The Diabetic Foot as a Proxy for Cardiovascular Events and Mortality Review

  • Isa DietrichEmail author
  • Gustavo Arruda Braga
  • Fernanda Gomes de Melo
  • Ana Carolina Calmon da Costa Silva Silva
Lipid and Metabolic Effects of Gastrointestinal Surgery (R. Cohen, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Lipid and Metabolic Effects of Gastrointestinal Surgery


Purpose of Review

This article reviewed very recent papers (2016) discussing or bringing clinical evidences of the possible common pathways leading to diabetic foot syndrome (DFS) and increased mortality rates.

Recent Findings

Diabetic patients with diabetic foot syndrome have a mortality rate greater than twofold when compared with non-ulcerated diabetics. In addition, the 5-year mortality rate following amputation is estimated at 39–68%, a life expectancy comparable to aggressive types of cancer or advanced congestive heart failure. The majority of patients with diabetic foot ulcer also present insulin resistance, central obesity, dyslipidemia, and hypertension that characterize the metabolic syndrome that, in turn, is associated with an elevated risk of major cardiovascular events. Sensory neuropathy is the primary cause of more the 60% of diabetic foot ulcer. Diabetic peripheral neuropathy is a microvascular complication of diabetes mellitus and in type 2 diabetes, not only hyperglycemia but also other metabolic alterations and persistent inflammatory status due to adiposity play a major role in axon injury. Elevated triglycerides have been showed to be an independent risk factor for lower extremity amputation in diabetic patients. Also, toxic adiposity, oxidative stress, mitochondrial dysfunction, activation of the polyol pathway, accumulation of advanced glycation end products (AGEs), and elevation of inflammatory markers are also implicated in diabetic vascular disease and neuropathy.


The hypotheses that the association between DFS and increased rates of mortality reflects the progression of micro- and macrovascular complications are reinforced by the additional association of DFU to renal failure and retinopathy.


Diabetic foot syndrome Diabetes Neuropathy Microvascular disease Cardiovascular events Cardiovascular mortality Foot ulcer 


Compliance with Ethical Standards

Conflict of Interest

Isa Dietrich, Gustavo Arruda Braga, Fernanda Gomes de Melo, and Ana Carolina Calmon da Costa Silva declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Global report on diabetes. World Health Organization. 2016. Available at:
  2. 2.
    Mantovani AM, Fregonesi CE, Palma MR, Ribeiro FE, Fernandes RA, Christofaro DG. Relationship between amputation and risk factors in individuals with diabetes mellitus: a study with Brazilian patients. Diabetes Metab Syndr. 2017;11(1):47–50.CrossRefPubMedGoogle Scholar
  3. 3.
    Chammas NK, Hill RL, Edmonds ME. Increased mortality in diabetic foot ulcer patients: the significance of ulcer type. J Diabetes Res. 2016;2016:2879809.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Volmer-Thole M, Lobmann R. Neuropathy and diabetic foot syndrome. Int J Mol Sci. 2016;17(6):917.CrossRefPubMedCentralGoogle Scholar
  5. 5.
    Amin N, Doupis J. Diabetic foot disease: from the evaluation of the “foot at risk” to the novel diabetic ulcer treatment modalities. World J Diabetes. 2016;7(7):153–64.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Noor S, Khan RU, Ahmad J.Understanding Diabetic Foot Infection and its Management, In Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2017;11(2):149–156. Google Scholar
  7. 7.
    Boyko EJ, et al. Increased mortality associated with diabetic foot ulcer. Diabet Med. 1996;13:967–72.CrossRefPubMedGoogle Scholar
  8. 8.
    Rani V, Deep G, Singh RK, Palle K. Yadav UC oxidative stress and metabolic disorders: pathogenesis and therapeutic strategies. Life Sci. 2016;148:183–93.CrossRefPubMedGoogle Scholar
  9. 9.
    Pop-Busui R, Ang L, Holmes C, Gallagher K, Feldman EL. Inflammation as a therapeutic target for diabetic neuropathies. Curr Diabetes Rep. 2016;16(3):29. Scholar
  10. 10.
    Gómez-Marcos MÁ, Recio-Rodríguez JI, Patino-Alonso MC, et al. Evolution of target organ damage and haemodynamic parameters over 4 years in patients with increased insulin resistance: the LOD-DIABETES prospective observational study. BMJ Open. 2016;6(6):e010400. Scholar
  11. 11.
    Begun A, Morbach S, Rümenapf G, Icks A. Study of disease progression and relevant risk factors in diabetic foot patients using a multistate continuous-time markov chain model. PLoS One. 2016;11(1):e0147533.
  12. 12.
    Callaghan BC, Xia R, Banerjee M, de Rekeneire N, Harris TB, Health ABC Study, et al. Metabolic syndrome components are associated with symptomatic polyneuropathy independent of glycemic status. Diabetes Care. 2016;39(5):801–7.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Miric DJ, Kisic BM, Filipovic-Danic S, et al. Xanthine oxidase activity in type 2 diabetes mellitus patients with and without diabetic peripheral neuropathy. J Diabetes Res. 2016;2016:4370490, 7 pages.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Razzaghi R, et al. The effects of vitamin D supplementation on wound healing and metabolic status in patients with diabetic foot ulcer: a randomized, double-blind, placebo-controlled trial. J Diabetes Complicat. 2017;31(4):766–72. Published online in 2016CrossRefPubMedGoogle Scholar
  15. 15.
    Tesfaye S, Vileikyte L, Rayman G, Sindrup SH, Perkins BA, Baconja M, et al. Painful diabetic peripheral neuropathy: consensus recommendations on diagnosis, assessment and management. Diabetes Metab Res Rev. 2011;27:629–38.CrossRefPubMedGoogle Scholar
  16. 16.
    Lanting SM, Twigg SM, Johnson NA, Baker MK, Caterson ID, Chuter VH. Non-invasive lower limb small arterial measures co-segregate strongly with foot complications in people with diabetes. J Diabetes Complicat. 2017;31(3):589–93.CrossRefPubMedGoogle Scholar
  17. 17.
    Juster-Switlyk K, Smith AG. Updates in diabetic peripheral neuropathy. F1000 Research. 2016;5:F1000 Faculty Rev-738.  https://doi:10.12688/f1000research.7898.1.
  18. 18.
    Çakici N, Fakkel TM, van Neck JW, Verhagen AP, Coert JH. Systematic review of treatments for diabetic peripheral neuropathy. Diabet Med. 2016;33:1466–76.CrossRefPubMedGoogle Scholar
  19. 19.
    Jeffcoate WJ, et al. Medial arterial calcification in diabetes and its relationship to neuropathy. Diabetologia. 2009;52:2478–88.CrossRefPubMedGoogle Scholar
  20. 20.
    • Jhamb S, Vangaveti VN, Malabu UH. Genetic and molecular basis of diabetic foot ulcers: clinical review. J Tissue Viability. 2016;25(4):229–36. Discusses possible molecular targets linking diabetic foot and cardiovascular events. CrossRefPubMedGoogle Scholar
  21. 21.
    Wang Z, Li L, Du R, Yan J, Liu N, Yuan W, et al. CML/RAGE signal induces calcification cascade in diabetes. Diabetol Metab Syndr. 2016;8:83.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kay AM, Simpson CL, Stewart JA Jr. The role of AGE/RAGE signaling in diabetes-mediated vascular calcification. J Diabetes Res. 2016;
  23. 23.
    •• Roustit M, Loader J, Deusenbery C, Baltzis D, Veves A. Endothelial dysfunction asa link between cardiovascular risk factors and peripheral neuropathy in diabetes. J Clin Endocrinol Metab. 2016;101:3401–8. Discusses common molecular pathways correlating distal peripheral neuropathy and endothelial dysfunction. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kuehl M, Stevens MJ. Cardiovascular autonomic neuropathies as complications of diabetes mellitus. Nat Rev Endocrinol. 2012;28:405–16.CrossRefGoogle Scholar
  25. 25.
    Scognamiglio R, Avogaro A, Casara D, Crepaldi C, Marin M, Palisi M, et al. Myocardial dysfunction and adrenergic cardiac innervation in patients with insulin-dependent diabetes mellitus. J Am Coll Cardiol. 1998;31:404–12.CrossRefPubMedGoogle Scholar
  26. 26.
    O'Sullivan JJ, Conroy RM, MacDonald K, McKenna TJ, Maurer BJ. Silent ischaemia in diabetic men with autonomic neuropathy. Br Heart J. 1991;66:313–5.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Yun JS, Cha SA, Lim TS, Lee EY, Song KH, Ahn YB, et al. Cardiovascular autonomic dysfunction predicts diabetic foot ulcers in patients with type 2 diabetes without diabetic polyneuropathy. Medicine (Baltimore). 2016;95:12.Google Scholar
  28. 28.
    Kaptoge S, Di Angelantonio E, Lowe G, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375(9709):132–40.CrossRefPubMedGoogle Scholar
  29. 29.
    Jernberg T, Lindahl B, James S, Larsson A, Hansson LO, Wallentin L. Cystatin C: a novel predictor of outcome in suspected or confirmed non-ST-elevation acute coronary syndrome. Circulation. 2004;110(16):2342–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med. 2005;352(20):2049–60.CrossRefPubMedGoogle Scholar
  31. 31.
    Ogawa Y, Goto T, Tamasawa N, Matsui J, Tando Y, Sugimoto K, et al. Serum cystatin C in diabetic patients. Not only an indicator for renal dysfunction in patients with overt nephropathy but also a predictor for cardiovascular events in patients without nephropathy. Diabetes Res Clin Pract. 2008;79(2):357–61.CrossRefPubMedGoogle Scholar
  32. 32.
    Zhao J, Deng W, Zhang Y, Zheng Y, Zhou L, Boey J, et al. Association between serum cystatin C and diabetic foot ulceration in patients with type 2 diabetes: a cross-sectional study. J Diabetes Res. 2016;
  33. 33.
    • Baltzis D, Roustit M, Grammatikopoulou MG, Katsaboukas D, Athanasiou V, Iakovou I, et al. Diabetic peripheral neuropathy as a predictor of asymptomatic myocardial ischemia in type 2 diabetes mellitus: a cross-sectional study. Adv Ther. 2016;33(10):1840–7. Correlates the presence of any peripheral stenosis and number of stenosed arteries with cardiac events. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Mohammedi K, Woodward M, Hirakawa Y, et al. Presentations of major peripheral arterial disease and risk of major outcomes in patients with type 2 diabetes: results from the ADVANCE-ON study. Cardiovasc Diabetol. Mohammedi et al. Cardiovasc Diabetol. 2016;15:129.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    McFarlane SI, Sowers JR. Aldosterone function in diabetes mellitus: effects on cardiovascular and renal disease. J Clin Endocrinol Metab. 2003;88(2):516–23. Scholar
  36. 36.
    Dòria M, Rosado V, Pacheco LR, Hernández M, Betriu À, Valls J, et al. Prevalence of diabetic foot disease in patients with diabetes mellitus under renal replacement therapy in Lleida, Spain. Biomed Res Int. 2016;2016:7217586, 8 pages. Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Isa Dietrich
    • 1
    • 2
    Email author
  • Gustavo Arruda Braga
    • 2
  • Fernanda Gomes de Melo
    • 2
  • Ana Carolina Calmon da Costa Silva Silva
    • 2
  1. 1.Liver, Pancreas and Islets Transplantation, Surgery Division, Department of GastroenterologyUniversity of São Paulo School of Medicine. LIM 37Cerqueira CesarBrazil
  2. 2.Division Obesity and Diabetes CenterOrganization Oswaldo Cruz German HospitalBela VistaBrazil

Personalised recommendations