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Diabetic foot ulcer is associated with cardiovascular-related mortality and morbidity – a systematic review and meta-analysis of 8062 patients

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Abstract

Objectives

To conduct a systematic review and meta-analysis of prevalence of cardiovascular-related morbidity and mortality in patients with diabetic foot ulcers (DFU), as well as compare risks of cardiovascular-related morbidity and mortality between diabetic patients with and without DFU.

Methods

A systematic search was conducted on Medline, Embase, and Cochrane databases for randomized controlled trials and observational studies which explored the association between DFU and cardiovascular-related morbidity & mortality, or compared differences in hazard ratios of cardiovascular diseases between diabetics with and without DFU. Frequentist, pairwise meta-analysis was performed on studies with two comparator arms, whereas single-arm studies reporting pooled incidences of cardiovascular-related mortality and morbidity were calculated based on exact binomial distributions. A random-effect meta-analysis model was used with heterogenicity of studies assessed using I2, τ2, and χ2 statistics.

Results

10 studies were identified and included in the systematic review & meta-analysis of 8602 patients. DFU was consistently found to have significant association with cardiovascular-related morbidity and mortality, with pooled prevalences of all cause cardiovascular-related morbidity (37.1%), IHD (44.7%), CHF (25.1%), CAD (11.7%), and CVA (10.9%), and all cause cardiovascular-related mortality (14.6%), fatal IHD (6.2%), fatal CHF (3.67%), fatal CAD (7.92%), and fatal CVA (1.99%). Diabetic patients with DFU were found to have significantly increased risk of IHD (RR 1.25), CVA (RR 2.03), and all-cause cardiovascular-related mortality (RR 2.59) compared to those without DFU.

Conclusions

The presence of DFU is associated with major adverse cardiac events. The alarming rates of cardiovascular-related morbidity and mortality in DFU patients highlight its potential role as a marker of cardiovascular complications and should prompt early clinical investigation and management.

Highlights

  • There is a paucity of literature exploring risks of cardiovascular-related morbidity and mortality in patients with diabetic foot ulcers (DFU).

  • This systematic review and meta-analysis of proportions and risk ratios show that DFU is significantly associated with cardiovascular-related morbidity and mortality, and diabetic patients with DFU are significantly more likely to suffer from IHD, CVA, and all-cause cardiovascular-related mortality compared to those without DFU.

  • Our findings highlight the urgent need for assessment and prompt treatment of cardiovascular-related comorbidities in patients with DFU, so to limit its disease progression and reduce the risk of cardiac morbidity and mortality.

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References

  1. M.W. Sohn, R.M. Stuck, M. Pinzur, T.A. Lee, E. Budiman-Mak, Lower-extremity amputation risk after charcot arthropathy and diabetic foot ulcer. Diabetes Care 33(1), 98–100 (2010). https://doi.org/10.2337/dc09-1497

    Article  PubMed  Google Scholar 

  2. K.W. Tan, B.S.L. Dickens, A.R. Cook, Projected burden of type 2 diabetes mellitus-related complications in Singapore until 2050: a Bayesian evidence synthesis. BMJ Open Diabetes Res Care 8(1), (2020). https://doi.org/10.1136/bmjdrc-2019-000928

  3. J.H. Tan, C.C. Hong, L. Shen, E.Y. Tay, J.K. Lee, A. Nather, Costs of Patients Admitted for Diabetic Foot Problems. Ann. Acad. Med. Singap. 44(12), 567–570 (2015)

    Article  PubMed  Google Scholar 

  4. A. Pinto, A. Tuttolomondo, D. Di Raimondo et al. Cardiovascular risk profile and morbidity in subjects affected by type 2 diabetes mellitus with and without diabetic foot. Metabolism 57(5), 676–682 (2008). https://doi.org/10.1016/j.metabol.2008.01.004

    Article  CAS  PubMed  Google Scholar 

  5. A. Tuttolomondo, C. Maida, A. Pinto, Diabetic Foot Syndrome as a Possible Cardiovascular Marker in Diabetic Patients. J. Diabetes Res. 2015, 268390 (2015). https://doi.org/10.1155/2015/268390

    Article  PubMed  PubMed Central  Google Scholar 

  6. M.J. Young, J.E. McCardle, L.E. Randall, J.I. Barclay, Improved survival of diabetic foot ulcer patients 1995–2008: possible impact of aggressive cardiovascular risk management. Diabetes Care 31(11), 2143–2147 (2008). https://doi.org/10.2337/dc08-1242

    Article  PubMed  PubMed Central  Google Scholar 

  7. J.R. Brownrigg, M. Griffin, C.O. Hughes et al. Influence of foot ulceration on cause-specific mortality in patients with diabetes mellitus. J. Vasc. Surg. 60(4), 982–986.e983 (2014). https://doi.org/10.1016/j.jvs.2014.04.052

    Article  PubMed  Google Scholar 

  8. J.A. Rubio, S. Jiménez, J.L. Lázaro-Martínez, Mortality in Patients with Diabetic Foot Ulcers: Causes, Risk Factors, and Their Association with Evolution and Severity of Ulcer. J. Clin. Med. 9(9) (2020). https://doi.org/10.3390/jcm9093009

  9. H. Forde, S. Wrigley, L.T. O’Murchadha et al. Five-year outcomes of patients attending a diabetic foot clinic in a tertiary referral centre. Ir. J. Med. Sci. 189(2), 511–515 (2020). https://doi.org/10.1007/s11845-019-02108-2

    Article  PubMed  Google Scholar 

  10. O.O. Adeleye, E.T. Ugwu, I.D. Gezawa, I. Okpe, I. Ezeani, M. Enamino, Predictors of intra-hospital mortality in patients with diabetic foot ulcers in Nigeria: data from the MEDFUN study. BMC Endocr. Disord. 20(1), 134 (2020). https://doi.org/10.1186/s12902-020-00614-4

    Article  PubMed  PubMed Central  Google Scholar 

  11. K. Jeyaraman, T. Berhane, M. Hamilton, A.P. Chandra, H. Falhammar, Mortality in patients with diabetic foot ulcer: a retrospective study of 513 cases from a single Centre in the Northern Territory of Australia. BMC Endocr. Disord. 19(1), 1 (2019). https://doi.org/10.1186/s12902-018-0327-2

    Article  PubMed  PubMed Central  Google Scholar 

  12. D.C. Jupiter, J.C. Thorud, C.J. Buckley, N. Shibuya, The impact of foot ulceration and amputation on mortality in diabetic patients. I: From ulceration to death, a systematic review. Int. Wound J. 13(5), 892–903 (2016). https://doi.org/10.1111/iwj.12404

    Article  PubMed  Google Scholar 

  13. J.R. Brownrigg, J. Davey, P.J. Holt et al. The association of ulceration of the foot with cardiovascular and all-cause mortality in patients with diabetes: a meta-analysis. Diabetologia 55(11), 2906–2912 (2012). https://doi.org/10.1007/s00125-012-2673-3

    Article  CAS  PubMed  Google Scholar 

  14. L. Chen, S. Sun, Y. Gao, X. Ran, Global mortality of diabetic foot ulcer: A systematic review and meta-analysis of observational studies. Diabetes Obes. Metab. 25(1), 36–45 (2023). https://doi.org/10.1111/dom.14840

    Article  PubMed  Google Scholar 

  15. M.J. Page, J.E. McKenzie, P.M. Bossuyt et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372, n71 (2021). https://doi.org/10.1136/bmj.n71

    Article  PubMed  PubMed Central  Google Scholar 

  16. M.M. Iversen, G.S. Tell, T. Riise et al. History of foot ulcer increases mortality among individuals with diabetes: ten-year follow-up of the Nord-Trøndelag Health Study, Norway. Diabetes Care 32(12), 2193–2199 (2009). https://doi.org/10.2337/dc09-0651

    Article  PubMed  PubMed Central  Google Scholar 

  17. J.A. Rubio, S. Jiménez, J. Álvarez, Clinical characteristics and mortality in patients treated in a Multidisciplinary Diabetic Foot Unit. Endocrino.l Diabetes Nutr. 64(5), 241–249 (2017). https://doi.org/10.1016/j.endinu.2017.02.012

    Article  Google Scholar 

  18. S. Junrungsee, N. Kosachunhanun, A. Wongthanee, K. Rerkasem, History of foot ulcers increases mortality among patients with diabetes in Northern Thailand. Diabet Med. 28(5), 608–611 (2011). https://doi.org/10.1111/j.1464-5491.2011.03262.x

    Article  CAS  PubMed  Google Scholar 

  19. M.W. Sohn, T.A. Lee, R.M. Stuck, R.G. Frykberg, E. Budiman-Mak, Mortality risk of Charcot arthropathy compared with that of diabetic foot ulcer and diabetes alone. Diabetes Care 32(5), 816–821 (2009). https://doi.org/10.2337/dc08-1695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. S. Saluja, S.G. Anderson, I. Hambleton et al. Foot ulceration and its association with mortality in diabetes mellitus: a meta-analysis. Diabet Med. 37(2), 211–218 (2020). https://doi.org/10.1111/dme.14151

    Article  CAS  PubMed  Google Scholar 

  21. L. Qiu, Y. Li, C. Yang et al. Influence of Foot Ulceration on All-Cause and Cardiovascular Mortality in Diabetic Patients: A Case-Control Study. J. Wound Ostomy Continence Nurs. 49(2), 175–179 (2022). https://doi.org/10.1097/won.0000000000000856

    Article  PubMed  Google Scholar 

  22. N.K. Chammas, R.L. Hill, M.E. Edmonds, Increased Mortality in Diabetic Foot Ulcer Patients: The Significance of Ulcer Type. J. Diabetes Res. 2016, 2879809 (2016). https://doi.org/10.1155/2016/2879809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. E. Everett, N. Mathioudakis, Update on management of diabetic foot ulcers. Ann. N. Y. Acad. Sci. 1411(1), 153–165 (2018). https://doi.org/10.1111/nyas.13569

    Article  PubMed  PubMed Central  Google Scholar 

  24. N. Pechlivani, R.A. Ajjan, Thrombosis and Vascular Inflammation in Diabetes: Mechanisms and Potential Therapeutic Targets. Front. Cardiovasc. Med. 5, 1 (2018). https://doi.org/10.3389/fcvm.2018.00001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. A. Berbudi, N. Rahmadika, A.I. Tjahjadi, R. Ruslami, Type 2 Diabetes and its Impact on the Immune System. Curr. Diabetes Rev. 16(5), 442–449 (2020). https://doi.org/10.2174/1573399815666191024085838

    Article  PubMed  PubMed Central  Google Scholar 

  26. B. Stancu, T. Ilyés, M. Farcas, H.F. Coman, B.A. Chiș, O.A. Andercou, Diabetic Foot Complications: A Retrospective Cohort Study. Int. J. Environ. Res. Public Health 20(1) (2022). https://doi.org/10.3390/ijerph20010187

  27. J. Wang, K. Chen, X. Li et al. Postoperative adverse events in patients with diabetes undergoing orthopedic and general surgery. Medicine 98(14), e15089 (2019). https://doi.org/10.1097/md.0000000000015089

    Article  PubMed  PubMed Central  Google Scholar 

  28. S. Sudhakaran, S.R. Surani, Guidelines for Perioperative Management of the Diabetic Patient. Surg. Res. Pract. 2015, 284063 (2015). https://doi.org/10.1155/2015/284063

    Article  PubMed  PubMed Central  Google Scholar 

  29. M. Zubair, A. Malik, J. Ahmad, Plasma adiponectin, IL-6, hsCRP, and TNF-α levels in subject with diabetic foot and their correlation with clinical variables in a North Indian tertiary care hospital. Indian J. Endocrinol. Metab. 16(5), 769–776 (2012). https://doi.org/10.4103/2230-8210.100672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. V. Chuter, F. Quigley, P. Tosenovsky et al. Australian guideline on diagnosis and management of peripheral artery disease: part of the 2021 Australian evidence-based guidelines for diabetes-related foot disease. J. Foot Ankle Res. 15(1), 51 (2022). https://doi.org/10.1186/s13047-022-00550-7

    Article  PubMed  PubMed Central  Google Scholar 

  31. S. Morbach, H. Furchert, U. Gröblinghoff et al. Long-term prognosis of diabetic foot patients and their limbs: amputation and death over the course of a decade. Diabetes Care 35(10), 2021–2027 (2012). https://doi.org/10.2337/dc12-0200

    Article  PubMed  PubMed Central  Google Scholar 

  32. L. Prompers, M. Huijberts, J. Apelqvist et al. High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia 50(1), 18–25 (2007). https://doi.org/10.1007/s00125-006-0491-1

    Article  CAS  PubMed  Google Scholar 

  33. C. Gazzaruso, A. Coppola, C. Falcone et al. Transcutaneous oxygen tension as a potential predictor of cardiovascular events in type 2 diabetes: comparison with ankle-brachial index. Diabetes Care 36(6), 1720–1725 (2013). https://doi.org/10.2337/dc12-1401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. B. Neal, V. Perkovic, D.R. Matthews, Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N. Engl. J. Med. 377(21), 2099 (2017). https://doi.org/10.1056/NEJMc1712572

    Article  PubMed  Google Scholar 

  35. S. Zerovnik, M. Kos, I. Locatelli, Cardiovascular morbidity and mortality in patients with type 2 diabetes using novel antidiabetic medicines as add-on therapy: an observational real-world study. BMJ Open 11(9), e051549 (2021). https://doi.org/10.1136/bmjopen-2021-051549

    Article  PubMed  PubMed Central  Google Scholar 

  36. R.M. See, Y.N. Teo, Y.H. Teo et al. Effects of Sodium-Glucose Cotransporter 2 on Amputation Events: A Systematic Review and Meta-Analysis of Randomized-Controlled Trials. Pharmacology 107(3-4), 123–130 (2022). https://doi.org/10.1159/000520903

    Article  CAS  PubMed  Google Scholar 

  37. D. Mozaffarian, Global Scourge of Cardiovascular Disease: Time for Health Care Systems Reform and Precision Population Health. J. Am. Coll. Cardiol. 70(1), 26–28 (2017). https://doi.org/10.1016/j.jacc.2017.05.007

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, National University Health System, Level 11 Tower Block, 1E, Lower Kent Ridge Road, Singapore, 119228, Singapore

    Brian Zhaojie Chin, Peng Lee & Choon Chiet Hong

  2. Department of Cardiology, National University Heart Centre Singapore, NUHS Tower Block Level 9, 1E Kent Ridge Road, Singapore, 119228, Singapore

    Ching-Hui Sia

  3. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block Level 10, 1E Kent Ridge Road, Singapore, 119228, Singapore

    Ching-Hui Sia

  4. Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block Level 10, 1E Kent Ridge Road, Singapore, 119228, Singapore

    Choon Chiet Hong

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Chin, B.Z., Lee, P., Sia, CH. et al. Diabetic foot ulcer is associated with cardiovascular-related mortality and morbidity – a systematic review and meta-analysis of 8062 patients. Endocrine (2024). https://doi.org/10.1007/s12020-024-03696-5

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