medical CenterOaklandUSA
  4. 4.Department of MedicineUniversity of California San FranciscoSan FranciscoUSA

Personalised recommendations