American Journal of Cardiovascular Drugs

, Volume 2, Issue 1, pp 15–21 | Cite as

Management of Co-Existing Diabetes Mellitus and Dyslipidemia

Defining the Role of Thiazolidinediones
Therapy in Practice


The observed reduction in macrovascular outcomes in the United Kingdom Progressive Diabetes Study (UKPDS) trial in patients with type 2 diabetes mellitus (DM), treated intensively with insulin or sulfonylureas, was of borderline significance (p = 0.052). This may be because of the role of factors other than glycemic control in the etiology of macrovascular disease. The UKPDS and other studies have suggested that lipid parameters are potent predictors of adverse outcomes in patients with type 2 DM. In patients with DM, dyslipidemia is characterized by elevated serum triglycerides and low high density lipoprotein-cholesterol (HDL-C) with normal total serum cholesterol levels and usually accompanied by an elevation of atherogenic, small, dense low density lipoprotein-cholesterol (LDL-C) particles. Dyslipidemia is only partly corrected by dietary and lifestyle modifications and pharmacological glycemic control in patients with DM. Several guidelines, including those published by the New Zealand Heart Foundation, suggest that lipid-modifying therapies are appropriate in patients considered to be at high or very high risk of a cardiac event. This includes patients with established vascular disease. Some recent studies suggest that patients with type 2 DM have risk comparable to patients without DM, but have experienced previous myocardial infarction (MI). Subgroup analysis of trials including the Scandinavian Simvastatin Survival Study (4S) and Cholesterol and Recurrent Events (CARE), which included patients with DM, have shown a significant reduction in adverse outcomes, although many patients with DM and dyslipidemia were excluded. Of lipid-lowering drugs, fibric acid derivatives are probably the most appropriate for patients with DM and dyslipidemia and their role is being evaluated in large, long-term outcome studies such as Fenofibrate Intervention and Event Lowering in Diabetes (FIELD). Thiazolidinediones, a new class of compound for treating patients with type 2 DM, primarily exert their glucose-lowering effect by increasing insulin sensitivity at the level of skeletal muscle, and to a lesser extent, at the liver by decreasing hepatic glucose output. Some of their actions are mediated through binding and activation of the peroxisome proliferator-activated receptor-γ, a nuclear receptor that has a regulatory role in differentiation of cells, especially adipocytes. The nonhypoglycemic effects of thiazolidinediones, therefore, offer additional potential mechanisms for benefit in patients with type 2 DM and insulin resistance. Thiazolidinediones increase serum HDL-C levels. Troglitazone and pioglitazone have been shown to decrease serum triglyceride levels. Rosiglitazone, conversely has no significant effect on serum triglyceride levels. All of the thiazolidinediones increase serum LDL-C levels (pioglitazone to a lesser extent), although changes in the size of the LDL fraction may render it less susceptible to oxidation and, therefore, less atherogenic. A randomized comparative trial needs to be undertaken to determine whether true differences exist between the thiazolidinediones. Longer studies need to be undertaken to assess their effect on cardiovascular outcomes.


  1. 1.
    King H, Rewers W, WHO Ad Hoc Diabetes Reporting Group. Global estimates for prevalence of diabetes mellitus and impaired glucose tolerance in adults. Diabetes Care 1993; 16: 157–77PubMedCrossRefGoogle Scholar
  2. 2.
    Ministry of Health. Diabetes Prevention and Control, The Public Health Issues. The Background Paper. Wellington: Ministry of Health, 1997Google Scholar
  3. 3.
    Simmons D. Diabetes and its complications in New Zealand: an epidemiological perspective. N Z Med J 1996; 109: 245–7PubMedGoogle Scholar
  4. 4.
    Florkowski CM, Scott RS, Moir CL, et al. Lipid but not glycemic parameters predict total mortality from non-insulin dependent diabetes mellitus in Canterbury, New Zealand. Diabet Med 1998; 15: 386–92PubMedCrossRefGoogle Scholar
  5. 5.
    The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977–86CrossRefGoogle Scholar
  6. 6.
    UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–53CrossRefGoogle Scholar
  7. 7.
    UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 854–65CrossRefGoogle Scholar
  8. 8.
    Stamler J, Vaccaro O, Neaton JD, et al. for The Multiple Risk Factor Intervention Trial Research Group. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the multiple risk factor intervention trial, Diabetes Care 1993; 16: 434–44PubMedCrossRefGoogle Scholar
  9. 9.
    Finch C, Zimmet P. Mortality from diabetes, In: Alberti KGMM, Krall LP, editors. The Diabetes Annual/4. Amsterdam: Elsevier Science Publishers, 1988: 1–16Google Scholar
  10. 10.
    Knuiman MW, Welborn TA, Whittall DE. An analysis of excess mortality rates for persons with non-insulin-dependent diabetes mellitus in Western Australia using the Cox proportional hazards regression model. Am J Epidemiol 1992; 135(6): 638–46PubMedGoogle Scholar
  11. 11.
    Turner RC, Millns H, Neil HAW, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom prospective diabetes mellitus study (UKPDS: 23). BMJ 1998; 316: 823–8PubMedCrossRefGoogle Scholar
  12. 12.
    Laakso M, Lehto S, Pentilla I, et al. Lipids and lipoproteins predicting coronary heart disease mortality and morbidity in patients with non-insulin-dependent diabetes. Circulation 1993; 88: 1421–30PubMedCrossRefGoogle Scholar
  13. 13.
    Austin MA, Breslow JL, Hennekens CH, et al. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 1988; 260: 1917–21PubMedCrossRefGoogle Scholar
  14. 14.
    Lyons TJ. Oxidized low-density lipoproteins: a role in the pathogenesis of atherosclerosis in diabetes? Diabet Med 1991; 8: 411–9PubMedCrossRefGoogle Scholar
  15. 15.
    American Diabetes Association. Consensus Statement: role of cardiovascular risk factors in prevention and treatment of macrovascular disease in diabetes. Diabetes Care 1989; 12: 573–9Google Scholar
  16. 16.
    Stern MP, Patterson JK, Haffner SM, et al. Lack of awareness and treatment of hyperlipidaemia in type II diabetes in a community survey. JAMA 1989; 262: 360–4PubMedCrossRefGoogle Scholar
  17. 17.
    Dyslipidaemia Advisory Group on behalf of the Scientific Committee of The National Heart Foundation of New Zealand. 1996 National Heart Foundation clinical guidelines for the assessment and management of dyslipidaemia. Dyslipidaemia Advisory Group on behalf of the scientific committee of the National Heart Foundation of New Zealand. N Z Med J. 1996 Jun 28; 109(1024): 224–31Google Scholar
  18. 18.
    Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in non-diabetic subjects with and without prior myocardial infarction, New Engl J Med 1998; 339: 229–234PubMedCrossRefGoogle Scholar
  19. 19.
    NZDA Position Paper: The nutritional management of diabetes in New Zealand. New Zealand Diabetic Association Inc: Wellington, 1997Google Scholar
  20. 20.
    Greenfield MS, Doberne L, Rosenthal M, et al. Lipid metabolism in non-insulin-dependent diabetes mellitus: effect of glipizide therapy. Arch Intern Med 1982; 142: 1498–500PubMedCrossRefGoogle Scholar
  21. 21.
    Pfeiffer MA, Brunzell JD, Best JD, et al. The response of plasma triglyceride, cholesterol, and lipoprotein lipase to treatment in non-insulin-dependent diabetic subjects without familial hypertriglyceridaemia. Diabetes 1983; 32: 525–31CrossRefGoogle Scholar
  22. 22.
    Stern MP, Mitchell BD, Haffner SM, et al. Does glycaemic control of type II diabetes suffice to control diabetic dyslipidaemia? A community perspective. Diabetes Care 1991; 15: 638–44CrossRefGoogle Scholar
  23. 23.
    Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: Primary prevention trial with Gemfibrozil in middle-aged men with dyslipidaemia. N Engl J Med 1987; 317: 1237–45PubMedCrossRefGoogle Scholar
  24. 24.
    Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–9Google Scholar
  25. 25.
    Sacks FM, Pfeffer A, Myoe LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001–9PubMedCrossRefGoogle Scholar
  26. 26.
    Elkeles RS, Diamond JR, Poulter C, et al. Cardiovascular outcomes in type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: the St Mary’s, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) study. Diabetes Care 1998 Apr; 21(4): 641–8PubMedCrossRefGoogle Scholar
  27. 27.
    Saltiel AR, Olefsky JM. Thiazolidinediones in the Treatment of Insulin Resistance and Type II Diabetes. Diabetes 1996; 45: 1661–9PubMedCrossRefGoogle Scholar
  28. 28.
    Bressler R, Johnson D. New pharmacological approaches to therapy of NIDDM. Diabetes Care 1992; 15(6): 792–805PubMedCrossRefGoogle Scholar
  29. 29.
    Auwerx J. PPAR-gamma, the ultimate thrifty gene. Diabetologia 1999; 42: 1033–49PubMedCrossRefGoogle Scholar
  30. 30.
    Vamecq J, Latruffe N. Peroxisome proliferator-activated receptors (PPARS) and their implications in disease. Curr Opin Endocrinol Diabetes 2000; 7: 8–18Google Scholar
  31. 31.
    Lebovitz HE, Dole JF, Patwardhan R, et al. Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 2001; 86: 280–8PubMedCrossRefGoogle Scholar
  32. 32.
    Aronoff S, Mathisen AL, Rosenblatt S, et al. Pioglitazone hydrochloride monotherapy improves glycaemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. Diabetes Care 2000; 23: 1605–11PubMedCrossRefGoogle Scholar
  33. 33.
    Raskin P, Rappaport EB, Cole ST, et al. Rosiglitazone short-term monotherapy lowers fasting and post-prandial blood glucose in patients with type II diabetes. Diabetologia 2000; 43: 278–84PubMedCrossRefGoogle Scholar
  34. 34.
    Nolan JJ, Jones NP, Patwardhan R, et al. Rosiglitazone taken once daily provides effective glycaemic control in patients with type 2 diabetes mellitus. Diabet Med 2000; 17: 287–94PubMedCrossRefGoogle Scholar
  35. 35.
    King AB. A comparison in a clinical setting of the efficacy and side effects of three thiazolidinediones [letter]. Diabetes Care 2000; 23: 557PubMedCrossRefGoogle Scholar
  36. 36.
    Tack CJ, Demacker PNM, Smits P, et al. Troglitazone decreases the proportion of small, dense, LDL and increases the resistance of LDL to oxidation in obese subjects. Diabetes Care 1998; 21: 796–9PubMedCrossRefGoogle Scholar
  37. 37.
    Cominacini L, Young MMR, Capriati A, et al. Troglitazone increases the resistance of low-density lipoprotein to oxidation in healthy volunteers. Diabetologia 1997; 82: 2108–16Google Scholar
  38. 38.
    Lefebvre AM, Peinado-Onsurbe J, Leitersdorf I, et al. Regulation of lipoprotein metabolism by thiazolidinediones occurs through a distinct but complimentary mechanism relative to the fibrates. Arterioscler Thromb Vasc Biol 1997; 17(9): 1756–64PubMedCrossRefGoogle Scholar
  39. 39.
    Yusuf S, Dagenais G, Pogue J, et al. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342: 154–60PubMedCrossRefGoogle Scholar
  40. 40.
    Ridker PM. High-sensitivity C-reactive Protein. Potential Adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001; 103: 1813–8PubMedCrossRefGoogle Scholar
  41. 41.
    Ebeling P, Teppo AM, Koistinen HA, et al. Troglitazone reduces hyperglycaemia and selectively acute-phase serum proteins in patients with Type II diabetes. Diabetologia 1999; 42(12): 1433–8PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  1. 1.Clinical Research Physician, Lipid &; Diabetes Research GroupChristchurch HospitalChristchurchNew Zealand

Personalised recommendations