Diabetes and Dislipidemia

  • Henry N. GinsbergEmail author
  • Maryam Khavandi
  • Gissette Reyes-Soffer
Reference work entry
Part of the Endocrinology book series (ENDOCR)


Diabetes mellitus is associated with significant increases in ASCVD. In T1DM, increased ASCVD is linked to hyperglycemia, renal disease, and hypertension, with dyslipidemia contributing when present. In T2DM, although the aforementioned complications of diabetes may each contribute to increased ASCVD, the dyslipidemia plays a more important role. Optimal glycemic control with diabetes medications can normalize plasma lipid levels in most individuals with T1DM. Insulin resistance is central to the pathophysiology of dyslipidemia in T2DM, with obesity and independently inherited detrimental lipid genes exacerbating the phenotype. Aggressive LDL lowering is key in individuals with T2DM because of their very high risk for ASCVD. High doses of potent statins are the first line of therapy followed by ezetimibe, which will be required to achieve LDL cholesterol levels well below 100 mg/dl. Therapy with lifestyle, and if needed, TG-lowering agents such as fibrates and omega-3 fatty acid concentrates can be used to treat hypertriglyceridemia, with the understanding that these agents have not consistently reduced ASCVD events. When individuals with T2DM also have very high levels of LDL


Diabetes mellitus Dyslipidemia Hypertriglyceridemia Hypercholesterolemia Very-low-density lipoproteins Chylomicrons Low-density lipoproteins High-density lipoproteins Apolipoprotein B Apolipoprotein A-I 


  1. Adeli K, Lewis GF. Intestinal lipoprotein overproduction in insulin-resistant states. Curr Opin Lipidol. 2008;19:221–8.CrossRefGoogle Scholar
  2. Adiels M, Boren J, Caslake MJ, Stewart P, Soro A, Westerbacka J, Wennberg B, Olofsson SO, Packard C, Taskinen MR. Overproduction of VDLD1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia. Arterioscler Thromb Vasc Biol. 2005;25:1697–703.CrossRefGoogle Scholar
  3. Adiels M, Olofsson SO, Taskinen MR, Boren J. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndroms. Artheroscler Thromb Vasc Biol. 2008;28:1225–36.CrossRefGoogle Scholar
  4. American Diabetes Association. Cardiovascular disease and risk management: standards of medical care in diabetes. Diabetes Care. 2018;41(Suppl 1):S86–S104.CrossRefGoogle Scholar
  5. American Heart Association. Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease: a science advisory from the American Heart Association. Circulation. 2017;135(15):e867–84.Google Scholar
  6. Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation. 1990;82(2):495–506.CrossRefGoogle Scholar
  7. Bezafibrate Infarction Prevention (BIP) Study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000;102:21–7.CrossRefGoogle Scholar
  8. Bishop JR, Stanford KI, Esko JD. Heparan sulfate proteoglycans and triglyceride-rich lipoprotein metabolism. Curr Opin Lipidol. 2008;19:307–13.CrossRefGoogle Scholar
  9. Boden WE, Probstfield JL, Anderson T, Chaitman BR, svignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.CrossRefGoogle Scholar
  10. Brinton EA, Eiseberg S, Breslow JL. Human HDL cholesterol levels are determined by apoA-I fractional catabolic rate, which correlates inverely with estimate of HDL particle size. Arterioscler Thromb. 1994;14:707–20.CrossRefGoogle Scholar
  11. Brunham LR, Kruit JK, Iqbal J, Fievet C, Timmins JM, Pape TD, Coburn BA, Bissada N, Staels B, Groen AK, Hussain MM, Parks JS, Kuipers F, Hayden MR. Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. J Clin Invest. 2006;116:1052–62.CrossRefGoogle Scholar
  12. Brunzell JD, Hazzard WR, Porte D Jr, Bierman EL. Evidence for a common, saturable, triglyceride removal mechanism for chylomicrons and very low density lipoproteins in man. J Clin Invest. 1973;52:1578–85.CrossRefGoogle Scholar
  13. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–97.CrossRefGoogle Scholar
  14. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264–72.CrossRefGoogle Scholar
  15. Cohn JS, Patterson BW, Uffelman KD, Davignon J, Steiner G. Rate of production of plasma and very-low-density lipoprotein (VLDL) apolipoprotein C-III is strongly related to the concentration and level of production of VLDL triglyceride in male subjects with different body weights and levels of insulin sensitivity. J Clin Endocrinol Metab. 2004;89(8):3949–55.CrossRefGoogle Scholar
  16. Cooper AD. Hepatic uptake of chylomicron remnants. J Lipid Res. 1997;38:2173–92. ReviewPubMedGoogle Scholar
  17. Dash S, Xiao C, Morgantini C, Lewis GF. New insights into the regulation of chylomicron production. Annu Rev Nutr. 2015;35:265–94.CrossRefGoogle Scholar
  18. Deeb SS, Zambon A, Carr MC. Hepatic lipase and dyslipidemia: interactions among genetic variants, obesity, gender, and diet. J Lipid Res. 2003;44:1279–86.CrossRefGoogle Scholar
  19. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–51.CrossRefGoogle Scholar
  20. Drozda JP Jr, Ferguson TB Jr, Jneid H, Krumholz HM, Nallamothu BK, Olin JW, Ting HH. ACC/AHA focused update of secondary prevention lipid performance measures: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures. J Am Coll Cardiol. 2015;67:558–87.CrossRefGoogle Scholar
  21. Dunn FL. Hyperlipidemia in diabetes mellitus. Diabetes Metab Rev. 1990;6:47–61.CrossRefGoogle Scholar
  22. Elam MB, Ginsberg HN, Lovato LC, Corson M, Largay J, Leiter LA, Lopez C, O’Connor PJ, Sweeney ME, Weiss D, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm R, Ismail-Beigi F, Goff DC Jr, Fleg JL, Rosenberg Y, Byington RP, ACCORDION Study Investigators. Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes. JAMA Cardiol. 2017;2:370–80.CrossRefGoogle Scholar
  23. ESC/EAS. Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016:39:2999–30581.Google Scholar
  24. Frick MH, Elo MO, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237–45.CrossRefGoogle Scholar
  25. Geiss LS, Wang J, Cheng YJ, Thompson TJ, Barker L, Li Y, Albright AL, Gregg EW. Prevalence and incidence trends for diagnosed diabetes among adults aged 20 to 79 years, United States, 1980–2012. JAMA. 2014;312:1218–26.CrossRefGoogle Scholar
  26. Ginsberg HN. Lipoprotein physiology in nondiabetic and diabetic states. Relationship to atherogenesis. Diabetes Care. 1991;14:839–55. ReviewCrossRefGoogle Scholar
  27. Ginsberg HN. Lipoprotein Physiology. In: Hoeg J, editor. Endocrinology and metabolism clinics of North America. Philadelphia: W.B. Saunders Co.; 1998.Google Scholar
  28. Ginsberg HN. Efficacy and mechanism of action of statins in the treatment of diabetic dyslipidemia. J Clin Endocrinol Metab. 2006;91:383–92.CrossRefGoogle Scholar
  29. Ginsberg HN, Fisher EA. The ever-expanding role of degradation in the regulation of apolipoprotein B metabolism. J Lipid Res. 2009;50:S162–6.CrossRefGoogle Scholar
  30. Ginsberg HN, Elam MB, Lovato LC, Crouse JR III, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–74.CrossRefGoogle Scholar
  31. GM D-T, 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;211:1–8.CrossRefGoogle Scholar
  32. Gordon SM, Deng J, Lu LJ, Davidson WS. Proteomic characterization of human plasma high density lipoprotein fractionated by gel filtration chromatography. J Proteome Res. 2010;9:5239–49.CrossRefGoogle Scholar
  33. Grefhorst A, Elzinga BM, Voshol PJ, Plösch T, Kok T, Bloks VW, van der Sluijs FH, Havekes LM, Romijn JA, Verkade HJ, Kuipers F. Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. J Biol Chem. 2002;277(37):34182–90.CrossRefGoogle Scholar
  34. Haffner SM. Management of dyslipidemia in adults with diabetes (technical review). Diabetes Care. 1998;21:160–78.CrossRefGoogle Scholar
  35. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarctions. N Engl J Med. 1998;339:229–34.CrossRefGoogle Scholar
  36. Hansen M, Sonne DP, Mikkelsen KH, Gluud LL, Vilsbøll T, Knop FK. Bile acid sequestrants for glycemic control in patients with type 2 diabetes: a systematic review with meta-analysis of randomized controlled trials. J Diabetes Complications. 2017;31:918–27.CrossRefGoogle Scholar
  37. Horowitz BS, Goldberg IJ, Merab J, Vanni T, Ramakrishnan R, Ginsberg HN. Increased plasma and renal clearance of an exchangeable pool of apolipoprotein A-I in subjects with low levels of high density lipoprotein cholesterol. J Clin Invest. 1993;91:1743–176.CrossRefGoogle Scholar
  38. Horton JD, Shimano H, Hamilton RL, Brown MS, Goldstein JL. Disruption of LDL receptor gene in transgenic SREBP-1a mice unmasks hyperlipidemia resulting from production of lipid-rich VLDL. J Clin Invest. 1999;103:1067–76.CrossRefGoogle Scholar
  39. Kannel WB, D’Agostino RB, Wilson PWF, Bleanger AJ, Gagnon DR. Diabetes, fibrinogen, and risk of cardiovascular disease: the Framingham experience. Am Heart J. 1990;120:672–6.CrossRefGoogle Scholar
  40. 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.CrossRefGoogle Scholar
  41. Keech A, Simes RJ, Barter P. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–61.CrossRefGoogle Scholar
  42. Kissebah AH, Alfarsi S, Evans DJ, Adams PW. Integrated regulation of very low density lipoprotein triglyceride and apolipoprotein-B kinetics in non-insulin-dependent diabetes mellitus. Diabetes. 1982;31:217–25.CrossRefGoogle Scholar
  43. Kobayashi J, Miyashita K, Nakajima K, Mabuchi H. Hepatic lipase: a comprehensive view of its role on plasma lipid and lipoprotein metabolism. J Atheroscler Thromb. 2015;22:1001–11.CrossRefGoogle Scholar
  44. Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, Wallendszus K, Craig M, Jiang L, Collins R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203–12.CrossRefGoogle Scholar
  45. Lewis GF, Uffelman KD, Szeto LW, Weller B, Steiner G. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. J Clin Invest. 1995;95:158–66.CrossRefGoogle Scholar
  46. Liu J, Hernandez-Ono A, Graham MJ, Galton VA, Ginsberg HN. Type 1 deiodinase regulates ApoA-I gene expression and ApoA-I synthesis independent of thyroid hormone signaling. Arterioscler Thromb Vasc Biol. 2016;36:1356–66.CrossRefGoogle Scholar
  47. Low Wang CC, Hess CN, Hiatt WR, Goldfine AB. Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus – mechanisms, management, and clinical considerations. Circulation. 2016;133:2459–502.CrossRefGoogle Scholar
  48. Ma W, Wu JH, Wang Q, Lemaitre RN, Mukamal KJ, Djoussé L, King IB, Song X, Biggs ML, Delaney JA, et al. Prospective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the Cardiovascular Health Study. Am J Clin Nutr. 2015;101:153–63.CrossRefGoogle Scholar
  49. Silverman MG, Ference BA, Im K, Wiviott SD, Giugliano RP, Grundy SM, Braunwald E, Sabatine MS. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA. 2016;316(12):1289–97. Scholar
  50. Moon BC, Hernandez-Ono A, Stiles B, Wu H, Ginsberg HN. Very low density lipoprotein apolipoprotein B secretion is regulated by hepatic triglyceride, and not insulin, in the liver-specific PTEN knockout mouse, a model of increased hepatic insulin signaling. Arterioscler Thromb Vasc Biol. 2012;32:236–46.CrossRefGoogle Scholar
  51. Nagashima K, Lopez C, Donovan D, Ngai C, Fontanez N, Bensadoun A, Fruchart-Najib J, Holleran S, Cohn JS, Ramakrishnan R, et al. Effects of the PPAR agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus. J Clin Invest. 2005;115:1323–32.CrossRefGoogle Scholar
  52. National Cholesterol Education Program. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143–421.CrossRefGoogle Scholar
  53. Olivecrona G. Role of lipoprotein lipase in lipid metabolism. Curr Opin Lipidol. 2016;27:233–41.CrossRefGoogle Scholar
  54. Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, Hall T, Troquay RP, Turner T, Visseren FL, Wijngaard P, Wright RS, Kastelein JJ. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2017;376:1430–40.CrossRefGoogle Scholar
  55. Riemens S, van Tol A, Sluiter W, Dullaart R. Elevated plasma cholesteryl ester transfer in NIDDM: relationships with apolipoprotein B-containing lipoproteins and phospholipid transfer protein. Atherosclerosis. 1998;140:71–9.CrossRefGoogle Scholar
  56. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El SM, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–99.CrossRefGoogle Scholar
  57. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesteroal Intervention Trial Study Group. N Engl J Med. 1999;341:410–8.CrossRefGoogle Scholar
  58. Ryden L, Standl E, Bartnik M, The Task Force on Diabetes and Cardiovascular Diseases of the European Socity of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD), et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. Eur Heart J. 2007;28:88–136.CrossRefGoogle Scholar
  59. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500–9.CrossRefGoogle Scholar
  60. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR, FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017a;376:1713–22.CrossRefGoogle Scholar
  61. Sabatine MS, Leiter LA, Wiviott SD, Giugliano RP, Deedwania P, De Ferrari GM, Murphy SA, Kuder JF, Gouni-Berthold I, Lewis BS, Handelsman Y, Pineda AL, Honarpour N, Keech AC, Sever PS, Pedersen TR. 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. 2017b;5:941–50.CrossRefGoogle Scholar
  62. Schwartz GG, Bessac L, Berdan LG, Bhatt DL, Bittner V, Diaz R, Goodman SG, Hanotin C, Harrington RA, Jukema JW, Mahaffey KW, Moryusef A, Pordy R, Roe MT, Rorick T, Sasiela WJ, Shirodaria C, Szarek M, Tamby JF, Tricoci P, White H, Zeiher A, Steg PG. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J. 2014;168(5):682–9.CrossRefGoogle Scholar
  63. Scott R, O’Brien R, Fulcher G, Pardy C, D’Emden M, Tse D, Taskinen MR, Ehnholm C, Keech A. Effects of fenofibrate treatment of 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 study. Diabetes Care. 2009;32:493–8.CrossRefGoogle Scholar
  64. Seidah NG. The proprotein convertases, 20 years later. Methods Mol Biol. 2011;768:23–57.CrossRefGoogle Scholar
  65. Shen WJ, Azhar S, Kraemer FB. SR-B1: a unique multifunctional receptor for cholesterol influx and efflux. Annu Rev Physiol. 2017. Scholar
  66. Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Lloyd-Jones DM, Blum CB, McBride P, Eckel RH, Schwartz JS, Goldberg AC, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889–934.CrossRefGoogle Scholar
  67. Tall AR, Rader DJ. Trials and tribulations of CETP inhibitors. Circ Res. 2018;122:106–12.CrossRefGoogle Scholar
  68. Taskinen M-R. Hyperlipidaemia in diabetes. In: Betteridge DJ, editor. Bailliere’s Clinical endocrinology and metabolism, vol. 4. London: Bailliere, Tindall; 1990. p. 743–75.Google Scholar
  69. Timmins JM, Lee JY, Boudyguina E, Kluckman KD, Brunham LR, Mulya A, Gebre AK, Coutinho JM, Colvin PL, Smith TL, Hayden MR, Maeda N, Parks JS. Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I. J Clin Invest. 2005;115:1333–42.CrossRefGoogle Scholar
  70. Trigatti B, Rigotti A, Krieger M. The role of the high-density lipoprotein receptor SR-BI in cholesterol metabolism. Curr Opin Lipidol. 2000;11:123–31.CrossRefGoogle Scholar
  71. Zhang Y-L, Hernandez-Ono A, Ko C, Yasunaga K, Huang L-S, Ginsberg HN. Regulation of hepatic apolipoprotein B-lipoprotein assembly and secretion by the availability of fatty acids 1: differential effects of delivering fatty acids via albumin or remnant-like emulsion particles. J Biol Chem. 2004;279:19362–74.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Henry N. Ginsberg
    • 1
    Email author
  • Maryam Khavandi
    • 2
  • Gissette Reyes-Soffer
    • 3
  1. 1.Department of MedicineIrving Institute for Clinical and Translational Research, Columbia University Vagelos College of Physicians and SurgeonsNew YorkUSA
  2. 2.Department of MedicineBassett Medical CenterNew YorkUSA
  3. 3.Department of MedicineColumbia University Vagelos College of Physicians and SurgeonsNew YorkUSA

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