Current Cardiology Reports

, 20:125 | Cite as

Diabetic Dyslipidemia: Epidemiology and Prevention of Cardiovascular Disease and Implications of Newer Therapies

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


Purpose of Review

Dyslipidemia in patients with T2DM confers significant additional risk of adverse outcomes to patients with cardiovascular disease (CVD). These patients carry residual risk of adverse outcomes despite optimal management with conventional therapy such as lifestyle changes and statin therapy. The role of both nonstatin monotherapy in statin-intolerant patients and combination therapy with statins in patients with high risk of CVD events has been well studied. We sought to review the role of newer therapies in risk reduction in these patients.

Recent Findings

Traditionally, non-statin options have included medications such as niacin, ezetimibe, fenofibrate, and n-3 fatty acids. Recently, drugs such as ezetimibe, inclisiran, and PCSK9 inhibitors have been studied with favorable results without an increased risk of developing new-onset diabetes. These medications hold the promise of increasing options to reduce cardiovascular risk in patients with T2DM.


The role of newer non-statin therapies in patients with diabetic dyslipidemia in combination with statins needs to be further explored.


Type 2 diabetes mellitus Dyslipidemia Statins Fibrates Ezetimibe Fish oil PCSK9 inhibitors Alirocumab Evolocumab Inclisiran 


Compliance with Ethical Standards

Conflict of Interest

Haider J. Warraich and Jamal S. Rana declare that they have no conflict of interest.

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.


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.CrossRefGoogle Scholar
  2. 2.
    Fox CS, Pencina MJ, Wilson PW, Paynter NP, Vasan RS, D'Agostino RB Sr. 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.CrossRefGoogle Scholar
  3. 3.
    Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241(19):2035–8.CrossRefGoogle Scholar
  4. 4.
    Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the global burden of disease study 2015. Lancet. 2016;388(10053):1545–602.CrossRefGoogle Scholar
  5. 5.
    Mortality GBD, Causes of Death C. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the global burden of disease study 2015. Lancet. 2016;388(10053):1459–544.CrossRefGoogle Scholar
  6. 6.
    Rawshani A, Rawshani A, Franzen S, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med. 2017;376(15):1407–18.CrossRefGoogle Scholar
  7. 7.
    Wu L, Parhofer KG. Diabetic dyslipidemia. Metab Clin Exp. 2014;63(12):1469–79.CrossRefGoogle Scholar
  8. 8.
    Wong ND, Chuang J, Zhao Y, Rosenblit PD. Residual dyslipidemia according to low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B among statin-treated US adults: National Health and nutrition examination survey 2009-2010. J Clin Lipidol. 2015;9(4):525–32.CrossRefGoogle Scholar
  9. 9.
    Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2960–84.CrossRefGoogle Scholar
  10. 10.
    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.CrossRefGoogle Scholar
  11. 11.
    Sigal RJ, Kenny GP, Boule NG, 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.CrossRefGoogle Scholar
  12. 12.
    Look ARG, Wing RR, Bolin P, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(2):145–54.CrossRefGoogle Scholar
  13. 13.
    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.CrossRefGoogle Scholar
  14. 14.
    Ruano G, Seip RL, Windemuth A, et al. Apolipoprotein A1 genotype affects the change in high density lipoprotein cholesterol subfractions with exercise training. Atherosclerosis. 2006;185(1):65–9.CrossRefGoogle Scholar
  15. 15.
    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.CrossRefGoogle Scholar
  16. 16.
    Salami JA, Warraich H, Valero-Elizondo J, Spatz ES, Desai NR, Rana JS, et al. National Trends in statin use and expenditures in the US adult population from 2002 to 2013: insights from the medical expenditure panel survey. JAMA Cardiol. 2017;2(1):56–65.CrossRefGoogle Scholar
  17. 17.
    Cholesterol Treatment Trialists C, Kearney PM, Blackwell L, 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
  18. 18.
    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.CrossRefGoogle Scholar
  19. 19.
    Rana JS, Liu JY, Moffet HH, Boklage SH, Khan I, Karter AJ. Risk of incident atherosclerotic cardiovascular disease events by achieved Atherogenic lipid levels among 62,428 statin-treated individuals with diabetes mellitus. Am J Cardiol. 2018;122:762–7.CrossRefGoogle Scholar
  20. 20.
    Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735–42.CrossRefGoogle Scholar
  21. 21.
    Salami JA, Warraich HJ, Valero-Elizondo J, et al. National Trends in Nonstatin Use and Expenditures Among the US Adult Population From 2002 to 2013: Insights from medical expenditure panel survey. J Am Heart Assoc. 2018;7(2).Google Scholar
  22. 22.
    Warraich HJ, Wong ND, Rana JS. Role for combination therapy in diabetic dyslipidemia. Curr Cardiol Rep. 2015;17(5):32.CrossRefGoogle Scholar
  23. 23.
    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.CrossRefGoogle Scholar
  24. 24.
    Group AS, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563–74.CrossRefGoogle Scholar
  25. 25.
    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.CrossRefGoogle Scholar
  26. 26.
    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.CrossRefGoogle Scholar
  27. 27.
    Aung T, Halsey J, Kromhout D, Gerstein HC, Marchioli R, Tavazzi L, et al. Associations of Omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol. 2018;3(3):225–34.CrossRefGoogle Scholar
  28. 28.
    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.CrossRefGoogle Scholar
  29. 29.
    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.CrossRefGoogle Scholar
  30. 30.
    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.CrossRefGoogle Scholar
  31. 31.
    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.CrossRefGoogle Scholar
  32. 32.
    Lee JM, Robson MD, Yu LM, 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.CrossRefGoogle Scholar
  33. 33.
    Investigators A-H, Boden WE, Probstfield JL, 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
  34. 34.
    Group HTC, Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203–12.CrossRefGoogle Scholar
  35. 35.
    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.CrossRefGoogle Scholar
  36. 36.
    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.CrossRefGoogle Scholar
  37. 37.
    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.CrossRefGoogle Scholar
  38. 38.
    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.CrossRefGoogle Scholar
  39. 39.
    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.CrossRefGoogle Scholar
  40. 40.
    •• Giugliano RP, Cannon CP, Blazing MA, et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (improved reduction of outcomes: Vytorin efficacy international trial). Circulation. 2018;137(15):1571–82 This prespecified secondary analysis of IMPROVE-IT showed that the benefit of ezetimibe was almost exclusively experienced by patients with diabetes.CrossRefGoogle Scholar
  41. 41.
    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.Google Scholar
  42. 42.
    Writing C, Lloyd-Jones DM, Morris PB, et al. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: a report of the American College of Cardiology Task Force on clinical expert consensus documents. J Am Coll Cardiol. 2016;68(1):92–125.CrossRefGoogle Scholar
  43. 43.
    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.CrossRefGoogle Scholar
  44. 44.
    Sattar N, Preiss D, Robinson JG, Djedjos CS, Elliott M, Somaratne R, et al. Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data. Lancet Diabetes Endocrinol. 2016;4(5):403–10.CrossRefGoogle Scholar
  45. 45.
    •• Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5(12):941–50 This prespecified substudy of FOURIER showed that evolocumab was safe and equally efficacious in diabetics and non-diabetics.CrossRefGoogle Scholar
  46. 46.
    Ginsberg HN, Farnier M, Robinson JG, Cannon CP, Sattar N, Baccara-Dinet MT, et al. Efficacy and safety of Alirocumab in individuals with diabetes mellitus: pooled analyses from five placebo-controlled phase 3 studies. Diabetes Ther. 2018;9(3):1317–34.CrossRefGoogle Scholar
  47. 47.
    Leiter LA, Cariou B, Muller-Wieland D, et al. Efficacy and safety of alirocumab in insulin-treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: the ODYSSEY DM-INSULIN randomized trial. Diabetes Obes Metab. 2017;19(12):1781–92.CrossRefGoogle Scholar
  48. 48.
    Ray KK, Leiter LA, Muller-Wieland D, et al. Alirocumab vs usual lipid-lowering care as add-on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia: the ODYSSEY DM-DYSLIPIDEMIA randomized trial. Diabetes Obes Metab. 2018;20(6):1479–89.CrossRefGoogle Scholar
  49. 49.
    Schwartz GG, Szarek M, Bhatt DL, Bittner V, Diaz R, Edelberg J, Goodman GG, Hanotin C, Harrington R, Jukema JW, Lecorps G, Moryusef A, Pordy R, Roe MT, White HD, Zeiher A, Steg G. Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab - ODYSSEY OUTCOMES. American College of Cardiology - 67th Scientific Sessions; 2018; Orlando.Google Scholar
  50. 50.
    Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2017;376(15):1430–40.CrossRefGoogle Scholar
  51. 51.
    Leiter L, Teoh H, Kallend D, Wright RS, Landmesser U, Wijngaard PL, Kastelein JJ, Ray KK. Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status without Worsening Glycemia. Diabetes. 2018; 67(Supplement 1). American Diabetes Association 2018.CrossRefGoogle Scholar
  52. 52.
    Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD Jr, DePalma S, et al. 2017 focused update of the 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: a report of the American College of Cardiology Task Force on expert consensus decision pathways. J Am Coll Cardiol. 2017;70(14):1785–822.CrossRefGoogle Scholar
  53. 53.
    American Diabetes A. 9. Cardiovascular disease and risk management: standards of medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S86–S104.CrossRefGoogle Scholar
  54. 54.
    Landmesser U, Chapman MJ, Farnier M, Gencer B, Gielen S, Hovingh GK, et al. European Society of Cardiology/European atherosclerosis society task force consensus statement on proprotein convertase subtilisin/kexin type 9 inhibitors: practical guidance for use in patients at very high cardiovascular risk. Eur Heart J. 2017;38(29):2245–55.PubMedGoogle Scholar
  55. 55.
    Rosenson RS, Hegele RA, Fazio S, Cannon CP. The evolving future of PCSK9 inhibitors. J Am Coll Cardiol. 2018;72(3):314–29.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Medicine, Division of CardiologyDuke University Medical CenterDurhamUSA
  2. 2.Division of Cardiology, Kaiser Permanente Medical CenterOaklandUSA
  3. 3.Department of MedicineUniversity of California San FranciscoSan FranciscoUSA

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