Skip to main content
Log in

Approaches to Prevention of Cardiovascular Complications and Events in Diabetes Mellitus

  • Therapy In Practice
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Diabetes mellitus affects about 8% of the adult population. The estimated number of patients with diabetes, presently about 170 million people, is expected to increase by 50–70% within the next 25 years.

Diabetes is an important component of the complex of ‘common’ cardiovascular risk factors, and is responsible for acceleration and worsening of atherothrombosis. Major cardiovascular events cause about 80% of the total mortality in diabetic patients. Diabetes also induces peculiar microangiopathic changes leading to diabetic nephropathy conducive to end-stage renal failure, and to diabetic retinopathy that may progress to vision loss and blindness.

In terms of major cardiovascular events, coronary heart disease and ischaemic stroke are the main causes of morbidity and mortality in diabetic patients. Peripheral arterial disease frequently occurs, and is more likely to be conducive to critical limb ischaemia and amputation than in the absence of diabetes.

Although there are a number of differences in the pathogenesis and clinical features of diabetic macroangiopathy and microangiopathy, these two entities often coexist and induce mutually worsening effects. Endothelial injury, dysfunction and damage are common starting points for both conditions. Causes of endothelial injury can be distinguished into those ‘common’ to nondiabetic atherothrombosis, such as hypertension, dyslipidaemia, smoking, hypercoagulability and platelet activation; and those more specific and in some cases ‘unique’ to diabetes and directly related to the metabolic derangement of the disease, such as (i) desulfation of glycosaminoglycans (GAGs) of the vascular matrix; (ii) formation of advanced glycation end-products (AGE) and their endothelial receptors (RAGE); (iii) oxidative and reductive stress; (iv) decline in nitric oxide production; (v) activation of the renin-angiotensin aldosterone system (RAAS); and (vi) endothelial inflammation caused by glucose, insulin, insulin precursors and AGE/RAGE.

Prevention of major cardiovascular events with the antithrombotic agent aspirin (acetylsalicylic acid) is widely recommended, but reportedly underutilised in patients with diabetes. However, some data suggest that aspirin may be less effective than expected in preventing cardiovascular events and especially mortality in patients with diabetes, as well as in slowing progression of retinopathy.

In contrast, a recent study found picotamide, a direct thromboxane inhibitor, to be superior to aspirin in diabetic patients. Clopidogrel was either equivalent or less active in diabetic versus nondiabetic patients, depending upon different clinical settings.

Recent studies have shown that some GAG compounds are able to reduce micro-and macroalbuminuria in diabetic nephropathy, and hard exudates in diabetic retinopathy, but it is as yet unknown whether these agents also influence the natural history of microvascular complications of diabetes. Lifestyle changes and physical exercise are also essential in preventing cardiovascular events in diabetic patients.

Available data on the control of the metabolic state and the main risk factors show that careful adjustment of blood sugar and glycated haemoglobin is more effective in counteracting microvascular damage than in preventing major cardiovascular events. The latter objective requires a more comprehensive approach to the whole constellation of risk factors both specific for diabetes and common to atherothrombosis. This approach includes lifestyle modifications, such as dietary changes and smoking cessation and the use of HMG-CoA reductase inhibitors (statins), which are able to correct the lipid status and to prevent major cardiovascular events independently of the baseline lipidaemic or cardiovascular status.

Tight control of hypertension is essential to reduce not only major cardiovascular events but also microvascular complications. Among antihypertensive measures, blockade of the RAAS by means of ACE inhibitors or angiotensin II receptor antagonists recently emerged as a potentially polyvalent approach, not only for treating hypertension and reducing cardiovascular events, but also to prevent or reduce albuminuria, counteract diabetic nephropathy and lower the occurrence of new type 2 diabetes in individuals at risk.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. American Diabetes Association. ADA clinical practice recommendations. Diabetes Care 2004; 27: S1–143

    Article  Google Scholar 

  2. Cheta D, Panaite C, Balas B, et al. Cardiovascular complications of diabetes mellitus: magnitude of the problem. In: Cheta D, editor. Vascular involvement in diabetes. Basel: Karger, 2005: 3–11

    Google Scholar 

  3. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology and management. JAMA 2002; 287: 2570–81

    Article  PubMed  CAS  Google Scholar 

  4. Braunwald E. Preface. In: Cheta D, editor. Vascular involvement in diabetes. Basel: Karger, 2005: XI

    Google Scholar 

  5. McAlpine RR, Morris AD, Emslie-Smith A, et al. The annual incidence of diabetic complications in a population with type 1 and 2 diabetes. Diabet Med 2005; 22: 348–52

    Article  PubMed  CAS  Google Scholar 

  6. Guja C, Ionescu-Tirgoviste C. Endothelial dysfunction and type 2 diabetes mellitus. In: Cheta D, editor. Vascular involvement in diabetes. Basel: Karger, 2005: 205–20

    Google Scholar 

  7. Rossi R, Nuzzo A, Grimaldi T, et al. Diabetes and cardiovascular disease: a close and dangerous connection. Heart Int 2005; 1: 18–23

    Google Scholar 

  8. Booth GL, Kapral MK, Fung K, et al. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet 2006; 368: 29–36

    Article  PubMed  Google Scholar 

  9. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998; 316: 823–8

    Article  PubMed  CAS  Google Scholar 

  10. Fuller JH, Stevens LK, Wang SL. Risk factors for cardiovascular mortality and morbidity: the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia 2001; 44 Suppl. 2: S54-64

    Google Scholar 

  11. Bartnik M, Ryden L, Ferrari R, et al. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe: the Euro Heart Survey on diabetes and the heart. Eur Heart J 2004; 25: 1880–90

    Article  PubMed  CAS  Google Scholar 

  12. Chyun D, Vaccarino V, Murillo J, et al. Acute myocardial infarction in the elderly with diabetes. Heart Lung 2002; 31: 327–39

    Article  PubMed  Google Scholar 

  13. Mamcarz A. Chmielewsky M. Braksator W, et al. Factors influencing cardiac complications in patients with type-2 diabetes mellitus and silent myocardial ischeamia: five-year follow-up. Pol Arch Med Wewn 2004; 112: 1433–43

    Google Scholar 

  14. Chyun D, Obata J, Kling J, et al. In-hospital mortality after acute myocardial infarction in patients with diabetes mellitus. Am J Crit Care 2000; 9: 168–79

    PubMed  CAS  Google Scholar 

  15. Lenzen M, Ryden L, Oehrvik J, et al. Diabetes known or newly detected, but not impaired glucose regulation, has a negative influence on 1-year outcome in patients with coronary artery disease: a report from the Euro Heart Survey on diabetes and the heart. Eur Heart J 2006; 27: 2969–74.

    Article  PubMed  Google Scholar 

  16. Corbett CF, Cook D, Setter SM. OASIS and beyond: improving outcomes for home health patients. Diabetes Educ 2003; 29: 83–9

    Article  PubMed  Google Scholar 

  17. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: analysis of 37 prospective cohort studies. BMJ 2006; 332: 73–8

    Article  PubMed  Google Scholar 

  18. Juutilainen A, Kortelainen S, Lehto S, et al. Gender difference in the impact of type 2 diabetes on coronary heart disease risk. Diabetes Care 2004; 27: 2898–904

    Article  PubMed  Google Scholar 

  19. Bartnick M, Malmberg K, Norhammar A, et al. Newly detected abnormal glucose tolerance: an important predictor of long-term outcome after myocardial infarction. Eur Heart J 2004; 25: 1990–7

    Article  CAS  Google Scholar 

  20. Norhammar A, Tenerz A, Nilsson G, et al. Glucose metabolism in patient with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 2002; 359: 2140–4

    Article  PubMed  CAS  Google Scholar 

  21. Wallander M, Bartnick M, Efendic S, et al. Beta cell dysfunction in patients with acute myocardial infarction but without previously known type 2 diabetes: a report from the GAMI study. Diabetologia 2005; 48: 2229–35

    Article  PubMed  CAS  Google Scholar 

  22. Haffner SN, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339: 229–34

    Article  PubMed  CAS  Google Scholar 

  23. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP). JAMA 2001; 285: 2486–97

    Article  Google Scholar 

  24. Evans JM, Wang J, Morris AD. Comparison of cardiovascular risk between patients with type 2 diabetes and those who had had a myocardial infarction. BMJ 2002; 324: 939–42

    Article  PubMed  Google Scholar 

  25. Danaei G, Lawes CM, Vander Hoorn S, et al. Global and regional mortality from ischaemic heart disease and stroke attributable to higher-than-optimum blood glucose concentration: comparative risk assessment. Lancet 2006; 368: 1651–9

    Article  PubMed  Google Scholar 

  26. Jorgensen H, Nakayama H, Raaschou HO, et al. Stroke in patients with diabetes: the Copenhagen Stroke Study. Stroke 1994; 25: 1977–84

    Article  PubMed  CAS  Google Scholar 

  27. Laing SP, Swerdlow AJ, Carpenter LM, et al. Mortality from cerebrovascular disease in a cohort of 23000 patients with insulin-treated diabetes. Stroke 2003; 34: 418–21

    Article  PubMed  Google Scholar 

  28. Mulnier HE, Seaman HE, Raleigh VS, et al. Risk of stroke in people with type 2 diabetes in the UK: a study using the general practice research database. Diabetologia 2006; 49: 2859–65

    Article  PubMed  CAS  Google Scholar 

  29. Karapanayiotides T, Piechowsky-Jozwiak B, van Melle G, et al. Stroke patterns, ethiology and prognosis in patients with diabetes mellitus. Neurology 2004; 62: 1558–62

    Article  PubMed  Google Scholar 

  30. Hu G, Sarti C, Jousilahti P, et al. The impact of history of hypertension and type 2 diabetes at baseline on the incidence of stroke and stroke mortality. Stroke 2005; 36: 2538–43

    Article  PubMed  Google Scholar 

  31. Hillen T, Coshal C, Tilling K, et al., on behalf of the South London Stroke Register. Cause of stroke recurrence is multifactorial: patterns, risk factors, and outcome of stroke recurrence in the South London Stroke Register. Stroke 2003; 34: 1457–63

    Article  PubMed  Google Scholar 

  32. Kragsterman B, Bjorck M, Lindbaeck J, et al. Long-term survival after carotid endarterectomy for asymptomatic stenosis. Stroke 2006; 37: 2886–91

    Article  PubMed  Google Scholar 

  33. Rajala U, Laakso M, Paivansalo M, et al. Blood pressure and atherosclerotic plaques in carotid, aortic and femoral arteries in elderly Finns with diabetes mellitus or impaired glucose tolerance. J Hum Hypertens 2005; 19: 85–91

    Article  PubMed  CAS  Google Scholar 

  34. Mohaved MR, Hashemzadeh M, Jamal MM. Diabetes mellitus is a strong, independent risk factor for atrial fibrillation and flutter in addition to other cardiovascular disease. Int J Cardiol 2005; 105: 315–8

    Article  Google Scholar 

  35. Lip GYH, Hart RG, Conway DSG. Antithrombotic therapy for atrial fibrillation. BMJ 2002; 325: 1022–5

    Article  PubMed  Google Scholar 

  36. Fonarow GC, Srikanthan P. Diabetic cardiomyopathy. Endocrinol Metab Clin North Am. 2006; 35: 575–99

    Article  PubMed  CAS  Google Scholar 

  37. Arauz A, Murillo L, Cantu C, et al. Prospective study of single and multiple lacunar infarct using magnetic resonance imaging: risk factors, recurrence and outcome in 175 consecutive cases. Stroke 2003; 34: 2453–8

    Article  PubMed  Google Scholar 

  38. Garg R, Chaudhuri A, Munschauer F, et al. Hyperglycemia, insulin and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy. Stroke 2006; 37: 267–73

    Article  PubMed  CAS  Google Scholar 

  39. American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care 2003; 26: 3333–41

    Article  Google Scholar 

  40. Jude EB, Oyibo SO, Chalmers N, et al. Peripheral arterial disease in diabetic and nondiabetic patients: a comparison of severity and outcome. Diabetes Care 2001; 24: 1433–7

    Article  PubMed  CAS  Google Scholar 

  41. Adler AI, Stevens RJ, Neil A, et al. UKPDS 59: hyperglycemia and other potentially modifiable risk factor for peripheral vascular disease in type 2 diabetes. Diabetes Care 2002; 25: 894–9

    Article  PubMed  Google Scholar 

  42. Marso SP, Hiatt WR. Peripheral arterial disease in patients with diabetes. J Am Coll Cardiol 2006; 7: 921–9

    Article  Google Scholar 

  43. Vereanu I, Patrascu T. The diabetic foot: vasculopathy versus neuropathy. In: Cheta D, editor. Vascular involvement in diabetes. Basel: Karger, 2005: 715–26

    Google Scholar 

  44. Dormandy J, Heeck L, Vig S. Predicting which patients will develop chronic critical leg ischemia. Semin Vasc Surg 1999; 12: 138–41

    PubMed  CAS  Google Scholar 

  45. Aboyans V. Criqui MH, Denenberg JO, et al. Risk factors for progression of peripheral arterial disease in large and small vessels. Circulation 2006; 6: 2623–9

    Google Scholar 

  46. Moss SE, Klein R, Klein BE. The 14-year incidence of lowerextremity amputation in a diabetic population: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Diabetes Care 1999; 22: 951–9

    Article  PubMed  CAS  Google Scholar 

  47. Lehto S, Niskanen L, Suhonen M, et al. Medial artery calcification: a neglected harbinger of cardiovascular complications in non-insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol 1996; 16: 978–83

    Article  PubMed  CAS  Google Scholar 

  48. Tentolouris N, Al-Sabbagh S, Walker MG, et al. Mortality in diabetic and nondiabetic patients after amputations performed from 1990 to 1995: a 5-year follow-up study. Diabetes Care 2004; 27: 1598–604

    Article  PubMed  Google Scholar 

  49. Jones EW, Mitchell JRA. Venous thrombosis in diabetes mellitus. Diabetologia 1983; 25: 502–5

    Article  PubMed  CAS  Google Scholar 

  50. Bergqvist D, Arnadottir M, Bergentz SE, et al. Juvenile diabetes mellitus a risk factor for postoperative venous thromboembolism? Acta Med Scand 1985; 217: 307–8

    Article  PubMed  CAS  Google Scholar 

  51. Petrauskiene V, Falk M, Waernbaum I, et al. The risk of venous thromboembolism is markedly elevated in patients with diabetes. Diabetologia 2005; 48: 1017–21

    Article  PubMed  CAS  Google Scholar 

  52. Heit JA, Silverstein MC, Mohr DN, et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost 2001;86: 452–63

    PubMed  CAS  Google Scholar 

  53. White RH, Gettner S, Newman JM, et al. Predictors of rehospitalization for symptomatic venous thromboembolism after total hip arthroplasthy. N Engl J Med 2000; 343: 1758–64

    Article  PubMed  CAS  Google Scholar 

  54. Kahn SR, Kearon C, Yulian JA, et al. Predictors of the post-thrombotic syndrome during long-term treatment of proximal deep vein thrombosis. J Thromb Haemost 2005; 3: 718–23

    Article  PubMed  CAS  Google Scholar 

  55. Bo S, Ciccone G, Rosato R, et al. Renal damage in patients with type 2 diabetes: a strong predictor of mortality. Diabet Med 2005; 22: 258–65

    Article  PubMed  CAS  Google Scholar 

  56. Spranger J, Pfeiffer AFH. Diabetic microvascular complications In: Morgensen CE, editor. Hypertension and diabetes. London: Lippincott Williams & Wilkins, 2002

    Google Scholar 

  57. Tarchini R, Bottini E, Botti P, et al. Type 2 diabetic nephropathy: clinical course and prevention, proposal, 2004. G Ital Nefrol 2005; 22: S15–19

    PubMed  Google Scholar 

  58. Gambaro G, van der Woude FJ. Glycosaminoglycans: use in treatment of diabetic nephropathy. J Am Soc Nephrol 2000; 11: 359–68

    PubMed  CAS  Google Scholar 

  59. Gimeno Orna JA, Boned Juliani B, Lou Arnal LM, et al. Microalbuminuria and clinical proteinuria as the main predicting factors of cardiovascular morbidity and mortality in patients with type 2 diabetes. Rev Clin Esp 2003; 203: 526–31

    Article  PubMed  CAS  Google Scholar 

  60. Trevisan R, Viberti G. Pathophysiology of diabetic nephropathy. In: LeRoith D, Taylor SI, Olefsky JM, editors. Diabetes mellitus: a fundamental and clinical text. Philadelphia (PA): Lippincott Williams & Wilkins, 2000

    Google Scholar 

  61. Koch M, Kutkuhn B, Grabensee B, et al. Apolipoprotein A, fibrinogen, age and history of stroke are predictors of death in dialyzed diabetic patients: a prospective study in 412 subjects. Nephrol Dial Transplant 1997; 12: 2603–11

    Article  PubMed  CAS  Google Scholar 

  62. Scheen AJ. Prevention of type 2 diabetes mellitus through inhibition of the renin-angiotensin system. Drugs 2004; 64: 2537–65

    Article  PubMed  CAS  Google Scholar 

  63. Jandeleit-Dahm KA, Tikellis C, Reid CM, et al. Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes? Hypertension 2005; 23: 463–73

    Article  CAS  Google Scholar 

  64. Scheen AJ. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus, part 2: overview of physiological and biochemical mechanisms. Diabetes Metab 2004; 30: 498–505

    Article  PubMed  CAS  Google Scholar 

  65. Klein R, Klein BE, Moss SE. Epidemiology of proliferative diabetic retinopathy. Diabetes Care 1992; 15: 1875–91

    Article  PubMed  CAS  Google Scholar 

  66. Lyons TJ, Jenkins AJ, Zheng D, et al. Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest Ophthalmol Vis Sci 2004; 45: 910–8

    Article  PubMed  Google Scholar 

  67. Moss SE, Klein R, Klein BE. Ten-year incidence of visual loss in a diabetic population. Ophthalmology 1994; 101: 1061–70

    PubMed  CAS  Google Scholar 

  68. Klein R, Klein BE, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy, XV: the long-term incidence of macular oedema. Ophthalmology 1995; 102: 7–16

    PubMed  CAS  Google Scholar 

  69. Juutilianen A, Lehto S, Ronnemaa T, et al. Retinopathy predicts cardiovascular mortality in type 2 diabetic men and women. Diabetes Care 2007; 30: 292–9

    Article  Google Scholar 

  70. Vinik A, Mitchell B, Maser R, et al. Diabetic autonomie neuropathy. Diabetes Care 2003; 26: 1553–62

    Article  PubMed  Google Scholar 

  71. Wackers FJT, Young LH, Inzucchi SE, et al. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD Study. Diabetes Care 2004; 27: 1954–61

    Article  PubMed  Google Scholar 

  72. Sampson MJ, Wilson S, Karagiannis P, et al. Progression of diabetic autonomie neuropathy over a decade in insulin-dependent diabetics. Q J Med 1990; 75: 635–46

    PubMed  CAS  Google Scholar 

  73. Deckert T, Feldt-Rasmussen D, Borch-Johnsen K, et al. Albuminuria reflects widespread vascular damage: the Steno hypothesis. Diabetologia 1989; 32: 219–26

    Article  PubMed  CAS  Google Scholar 

  74. Sun M, Yokoyama M, Ishiwata T, et al. Deposition of advanced glycation end-products (AGE) and expression of the receptor for AGE in cardiovascular tissue of the diabetic rat. Int J Exp Pathol 1998; 79: 207–22

    PubMed  CAS  Google Scholar 

  75. Zee RYL, Romero JR, Gould JL, et al. Polymorphisms in the advanced glycosylation end product-specific receptor gene and risk of incident myocardial infarction or ischemic stroke. Stroke 2006; 37: 1686–90

    Article  PubMed  CAS  Google Scholar 

  76. Cahuana GM, Tejedo JR, Jimenez J, et al. Involvement of advanced lipoxidation end products (ALE) and protein oxidation in the apoptotic actions of nitric oxide in insulin secreting RINm5F cells. Biochem Pharmacol 2003; 15: 1963–71

    Article  CAS  Google Scholar 

  77. Simionescu N, Popov D. Endothelial dysfunction in diabetes. In: Cheta D, editor. Vascular involvement in diabetes. Basel: Karger, 2005: 15–34

    Google Scholar 

  78. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348: 383–93

    Article  PubMed  Google Scholar 

  79. Goldsmith DJA, Smith A, Bakri K, et al. Endothelial dysfunction, atherosclerosis and arteriosclerosis in diabetic patients with and without renal involvement. In: Cheta D, editor. Vascular involvement in diabetes. Basel: Karger, 2005: 289–301

    Google Scholar 

  80. Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care 1996; 19: 257–67

    Article  PubMed  CAS  Google Scholar 

  81. Hogikyan RV, Galecki AT, Pitt B, et al. Specific impairment of endothelium-dependent vasodilation in subjects with type 2 diabetes independent of obesity. J Clin Endocrinol Metab 1998; 83: 1946–52

    Article  PubMed  CAS  Google Scholar 

  82. O’Neill MS, Veves A, Zanobetti A, et al. Diabetes enhances vulnerability to particulate air pollution-associated impairment in vascular reactivity and endothelial function. Circulation 2005; 111: 2913–20

    Article  PubMed  Google Scholar 

  83. Chappey O, Dosquet C, Wautier PM, et al. AGE products, oxidant stress and vascular lesions. Eur J Clin Invest 1997; 27: 97–108

    Article  PubMed  CAS  Google Scholar 

  84. Schmidt AM, Yan SD, Wautier JL, et al. Activation of receptor for advanced glycation end-products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ Res 1999; 84: 489–97

    Article  PubMed  CAS  Google Scholar 

  85. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006; 116: 1793–801

    Article  PubMed  CAS  Google Scholar 

  86. Semenkovich CF. Insulin resistance and atherosclerosis. J Clin Invest 2006; 116: 1813–22

    Article  PubMed  CAS  Google Scholar 

  87. Viles-Gonzales JF, Fuster V, Badimon JJ. Links between inflammation and thrombogenicity in atherosclerosis. Curr Mol Med 2006; 6: 489–99

    Article  Google Scholar 

  88. Madonna R, Pandolfi A, Massaro M, et al. Insulin enhances vascular cell adhesion molecule (VCAM-1) expression in human cultured endothelial cells through a pro-atherogenic p38MAP-kinase-mediated pathway. Diabetologia 2004; 47: 532–6

    Article  PubMed  CAS  Google Scholar 

  89. Walcher D, Aleksic M, Jerg V, et al. C-peptide induces chemotaxis of human CD4 positive cells: involvement of pertussis toxin-sensitive G-proteins and phosphoinositide 3-kinase. Diabetes 2004; 53: 1664–70

    Article  PubMed  CAS  Google Scholar 

  90. Marx N, Walcher D, Raichle C, et al. C-peptide colocalizes with macrophages in early arteriosclerotic lesions of diabetic subjects and induces monocyte chemotaxis in vitro. Arterioscler Thromb Vasc Biol 2004; 24: 540–5

    Article  PubMed  CAS  Google Scholar 

  91. Festa A, D’Agostino R Jr, Howard G, et al. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000; 102: 42–7

    Article  PubMed  CAS  Google Scholar 

  92. Sjoholm A, Nystrom T. Endothelial inflammation in insulin resistance. Lancet 2005; 365: 610–2

    PubMed  Google Scholar 

  93. Nechifor M. Involvement of eicosanoid metabolism in vascular complications of diabetes mellitus. In: Cheta D, editor. Vascular involvement in diabetes. Basel: Karger, 2005: 63–80

    Google Scholar 

  94. Davi G, Catalano I, Averna M. Thromboxane biosynthesis and platelet function in type 2 diabetes mellitus. N Engl J Med 1990; 322: 1769–74

    Article  PubMed  CAS  Google Scholar 

  95. Hanasaki K, Nakano K, Kasai H, et al. Specific receptors for thromboxane A2 in cultured vascular endothelial cells in rat aorta. Biochem Biophys Res Commun 1988; 151: 1352–7

    Article  PubMed  CAS  Google Scholar 

  96. Ford-Hutchinson AW. Leukotrienes: their formation and role as inflammatory mediators. Fed Proc 1985; 44: 25–45

    PubMed  CAS  Google Scholar 

  97. Brezinsky ME, Gimbrone MA, Nicolaou KC. Lipoxins stimulate prostacyclin generation by human endothelial cells. FEBS Lett 1989; 245: 167–72

    Article  Google Scholar 

  98. Liu T, Stern A, Roberts LJ, et al. Isoprostanes: novel prostaglandin-like products of the free radical-catalysed peroxidation of arachidonic acid. J Biomed Sci 1999; 6: 226–35

    Article  PubMed  CAS  Google Scholar 

  99. Ostermann H, Van de Loo J. Factors of the haemostatic system in diabetic patients: a survey of controlled studies. Heamostasis 1986; 16: 386–416

    CAS  Google Scholar 

  100. Di Minno G, Silver MJ, Cerbone AM, et al. Trial of repeated low-dose aspirin in diabetic angiopathy. Blood 1986; 68: 886–91

    Google Scholar 

  101. Tan KT, Tayebjee MH, Lim HS, et al. Clinically apparent atherosclerotic disease in diabetes is associated with an increase in platelet microparticle levels. Diabet Med 2005; 22: 1657–62

    Article  PubMed  CAS  Google Scholar 

  102. Bavbek N, Kargili A, Kaftan O, et al. Elevated concentrations of soluble adhesion molecules and large platelets in diabetic patients: are they markers of vascular disease and diabetic nephropathy? Clin Appl Thromb Haemost 2007. In press

  103. Tschoepe D, Roesen P, Schwippert B, et al. Platelets in diabetes: the role in the haemostatic regulation and atherosclerosis. Sem Thromb Haemost 1993; 19: 122–8

    Article  CAS  Google Scholar 

  104. Lecrubier C, Scarabin PY, Grauso F, et al. Platelet aggregation related to age in diabetes mellitus. Haemostasis 1980; 9: 43–51

    PubMed  CAS  Google Scholar 

  105. Ferroni P, Basili S, Falco A, et al. Platelet activation in type 2 diabetes mellitus. J Thromb Haemost 2004; 2: 1282–91

    Article  PubMed  CAS  Google Scholar 

  106. Ceriello A. Coagulation activation in diabetes mellitus: the role of hyperglycaemia and therapeutic prospects. Diabetologia 1991; 34: 457–62

    Article  Google Scholar 

  107. Ceriello A. Fibrinogen and diabetes mellitus: is it time for intervention trials? Diabetologia 1997; 33: 731–4

    Article  Google Scholar 

  108. Sommeijer DW, Hansen HR, van Oerle R, et al. Soluble tissue factor is a candidate marker for progression of microvascular disease in patients with type 2 diabetes. J Thromb Haemost 2006; 4: 574–80

    Article  PubMed  CAS  Google Scholar 

  109. Sauls DL, Banini AE, Boyd LC, et al. Elevated prothrombin level and shortened clotting times in subjects with type 2 diabetes. J Thromb Haemost 2007; 5: 638–9

    Article  PubMed  CAS  Google Scholar 

  110. Ceriello A, Giugliano D, Quatraro A, et al. Evidence for a hyperglycaemia-dependent decrease of antithrombin III: thrombin complex formation in humans. Diabetologia 1990; 33: 163–7

    Article  PubMed  CAS  Google Scholar 

  111. Gonzalez J, Colwell JA, Sarji KE, et al. Effect of metabolic control with insulin on plasma von Willebrand factor activity (VIII R: WF) in diabetes mellitus. Thromb Res 1980; 17: 261–6

    Article  PubMed  CAS  Google Scholar 

  112. Juhan-Vague I, Roul C, Alessi MC, et al. Increased plasma plasminogen activator inhbitor-1 levels: a possible link between insulin resistance and atherothrombosis. Diabetologia 1991; 34: 457–62

    Article  PubMed  CAS  Google Scholar 

  113. Hornsby WG, Boggess KA, Lyons TJ, et al. Hemostatic alterations with exercise conditioning in NIDDM. Diabetes Care 1990; 13: 87–92

    Article  PubMed  CAS  Google Scholar 

  114. Jokl R, Klein RL, Lopes-Virella MF, et al. Release of platelet plasminogen activator inhibitor 1 in whole blood is increased in patients with type 2 diabetes. Diabetes Care 1995; 18: 1150–5

    Article  PubMed  CAS  Google Scholar 

  115. Schneider DJ, Nordt TK, Sobel BE. Stimulation by proinsulin of expression of plasminogen activator inhibitor type 1 in endothelial cells. Diabetes 1992; 41: 890–5

    Article  PubMed  CAS  Google Scholar 

  116. Seljeflot I, Larsen JR, Dahl-Jorgensen K, et al. Fibrinolytic activity is highly influenced by long-term glycemie control in type 1 diabetic patients. J Thromb Haemost 2006; 4: 686–8

    Article  PubMed  CAS  Google Scholar 

  117. Machin A, Silverman SH, Lip GYH. Peripheral vascular disease and Virchow’s triad for thrombogenesis. Q J Med 2002; 95: 199–210

    Article  Google Scholar 

  118. Carr ME. Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 2001; 15: 44–54

    Article  PubMed  CAS  Google Scholar 

  119. Adler AI, STratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000; 321: 412–9

    Article  PubMed  CAS  Google Scholar 

  120. Rossi R, Turco V, Origliani G, et al. Type 2 diabetes mellitus is a risk factor for the development of hypertension in postmenopausal women. J Hyperten 2006; 24: 2017–22.

    Article  CAS  Google Scholar 

  121. Zhang Y, Lee ET, Devereux RB, et al. Prehypertension, diabetes, and cardiovascular disease risk in a population-based sample: the Strong Heart Study. Hypertension 2006; 47: 410–4

    Article  PubMed  CAS  Google Scholar 

  122. Allemann S, Diem P, Egger M, et al. Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus: meta-analysis of randomised controlled trials. Curr Med Res Opin 2006 22; 617–23

    Article  PubMed  CAS  Google Scholar 

  123. Kahn HS. The lipid accumulation product is better than BMI for identifying diabetes: a population-based comparison. Diabetes Care 2006; 29: 151–3

    Article  PubMed  Google Scholar 

  124. Haire-Joshu D, Glassow RE, Tibbs TL. Smoking and diabetes. Diabetes Care 1999; 22: 1887–989

    Article  PubMed  CAS  Google Scholar 

  125. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354: 1567–77

    Article  PubMed  CAS  Google Scholar 

  126. Violi F, Criqui M, Longoni A, et al. Relation between risk factors and cardiovascular complications in patients with peripheral vascular disease: results from the ADEP study. Atherosclerosis 1996; 120: 25–35

    Article  PubMed  CAS  Google Scholar 

  127. Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996; 334: 952–7

    Article  PubMed  CAS  Google Scholar 

  128. Zethelius B, Lithel H, Hales CN, et al. Insulin sensitivity, pro insulin and insulin as predictors of coronary heart disease: a population-based 10-year follow-up study in 70-year old men using the euglycaemic insulin clamp. Diabetologia 2005; 48: 862–7

    Article  PubMed  CAS  Google Scholar 

  129. Bonora E, Formentini G, Calcaterra F, et al. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Diabetes Care 2002; 25: 1135–41

    Article  PubMed  Google Scholar 

  130. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405–12

    Article  PubMed  CAS  Google Scholar 

  131. Meerwaldt R, Lutgers HL, Links TP, et al. Skin autofluorescence is a strong predictor of cardiac mortality in diabetes. Diabetes Care 2007; 30: 107–12

    Article  PubMed  CAS  Google Scholar 

  132. Leelawattana R, Rattarasarn C, Lim A, et al. Causes of death, incidence and risk factors of cardiovascular disease in Thai type 2 diabetic patients: a 5 year follow-up study. Diabetes Res Clin Pract 2003; 60: 183–9

    Article  PubMed  Google Scholar 

  133. Chiodini I, Adda G, Scillitani A, et al. Cortisol secretion in patients with type 2 diabetes: relationship with chronic complications. Diabetes Care 2007; 30: 83–8

    Article  PubMed  CAS  Google Scholar 

  134. Linneman B, Janka HU. Prolonged QTc interval and elevated heart rate identify the type 2 diabetic patient at high risk for cardiovascular death: the Bremen Diabetes Study. Exp Clin Endocrinol Diabetes 2003; 111: 215–22

    Article  Google Scholar 

  135. Banskota NK, Taub R, Zeller K, et al. Insulin, insulin-like growth factor I, and platelet-derived growth factor interact additively in the induction of the protoncogene c-myc and cellular proliferation in cultured bovine aortic smooth muscle cells. Mol Endocrinol 1989; 8: 1183–90

    Article  Google Scholar 

  136. Cimminiello C, Milani M. Diabetes mellitus and peripheral vascular disease: is aspirin effective in preventing vascular events? Diabetologia 1996; 39: 1402–4

    Article  PubMed  CAS  Google Scholar 

  137. Sivenius J, Laakso M, Riekkeinen P, et al. European stroke prevention study: effectiveness of antiplatelet therapy in diabetic patients in secondary prevention of stroke. Stroke 1992; 23: 851–4

    Article  PubMed  CAS  Google Scholar 

  138. Cimminiello C. Is aspirin effective in diabetic patients? No. J Thromb Haemost 2005; 3: 2615–6

    Article  PubMed  CAS  Google Scholar 

  139. Sacco M, Pellegrini F, Roncaglioni MC, et al., on behalf of the PPP Collaborative Group. Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial. Diabetes Care 2003; 26: 3264–72

    Article  PubMed  CAS  Google Scholar 

  140. ETDRS Investigators. Aspirin effects on mortality and morbidity in patients with diabetes mellitus: Early Treatment Diabetic Retinopathy Study report 14. JAMA 1992; 268: 1292–300

    Article  Google Scholar 

  141. The DAMAD Study Group. Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy: a multicenter randomized controlled clinical trial. Diabetes 1989; 38: 491–8

    Article  Google Scholar 

  142. Antithrombotic Trialists’ Collaboration. Collaborative Meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71–86

    Article  Google Scholar 

  143. Colwell JA, Bingham SF, Abraira C, et al. Veterans Administration Cooperative Study on antiplatelet agents in diabetic patients after amputation for gangrene, II: effects of aspirin and dipyridamole on atherosclerotic vascular disease rates. Diabetes Care 1986; 9: 140–8

    Article  PubMed  CAS  Google Scholar 

  144. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomized, double-blind, placebo-controlled trial. Lancet 2004; 364: 331–7

    Article  PubMed  CAS  Google Scholar 

  145. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354: 1706–17

    Article  PubMed  CAS  Google Scholar 

  146. Colwell JA. Is aspirin effective in diabetic patients? Yes. J Thromb Haemost 2005; 3: 2612–4

    Article  PubMed  CAS  Google Scholar 

  147. American Diabetes Association. Aspirin therapy in diabetes. Diabetes Care 2004; 27: S72–3

    Article  Google Scholar 

  148. American Heart Association. AHA scientific statement: AHA guidelines for primary prevention of cardiovascular disease and stroke -2002 update. Circulation 2002; 106: 288–91

    Google Scholar 

  149. US Preventive Services Task Force. Aspirin for the primary prevention of cardiovascular events: summary of the evidence. Ann Intern Med 2002; 136: 161–72

    Google Scholar 

  150. The Task Force on the Use of Antiplatelet Agents in Patients with Atherosclerotic Cardiovascular Disease of the European Society of Cardiology. Expert consensus document on the use of antiplatelet agents. Eur Heart J 2004; 25: 166–81

    Article  Google Scholar 

  151. Song SH, Brown PM. Coronary heart disease risk assessment in diabetes mellitus: comparison of the UKPDS risk engine with Framingham risk assessment function and its clinical implications. Diabetic Med 2004; 21: 238–45

    Article  PubMed  CAS  Google Scholar 

  152. Colwell JA. Aspirin therapy in diabetes is underutilized. Diabetes Care 2001; 24: 195–6

    Article  PubMed  CAS  Google Scholar 

  153. Neri Serneri GG, Coccheri S, Marubini E, et al., on behalf of the the Drug evaluation in Atherosclerotic Vascular disease In Diabetics (DAVID) Study Group. Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID Study. Eur Heart J 2004; 25: 1845–52

    Article  PubMed  CAS  Google Scholar 

  154. Cleland JGF. Preventing atherosclerotic events with aspirin. BMJ 2002; 324: 103–5

    Article  PubMed  Google Scholar 

  155. Bhatt DL, Marso SP, Hirsh AT, et al. Amplified benefit of clopidrogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol 2002; 90: 625–8

    Article  PubMed  Google Scholar 

  156. Angiolillo DJ, Bernardo E, Ramirez C, et al. Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. J Am Coll Cardiol 2006; 48: 298–304

    Article  PubMed  CAS  Google Scholar 

  157. Sibbing D, von Beckerath O, Schomig A, et al. Diabetes mellitus and platelet function after administration of aspirin and a single 600mg dose of clopidogrel. J Thromb Hemost 2006; 4: 2566–8

    Article  CAS  Google Scholar 

  158. Angiolillo DJ, Shoemaker SB, Desai B, et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OP-TIMUS) study. Circulation 2007; 115: 708–16

    Article  PubMed  CAS  Google Scholar 

  159. Roffi M, Chew DP, Mukherjee D, et al. Platelet glycoprotein IIb-IIIa inhibitors reduce mortality in diabetic patient with non-ST-segment-elevation acute coronary syndromes. Circulation 2001; 104: 2767–71

    Article  PubMed  CAS  Google Scholar 

  160. Colwell JA. Antiplatelet agents for the prevention of cardiovascular disease in diabetes mellitus. Am J Cardiovasc Drugs 2004; 4: 87–106

    Article  PubMed  CAS  Google Scholar 

  161. TIMAD Study Group. Ticlopidine treatment reduces the progression of non-prolipherative diabetic retinopathy. Arch Ophthalmol 1990; 108: 1577–83

    Article  Google Scholar 

  162. Early Treatment Diabetic Retinopathy Study Research Group. Effects of aspirin treatment on diabetic retinopathy: ETDRS report no. 8. Ophthalmology 1991; 98: 757–65

    Google Scholar 

  163. Otsuki M, Hashimoto K, Morimoto Y, et al. Circulating vascular cell adhesion molecule-1 (VCAM-1) in atherosclerotic NIDDM patients. Diabetes 1997; 46: 2096–101

    Article  PubMed  CAS  Google Scholar 

  164. Ceriello A, Motz E. Prevention of vascular events in diabetes mellitus: which ‘antithrombotic’ therapy? Diabetologia 1996; 39: 1405–6

    Article  PubMed  CAS  Google Scholar 

  165. Meade TW, Brennan PJ. Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomised controlled trial. BMJ 2000; 321: 13–7

    Article  PubMed  CAS  Google Scholar 

  166. Pulcinelli FM, Riondino S, Celestini A, et al. Persistent production of platelet thromboxane A2 in patients chronically treated with aspirin. J Thromb Haemost 2005; 3: 2784–9

    Article  PubMed  CAS  Google Scholar 

  167. Watala C, Golansky J, Pluta J, et al. Reduced sensitivity of platelets from type 2 diabetes patients to acetylsalicylic acid (aspirin): its relation to metabolic control. Thromb Res 2004; 113: 101–13

    Article  PubMed  CAS  Google Scholar 

  168. Di Minno G, Violi F. Aspirin resistance and diabetic angiopathy: back to the future. Thromb Res 2004; 113: 97–9

    Article  PubMed  CAS  Google Scholar 

  169. Fateh-Moghadam S, Plockinger U, Cabeza N, et al. Prevalence of aspirin resistance in patients with type 2 diabetes. Acta Diabetol 2005; 42: 99–103

    Article  PubMed  CAS  Google Scholar 

  170. Pulcinelli FM, Biasucci LM, Giubilato S, et al. Reduced platelet sensitivity to aspirin in type 2 diabetic subjects compared to nondiabetics. American College of Cardiology 55th Annual Scientific Session; 2006 Mar 11–14; Atlanta (GA): presentation 1023-165

  171. Watala C, Pluta J, Golansky J, et al. Increased protein glycation in diabetes mellitus is associated with decreased aspirin-mediated protein acetylation and reduced sensitivity of blood platelets to aspirin. J Mol Med 2005; 83: 148–58

    Article  PubMed  CAS  Google Scholar 

  172. Mullarkey CJ, Edelstein D, Brownlee M. Free radical generation by early glycation products: a mechanism for accelerated atherogenesis in diabetes. Biochem Biophys Res Commun 1990; 173: 932–9

    Article  PubMed  CAS  Google Scholar 

  173. Neri Serneri GG, Abbate R, Gensini GF, et al. TXA2 production by human arteries and veins. Prostaglandins 1983; 25: 753–65

    Article  PubMed  CAS  Google Scholar 

  174. Samama M, Conard J. Antithrombotic therapy in unique patient cohorts: diabetes, pregnancy, hypercoagulable syndromes, renal insufficiency. In: Kristensen SD, De Caterina R, Moliterno DJ, editors. Therapeutic strategies in thrombosis. Oxford: Clinical Publishing, 2006

    Google Scholar 

  175. Bueller HR, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease: the 7th ACCP Conference on antithrombotic and thrombolytic therapy. Chest 2004; 126 (3 Suppl.): 401-28S

    Google Scholar 

  176. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomised control trials. Arch Intern Med 1994; 154: 1449–57

    Article  Google Scholar 

  177. Varughese GI, Patel JV, Tomson J, et al. The prothrombotic risk of diabetes mellitus in atrial fibrillation and heart failure. J Thromb Haemost 2005; 3: 2811–3

    Article  PubMed  CAS  Google Scholar 

  178. Wehinger C, Stollberger C, Langer T, et al. Evaluation of risk factors for stroke/embolism and of complications due to anticoagulant therapy in atrial fibrillation. Stroke 2001; 32: 2246–52

    Article  PubMed  CAS  Google Scholar 

  179. Wittkowsky AK, Warfarin and other coumadin derivatives: pharmacokinetics, pharmacodynamics and drug interactions. Sem Vasc Med 2003; 3: 221–30

    Google Scholar 

  180. Gambaro G, Baggio B. Growth factors and the kidney in diabetes mellitus. Crit Rev Clin Lab Sci 1998; 35: 117–51

    Article  PubMed  CAS  Google Scholar 

  181. Wolf G, Ziyadeh FN, Zahner G, et al. Angiotensin II-stimulated expression of transforming growth factor beta in renal proximal tubular cells: attenuation after stable transfection with cmass oncogene. Kidney Int 1995; 48: 1818–27

    Article  PubMed  CAS  Google Scholar 

  182. Lovell HG. Angiotensin converting enzyme inhibitors in normotensive diabetic patients with microalbuminuria. Coch-rane Database Syst Rev 2001; 1: CD002183

    Google Scholar 

  183. Vernier RL, Steffes MW, Sissons-Ross S, et al. Heparan-sulphate proteoglycan in the glomerular membrane basement in type 1 diabetes mellitus. Kidney Int 1992; 41: 1070–80

    Article  PubMed  CAS  Google Scholar 

  184. Wasty F, Alavi MZ, Moore S. Distribution of glycosaminogly-cans in the intima in the human aorta: changes in atherosclerosis and diabetes mellitus. Diabetologia 1993; 36: 316–22

    Article  PubMed  CAS  Google Scholar 

  185. Myrup B, Hansen PM, Jensen T, et al. Effect of low-dose heparin on urinary albumin excretion in insulin-dependent diabetes mellitus. Lancet 1995; 345: 421–2

    Article  PubMed  CAS  Google Scholar 

  186. Van der Pijl JW, van der Woude FJ, Geelhoed-Duijvestijn PHLM, et al. Danaparoid sodium lowers proteinuria in diabetic nephropathy. J Am Soc Nephrol 1997; 8: 456–62

    PubMed  Google Scholar 

  187. Gambaro G, Skrha J, Ceriello A. Glycosaminoglycan therapy for long-term diabetic complications? Diabetologia 1998; 41: 975–9

    Article  PubMed  CAS  Google Scholar 

  188. Gambaro G. Cavazzana AO, Luzi P, et al. Glycosaminoglycans prevent morphological renal alterations and albuminuria in diabetic rats. Kidney Int 1992; 42: 285–91

    CAS  Google Scholar 

  189. Gambaro G, Kinalska I, Oksa A, et al. Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type I and type 2 diabetic patients: the Di.N.A.S. randomized trial. J Am Soc Nephrol 2002; 13: 1615–25

    Article  CAS  Google Scholar 

  190. Achour A, Kacem M, Dibej K, et al. One year course of oral sulodexide in the management of diabetic nephropathy. J Nephrol 2005; 18: 568–74

    PubMed  CAS  Google Scholar 

  191. Condorelli M, Chiariello M, Dagianti A, et al. IPO-V2: a prospective multicenter, randomized, comparative clinical investigation of effects of sulodexide in preventing cardiovascular accidents in the first year after acute myocardial infarction. J Am Coll Cardiol 1994; 23: 27–34

    Article  PubMed  CAS  Google Scholar 

  192. Coccheri S, Scondotto G, Agnelli G, et al. Sulodexide in the treatment of intermittent claudication: results of a randomized, double-blind, multicentre, placebo-controlled study. Eur Heart J 2002; 23: 1057–65

    Article  PubMed  CAS  Google Scholar 

  193. Boeri D, Maiello M, Lorenzi M. Increased prevalence of microthromboses in retinal capillaries of diabetic individuals. Diabetes 2001; 50: 1432–9

    Article  PubMed  CAS  Google Scholar 

  194. Cimponeriu D, Apostol P, Radu I, et al. Genetic bases of vascular complications in diabetes mellitus. In: Cheta D, editor. Vascular involvement in diabetes. Basel: Karger, 2005: 81–119

    Google Scholar 

  195. Henricsson M, Berntorp K, Fernlud P, et al. Progression of retinopathy in insulin-treated type 2 diabetic patients. Diabetes Care 2002; 25: 381–5

    Article  PubMed  Google Scholar 

  196. Negrisanu G, Diaconu L. Glycosaminoglycans in diabetic vasculopathy: hypotheses and current evidence. In: Cheta D, editor. Vascular involvement in diabetes. Basel: Karger, 2005: 625–44

    Google Scholar 

  197. Van der Pijl JW, van der Woude FJ, Swart W, et al. Effect of danaparoid sodium on hard exudates in diabetic retinopathy. Lancet 1997; 350: 1743–5

    Article  PubMed  Google Scholar 

  198. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular disease in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation 2007; 115: 114–26

    Article  PubMed  Google Scholar 

  199. Ryden L, Standl E, Bartnik M, et al., on behalf of Task Force Members. Guidelines on diabetes, pre-diabetes, and cardiovascular disease: executive summary. Eur Heart J 2007; 28: 88–136

    Article  PubMed  CAS  Google Scholar 

  200. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complica-tions in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854–65

    Article  Google Scholar 

  201. Vosper H, Khoudoli GA, Graham TL, et al. Peroxisome prolipherator-activated receptors agonists, hyperlipidemia and atherosclerosis. Pharmacol Ther 2002; 95: 47–62

    Article  PubMed  CAS  Google Scholar 

  202. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomized controlled trial. Lancet 2005; 366: 1279–89

    Article  PubMed  CAS  Google Scholar 

  203. Richter B, Bandeira-Echtler E, Bergerhoff K, et al. Pioglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev 2006; 18: CD006060

  204. Gerstein HC, Yusuf S, Bosch J, et al. DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006; 368: 1096–105

    PubMed  CAS  Google Scholar 

  205. Wannamethee SG, Shaper AG, Walker M. Overweight and obesity and weight change in middle aged men: impact on cardiovascular disease and diabetes. J Epidemiol Community Health 2005; 59: 134–9

    Article  PubMed  Google Scholar 

  206. Grundy SM, Cleeman JI, Mertz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program adult treatment: panel III guidelines. Circulation 2004; 110: 227–39

    Article  PubMed  Google Scholar 

  207. Vijan S, Hayward RA, American College of Physicians. Pharmacologic lipid-lowering therapy in type 2 diabetes mellitus: background paper for the American College of Physicians. Ann Intern Med 2004; 140: 650–8

    PubMed  CAS  Google Scholar 

  208. Collins R, Armitage J, Parish S, et al., on behalf of the Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361: 2005–16

    Article  PubMed  Google Scholar 

  209. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364: 685–96

    Article  PubMed  CAS  Google Scholar 

  210. Knopp RG, d’Emden M, Smilde JG, et al. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN). Diabetes Care 2006; 29: 1478–85

    Article  PubMed  CAS  Google Scholar 

  211. Shepherd J, Barter P, Carmena R, et al. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study. Diabetes Care 2006; 29: 1220–6

    Article  PubMed  CAS  Google Scholar 

  212. Wolffenbuttel BH, Franken AA, Vincent HH, et al. Cholesterol-lowering effects of rosuvastatin compared with atorvastatin in patients with type 2 diabetes: CORRAL study. J Intern Med 2005; 257: 531–9

    Article  PubMed  CAS  Google Scholar 

  213. Betteridge DJ, Gibson JM. Effects of rosuvastatin on lipids, lipoproteins and apolipoproteins in the dyslipidemia of diabetes. Diabet Med 2007 Mar 15. Epub

  214. Goldberg RB, Guyton JR, Mazzone T, et al. Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia: the VYTAL study. Mayo Clin Proc 2006; 81: 1579–88

    Article  PubMed  CAS  Google Scholar 

  215. Chu CS, Lee KT, Lee MY, et al. Effects of rosiglitazone alone and in combination with atorvastatin on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Am J Cardiol 2006; 97: 646–50

    Article  PubMed  CAS  Google Scholar 

  216. 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): randomised controlled trial. Lancet 2005; 26: 1849–61

    Google Scholar 

  217. Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 2001; 357: 905–10

    Article  Google Scholar 

  218. Keating GM, Croom KF. Fenofibrate: a review of its use in primary dyslipidemia, the metabolic syndrome and type 2 diabetes mellitus. Drugs 2007; 67 (1): 121–53

    Article  PubMed  CAS  Google Scholar 

  219. Wierzbicki AS. FIELDS of dreams, fields of tears: a perspective on the fibrate trial. Int J Clin Pract 2006; 60: 442–9

    Article  PubMed  CAS  Google Scholar 

  220. Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke. Stroke 2006; 37: 577–617

    Article  PubMed  Google Scholar 

  221. UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ 1998; 317: 703–13

    Article  Google Scholar 

  222. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPP) randomized trial. Lancet 1999; 353: 611–6

    Article  PubMed  CAS  Google Scholar 

  223. Tatti P, Pahor M, Byington RP, et al. Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998; 21: 597–603

    Article  PubMed  CAS  Google Scholar 

  224. Goff DC. Landmark study: the ALLHAT Study. Clin Diabetes 2003; 21: 102–4

    Article  Google Scholar 

  225. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253–9

    Article  Google Scholar 

  226. Verma S, Leiter LA, Lonn EM, et al. Perindopril in diabetes: perspective from the EUROPA substudy, PERSUADE. Eur Heart J 2005; 26: 1347–9

    Article  PubMed  CAS  Google Scholar 

  227. Solomon SD, Rice MM, A Jablonski K, et al. Renal function and effectiveness of angiotensin-converting enzyme inhibitor therapy in patients with chronic stable coronary disease in the Prevention of Events with ACE inhibition (PEACE) trial. Circulation 2006; 114: 26–31

    Article  PubMed  CAS  Google Scholar 

  228. Ruggenenti P, Fassi A, Ilieva AP, et al. Preventing microalbuminuria in type 2 diabetes: Bergamo Nephrologie Diabetes Complications Trial (BENEDICT) Investigators. N Engl J Med 2004; 351: 1941–51

    Article  PubMed  CAS  Google Scholar 

  229. Strippoli GF, Craig M, Schena FP, et al. Antihypertensive agents for primary prevention of diabetic nephropathy. J Am Soc Nephrol 2005; 16: 3081–91

    Article  PubMed  CAS  Google Scholar 

  230. Deferrari G, Ravera M, Deferrari L, et al. Renal and cardiovascular protection in type 2 diabetes mellitus: angiotensin II receptor blockers. J Am Soc Nephrol 2002; 3: S224–9

    Article  CAS  Google Scholar 

  231. Lindholm LH, Ibsen H, Dahlof B. Devereux RB, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 1004–10

    CAS  Google Scholar 

  232. Strippoli GF, Craig M, Deeks JJ, et al. Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonist on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ 2004; 329: 828

    Article  PubMed  CAS  Google Scholar 

  233. Fardoun RZ. Carvedilol versus cardioselective beta-blockers for the treatment of hypertension in patients with type 2 diabetes mellitus. Pharmacotheraphy 2006; 26: 1491–500

    Article  CAS  Google Scholar 

  234. Poierer L, Cleroux J, Nadeau A, et al. Effects of nebivolol and atenolol on insulin sensitivity and haemodynamics in hypertensive patients. Hypertens 2001; 19: 1429–35

    Article  Google Scholar 

  235. Scheen AJ. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus, part 1: a meta-analysis of randomised clinical trials. Diabetes Metab 2004; 30: 487–96

    Article  PubMed  CAS  Google Scholar 

  236. McCall KL, Craddock D, Edwards K. Effect of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers on the rate of new-onset diabetes mellitus: a review and pooled analysis. Pharmacotherapy 2006; 29: 1297–306

    Article  Google Scholar 

  237. Dahlof B, Sver PS, Poulter NR, et al. ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: 895–906

    Google Scholar 

  238. The DREAM Trial Investigators, Bosch J, Yusuf S, et al. Effect of ramipril on the incidence of diabetes. N Engl J Med 2006; 355: 1551–62

    Article  PubMed  Google Scholar 

  239. Elliot WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 2007; 369: 201–7

    Article  CAS  Google Scholar 

  240. Williams ME, Tuttle KR. The next generation of diabetic nephropathy therapies: an update. Adv Chronic Kidney Dis 2005; 12: 212–22

    Article  PubMed  Google Scholar 

  241. Signorelli S, Neri S, Di Pino L, et al. Effect of PLC on functional parameters and oxidative profile in type 2 diabetes-associated PAD. Diabetes Res Clin Pract 2006; 72: 231–7

    Article  CAS  Google Scholar 

  242. Ekberg K, Brismar T, Johansson BL, et al. C-peptide replacement therapy and sensory nerve function in type 1 diabetic neuropathy. Diabetes Care 2007; 30: 71–6

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The author did not receive any specific funding for the preparation of this manuscript. The author has not received any research grants during the last 5 years from pharmaceutical companies that manufacture the drugs discussed in this review. The author would like to acknowledge the collaboration of Dr Donatella Orlando in the literature search and organisation of this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sergio Coccheri.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Coccheri, S. Approaches to Prevention of Cardiovascular Complications and Events in Diabetes Mellitus. Drugs 67, 997–1026 (2007). https://doi.org/10.2165/00003495-200767070-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-200767070-00005

Keywords

Navigation