Bundó et al. Journal of Journal of Foot and Ankle Research (2023) 16:8 https://doi.org/10.1186/s13047-023-00602-6 Foot and Ankle Research RESEARCH Open Access Prediction of outcomes in subjects with type 2 diabetes and diabetic foot ulcers in Catalonian primary care centers: a multicenter observational study Magdalena Bundó1,2, Bogdan Vlacho1,3,4,5, Judit Llussà6, Isabel Bobé7, Meritxell Aivar8, Carmen Ciria9, Ana Martínez‑Sánchez10, Jordi Real1,11, Manel Mata‑Cases1,5,7, Xavier Cos1,12,13, Montserrat Dòria14, Jordi Viade15, Josep Franch‑Nadal1,5,16*   and Dídac Mauricio1,4,14,5,17*    Abstract Background Diabetic foot and lower limb complications are an important cause of morbidity and mortality among persons with diabetes mellitus. Very few studies have been carried out in the primary care settings. The main objec- tive was to assess the prognosis of diabetic foot ulcer (DFU) in patients from primary care centers in Catalonia, Spain, during a 12-month follow-up period. Methods We included participants with type 2 diabetes and a new DFU between February 2018 and July 2019. We estimated the incidence of mortality, amputations, recurrence and healing of DFU during the follow-up period. A multivariable analysis was performed to assess the association of these outcomes and risk factors. Results During the follow-up period, 9.7% of participants died, 12.1% required amputation, 29.2% had a DFU recur- rence, and 73.8% healed. Having a caregiver, ischemia or infection were associated with higher mortality risk (hazard ratio [HR]:3.63, 95% confidence interval [CI]:1.05; 12.61, HR: 6.41, 95%CI: 2.25; 18.30, HR: 3.06, 95%CI: 1.05; 8.94, respec- tively). Diabetic retinopathy was an independent risk factor for amputation events (HR: 3.39, 95%CI: 1.37; 8.39). Increas- ing age decreased the risk for a DFU recurrence, while having a caregiver increased the risk for this event (HR: 0.97, 95%CI: 0.94; 0.99). The need for a caregiver and infection decreased the probability of DFU healing (HR: 0.57, 95%CI: 0.39; 0.83, HR: 0.64, 95%CI: 0.42; 0.98, respectively). High scores for PEDIS (≥7) or SINBAD (≥3) were associated with an increased risk for DFU recurrence and a lower probability of DFU healing, respectively. Conclusions We observed high morbidity among subjects with a new DFU in our primary healthcare facilities. Peripheral arterial disease, infection, and microvascular complications increased the risk of poor clinical outcomes among subjects with DFU. *Correspondence: Josep Franch‑Nadal josep.franch@gmail.com Dídac Mauricio didacmauricio@gmail.com Full list of author information is available at the end of the article © The Author(s) 2023. 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The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Bundó et al. Journal of Foot and Ankle Research (2023) 16:8 Page 2 of 11 Background observational study in 36 primary care healthcare cent- Diabetic foot and lower limb complications are an important ers in Catalonia. The health care system in Catalonia is cause of morbidity and mortality among people with dia- public and universal to all residents. In each primary betes mellitus (DM) [1, 2]. People with diabetic foot ulcers care center, the health care user (patient) is allocated a (DFU) require more hospital visits and admissions than medical doctor and a nurse. The primary healthcare cent- those without this complication [3]. Disease-related compli- ers act as gatekeepers to access other healthcare levels cations such as DFU can negatively impact the patient’s qual- (secondary and tertiary care). In our study, people with ity of life, as well as increase healthcare costs [1, 2]. T2DM with a new DFU who attended one of the par- Primary healthcare centers are the patient’s first con- ticipating centers were included between February 1­ st, tact with the health system in many countries, and its 2018 and July 3­ 1st, 2019. The follow-up period was up to role in the prevention and treatment of chronic condi- 12 months or until premature discontinuation (death or tions such as DM and its complications is fundamental. loss to follow-up). The detailed methodology has been Therefore, the task of primary health professionals is previously published [15]. crucial for the prevention, early detection, and treat- ment of diabetic foot complications. Increasing the Study procedures knowledge and awareness of the risk factors that worsen During the first month after the inclusion, weekly follow- the prognosis of people with DFU at this level of the up visits for each participant were performed. After the healthcare system (i.e. primary care) is necessary to act first month, in case of active foot ulcers, follow-up vis- in a more focused, resourceful and decisive way. So far, its were scheduled monthly or more frequently when several studies on the prognosis of the diabetic foot and deemed necessary by the treating team. Upon foot ulcer its associated contributing factors have been carried out healing, follow-up visits were scheduled every three in hospital settings, in specialized diabetes clinics and months or until the end of the follow-up period. All of multidisciplinary foot centers [4–11]. However, very few the study procedures, data collection check-ups and ful- studies have been carried out in the primary care setting filment of good clinical practice were externally moni- [12, 13], and therefore the existing data at this level of the tored to ensure correct study practices. healthcare system are scarce. The International Working Group of the Diabetic Foot Definition of diabetic foot ulcer, study variables (IWGDF) has published an evidence-based guideline and outcomes concerning the classification of DFU and the use of clas- We defined a foot ulcer as a full-thickness lesion below sification systems in routine clinical practice [14]. Three the ankle, regardless of the presence of neuropathy and/ types of classifications have been defined: patient-related or peripheral artery disease. In individuals with more (morbidity of the patient, e.g., presence of chronic kidney than one ulcer at baseline, the most clinically relevant disease), limb-related (peripheral artery disease and loss lesion was selected as the index DFU. of protective sensation), and ulcer-related (area, depth, At the inclusion, for each participant in the study, we localization, number, and infection). The IWGDF [14] collected the following demographic and clinical infor- recommends these classifications to facilitate communi- mation (variables): socio-demographic characteristics cation among health professionals, for treatment guid- (age, gender, and self-reported ethnicity), toxic habits ance, and for audits of clinical outcomes in healthcare (smoking, alcohol intake), cardiovascular risk factors and units and populations, but does not recommend their use concomitant disease (hypertension, hyperlipidemia, pre- for prognostic purposes in patients with DM foot ulcers. vious history of stroke, ischemic heart disease, peripheral Indeed, there is a lack of information on the applicability artery disease, and heart failure), and data on diabetes of the different DFU classifications and their prognostic (disease duration, antidiabetic treatment, and previous value in primary care. diagnosis of diabetic microvascular complications such We carried out a multicenter study in Catalonia (Spain), as retinopathy, nephropathy, and peripheral neuropa- where the annual incidence of the occurrence of a new thy), and previous history of amputation or foot ulcers. DFU during the recruitment period was 0.42% [15]. In addition, for all participants, laboratory parameters were requested at inclusion for HbA1c, lipid profile, kid- Methods ney function, and clinical parameters such as body mass Aim, design and setting of the study index (BMI) and blood pressure were measured. We also The aim of the current study was to assess the clinical collected information related to visual acuity, degree of progression of DFU during a 12-month follow-up period mobility, caregiver access, and any podiatrist visits. in people with type 2 diabetes (T2DM) with a diagnosis At all study visits, the site researchers also collected of a new DFU. We conducted a prospective single-cohort information related to the DFU, such as duration, Bundó et al. Journal of Foot and Ankle Research (2023) 16:8 Page 3 of 11 location, the extension of ulcer after surgical debride- total person-time at risk during the follow-up period, ment (longest diameter multiplied by the second longest stratified by type of the DFU (ischemic, neuro-ischemic diameter of the ulcer), ulcer´s depth (superficial ulcer: or neuropathic). After this, we performed a univari- loss of superficial substance which does not penetrate ate and multivariable proportional hazards analysis to beyond the dermis; deep ulcer: loss of substance below assess the association of the main study outcomes and the dermis to subcutaneous structures or joint or bone risk factors, considering the follow-up time. The vari- exposure), presence or absence of infection, and infection ables included in the multivariable models were selected severity. based on the clinical criteria. A complete case-analysis The primary study outcomes were: mortality, amputa- was performed. Estimated measures of association were tion, recurrence and healing of DFU. Mortality was con- expressed as crude and adjusted hazards ratios (HRs) and sidered as death for any reason. The amputation event their 95% confidence intervals (95%CI). HRs are a meas- included both minor and major amputations. We defined ure of how often a particular event happens in one group a minor amputation as any surgical procedure resulting compared to how often it happens in another group over in an amputation of any part of the limb below the foot time. A HR of 1 indicates a lack of an association between ankle, and major amputation was defined as any ampu- the variable (e.g. age) and the event happening (e.g. mor- tation above the foot ankle. DFU recurrence was consid- tality), a HR greater than 1 indicates an increased risk of ered if a new ulcer appeared during the follow-up period the event happening, and a HR below 1 suggests a lower once the index ulcer had healed entirely. The healed DFU risk of the event happening. To prevent variable colline- was defined as a fully epithelialized lesion (with or with- arity, two different multivariable models were performed out amputation). for the PEDIS and SIMBAD variables. We used the cox. We used two DFU classification systems: the PEDIS zph function from the survival package in R (R statisti- classification [16], which evaluates variables such as cal software) to check the proportional hazards assump- Perfusion, Extent, Depth, Infection and Sensation, and tion of the Cox models [19]. Furthermore, we included the SINBAD classification [17] which includes variables R2 Nagelkerke as an appropriate measure of goodness related to the ulcer Site, Ischemia, Neuropathy, Bacte- of fit for each model. Additionally, assumptions of PH rial Infection and Depth based on a scale of 0 to 6. For Cox model were checked for each parameter [20, 21]. the PEDIS we used a scoring system (0 to 12) developed Thereafter, additional reduced models were done remov- by Chuan et al. [18] to facilitate the use of the PEDIS ing statistical non-significant variables. For this analysis in clinical practice. A PEDIS score of at least seven was we used the function cox.zph from {survival} R package considered clinically important, based on the study by (Version 3.3–1). The statistical analyses were performed Chuan et al. that found that patients with a PEDIS score using R3.6.1 (https://​www.r-​proje​ct.​org). of at least seven had an increased risk for the compos- ite endpoint of non-healing amputation and death [18]. Results For the SINBAD classification, we used a scoring sys- A total of 256 participants were included. The baseline tem (between 0 and 6) that was created by Ince et al. characteristics are presented in Table 1. Their mean age [17]; we considered a SINBAD score of at least three to was 72.2 (12.7) years. Mean diabetes duration was 13.5 be clinically important based on the study by Ince et al. (8.1) years, 69.5% were male, 51.6% were treated with [17] reporting that patients with a score of at least three insulin, 27.3% had a previous history of DFU, and 8.9% had a higher risk of non-healing of the ulcer (including had a previous amputation. Regarding comorbidities, amputation and death). 64.5% of participants had peripheral neuropathy, 65.5% had peripheral artery disease, 32% had diabetic retinopa- Statistical methods thy, and 57.8% had chronic kidney disease. Initially we carried out a descriptive analysis of the par- The highest mortality, amputation and DFU recurrence ticipants. The qualitative variables were described for rates were observed among the 113 (44.1%) participants number and frequency, and the quantitative variables with peripheral neuropathy and peripheral artery dis- were summarized by measures of central tendency and ease, while the highest healing rate and shortest time to dispersion (mean, median, standard deviation, inter- healing were observed among those without peripheral quartile range). Subsequently we estimated the incidence neuropathy or peripheral artery disease. Supplementary (cumulative and event rates) for different study outcomes Table 1 shows the events rates and cumulative incidence (mortality, amputations, recurrence and healing of DFU) for the different types of DFU. during the follow-up to determine the evolution of the In the un-adjusted HR analysis, age, being female, the ulcers and the prognosis. Each event rate was estimated presence of macrovascular complications, problems with as the number of new cases of the event divided by the mobility and the need for a caregiver was associated Bundó et al. Journal of Foot and Ankle Research (2023) 16:8 Page 4 of 11 Table 1 Baseline characteristics of the study participants Table 1 (Continued) Variable All participants Variable All participants (n = 256) (n = 256) Age, mean (SD), years 72.2 (12.7) Ulcer type,n (%) Gender, n (%) Neuropathic ulcers 52 (20.3) Male 178 (69.5) Neuro-ischemic ulcers 113 (44.1) Toxic habits, n (%) Ischemic ulcers 52 (20.3) Smokers 50 (19.5) Without peripheral neuropathy or ischemic 39 (15.3) disease Former smokers 88 (34.4) Infection status,n (%) Non-smokers 118 (46.1) No infection 150 (58.6) High-risk alcohol intake 14 (5.4) Infection 106 (41.4) Comorbidities, n (%) Neuropathy and infection 67 (26.1) Hypertension 207 (80.9) PAD and infection 65 (25.3) Hyperlipidemia 175 (68.4) SINBAD classification Stroke 37 (14.5) SINBAD, mean (SD) 2.48 (1.17) Ischemic heart disease 55 (21.5) SINBAD < 3 139 (54.3) Hearth failure 50 (19.5) SINBAD ≥ 3 117 (45.7) Peripheral artery disease 165 (64.5) PEDIS classification Macrovascular complications 101 (39.5) PEDIS, mean (SD) 5.21 (1.87) Retinopathy 82 (32.0) PEDIS < 7 191 (74.6%) Kidney disease 148 (57.8) PEDIS ≥ 7 65 (25.4%) Peripheral neuropathy 165 (64.5) BMI Body mass index, DFU Diabetic foot ulcer, HbA1c Glycated hemoglobin, Clinical variables PAD Peripheral arterial disease, SD Standard deviation; * superficial ulcer: loss of Diabetes duration, mean (SD), years 13.5 (8.1) superficial substance which does not penetrate beyond the dermis; deep ulcer: BMI, mean (SD), 29.6 (5.35)) loss of substance below the dermis to subcutaneous structures or joint or bone exposure HbA1c, mean (SD), %HbA1c, mean (SD), 7.9 (1.9) 61.3 (14.6) mmol/mol Foot characteristics,n(%) Previous history of DFU 70 (27.3) with an increased risk of mortality. Diabetic retinopathy, Any previous amputation 23 (8.9) chronic kidney disease, previous amputation history, or Any previous major amputation 2 (0.8) a baseline SINBAD score of 3 points or higher was asso- Foot deformities 104 (40.6) ciated with an increased risk of amputation. Diabetic Inadequate footwear 167 (65.2) retinopathy, a personal history of ulcers or amputations, Decreased visual acuity 112 (43.8) or a baseline PEDIS score of 7 points or higher increased Problems with mobility 106 (41.4) the risk for DFU recurrence, while age and being female Need of a caregiver 89 (34.8) decreased the risk for this event. Regarding non-healing, At least one podiatrist visit in the previous year 125 (48.8) a higher risk was associated with diabetes duration, dia- Ulcer site, n (%) betic retinopathy, chronic kidney disease, a personal his- Toes, plantar 31 (12.1) tory of amputation, frailty variables (mobility or having Toes, dorsal or interdigital aspect 112 (43.8) a caregiver), ischemia, infection and DFU depth. Table 2 Dorsal or lateral aspect of the foot 53 (20.7) shows the results of the unadjusted HR for the different Plantar forefoot or midfoot 23 (8.9) study outcomes and variables. Heel 37 (14.5) Regarding the multivariable analysis, the need for a Depth of the ulcer* caregiver, ischemia or infection were associated with a higher mortality risk. Diabetic retinopathy was an inde- Superficial ulcer 197 (77.0) pendent risk factor for amputation events. Increasing age Deep ulcer 59 (23.0) decreased the risk for a DFU recurrence, while having a Extension of the ulcer** caregiver increased the risk for this event. The need for ≤ 1 ­cm2    144 (56.2) a caregiver and the presence of infection decreased the   > ­1cm2 112 (43.8) probability of healing in the main model. For the addi- tional multivariable models, a PEDIS score of 7 points or higher was only associated with an increased risk of developing a new ulcer, while a SINBAD score of 3 points Bundó et al. Journal of Foot and Ankle Research (2023) 16:8 Page 5 of 11 or higher was only associated with a lower probability of Table 2 and 3 and Fig. 2 shows the multivariable analy- healing. Table 2 and Fig. 1 show the multivariable analysis sis for the PEDIS and SINBAD models. Checking the of risk factors for the main model, while Supplementary assumptions of PH Cox model, we observed that in the Table 2 Un-adjusted and adjusted hazards ratios for the main study outcomes Events Mortality Amputations DFU recurrence DFU healing (n = 25) (n = 31) (n = 75) (n = 189) Risk factors at baseline Un Adjusted Adjusted Un Adjusted Adjusted Un Adjusted Adjusted Un Adjusted Adjusted HR HR HR HR HR HR HR HR [95%CI] [95%CI] [95%CI] [95%CI] [95%CI] [95%CI] [95%CI] [95%CI] Age (SD) *1.06 1.00 1.01 1.02 *0.98 *0.97 0.99 0.98 [1.02;1.10] [0.94; 1.05] [0.98;1.04] [0.97; 1.06] [0.97;1.00] [0.95; 0.99] [0.98;1.00] [0.97; 1.00] Sex (female), ref.: male *2.58 2.01 0.82 0.71 0.58 NA 1.01 1.17 [1.17;5.65] [0.71; 5.72] [0.37;1.83] [0.24; 2.05] [0.33;1.01] [0.74;1.38] [0.83; 1.64] Current smoker, ref.: no 0.42 0.38 1.47 1.77 1.48 1.22 1.06 0.75 [0.12;1.44] [0.07; 2.13] [0.63;3.44] [0.65; 4.82] [0.84;2.60] [0.67; 2.22] [0.73;1.55] [0.50; 1.13] Any alcohol risk, ref.: no 0.91 1.41 1.97 2.04 1.48 1.35 0.83 NA [0.40;2.07] [0.47; 4.20] [0.97;4.01] [0.82; 5.05] [0.84;2.60] [0.98; 1.04] [0.61;1.11] Diabetes duration 1.02 1.00 1.02 0.98 *1.02 1.01 *0.98 0.98 [0.98;1.06] [0.95; 1.06] [0.98;1.06] [0.94; 1.03] [1.00;1.05] [0.98; 1.04] [0.96;0.99] [0.97; 1.01] Hypertension, ref.: no 1.61 0.78 1.12 0.78 0.75 0.85 0.81 0.98 [0.48;5.39] [0.18; 3.40] [0.43;2.93] [0.22; 2.86] [0.43;1.31] [0.42; 1.72] [0.57;1.16] [0.66; 1.45] Dislipidemia, ref.: no 0.82 0.57 0.82 0.48 0.74 0.64 0.95 1.06 [0.36;1.86] [0.22; 1.52] [0.39;1.71] [0.20; 1.15] [0.46;1.18] [0.38; 1.07] [0.70;1.29] [0.77; 1.47] Macrovascular complications, *3.67 1.08 1.19 1.37 1.38 1.31 0.81 1.00 ref.: no [1.58;8.52] [0.12; 10.12] [0.58;2.43] [0.25; 7.63] [0.87;2.18] [0.56; 3.07] [0.60;1.09] [0.62 1.60] Retinopathy, ref.: no 1.17 1.03 *2.97 *3.39 *1.64 1.17 *0.64 0.67 [0.50;2.72] [0.37; 2.86] [1.46;6.04] [1.37; 8.39] [1.03;2.61] [0.69; 1.98] [0.47;0.88] [0.47; 0.96] Chronic kidney disease (CKD), 2.11 0.79 *2.15 1.60 1.48 1.68 *0.55 0.73 ref.: no [0.96;4.66] [0.28; 2.22] [1.06;4.36] [0.66; 3.86] [0.92;2.37] [0.96; 2.94] [0.40;0.77] [0.51; 1.06 History of previous ulcers, 0.73 0.80 1.76 1.28 *1.85 NA 0.73 NA ref.: no [0.27;1.94] [0.23; 2.80] [0.85;3.64] [0.42; 3.91] [1.14;2.99] [0.52;1.00] History of previous amputa- 0.46 0.34 *3.08 1.30 *2.78 2.62 *0.55 0.64 tion, ref.: no [0.06;3.44] [0.03; 3.47] [1.32;7.18] [0.36; 4.70] [1.48;5.19] [1.26; 5.45] [0.33;0.94] [0.37; 1.11] HbA1c (%) 0.99 1.04 1.09 0.96 1.03 0.98 0.98 1.00 [0.79;1.24] [0.79; 1.36] [0.90;1.30] [0.77; 1.20] [0.91;1.16] [0.86; 1.12] [0.90;1.06] [0.91; 1.08] BMI 1.00 1.00 0.97 1.01 0.98 0.97 1.02 NA [0.93;1.08] [0.91; 1.10] [0.90;1.04] [0.92; 1.10] [0.93;1.02] [0.92; 1.02] [0.99;1.05] Decreased visual acuity, ref.: no 1.03 0.57 1.20 0.63 1.16 0.93 0.80 1.20 [0.47;2.26] [0.22; 1.51] [0.59;2.43] [0.27; 1.46] [0.74;1.83] [0.55; 1.57] [0.60;1.07] [0.87; 1.66] Problems with mobility, ref.: no *3.90 2.87 1.56 1.23 1.16 1.16 *0.64 NA [1.63;9.35] [0.84; 9.84] [0.77;3.15] [0.47; 3.24] [0.74;1.83] [0.65; 2.07] [0.48;0.86 Need of a caregiver, ref.: no *5.63 *3.63 2.00 2.26 1.51 *1.81 *0.52 *0.55 [2.35;13.5] [1.05; 12.61] [0.99;4.06] [0.92; 5.55] [0.95;2.40] [1.03; 3.19] [0.38;0.72] [0.39; 0.79] Ischemia, ref.: no *4.30 *6.41 *2.20 1.52 1.56 1.47 *0.62 0.84 [1.90;9.74] [2.25; 18.30] [1.08;4.45] [0.59; 3.87] [0.98;2.50] [0.83; 2.62] [0.45;0.85] [0.59; 1.18] Infection, ref.: no 1.07 *3.06 *3.33 2.26 1.38 1.50 *0.57 *0.63 [0.48;2.38] [1.05; 8.94] [1.57;7.08] [0.69; 7.36] [0.88;2.17] [0.76; 93] [0.42;0.77] [0.42; 0.96] Deep or very deep (Ref: 0.50 *0.09 *2.94 1.95 1.49 0.68 *0.55 0.64 superficial) [0.15;1.69] [0.02; 0.54] [1.45;5.97] [0.61; 6.24] [0.90;2.45] [0.30; 1.54] [0.38;0.80] [0.38; 1.07] DFU Extension: > 1 cm, ref. ≤1 1.09 0.72 0.85 1.84 1.07 NA 1.00 NA [0.88;1.34] [0.26; 1.94] [0.69;1.05] [0.82; 4.15] [0.94;1.21] [0.92;1.08] R2 Nagelkerke 0.217 0.218 0.126 0.234 Global p-value** 0.572 0.795 0.146 0.837 *In bold: statistically significant HR; BMI Body mass index, CI Confidence interval, DFU Diabetic foot ulcer, HbA1c Glycated hemoglobin, HR Hazard ratio, SD Standard deviation ** Proportional Hazards Assumption of a Cox Regression test NA: Estimation not evaluable because it cannot be assumed that it meets the Proportional Hazards Assumption of the COX models Bundó et al. Journal of Foot and Ankle Research (2023) 16:8 Page 6 of 11 Fig. 1 Associations of the main study outcomes with different risk factors, A) Mortality B) Amputations C) DFU recurrence D) DFU healing, BMI: body mass index; CKD: chronic kidney disease; CI: confidence intervals; DFU: diabetic foot ulcer; HbA1c: glycated hemoglobin; HR: hazard ratio additional reduced models the assumption of PH was not studies conducted in primary care settings, similar to rejected. In these reduced models, similar results were ours, Boyko et al. [12] performed a study in US veter- observed for the probability of occurrence of the study ans with a follow-up period of 22 years, where all of the events (recurrence and healing of DFU). These additional participants were males. The study carried out by Muller models are presented in Supplementary Table 4.1–4.12. et al. [13], which assessed the annual incidence of DFU and amputations among T2DM people registered in a Discussion database of 4,500 people with different chronic condi- Among the 256 participants with T2DM and a new DFU tions, used a different methodology to ours; around 677 in this multicenter prospective cohort study from differ- people with diabetes per year were studied between 1993 ent primary care centers in Catalonia, we found a high and 1998, with a reported annual incidence of DFU and risk for mortality, amputations and recurrence of a new amputation of 2.1% and 0.6%, respectively, however, the DFU. So far, similar studies to ours have been carried authors provided very few clinical data, precluding a out in a hospital setting or in multidisciplinary foot-care comparison with participants from our study. centers [4–11]. These studies differ from ours, especially In our cohort, we found a mortality rate of 9.7%. Three in the level of the healthcare system where participants hospital-based studies have reported mortality rates in were recruited, and also for the inclusion criteria, the people with DFU with similar follow-up periods to our definition of the foot ulcer, and the follow-up time, which study [6,8.9]. In the study by Prompers et al. [6] with make comparisons with our findings difficult. From the patients from 14 European hospitals, the authors reported Bundó et al. Journal of Foot and Ankle Research (2023) 16:8 Page 7 of 11 Fig. 2 Associations of the main study outcomes with different risk factors in PEDIS and SINBAD models, A) Mortality B) Amputations C) DFU recurrence D) DFU healing, BMI: body mass index; CKD: chronic kidney disease; CI: confidence intervals; DFU: diabetic foot ulcer; HbA1c: glycated hemoglobin; HR: hazard ratio lower mortality rates (6%). However, these people were among the people included in the study from Germany much younger (mean age 65 years) compared with our and the large number of smokers (43%) in the study participants (mean age 72.2 years). The other two hospi- from China, could partially explain these high mortality tal-based studies with similar follow-up periods reported rates. As early as 1990, Apelqvist [22] warned that dia- mortality rates much higher than in our study. The study betic patients with a foot ulcer are at high risk of death. carried out in Germany [8] with type 1 and type 2 diabetic A meta-analysis performed by Saluja et al. [23] and by patients showed a mortality rate of 15.4%, while a study Brownrigg et al. [24] showed that DFU is associated with carried out in China by Jiang et al. [9] reported mortal- an increased risk of all-cause mortality compared to those ity rates of 14.4%. The higher prevalence of comorbidities without foot ulceration. In our study, in the adjusted Bundó et al. Journal of Foot and Ankle Research (2023) 16:8 Page 8 of 11 model we did not find that macrovascular events (stroke, highlights that infection is the main variable that inter- ischemic heart disease, heart failure) were associated feres with healing. In a study by Prompers et al. [26] no with an increased risk of mortality in people with DFU as differences were observed for major amputation or heal- has been reported previously by other authors [5, 11]. In ing rate between neuropathic ulcers with and without the meta-analysis conducted by Brownrigg et al. [24] the infection, although infection was a risk factor for minor authors observed similar findings to ours regarding cardi- amputation. In contrast, infection was an independent ovascular events and mortality between people with DFU predictor of poor outcome in patients with peripheral and without DFU. In our study, we found an increase in arterial disease, but the prevalence of infection varied mortality among women compared to men, which some markedly between the centers (28–74%)[26]. authors have previously described and attributed to a Needing a caregiver was associated with an increased greater frailty in women with DFU [25]. We also observed risk of mortality and with DFU recurrence, while it was that ischemia and infection increased the risk of death in negatively associated with ulcer healing. The need for a our multivariable analysis. These variables are well-known caregiver may be regarded as a surrogate of frailty. It is well risk factors for a poor prognosis in subjects with DFU [26, known that frailty is a clinical syndrome associated with 27]. The inverse relationship between ulcer depth and dependence and mortality in the older adults, including mortality may be explained by the difficulty in measuring those with diabetes. Moreover, frailty may be a more pow- ulcer depth on many occasions [17, 28]. erful prognostic marker than the burden of comorbidity Regarding amputations, we observed 31 (9.7%) events itself [36–38]. This was also the case in the study by Gersh- during the follow-up period, much higher than the ater et al. [7], where the authors analyzed a cohort of 2,480 annual incidence of this event (0.6%) reported in the diabetics with a first ulcer and observed that patients with cohort study by Muller et al. [13]. In similar hospital- an informal caregiver patient were more likely to have a based studies, the incidences of amputation events major amputation or to have died before healing compared ranged from 0.05 to 19% [6, 11, 29]. Significant varia- to those who did not have a caregiver (odds ratio (OR): tion exists in the incidence of lower limb amputation 2.16, 95% CI 0.43 – 3.28. p < 0.005). The role of informal even within the same country [30, 31]. We found that caregivers remains largely unexplored, and its importance the association between amputation and retinopathy was is fundamental in the care of a patient with an ulcer [39]. consistent throughout all the models performed. This There are many classifications of people with diabe- association was previously described in other studies [32] tes mellitus and DFU [14]. The PEDIS classification was and indicates the importance of performing ophthalmic designed as an aid for prospective research [14]. Using this examinations in patients with DFU and increasing foot classification, Chuan et al. [18] created a scoring system care at the moment of diagnosis of diabetic retinopathy. with 364 diabetic foot patients treated in a hospital with Overall, 29.2% of participants in our study experienced a a mean follow up of 25 months. The study outcomes were recurrence of a new foot ulcer during the follow-up. There healed DFU and a combination of unhealed DFU, amputa- is great variability between the studies regarding this out- tion and death. They observed that a PEDIS classification come, ranging, for example, from 25% in a study by Muller score with a value of at least seven was associated with et al. [13], 32% in a study by Jiang et al. [9] and 43% in a the worst clinical prognosis of the patients. In our study, a study by Winkley et al. [5]. Age was negatively associated PEDIS score of ≥ 7 was associated with an increased risk of with DFU recurrence, however it is possible that some of ulcer recurrence during the follow-up period. the older adults in our study died before the DFU recur- Ince et al. [17] conducted a study with diabetic patients rence, and therefore this result should be interpreted with with foot ulcers from the UK, Germany, Tanzania and caution. The relationship between the history of ulcers or Pakistan to determine the prognostic value of the SINBAD amputation and recurrence of ulcers found in the univariate classification score for healing vs no healing, including analysis disappeared in the multivariable analysis, however amputation or death. The authors observed that despite this is in contrast to previous studies where both variables all the differences between countries, ulcers with a SIN- (history of ulcers or amputation) have been reported to be BAD score of at least 3 had a worse clinical prognosis. In poor prognostic factors for DFU recurrence [33]. the annual report of the UK National Diabetes Foot Care Regarding DFU healing, we found that in 73.8% of Audit [40] from 2018, with 19,453 patients with DFU, the participants the index ulcer healed with or without SINBAD classification was also used for the same purpose. amputation. Similar results were reported previously by It was observed that patients with a SINBAD score equal other authors [4, 6, 7, 34]. No relationship was observed to or greater than 3 were less likely to be alive and ulcer- between the ulcer’s depth, extension and healing, adjust- free at 12 and 24 months. Our study observed that a SIN- ing for different variables, in contrast to what has been BAD score ≥ 3 was associated with a risk of non-healing reported by other authors [26, 34, 35]. Our analysis during the 12 months follow up period. Bundó et al. Journal of Foot and Ankle Research (2023) 16:8 Page 9 of 11 This study has some limitations. We have no informa- Acknowledgements This study was possible thanks to the commitment of physicians and nurses tion on follow-up in 34 patients who discontinued the working in the Institut Català de la Salut (ICS), Mútua Terrassa, Alberta Salut and study. Some limitations, such as possible underreport- Badalona Serveis Assistencials (Supplementary Table 4). We thank the profession- ing, selection bias, and the absence of socioeconomic als who provided scientific, clinical and administrative support (Supplementary Table 5). We thank the Foundation redGDPS for support in conducting this study. data, as well as the absence of the prevalence of mental We thank Amanda Prowse for editorial support of this manuscript. health disorders (depression and anxiety) were previously acknowledged in a prior study [15]. Authors’ contributions MB, JL, I.B, M.A, C.C, A.M-S, M.D, J. V, X.C, M.M-C, J.F-N, BV, and DM contributed to study design and discussion. JR was involved in data management and Conclusions statistical analyses. M.B and BV wrote the first draft of the manuscript. All In conclusion, we observed high morbidity among subjects authors contributed to the analysis and interpretation of the data, provided critical input during the development of the manuscript and approved the with a new DFU seen in primary healthcare. As described final version for submission. MB had full access to all data in the study and in previous studies, peripheral arterial disease, infection, takes responsibility for data integrity and data analysis accuracy. The author(s) and microvascular complications increased the risk of read and approved the final manuscript. poor clinical outcomes. Further large population-based Funding primary healthcare studies are needed to evaluate the This study was supported by the Primary Care Diabetes Europe (PCDE) [grant association between different risk factors, especially frailty number PCDE2019/4]. The UAB-Novartis Chair of Teaching and Research in Family Medicine partially supported the project with an unrestricted grant. and severity outcomes of DFUs. Additionally, primary Primary Care Diabetes Europe (PCDE),PCDE2019/4,Magdalena Bundó healthcare professionals play a fundamental role in educat- ing people with DM and preventing complications, such Availability of data and materials The data that support the findings of this study are available from the Fun- as the diabetic foot. Likewise, these professionals must dación redGDPS. Restrictions apply to the availability of these data, due to the be aware of the importance of ruling out the presence of nature of the confidential data of the participants of the study. ischemia and infection in the evaluation and follow-up of DFUs, and to make a prompt referral to secondary/tertiary Declarations levels of care when necessary. Coordination between levels Ethics approval and consent to participate of healthcare must be fluid and coordinated. The IWGDF The study was approved by the IDIAP Jordi Gol Ethics Committee (protocol [14] advises using the SINBAD classification in commu- approval number P16 / 127), and all included participants signed a written nication between professionals in its latest recommenda- informed consent form. tions. Based on our experience, we believe it can also be a Consent for publication helpful tool for DFU disease course prognosis. Not applicable. Competing interests Abbreviations Manel Mata-Cases has received advisory and/or speaking fees from Astra-Zen- DM Diabetes mellitus eca, Bayer, Boehringer Ingelheim, GSK, Lilly, MSD, NOVARTIS, NovoNordisk, and IWGDF International Working Group of the Diabetic Foot Sanofi; he has received research grants to the institution from Astra-Zeneca, DFU Diabetic foot ulcers GSK, Lilly, MSD, Novartis, NovoNordisk, and Sanofi; he has received research HRs Hazards ratios grants from Institut Universitari d’Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol) (Barcelona, Spain), Instituto de Salud Carlos III (Madrid, Spain), Generalitat de Catalunya. Peris 2016–2020. The Strategic Plan for Health Supplementary Information Research and Innovation (Barcelona, Spain). The online version contains supplementary material available at https://​doi.​ Josep Franch-Nadal has received advisory and/or speaking fees from Astra- org/​10.​1186/​s13047-​023-​00602-6. Zeneca, Ascensia, Boehringer Ingelheim, GSK, Lilly, MSD, Novartis, NovoNord- isk, and Sanofi; he has received research grants to the institution from Astra- Zeneca, GSK, Lilly, MSD, Novartis, NovoNordisk, Sanofi, and Boehringer. Additional file 1: Supplementary Table 1. Event rates for different Dídac Mauricio has received advisory and/or speaking fees from Astra-Zeneca, types of DFU. Supplementary Table 2. Adjusted HR for different study Ascensia, Boehringer Ingelheim, Lilly, MSD, NovoNordisk, and Sanofi; he has outcomes in the PEDIS models. Supplementary Table 3. Adjusted HR received research grants to the institution from Astra-Zeneca, GSK, Lilly, MSD, for different study outcomes in the SINBAD model. Supplementary Novartis, NovoNordisk, Sanofi, and Boehringer. Table 4.1 DFU recurrence as outcome. Supplementary Table 4.2 Sup- Magdalena Bundó, Judit Llussà, Isabel Bobé, Meritxell Aivar, Carmen Ciria, Ana plementary Table 4.2 DFU recurrence as outcome. Supplementary Martínez-Sánchez have received advisory and speaking fees from MSD. Table 4.3 DFU healing as outcome. Supplementary Table 4.4 DFU Xavier Cos has received speaker’s bureau and advisory board honoraria from healing as outcome. Supplementary Table 4.5 PEDIS models for DFU AstraZeneca, Boehringer Ingelheim, Esteve, Lilly Diabetes, Novo Nordisk A/S, recurrence as outcome. Supplementary Table 4.6 PEDIS models for Roche, and Sanofi. DFU recurrence as outcome. Supplementary Table 4.7 PEDIS models for Jordi Real, Montserrat Dòria, Jordi Viade, and Bogdan Vlacho have no conflicts DFU healing as outcome. Supplementary Table 4.8 PEDIS models for of interest to declare. DFU healing as outcome. Supplementary Table 4.9 SINBAD models for DFU recurrence as outcome. Supplementary Table 4.10 SINBAD models Author details for DFU recurrence as outcome. Supplementary Table 4.11 SINBAD 1 DAP-Cat Group. Unitat de Suport a La Recerca Barcelona Ciutat, Institut models for DFU healing as outcome. Supplementary Table 4.12 SINBAD Universitari d’Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), 375, models for DFU healing as outcome. Supplementary table 5. Study site Entresuelo. 08025, Barcelona, Spain. 2 Primary Health Care Center Ronda Prim, investigators. Supplementary table 6. Scientific, clinical and administra- Gerència d’Àmbit d’Atenció Primària Metropolitana Nord de Barcelona, Institut tive support. Català de La Salut, Mataró, Spain. 3 Pharmacology Department, Universitat Bundó et al. Journal of Foot and Ankle Research (2023) 16:8 Page 10 of 11 Autònoma de Barcelona (UAB), Cerdanyola del Vallès, Spain. 4 Institut de 13. Muller IS, De Grauw WJC, Van Gerwen WHEM, et al (2002). 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