Dyslipidemia is one of the key risk factors for cardiovascular disease (CVD) in diabetes mellitus. Despite the mounting clinical trial data, the management of dyslipidemia other than lowering the low density lipoprotein cholesterol (LDL-c) continues to be controversial. The characteristic features of diabetic dyslipidemia are high plasma triglyceride concentration, reduced high density lipoprotein cholesterol (HDL-c) concentration, and increased concentration of small dense LDL particles. These changes are caused by increased free fatty acid flux secondary to insulin resistance and aggravated by increased inflammatory adipokines. The availability of several lipid-lowering drugs and nutritional supplements offers novel and effective options for achieving target lipid levels in people with diabetes. While initiation of drug therapy based on differences in the lipid profile is an option, most practice guidelines recommend statins as first-line therapy. Although the evidence for clinical utility of combination of statins with fibrates or nicotinic acid in reducing cardiovascular events remains inconclusive, the preponderance of evidence suggests that a subgroup who have high triglycerides and low HDL-c levels may benefit from combination therapy of statins and fibrates. The goal of therapy is to achieve at least 30–40 % reduction in LDL-c levels. Preferably the LDL-c should be less than 100 mg/dL in low-risk people and less than 70 mg/dL in those at high risk, including people with established CVD.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
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;164:1422–6.
Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2009;5:150–9.
Mooradian AD. Cardiovascular disease in type 2 diabetes mellitus: current management guidelines. Arch Intern Med. 2003;163:33–40.
Kannel WB. Lipids, diabetes, and coronary heart disease: insights from the Framingham Study. Am Heart J. 1985;110:1100–7.
Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior history of myocardial infarction. N Engl J Med. 1998;339:229–34.
Hachem SB, Mooradian AD. Familial dyslipidaemias: an overview of genetics, pathophysiology and management. Drugs. 2006;66:1949–69.
Chahil TJ, Ginsberg HN. Diabetic dyslipidemia. Endocrinol Metab Clin North Am. 2006;35:491–510.
Jacobs MJ, Kleisli T, Pio JR, Malik S, L’Italien GJ, Chen RS, Wong ND. Prevalence and control of dyslipidemia among persons with diabetes in the United States. Diabetes Res Clin Pract. 2005;70:263–9.
U.K. Prospective Diabetes Study 27. Plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes Care. 1997;20:1683–87.
Malave H, Castro M, Burkle J, Voros S, Dayspring T, Honigberg R, Pourfarzib R. Evaluation of Low-density lipoprotein particle number distribution in patients with type 2 diabetes mellitus with low-density lipoprotein cholesterol <50 mg/dl and non-high-density lipoprotein cholesterol <80 mg/dl. Am J Cardiol. 2012;110:662–5.
Parish S, Offer A, Clarke R, Hopewell JC, Hill MR, Otvos JD, Armitage J, Collins RR, Heart Protection Study Collaborative Group. Lipids and lipoproteins and risk of different vascular events in the MRC/BHF heart protection study. Circulation. 2012;125:2469–78.
Johnson JL, Slentz CA, Duscha BD, Samsa GP, McCartney JS, Houmard JA, Kraus WE. Gender and racial differences in lipoprotein subclass distributions: the STRRIDE study. Atherosclerosis. 2004;176:371–7.
Mooradian AD, Haas MJ, Wehmeier KR, Wong NC. Obesity-related changes in high density lipoprotein metabolism. Obesity. 2008;16:1152–60.
Mooradian AD, Haas MJ, Wong NC. Transcriptional control of apolipoprotein A-I gene expression in diabetes mellitus. Diabetes. 2004;53:513–20.
Mooradian AD, Albert SG, Haas MJ. Low serum high-density lipoprotein cholesterol in obese subjects with normal serum triglycerides: the role of insulin resistance and inflammatory cytokines. Diabetes Obes Metab. 2007;9:441–3.
Haas MJ, Mooradian AD. Regulation of high-density lipoprotein by inflammatory cytokines: establishing links between immune dysfunction and cardiovascular disease. Diabetes Metab Res Rev. 2010;26:90–9.
Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomized trials of statins: a meta-analysis. Lancet. 2008;371:117–25.
Frick MH, Elo O, 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.
Rubins HB, Robins SJ, Collins D, 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 Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410–8.
Otvos JD, Collins D, Freedman DS, Shalaurova I, Schaefer EJ, McNamara JR, Bloomfield HE, Robins SJ. Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation. 2006;113:1556–63.
Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomized controlled trial. Lancet. 2005;366:1849–61.
Scott R, O’Brien R, Fulcher G, 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;32:493–8.
ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC, Simons-Morton DG, Byington RP. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–74.
Chehade JM, Mooradian AD. A rational approach to drug therapy of type 2 diabetes mellitus. Drugs. 2000;60:95–113.
Bell DS, O’Keefe JH, Jellinger P. Postprandial dysmetabolism: the missing link between diabetes and cardiovascular events? Endocr Pract. 2008;14:112–24.
Monnier L, Mas E, Ginet C, et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006;295:1681–7.
Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281:2005–12.
Hollenbeck CB, Chen YD, Greenfield MS, Lardinois CK, Reaven GM. Reduced plasma high density lipoprotein-cholesterol concentrations need not increase when hyperglycemia is controlled with insulin in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1986;62:605–8.
Bantle JP, Wylie-Rosett J, Albright AL, et al. Nutrition recommendations and interventions for diabetes: a position statement of the American Diabetes Association. Diabetes Care. 2008;31(Suppl 1):S61–78.
Grundy SM. Approach to lipoprotein management in 2001 National Cholesterol Guidelines. Am J Cardiol. 2002;90:11i–21i.
American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36(Suppl 1):S11–66.
Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr. 2003;77:1146–55.
Meksawan K, Pendergast DR, Leddy JJ, Mason M, Horvath PJ, Awad AB. Effect of low and high fat diets on nutrient intakes and selected cardiovascular risk factors in sedentary men and women. J Am Coll Nutr. 2004;23:131–40.
Mooradian AD, Haas MJ, Wong NC. The effect of select nutrients on serum high-density lipoprotein cholesterol and apolipoprotein A-I levels. Endocr Rev. 2006;27:2–16.
Lichtenstein AH. Thematic review series: patient oriented research. Dietary fat, carbohydrate, and protein: effects on plasma lipoprotein patterns. J Lipid Res. 2006;47:1661–7.
Nordmann AJ, Suter-Zimmermann K, Bucher HC, Shai I, Tuttle KR, Estruch R, Briel M. Meta-analysis comparing Mediterranean to low-fat diets for modification of cardiovascular risk factors. Am J Med. 2011;124:841–51.
Mooradian AD. Obesity: a rational target for managing diabetes mellitus. Growth Horm IGF Res. 2011;11(Suppl A):S79–83.
Giannopoulou I, Ploutz-Snyder LL, Carhart R, Weinstock RS, Fernhall B, Goulopoulou S, Kanaley JA. Exercise is required for visceral fat loss in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab. 2005;90:1511–8.
Sigal RJ, Kenny GP, Boulé 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;147:357–69.
Williams PT. The relationships of vigorous exercise, alcohol, and adiposity to low and high high-density lipoprotein-cholesterol levels. Metabolism. 2004;53:700–9.
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. Metabolism. 2002;51:774–8.
Halverstadt A, Phares DA, Ferrell RE, Wilund KR, Goldberg AP, Hagberg JM. High-density lipoproteincholesterol, its subfractions, and responses to exercise training are dependent on endothelial lipase genotype. Metabolism. 2003;52:1505–11.
Alam S, Stolinski M, Pentecost C, Boroujerdi MA, Jones RH, Sonksen PH, Umpleby AM. The effect of a six-month exercise program on very low-density lipoprotein apolipoprotein B secretion in type 2 diabetes. J Clin Endocrinol Metab. 2004;89:688–94.
Garanty-Bogacka B, Syrenicz M, Goral J, Krupa B, Syrenicz J, Walczak M, Syrenicz A. Changes in inflammatory biomarkers after successful lifestyle intervention in obese children. Endokrynol Pol. 2011;62:499–505.
Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–8.
Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ, JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207.
Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, Witztum JL, American Diabetes Association, American College of Cardiology Foundation. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008;31:811–22.
Jellinger PS, Smith DA, Mehta AE, et al. American Association of Clinical Endocrinologists’ guidelines for management of dyslipidemia and prevention of atherosclerosis. Endocr Pract. 2012;18(Suppl 1):1–78.
Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004;44:720–32.
Contois JH, McConnell JP, Sethi AA, Csako G, Devaraj S, Hoefner DM, Warnick GR, AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices. Apolipoprotein B and cardiovascular disease risk: position statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices. Clin Chem. 2009;55:407–19.
Cannon CP, Braunwald E, Mccabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–504.
de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, Rouleau JL, Pedersen TR, Gardner LH, Mukherjee R, Ramsey KE, Palmisano J, Bilheimer DW, Pfeffer MA, Califf RM, Braunwald E. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004;292:1307–16.
Larosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK, TNT Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–35.
Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437–45.
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;376:1658–69.
Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735–42.
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;32:1924–9.
Bays HE, Neff D, Tomassini JE, Tershakovec AM. Ezetimibe: cholesterol lowering and beyond. Expert Rev Cardiovasc Ther. 2008;6:447–70.
Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358:1431–43.
Fleg JL, Mete M, Howard BV, 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;52:2198–205.
Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009;361:2113–22.
Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359:1343–56.
Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377:2181–92.
Villines TC, Stanek EJ, Devine PJ, et al. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol. 2010;55:2721–6.
Morrone D, Weintraub WS, Toth PP, et al. Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis. 2012;223:251–61.
Davidson MH, Dillon MA, Gordon B, et al. Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects. Arch Intern Med. 1999;159:1893–900.
Zieve FJ, Kalin MF, Schwartz SL, Jones MR, Bailey WL. Results of the Glucose-Lowering effect of Welchol Study (GLOWS): a randomized, double-blind, placebo-controlled pilot study evaluating the effect of colesevelam hydrochloride on glycemic control in subjects with type 2 diabetes. Clin Ther. 2007;29:74–83.
Bays HE, Goldberg RB, Truitt KE, Jones MR. Colesevelam hydrochloride therapy in patients with type 2 diabetes mellitus treated with metformin: glucose and lipid effects. Arch Intern Med. 2008;168:1975–83.
Fonseca VA, Rosenstock J, Wang AC, Truitt KE, Jones MR. Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care. 2008;31:1479–84.
Goldberg RB, Fonseca VA, Truitt KE, Jones MR. Efficacy and safety of colesevelam in patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-based therapy. Arch Intern Med. 2008;168:1531–40.
Bays HE, Ballantyne C. What is the deal with niacin development: is laropiprant add-on therapy a winning strategy to beat a straight flush? Curr Opin Lipidol. 2009;20:467–76.
European Medicines Agency (2013). Tredaptive, Pelzont and Trevaclyn. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Tredaptive,_Pelzont_and_Trevaclyn/human_referral_prac_000014.jsp&mid=WC0b01ac05805c516f. Accessed 18 Jan 2013.
Medscape Today. Niacin/laropiprant products to be suspended worldwide [media release]. 11 Jan 2013. http://www.medscape.com/viewarticle/777519. Accessed 19 Feb 2013.
Grundy SM, Vega GL, McGovern ME, et al. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial. Arch Inter Med. 2002;162:1568–76.
Elam MB, Hunninghake DB, Davis KB, et al. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: a randomized trial. Arterial Disease Multiple Intervention Trial. JAMA. 2000;284:1263–70.
Canner PL, Furberg CD, Terrin ML, McGovern ME. Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol. 2005;95:254–7.
AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-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.
Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis. 2006;189:19–30.
Bays HE, Maki KC, McKenney J, et al. Long-term up to 24-month efficacy and safety of concomitant prescription omega-3-acid ethyl esters and simvastatin in hyper-triglyceridemic patients. Curr Med Res Opin. 2010;26:907–15.
Marchioli R, Schweiger C, Tavazzi L, Valagussa F. Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. Lipids. 2001;36(Suppl):S119–26.
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;369:1090–8.
Abuissa H, O’Keefe JH Jr, Harris W, Lavie CJ. Autonomic function, omega-3, and cardiovascular risk. Chest. 2005;127:1088–91.
ORIGIN Trial Investigators, Bosch J, Gerstein HC, Dagenais GR, et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367:309–18.
The authors thank the nursing and pharmacy staff and the residents and students training in the Division of Endocrinology, for their valuable discussions.
Conflict of interest
About this article
Cite this article
Chehade, J.M., Gladysz, M. & Mooradian, A.D. Dyslipidemia in Type 2 Diabetes: Prevalence, Pathophysiology, and Management. Drugs 73, 327–339 (2013). https://doi.org/10.1007/s40265-013-0023-5
- High Density Lipoprotein Cholesterol
- Cholesteryl Ester Transfer Protein