Top

Open Access 07-11-2024 | Myocardial Infarction | Article

Increased risk of major adverse cardiovascular events in patients with deep and infected diabetes-related foot ulcers

Authors: Nick S. R. Lan, Jonathan Hiew, Ivana Ferreira, J. Carsten Ritter, Laurens Manning, P. Gerry Fegan, Girish Dwivedi, Emma J. Hamilton

Published in: Diabetologia

Abstract

Aims/hypothesis

Diabetes-related foot ulceration (DFU) is associated with increased cardiovascular risk, but the mechanisms remain unclear. Inflammation and infection are mediators of CVD, which may be important in DFU.

Methods

Prospectively collected data from patients attending a multidisciplinary DFU service were analysed. A deep ulcer was defined as one that reached muscle, tendon or deeper structures. Patients were categorised into four DFU groups: not deep and no infection (D−/I−), not deep but infected (D−/I+), deep with no infection (D+/I−) or deep with infection (D+/I+). Incident major adverse cardiovascular events (MACE) were defined as hospitalisation for myocardial infarction, stroke or transient ischaemic attack, or heart failure. Survival analyses were performed using the logrank test and multivariate Cox regression.

Results

Of 513 patients, 241 (47.0%) were in the D−/I− group, 110 (21.4%) were in the D−/I+ group, 35 (6.8%) were in the D+/I− group and 127 (24.8%) were in the D+/I+ group. MACE or all-cause mortality occurred in 75 patients (14.6%), and MACE alone occurred in 46 patients (9.0%) after median follow-up of 381 days (IQR 220–551) and 404 days (IQR 228–576), respectively. Infection was associated with significantly higher MACE or all-cause mortality (21.5% vs 8.7%; p<0.001) and MACE alone (13.5% vs 5.1%; p=0.003). MACE or all-cause mortality was significantly higher in the D+/I+ group (D−/I− 7.9%; D−/I+ 15.5%; D+/I− 14.3%; D+/I+ 26.8%; p<0.001), as was MACE alone (D−/I− 5.0%; D−/I+ 10.9%; D+/I− 5.7%; D+/I+ 15.7%; p=0.017). Infection and a deep ulcer were independent predictors of adverse outcomes.

Conclusions/interpretation

Deep and/or infected DFUs are associated with increased cardiovascular risk compared with DFUs that are not deep or infected. These findings provide a potential mechanistic explanation that requires investigation.

Graphical Abstract

Available only for authorised users

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

Rastogi A, Goyal G, Kesavan R et al (2020) Long term outcomes after incident diabetic foot ulcer: multicenter large cohort prospective study (EDI−FOCUS investigators) epidemiology of diabetic foot complications study: epidemiology of diabetic foot complications study. Diabetes Res Clin Pract 162:108113. https://doi.org/10.1016/j.diabres.2020.108113CrossRefPubMed

Chammas NK, Hill RL, Edmonds ME (2016) Increased mortality in diabetic foot ulcer patients: the significance of ulcer type. J Diabetes Res 2016:2879809. https://doi.org/10.1155/2016/2879809CrossRefPubMedPubMedCentral

Chin BZ, Lee P, Sia CH, Hong CC (2024) Diabetic foot ulcer is associated with cardiovascular-related mortality and morbidity – a systematic review and meta-analysis of 8062 patients. Endocrine 84:852–863. https://doi.org/10.1007/s12020-024-03696-5CrossRefPubMed

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

Waheed FNM, Vangaveti VN, Malabu UH (2022) Ischemic heart disease and its risk factors in patients with diabetic foot ulcers: a systematic review and meta-analysis. Diabetes Metab Syndr 16(2):102414. https://doi.org/10.1016/j.dsx.2022.102414CrossRefPubMed

Schaper NC, van Netten JJ, Apelqvist J et al (2024) Practical guidelines on the prevention and management of diabetes-related foot disease (IWGDF 2023 update). Diabetes Metab Res Rev 40(3):e3657. https://doi.org/10.1002/dmrr.3657

Brownrigg JR, de Lusignan S, McGovern A et al (2014) Peripheral neuropathy and the risk of cardiovascular events in type 2 diabetes mellitus. Heart 100(23):1837–1843. https://doi.org/10.1136/heartjnl-2014-305657CrossRefPubMed

Dietrich I, Braga GA, de MeloCosta Silva Silva FGACC (2017) The diabetic foot as a proxy for cardiovascular events and mortality review. Curr Atheroscler Rep 19(11):44. https://doi.org/10.1007/s11883-017-0680-zCrossRefPubMed

10.

Brennan MB, Hess TM, Bartle B et al (2017) Diabetic foot ulcer severity predicts mortality among veterans with type 2 diabetes. J Diabetes Complications 31(3):556–561. https://doi.org/10.1016/j.jdiacomp.2016.11.020CrossRefPubMed

11.

Rubio JA, Jiménez S, Lázaro-Martínez JL (2020) Mortality in patients with diabetic foot ulcers: causes, risk factors, and their association with evolution and severity of ulcer. J Clin Med 9(9):3009. https://doi.org/10.3390/jcm9093009CrossRefPubMedPubMedCentral

12.

Sen P, Demirdal T (2020) Evaluation of mortality risk factors in diabetic foot infections. Int Wound J 17(4):880–889. https://doi.org/10.1111/iwj.13343CrossRefPubMedPubMedCentral

13.

Popa AD, Gavril RS, Popa IV et al (2023) Survival prediction in diabetic foot ulcers: a machine learning approach. J Clin Med 12(18):5816. https://doi.org/10.3390/jcm12185816CrossRefPubMedPubMedCentral

14.

Gazzaruso C, Gallotti P, Pujia A, Montalcini T, Giustina A, Coppola A (2021) Predictors of healing, ulcer recurrence and persistence, amputation and mortality in type 2 diabetic patients with diabetic foot: a 10-year retrospective cohort study. Endocrine 71(1):59–68. https://doi.org/10.1007/s12020-020-02431-0CrossRefPubMed

15.

Libby P, Loscalzo J, Ridker PM et al (2018) Inflammation, immunity, and infection in atherothrombosis: JACC review topic of the week. J Am Coll Cardiol 72(17):2071–2081. https://doi.org/10.1016/j.jacc.2018.08.1043CrossRefPubMedPubMedCentral

16.

Murphy SP, Kakkar R, McCarthy CP, Januzzi JL Jr (2020) Inflammation in heart failure: JACC state-of-the-art review. J Am Coll Cardiol 75(11):1324–1340. https://doi.org/10.1016/j.jacc.2020.01.014CrossRefPubMed

17.

Hansildaar R, Vedder D, Baniaamam M, Tausche AK, Gerritsen M, Nurmohamed MT (2021) Cardiovascular risk in inflammatory arthritis: rheumatoid arthritis and gout. Lancet Rheumatol 3(1):e58–e70. https://doi.org/10.1016/s2665-9913(20)30221-6CrossRefPubMed

18.

Ferguson LD, Siebert S, McInnes IB, Sattar N (2019) Cardiometabolic comorbidities in RA and PsA: lessons learned and future directions. Nat Rev Rheumatol 15(8):461–474. https://doi.org/10.1038/s41584-019-0256-0CrossRefPubMed

19.

Wu H, Hu T, Hao H, Hill MA, Xu C, Liu Z (2022) Inflammatory bowel disease and cardiovascular diseases: a concise review. Eur Heart J Open 2(1):oeab029. https://doi.org/10.1093/ehjopen/oeab029CrossRefPubMed

20.

Stotts C, Corrales-Medina VF, Rayner KJ (2023) Pneumonia-induced inflammation, resolution and cardiovascular disease: causes, consequences and clinical opportunities. Circ Res 132(6):751–774. https://doi.org/10.1161/circresaha.122.321636CrossRefPubMed

21.

Xie Y, Xu E, Bowe B, Al-Aly Z (2022) Long-term cardiovascular outcomes of COVID-19. Nat Med 28(3):583–590. https://doi.org/10.1038/s41591-022-01689-3CrossRefPubMedPubMedCentral

22.

Ntsekhe M, Baker JV (2023) Cardiovascular disease among persons living with HIV: new insights into pathogenesis and clinical manifestations in a global context. Circulation 147(1):83–100. https://doi.org/10.1161/circulationaha.122.057443CrossRefPubMed

23.

Weigelt C, Rose B, Poschen U et al (2009) Immune mediators in patients with acute diabetic foot syndrome. Diabetes Care 32(8):1491–1496. https://doi.org/10.2337/dc08-2318CrossRefPubMedPubMedCentral

24.

Tuttolomondo A, La Placa S, Di Raimondo D et al (2010) Adiponectin, resistin and IL-6 plasma levels in subjects with diabetic foot and possible correlations with clinical variables and cardiovascular co-morbidity. Cardiovasc Diabetol 9:50. https://doi.org/10.1186/1475-2840-9-50CrossRefPubMedPubMedCentral

25.

Zubair M, Malik A, Ahmad J (2012) 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. https://doi.org/10.4103/2230-8210.100672CrossRefPubMedPubMedCentral

26.

Goldfine AB, Shoelson SE (2017) Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk. J Clin Invest 127(1):83–93. https://doi.org/10.1172/jci88884CrossRefPubMedPubMedCentral

27.

Senneville É, Albalawi Z, van Asten SA et al (2024) IWGDF/IDSA guidelines on the diagnosis and treatment of diabetes-related foot infections (IWGDF/IDSA 2023). Diabetes Metab Res Rev 40(3):e3687. https://doi.org/10.1002/dmrr.3687CrossRefPubMed

28.

Worsley AL, Lui DH, Ntow-Boahene W, Song W, Good L, Tsui J (2023) The importance of inflammation control for the treatment of chronic diabetic wounds. Int Wound J 20(6):2346–2359. https://doi.org/10.1111/iwj.14048CrossRefPubMed

29.

Australian Bureau of Statistics (2023) Socio-economic indexes for areas. Available from https://www.abs.gov.au/websitedbs/censushome.nsf/home/seifa. Accessed 16 August 2024

30.

Hamilton EJ, Scheepers J, Ryan H et al (2021) Australian guideline on wound classification of diabetes-related foot ulcers: part of the 2021 Australian evidence-based guidelines for diabetes-related foot disease. J Foot Ankle Res 14(1):60. https://doi.org/10.1186/s13047-021-00503-6CrossRefPubMedPubMedCentral

31.

McDermott K, Fang M, Boulton AJM, Selvin E, Hicks CW (2023) Etiology, epidemiology, and disparities in the burden of diabetic foot ulcers. Diabetes Care 46(1):209–221. https://doi.org/10.2337/dci22-0043CrossRefPubMed

32.

Skrepnek GH, Mills JL Sr, Lavery LA, Armstrong DG (2017) Health care service and outcomes among an estimated 6.7 million ambulatory care diabetic foot cases in the US. Diabetes Care 40(7):936–942. https://doi.org/10.2337/dc16-2189CrossRefPubMed

33.

Armstrong DG, Boulton AJM, Bus SA (2017) Diabetic foot ulcers and their recurrence. N Engl J Med 376(24):2367–2375. https://doi.org/10.1056/NEJMra1615439CrossRefPubMed

34.

Pinto A, Tuttolomondo A, Di Raimondo D et al (2007) Ischemic stroke in patients with diabetic foot. Int Angiol 26(3):266–269PubMed

35.

Walsh JW, Hoffstad OJ, Sullivan MO, Margolis DJ (2016) Association of diabetic foot ulcer and death in a population-based cohort from the United Kingdom. Diabet Med 33(11):1493–1498. https://doi.org/10.1111/dme.13054CrossRefPubMed

36.

Stedman M, Robinson A, Dunn G et al (2023) Diabetes foot complications and standardized mortality rate in type 2 diabetes. Diabetes Obes Metab 25(12):3662–3670. https://doi.org/10.1111/dom.15260CrossRefPubMed

37.

Iversen MM, Tell GS, Riise T et al (2009) 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. https://doi.org/10.2337/dc09-0651CrossRefPubMedPubMedCentral

38.

Tuttolomondo A, Maida C, Pinto A (2015) Diabetic foot syndrome: immune–inflammatory features as possible cardiovascular markers in diabetes. World J Orthop 6(1):62–76. https://doi.org/10.5312/wjo.v6.i1.62CrossRefPubMedPubMedCentral

39.

Ridker PM, Everett BM, Thuren T et al (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377(12):1119–1131. https://doi.org/10.1056/NEJMoa1707914CrossRefPubMed

40.

Nidorf SM, Fiolet ATL, Mosterd A et al (2020) Colchicine in patients with chronic coronary disease. N Engl J Med 383(19):1838–1847. https://doi.org/10.1056/NEJMoa2021372CrossRefPubMed

41.

Sanz M, Marco Del Castillo A, Jepsen S et al (2020) Periodontitis and cardiovascular diseases: consensus report. J Clin Periodontol 47(3):268–288. https://doi.org/10.1111/jcpe.13189CrossRefPubMedPubMedCentral

42.

Dalager-Pedersen M, Søgaard M, Schønheyder HC, Nielsen H, Thomsen RW (2014) Risk for myocardial infarction and stroke after community-acquired bacteremia: a 20-year population-based cohort study. Circulation 129(13):1387–1396. https://doi.org/10.1161/circulationaha.113.006699CrossRefPubMed

43.

Corrales-Medina VF, deKemp RA, Chirinos JA et al (2021) Persistent lung inflammation after clinical resolution of community-acquired pneumonia as measured by ¹⁸FDG-PET/CT imaging. Chest 160(2):446–453. https://doi.org/10.1016/j.chest.2021.02.048CrossRefPubMedPubMedCentral

44.

Gallagher KA, Mills JL, Armstrong DG et al (2024) Current status and principles for the treatment and prevention of diabetic foot ulcers in the cardiovascular patient population: a scientific statement from the American Heart Association. Circulation 149(4):e232–e253. https://doi.org/10.1161/cir.0000000000001192CrossRefPubMed

45.

Young MJ, McCardle JE, Randall LE, Barclay JI (2008) Improved survival of diabetic foot ulcer patients 1995–2008: possible impact of aggressive cardiovascular risk management. Diabetes Care 31(11):2143–2147. https://doi.org/10.2337/dc08-1242CrossRefPubMedPubMedCentral

46.

Del Cuore A, Pipitone RM, Casuccio A et al (2023) Metabolic memory in diabetic foot syndrome (DFS): MICRO-RNAs, single nucleotide polymorphisms (SNPs) frequency and their relationship with indices of endothelial function and adipo-inflammatory dysfunction. Cardiovasc Diabetol 22(1):148. https://doi.org/10.1186/s12933-023-01880-xCrossRefPubMedPubMedCentral

47.

Amadou C, Carlier A, Amouyal C et al (2020) Five-year mortality in patients with diabetic foot ulcer during 2009–2010 was lower than expected. Diabetes Metab 46(3):230–235. https://doi.org/10.1016/j.diabet.2019.04.010CrossRefPubMed

48.

McGuire DK, Shih WJ, Cosentino F et al (2021) Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol 6(2):148–158. https://doi.org/10.1001/jamacardio.2020.4511CrossRefPubMed

49.

Neal B, Perkovic V, Mahaffey KW et al (2017) Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377(7):644–657. https://doi.org/10.1056/NEJMoa1611925CrossRefPubMed

50.

Fitridge R, Chuter V, Mills J et al (2024) The intersocietal IWGDF, ESVS, SVS guidelines on peripheral artery disease in people with diabetes and a foot ulcer. Diabetes Metab Res Rev 40(3):e3686. https://doi.org/10.1002/dmrr.3686CrossRefPubMed

Title: Increased risk of major adverse cardiovascular events in patients with deep and infected diabetes-related foot ulcers
Authors: Nick S. R. Lan
Jonathan Hiew
Ivana Ferreira
J. Carsten Ritter
Laurens Manning
P. Gerry Fegan
Girish Dwivedi
Emma J. Hamilton
Publication date: 07-11-2024
Publisher: Springer Berlin Heidelberg
Keywords: Myocardial Infarction
Heart Failure
Published in: Diabetologia
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-024-06316-z

Keynote series | Spotlight on menopause

Menopause
Video Series

Menopause can have a significant impact on the body, with effects ranging beyond the endocrine and reproductive systems. Learn about the broader systemic effects of menopause, so you can help patients in your clinics through the transition.

Launching: Thursday 12th December 2024

Prof. Martha Hickey

Dr. Claudia Barth

Dr. Samar El Khoudary

Developed by: Springer Medicine

Keynote webinar | Spotlight on adolescent vaping

Live
Webinar | 29-01-2025 | 18:00 (CET)

Growing numbers of young people are using e-cigarettes, despite warnings of respiratory effects and addiction. How can doctors tackle the epidemic, and what health effects should you prepare to manage in your clinics?

Watch it live: Wednesday 29th January, 18:00-19:30 CET

Prof. Ann McNeill

Dr. Debbie Robson

Benji Horwell

Developed by: Springer Medicine

Join the webinar

Keynote webinar | Spotlight on modern management of frailty

Frailty in Geriatric Patients
On-demand webinar

Frailty has a significant impact on health and wellbeing, especially in older adults. Our experts explain the factors that contribute to the development of frailty and how you can manage the condition and reduce the risk of disability, dependency, and mortality in your patients.

Prof. Alfonso Cruz-Jentoft

Prof. Barbara C. van Munster

Prof. Mirko Petrovic

Developed by: Springer Medicine

Watch now

A quick guide to ECGs

Electrocardiography
Training Course

Improve your ECG interpretation skills with this comprehensive, rapid, interactive course. Expert advice provides detailed feedback as you work through 50 ECGs covering the most common cardiac presentations to ensure your practice stays up to date.

PD Dr. Carsten W. Israel

Developed by: Springer Medizin

Start the cases

At a glance: The STEP trials

Obesity
Clinical Trial Summary

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote series | Spotlight on menopause

Springer Medicine

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Graphical Abstract

Please log in to get access to this content

Keynote series | Spotlight on menopause

Keynote webinar | Spotlight on adolescent vaping

Keynote webinar | Spotlight on modern management of frailty

A quick guide to ECGs

At a glance: The STEP trials