Skip to main content
SpringerLink
Log in

Metformin: Effects on Micro and Macrovascular Complications in Type 2 Diabetes

  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Introduction

The antihyperglycaemic agent metformin is widely used in the treatment of type 2 diabetes. Data from the UK Prospective Diabetes Study and retrospective analyses of large healthcare databases concur that metformin reduces the incidence of myocardial infarction and increases survival in these patients. This apparently vasoprotective effect appears to be independent of the blood glucose-lowering efficacy.

Effects of metformin

Metformin has long been known to reduce the development of atherosclerotic lesions in animal models, and clinical studies have shown the drug to reduce surrogate measures such as carotid intima-media thickness. The anti-atherogenic effects of metformin include reductions in insulin resistance, hyperinsulinaemia and obesity. There may be modest favourable effects against dyslipidaemia, reductions in pro-inflammatory cytokines and monocyte adhesion molecules, and improved glycation status, benefiting endothelial function in the macro- and micro-vasculature. Additionally metformin exerts anti-thrombotic effects, contributing to overall reductions in athero-thrombotic risk in type 2 diabetic patients.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Bailey CJ, Campbell IW, Chan JCN, et al. Metformin. The gold standard. Chichester: Wiley; 2007. p. 288.

    Google Scholar 

  2. Nathan DM, Buse JB, Davidson MB, Heine RJ, et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetologia. 2006;49:1711–21.

    Article  PubMed  CAS  Google Scholar 

  3. Krentz AJ, Bailey CJ. Oral antidiabetic agents: current role in type 2 diabetes mellitus. Drugs. 2005;65:384–411.

    Article  Google Scholar 

  4. Bailey CJ. Biguanides and NIDDM. Diabetes Care. 1992;15:755–72.

    Article  PubMed  CAS  Google Scholar 

  5. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:574–9.

    Article  PubMed  CAS  Google Scholar 

  6. Wiernsperger NF, Bailey CJ. The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms. Drugs. 1999;58:31–9.

    Article  PubMed  CAS  Google Scholar 

  7. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–74.

    PubMed  CAS  Google Scholar 

  8. Cusi K, DeFronzo RA. Metformin: a review of its metabolic effects. Diabetes Revs. 1998;6:89–130.

    Google Scholar 

  9. Howlett HCS, Bailey CJ. Risk-benefit assessment of metformin in type 2 diabetes. Drug Safety. 1999;20:489–503.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. Eckel RH, G rundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:1415–28.

    Article  PubMed  CAS  Google Scholar 

  12. 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;352:837–53.

    Article  Google Scholar 

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

    Article  Google Scholar 

  14. Holman RR. Invited presentation at 18th International Diabetes Federation Congress, Paris, 2003.

  15. Kao J, Tobis J, McClelland RL, et al. Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol. 2004;93:1347–50.

    Article  PubMed  CAS  Google Scholar 

  16. Kahn SE, Haffner SM, Heise MA, Herman WH, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427–43.

    Article  PubMed  CAS  Google Scholar 

  17. Cleland JGF, Atkin SL. Thiazolidinediones, deadly sins, surrogates and elephants. Lancet. 2007;370:1103–4.

    Article  PubMed  Google Scholar 

  18. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–8.

    Article  PubMed  CAS  Google Scholar 

  19. Evans JM, Ogston SA, Emslie-Smith MA, Morris A. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulphonylureas and metformin. Diabetologia. 2006;49:930–6.

    Article  PubMed  CAS  Google Scholar 

  20. Nichols GA, Koro CE, Gullion CM, et al. The incidence of congestive heart failure associated with antidiabetic therapies. Diabetes Metab Res Rev. 2005;21:51–7.

    Article  PubMed  CAS  Google Scholar 

  21. McAfee AT, Koro C, Landon J, et al. Coronary heart disease outcomes in patients receiving antidiabetic agents. Pharmacoepidemiol Drug Safety. 2007;16:711–25.

    Article  Google Scholar 

  22. Johnson JA, Majumdar SR, Simpson SH, Toth EL. Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care. 2002;25:2244–8.

    Article  PubMed  CAS  Google Scholar 

  23. Johnson JA, Simpson SH, Toth EL, Majumbar SR. Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with type 2 diabetes. Diabetic Med. 2005;22:497–502.

    Article  PubMed  CAS  Google Scholar 

  24. Eurich DT, Majumdar SR, McAlister FA, et al. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care. 2005;28:2345–51.

    Article  PubMed  CAS  Google Scholar 

  25. Masudi FA, Inzucchi SE, Wang Y, et al. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation. 2005;111:583–90.

    Article  CAS  Google Scholar 

  26. Eurich DT, McAlister FA, Blackburn DF, et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. Br Med J. 2007;335:458–9. DOI 10.1136/bmj.39314.620174.80.

    Article  CAS  Google Scholar 

  27. Roberts F, Ryan GJ. The safety of metformin in heart failure. Ann Pharmacother. 2007;41:462–6.

    Google Scholar 

  28. Jones GC, Macklin JP, Alexander WD. Contraindications to the use of metformin. Br Med J. 2003;326:4–5.

    Article  CAS  Google Scholar 

  29. Inzucchi SE. Metformin and heart failure: innocent until proven guilty. Diabetes Care. 2005;28:2585–7.

    Article  PubMed  Google Scholar 

  30. Holstein A, Stumvoll M. Contraindications can damage your health—is metformin a case in point? Diabetologia. 2005;48:2454–9.

    Article  PubMed  CAS  Google Scholar 

  31. Katakami N, Yamaski Y, Hayaishi-Okano R, et al. Metformin and gliclazide rather than glibenclamide attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes. Diabetologia. 2004;47:1906–13.

    Article  PubMed  CAS  Google Scholar 

  32. Matsumoto K, Sera Y, Abbe Y, et al. Metformin attenuates progression of carotid arterial wall thickness in patients with type 2 diabetes. Diabetes Res Clin Prac. 2004;64:2205–8.

    Article  CAS  Google Scholar 

  33. Orio F, Palomba S, Cascella T, et al. Improvement in endothelial structure and function after metformin treatment in young normal weight women with polycystic ovary syndrome: results of a 6-month study. J Clin Endocrinol Metab. 2005;90:6072–6.

    Article  PubMed  CAS  Google Scholar 

  34. Li L, Mamputu JC, Wiernsperger N, Renier G. Signalling pathways involved in human vascular smooth muscle cell proliferation and matrix metalloproteinase-2 expression induced by leptin: inhibitory effect of metformin. Diabetes. 2005;54:2227–34.

    Article  PubMed  CAS  Google Scholar 

  35. Sirtori CR, Franceschini G, Gianfranceschi G, et al. Metformin improves peripheral vascular in nonhyperlipidemic patients with arterial disease. J Cardiovasc Pharmacol. 1984;6:914–23.

    Article  PubMed  CAS  Google Scholar 

  36. Montaguti U, Cellin D, Ceredi C, Descovitch GC. Efficacy of the long-term administration of metformin in hyperlipidaemic patients. Res Clin Forums. 1979;1:95–103.

    Google Scholar 

  37. Wheatcroft SB, Williams IL, Shah AM, Kearney MT. Pathophysiological implications of insulin resistance on vascular endothelial function. Diabetic Med. 2003;20:255–68.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  39. Lyon CJ, Law RE, Hsueh WA. Adiposity, inflammation and atherogenesis. Endocrinology. 2003;144:2195–200.

    Article  PubMed  CAS  Google Scholar 

  40. Saenz A, Fernandez-Esteban I, Mataix A et al. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews, 2005, CD002966.

  41. Schafers RF. Do effects on blood pressure contribute to improved clinical outcomes with metformin? Diabetes Metab. 2003;29:62–70.

    Google Scholar 

  42. Wulffele MG, Kooy A, de Zeeuw D, et al. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med. 2004;256:1–14.

    Article  PubMed  CAS  Google Scholar 

  43. Lawrence JM, Reid J, Taylor GJ, et al. Favorable effects of pioglitazone and metformin compared with gliclazide on lipoprotein subfractions in overweight patients with early type 2 diabetes. Diabetes Care. 2004;27:41–6.

    Article  PubMed  CAS  Google Scholar 

  44. Ohira M, Miyashita Y, Ebisuno M, et al. Effect of metformin on serum lipoprotein lipase mass levels and LDL particle size in type 2 diabetes mellitus patients. Diabetes Res Clin Pract. 2007;78:34–41.

    Article  PubMed  CAS  Google Scholar 

  45. Chu NV, Kong AP, Kim DD, et al. Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes. Diabetes Care. 2002;25:542–9.

    Article  PubMed  CAS  Google Scholar 

  46. Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001;37:1344–50.

    Article  PubMed  CAS  Google Scholar 

  47. De Aguiar LG, Bahia LR, Villela N, et al. Metformin improves endothelial vascular reactivity in first degree relatives of type 2 diabetic patients with metabolic syndrome and normal glucose tolerance. Diabetes Care. 2006;29:1083–9.

    Article  PubMed  CAS  Google Scholar 

  48. Vitale C, Mercuro G, Cornoldi F, et al. Metformin improves endothelial function in patients with metabolic syndrome. J Intern Med. 2005;258:250–6.

    Article  PubMed  CAS  Google Scholar 

  49. Marfella R, Acampora R, Verrazzo G, et al. Metformin improves hemodynamic and fheological responses to L-arginine in NIDDM patients. Diabetes Care. 1996;19:934–9.

    Article  PubMed  CAS  Google Scholar 

  50. Asagami T, Abbasi F, Stuelinger M, et al. Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes. Metabolism. 2002;51:843–6.

    Article  PubMed  CAS  Google Scholar 

  51. Natale A, Baldeweg S, Toschi E, et al. Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes. Diabetes Care. 2004;27:1349–57.

    Article  Google Scholar 

  52. Kautzky-Willer A, ra A, Winzer C, et al. Insulin sensitivity during oral glucose tolerance test and its relation to parameters of glucose metabolism and endothelial function in type 2 diabetes subjects under metformin of thiazolidinedione. Diab Obesity Metab. 2006;8:561–7.

    Article  CAS  Google Scholar 

  53. Carantoni M, Abbasi F, Chu L, et al. Adherence of mononuclear cells to endothelium in vitro is increased in NIDDM. Diabetes Care. 1997;20:1462–6.

    Article  PubMed  CAS  Google Scholar 

  54. Mamputu JC, Wiernsperger N, Renier G. Metformin inhibits monocyte adhesion to endothelial cells and foam cell formation. Br J Diabetes Vasc Dis. 2003;3:302–10.

    CAS  Google Scholar 

  55. De Jager J, Kooy A, Lehert P. Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized placebo-controlled trial. J Intern Med. 2005;257:100–9.

    Article  PubMed  Google Scholar 

  56. Skrha J, Praznv M, Milgertova J, et al. Oxidative stress and endothelium influenced by metformin in type 2 diabetes mellitus. Eur J Clin Pharmacol. 2007;63:1107–14.

    Article  PubMed  CAS  Google Scholar 

  57. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–74.

    Article  PubMed  CAS  Google Scholar 

  58. Carter AM, Bennett CE, Bostock JA, Grant PJ. Metformin reduces C-reactive protein but not complement factor C3 in overweight patients with type 2 diabetes mellitus. Diabetic Med. 2005;22:1282–4.

    Article  PubMed  CAS  Google Scholar 

  59. Akbar DH. Effect of metformin and sulfonylurea on C-reactive protein level in well-controlled type 2 diabetics with metabolic syndrome. Endocrine. 2005;20:215–8.

    Article  Google Scholar 

  60. Morin-Papunen L, Rautio K, Ruokonen A, et al. Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88:4649–54.

    Article  PubMed  CAS  Google Scholar 

  61. Caballero AE, Degado A, Aguillar-Salinas CA, et al. The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo-controlled, randomized clinical trial. J Clin Endocrinol Metab. 2004;89:3943–8.

    Article  PubMed  CAS  Google Scholar 

  62. Hattori Y, Suzuki K, Hattori S, et al. Metformin inhibits cytokine-induced nuclear factor kappa B activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension. 2006;47:1183–8.

    Article  PubMed  CAS  Google Scholar 

  63. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114:597–605.

    Article  PubMed  CAS  Google Scholar 

  64. Meifen C, Jie X, Linuo Z, et al. Nonenzymatical glycation of protein in vitro and its inhibition by aminoguanidine or metformin. Acta Acad Med Shanghai. 1998;25:35–8.

    Google Scholar 

  65. Beisswenger P, Howell S, Touchette A, et al. Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Diabetes. 1999;48:198–202.

    Article  PubMed  CAS  Google Scholar 

  66. Wiernsperger NF. 50 years later: is metformin a vascular drug with antidiabetic properties? Br J Diabetes Vasc Dis. 2007;7:204–10.

    Article  CAS  Google Scholar 

  67. Pavlovic D, Kocic R, Kocic G, et al. Effect of four-week metformin treatment on plasma and erythrocyte antioxidative defense enzymes in newly diagnosed obese patients with type 2 diabetes. Diabetes Obesity Metab. 2000;2:251–6.

    Article  CAS  Google Scholar 

  68. Ouslimani N, Peynet J, Bonnefont-Rousselot D, et al. Metformin decreases intracellular production of reactive oxygen species in aortic endothelial cells. Metabolism. 2005;54:829–34.

    Article  PubMed  CAS  Google Scholar 

  69. Mahrouf M, Ouslimani N, Peynet J, et al. Metformin reduces angiotensin-mediated intracellular production of reactive oxygen species in endothelial cells through the inhibition of protein kinase C. Biochem Pharmacol. 2006;72:176–83.

    Article  PubMed  CAS  Google Scholar 

  70. Onaran I, Guven GS, Ozdas SB, et al. Metformin does not prevent DNA damage in lymphocytes despite its antioxidant properties against cumene hydroperoxide-induced oxidative stress. Mutation Res. 2006;611:1–8.

    PubMed  CAS  Google Scholar 

  71. Gargiulo P, Caccese D, Pignatelli P, et al. Metformin decreases platelet superoxide anion production in diabetic patients. Diabetes Metabolism Res Revs. 2002;18:156–9.

    Article  CAS  Google Scholar 

  72. Tessier D, Maheux P, Khalil A, Fulop T. Effects of gliclazide versus metformin on the clinical profile and lipid peroxidation markers in type 2 diabetes. Metabolism. 1999;48:897–903.

    Article  PubMed  CAS  Google Scholar 

  73. Wiernsperger NF. Metformin: intrinsic vasculoprotective properties. Diabetes Technol Therap. 2000;2:259–72.

    Article  CAS  Google Scholar 

  74. Mamputu JC, Wiernsperger NF, Renier G. Antiatherogenic properties of metformin: the experimental evidence. Diabetes Metab. 2003;29:6S71–76.

    Article  PubMed  CAS  Google Scholar 

  75. Marquie G. Effect of metformin on lipid metabolism in the rabbit aortic wall. Atherosclerosis. 1978;30:165–70.

    Article  PubMed  CAS  Google Scholar 

  76. Marquie G. Metformin action on lipid metabolism in lesions of experimental aortic atherosclerosis of rabbits. Atherosclerosis. 1983;47:7–17.

    Article  PubMed  CAS  Google Scholar 

  77. Chakrabarti R, Hocking ED, Fearnley GR. Fibrinolytic effect of metformin in coronary artery disease. Lancet. 1965;II:256–9.

    Article  Google Scholar 

  78. Hocking ED, Chakrabarti R, Evans J, Fearnley GR. Effects of biguanides and atromid on fibrinolysis. J Atheroscl Res. 1967;7:121–30.

    CAS  Google Scholar 

  79. Vague PH, Juhan-Vague I, Alessi MC, et al. Metformin decreases the high plasminogen activation inhibitor activity, plasma insulin and triglyceride levels in non-diabetic obese subjects. Thromb Haemostasis. 1987;57:326–8.

    CAS  Google Scholar 

  80. Grant PJ, Strickl;and MH, Booth NA, Prentice CRM. Metformin causes a reduction in basal and post-venous occlusion plasminogen activator inhibitor-1 in type 2 diabetic patients. Diabetic Med. 1991;8:361–5.

    Article  PubMed  CAS  Google Scholar 

  81. Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. Diabetes Care. 1993;16:621–9.

    Article  PubMed  CAS  Google Scholar 

  82. Grant PJ. The effect of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care. 1996;19:64–6.

    Article  PubMed  CAS  Google Scholar 

  83. Grant PJ. Metformin reduces circulating factor VII concentrations in patients with type 2 diabetes mellitus. Thromb Haemostasis 1998;80:209.

    Article  CAS  Google Scholar 

  84. He G, Pedersen SB, Bruun JM, et al. Metformin, but not thiazolidinediones, inhibits plasminogen activator inhibitor-1 production in human adipose tissue. Horm Metab Res. 2003;35:18–23.

    Article  PubMed  CAS  Google Scholar 

  85. Standeven KF, Ariens RAS, Whitaker P, et al. The effect of dimethyl biguanide on thrombin activity FXIII activation, fibrin polymerization and fibrin clot formation. Diabetes. 2002;51:189–97.

    Article  PubMed  CAS  Google Scholar 

  86. Grant PJ. Beneficial effects of metformin on haemostasis and vascular function in man. Diabetes Metab. 2003;29:6S44–52.

    PubMed  CAS  Google Scholar 

  87. Janka HU. Platelet and endothelial function tests during metformin treatment in diabetes mellitus. Horm Metab Res. 1985;12:120–2.

    Google Scholar 

  88. Gregorio F, Ambrosi F, Manfrini S. Poorly controlled elderly type 2 diabetic patients: the effects of increasing sulphonylurea dosages or adding metformin. Diabetic Med. 1999;16:1016–24.

    Article  PubMed  CAS  Google Scholar 

  89. Weichert W, Breddin K. Antithrombotic effects of metformin in laser injured arteries. Diabetes Metab. 1988;14:540–43.

    Google Scholar 

  90. Massad L, Plotkine M, Allix M, Boulu RG. Antithrombic drugs in a carotid occlusion model: beneficial effect of the antidiabetic agent metformin. Diabetes Metab. 1988;14:544–48.

    Google Scholar 

  91. Klein R. Hyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care. 1995;18:258–68.

    Article  PubMed  CAS  Google Scholar 

  92. 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;329:977–86.

    Article  Google Scholar 

  93. Wiernsperger NF, Bouskela E. Microcirculation in insulin resistance and diabetes: more than just a complication. Diabetes Metab. 2003;29:6S77–87.

    Article  PubMed  CAS  Google Scholar 

  94. Tooke JE. Microvascular function in human diabetes: a physiological perspective. Diabetes. 1995;44:721–6.

    Article  PubMed  CAS  Google Scholar 

  95. Stansberry KB, Shapiro SA, Hill MA, et al. Impaired peripheral vasomotion in diabetes. Diabetes Care. 1996;19:715–21.

    Article  PubMed  CAS  Google Scholar 

  96. Sartoretto JL, Melo GA, Carvalho MH, et al. Metformin treatment restores the altered micro-vascular reactivity in neonatal streptozotocin-induced diabetic rats by increasing NOS activity, but not NOS expression. Life Sci. 2005;77:2676–89.

    Article  PubMed  CAS  Google Scholar 

  97. Rapin JR, Lespinasse P, Yoa R. Effect of metformin on diabetic erythrocyte deformability in the presence of insulin: in vitro study on erythrocytes from diabetic patients. Diabetes Metab. 1988;14:610–12.

    Google Scholar 

  98. Valensi P, Behar A, Andre P, et al. The effects of metformin on the capillary permeability to albumin in women patients with cyclic edema. Angiology. 1995;46:401–8.

    PubMed  CAS  Google Scholar 

  99. Jyothirmayi GN, Soni BJ, Masurekar M, et al. Effects of metformin on collagen glycation and diastolic dysfunction in diabetic myocardium. J Cardiovasc Pharmacol Therap. 1998;3:319–26.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK

    Clifford J. Bailey

Authors
  1. Clifford J. Bailey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Clifford J. Bailey.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bailey, C.J. Metformin: Effects on Micro and Macrovascular Complications in Type 2 Diabetes. Cardiovasc Drugs Ther 22, 215–224 (2008). https://doi.org/10.1007/s10557-008-6092-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-008-6092-0

Key words

Search

Navigation