TYPE Original Research PUBLISHED 24 October 2022 DOI 10.3389/fendo.2022.1024904 Prevalence and risk factors of OPEN ACCESS diabetic foot disease among the EDITED BY Sen Li, Beijing University of Chinese Medicine, people with type 2 diabetes China REVIEWED BY using real-world practice data Legese Kumsa, Addis Ababa University, Ethiopia Srikanth Bellary, from Catalonia during 2018 Aston University, United Kingdom Michael Edwin Edmonds, King’s College Hospital NHS Magdalena Bundó 1,2†, Bogdan Vlacho 1,3,4†, Judit Llussà 5, Foundation Trust, United Kingdom Ramon Puig-Treserra 1, Manel Mata-Cases 1,6,7, Xavier Cos 1,8,9, *CORRESPONDENCE Edward B. Jude 10,11, Josep Franch-Nadal 1,7,12* Dı´dac Mauricio didacmauricio@gmail.com and Dı́dac Mauricio 1,4,7,13,14* Josep Franch-Nadal josep.franch@gmail.com 1 Diabetes des de Atención Primaria-Cat group. Unitat de Suport a la Recerca Barcelona Ciutat, † Institut Universitari d’Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Barcelona, Spain, These authors have contributed 2 Primary Health Care Center Ronda Prim, Gerència d’Àmbit d’Atenció Primària Metropolitana Nord equally to this work and share de Barcelona, Institut Català de la Salut, Mataró, Spain, 3 Department of Pharmacology, Universitat first authorship Autònoma de Barcelona (UAB), Cerdanyola del Vallès, Spain, 4 Institut de Recerca Hospital de la SPECIALTY SECTION Santa Creu i Sant Pau, Barcelona, Spain, 5 Primary Health Care Centre Sant Roc, Gerència d’Àmbit This article was submitted to d’Atenció Primària Metropolitana Nord de Barcelona, Institut Català de la Salut, Mataró, Spain Clinical Diabetes, Catalan Health Institute, Badalona, Spain, 6 Primary Health Care Center La Mina, Gerència d’Àmbit a section of the journal d’Atenció Primària Barcelona Ciutat, Institut Català de la Salut, Sant Adrià de Besòs, Spain, 7 Centro Frontiers in Endocrinology de Investigación Biomédica en Red (CIBER) of Diabetes and Associated Metabolic Diseases Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas RECEIVED 22 August 2022 (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain, 8 Primary Health Care Center Sant ACCEPTED 10 October 2022 Martı´ de Provençals, Gerència d’Àmbit d’Atenció Primària Barcelona Ciutat, Institut Català de la PUBLISHED 24 October 2022 Salut, Barcelona, Spain, 9 Innovation Office, Institut Català de la Salut, Barcelona, Spain, 10 Tameside and Glossop Integrated Care National Health Service (NHS) Foundation Trust, Tameside on Lyne, CITATION United Kingdom, 11 University of Manchester, Manchester, United Kingdom, 12 Primary Health Care Bundó M, Vlacho B, Llussà J, Puig- Center Raval Sud, Gerència d’Àmbit d’Atenció Primària Barcelona Ciutat, Institut Català de la Salut, Treserra R, Mata-Cases M, Cos X, Barcelona, Spain, 13 Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Jude EB, Franch-Nadal J and Pau, Barcelona, Spain, 14 Department of Medicine, University of Vic - Central University of Catalonia, Mauricio D (2022) Prevalence and risk Vic, Spain factors of diabetic foot disease among the people with type 2 diabetes using real-world practice data from Catalonia during 2018. Front. Endocrinol. 13:1024904. Background: Our study aimed to assess the prevalence of diabetic foot disease doi: 10.3389/fendo.2022.1024904 (DFD) and its associated risk factors among subjects attending primary care COPYRIGHT © 2022 Bundó, Vlacho, Llussà, Puig- centers in Catalonia (Spain). Treserra, Mata-Cases, Cos, Jude, Franch-Nadal and Mauricio. This is an Methods: We undertook a cross-sectional analysis of data from the primary open-access article distributed under the terms of the Creative Commons health care (SIDIAP) database. The presence of comorbidities and concomitant Attribution License (CC BY). The use, medication were analyzed for subjects with or without DFD. DFD prevalence distribution or reproduction in other was estimated from 1st January 2018 to 31st December 2018. forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the Results: During the 12-month observational period, out of 394,266 people with original publication in this journal is type 2 diabetes, we identified 3,277 (0.83%) active episodes of DFD in the cited, in accordance with accepted academic practice. No use, database. The majority of these episodes were foot ulcers (82%). The mean age distribution or reproduction is of patients with DFD was 70.3 (± 12.5) years and 55% were male. In the permitted which does not comply with multivariable descriptive models, male gender, diabetes duration, these terms. hypertension, macrovascular, microvascular complications, and insulin and antiplatelet agents were strongly associated with DFD. A previous history of Frontiers in Endocrinology 01 frontiersin.org Bundó et al. 10.3389/fendo.2022.1024904 DFD was the stronger risk factor for DFD occurrence in subjects with T2DM (OR: 13.19, 95%CI: 11.81; 14.72). Conclusions: In this real-world primary care practice database, we found a lower prevalence of DFD compared to similar previous studies. Risk factors such as male sex, duration of diabetes, diabetes complications and previous history of DFD were associated with the presence of DFD. KEYWORDS Catalonia, diabetic foot disease, primary healthcare, prevalence, SIDIAP Introduction care settings. Our study aimed to estimate the prevalence of the DFD and its associated risk factors in subjects who attended the Diabetic foot disease (DFD) and its complications herald the centers of the largest public healthcare provider in Catalonia in high morbidity and mortality among patients with type 2 2018 (northeast region of Spain). diabetes mellitus (T2DM). Globally, it is estimated that the subjects with DFD have a similar life expectancy compared to some frequent cancer types such as colon and breast (1). Materials and methods Actually, DFD is the leading cause of hospitalization among T2DM subjects (2). In Catalonia (Spain), people with T2DM and Study population DFD are three times at higher risk for hospital admission, and even five times more for admissions to socio-sanitary facilities At the “cut-off” date (31st December 2018), we included all (day care facilities and residences) than the rest the population live adult subjects (age > 18 years) in the database with a (3). This entails a higher health cost and a decreased quality of diagnosis of T2DM defined as the presence of diagnostic codes life of these subjects. (International Statistical Classification of Diseases and Related There is a 25% risk probability of developing a foot ulcer Health Problems 10th Revision-ICD-10): E11 and E14. Subjects among people with diabetes during the disease course (4). DFD with other types of diabetes, such as type 1, secondary, will evolve towards healing, amputation, or even death gestational or other types of diabetes (ICD-10: E10, E12, O24 depending on the severity, underlying comorbidities, and care or E13) were excluded from the analysis. received. The prevalence of DFD varies among countries and even within different regions in the same country (5, 6). This variability could be due to differences in the type of population Study intervention and data source studied, the definition of foot ulcers, and the methodology used to identify the cases and the setting where the study was We performed a cross-sectional study using the primary performed (primary vs secondary care) (7). health care population SIDIAP database from 1st January 2018 Catalonia is situated in the northeast of Spain with a until 31st December 2018. The SIDIAP (Sistema d’Informació population of 7.5 million whose capital is the city of Barcelona. per al desenvolupament de la Investigació en Atenció Primària) The primary care electronic medical records started in 2006 and database includes the routinely collected healthcare data from currently the health system is entirely electronic. Due to this users attending the primary healthcare centers from Institut process, large amounts of routinely collected electronic health Català de la Salut (ICS) (8). The cross-sectional analysis was data are available through different population databases. chosen as well validated method in epidemiology to collect and Measuring the real burden of DFD could help us to better analyze the data from many different individuals from our quantify the impact of this highly complex and costly diabetes primary health care database at a single point in time and to complication on life expectancy and morbidity among persons investigate the association between a putative risk factors and a with T2DM in our primary health care settings. Moreover, it health outcome (9, 10). ICS is the major local public healthcare could help us to identify factors associated with this condition provider, covering 80% (5,564,292 users) of the Catalonian more efficiently. So far, to the best of our knowledge, there are no population. The SIDIAP database is a well-validated primary real-world data (RWD) studies on DFD in our primary health health database in diabetes research in Spain (11). Frontiers in Endocrinology 02 frontiersin.org Bundó et al. 10.3389/fendo.2022.1024904 Study variables and comparison variable “previous history of DFD” with this approach. As a history of DFD, we considered all previous episodes that We defined a DFD episode as the presence of one or a occurred before 1st January 2018 the period to estimated DFD combination of different diagnostic codes and sub-codes for prevalence, i.e. the 2018-year period). lower-extremity ulcers (ICD-10: L97, E11.621), osteomyelitis To evaluate the association between different factors and (ICD-10: M86), gangrene (ICD-10: I96, E11.52), lower- DFD, we performed multivariable logistic models to describe the extremity amputation (ICD-10: Z89), or surgical detachment association between the different clinically important variables procedures-0Y6) or Charcot neuroarthropathy (M14.6, E11.61) and the presence of DFD during the study period. Furthermore, at the cut-off date. All those diagnostic codes and procedures additional models were performed to evaluate the association referring to amputations below the ankle were defined as minor between antidiabetic drugs and presence of or history of amputations and included amputations of one or more toes and previous DFD (before 2018). All the analyzes were done with trans-metatarsal amputations. Those amputations above and R statistical software version 3.5.1. through the foot or ankle were defined as major amputations (12, 13). The diagnostic codes related to low-extremity amputations but without specific locations were considered Results non-specific amputations. During the study period, we also analyzed the prevalence of other comorbidities such as Between 1st January 2018 and 31st December 2018, a total of hypertension and hyperlipidaemia identified by ICD-10 394,376 live subjects were identified in the database. Of these diagnostic codes and/or pharmacologic treatment, subjects, 110 were excluded due to the double codification of macrovascular (coronary heart diseases, cerebral vascular other types of diabetes. Thus, we finally included 394,266 accident and heart failure) and microvascular complications subjects meeting the study eligibility criteria. Figure 1 shows (diabetic retinopathy, diabetic neuropathy, and chronic kidney the study flowchart. disease, the latter defined as a combination of CKD-EPI glomerular filtration rate <60 ml/min/1,73m 2 and/or an albumin/creatinine ratio >30mg). We also analyzed other Characteristics of subjects with and clinical variables, such as diabetes duration, body mass index without DFD (BMI), and systolic and diastolic blood pressure. Variables related to lipid, renal profile, glycosylated hemoglobin Table 1 shows the clinical characteristics of the study subjects. (HbA1c), and pharmacologic treatments were also extracted The mean age was 70.3 ( ± 12.5) years, with a male predominance from the database and analyzed. (55%). DFD episodes were more frequent among people aged 75 Two groups of subjects were created, i.e. groups with and or older. There were more current smokers and “at-risk” alcohol without an episode of DFD that occurred during 2018. We users in the group with DFD than in the non-DFD group. compared the groups for different clinical characteristics at “cut- We observed a worse comorbidity profile among people with off” date. DFD. These subjects had longer diabetes duration (3.7 years longer) than those without DFD. Microvascular and macrovascular complications were more prevalent among participants with Statistical analysis DFD. We observed minimum differences in BMI and blood pressure between groups, and slightly poorer glycemic control We described all the variables during the study period. The among subjects with DFD. The lipid profile was poorer among mean values and standard deviation for continuous variables subjects without DFD, while we observed lower glomerular were estimated, while we calculated the number and frequencies filtration rates among those with DFD. for categorical variables. Regarding antidiabetic treatment, lifestyle and dietary The prevalence of DFD was calculated as the proportion of measures, non-insulin antidiabetic drugs (NIAD) as a single subjects with DFD divided by the total number of alive people therapy and dual therapy were more frequent among subjects with T2DM in the database. In the case of multiple episodes of without DFD. Accordingly, insulin alone or in combination was DFD in different moments, we counted the episodes only once more frequently used as a treatment option among the subjects per person and the episode closest to the cut-off date to prevent with DFD. We also observed a higher prevalence of other possible overestimation of the DFD prevalence in the database. concomitant drug treatments among subjects with DFD, We calculated the prevalence of active episodes of DFD during especially antiplatelet agents. The results of antidiabetic and 2018 (a 12-month period from the cut-off date). We created the other concomitant treatments are summarized in Table 2. Frontiers in Endocrinology 03 frontiersin.org Bundó et al. 10.3389/fendo.2022.1024904 FIGURE 1 Study flowchart DFD: diabetic foot disease; n: number. DFD prevalence macrovascular and microvascular categories. The presence of hyperlipidaemia was negatively associated with DFD. During the last 12 months from the “cut-off” date (31/12/ In the additional models that included antidiabetic 2018), we identified 3,277 (0.83%) active episodes of DFD, of treatment, insulin use was associated with DFD episodes which 82% were due to active foot ulcers. During this period, (Supplement Table 2 and Figure 3A). In contrast, treatment 28.8% of subjects underwent lower-limb amputations, while with NIAD or lifestyle and dietary measures were negatively 7.9% of subjects had foot gangrene. The prevalence of DFD is associated with DFD. A previous history of DFD was strongly summarized in Table 3. associated (OR: 13.19, 95%CI: 11.82; 14.72) with the DFD events in this additional model (Supplement Table 3 and Figure 3B). Factors related to the DFD Discussion Supplement Table 1 and Figure 2 show different comorbidity models. In all the multivariable descriptive models, male sex, Our real-world evidence study from the SIDIAP primary diabetes duration, at-risk alcohol use and higher BMI were care database in Catalonia in the 12-month 2018 period found independent risk factors for DFD. Concerning the that the prevalence of diabetic foot disease among live T2DM c o m o r b i d i t i e s , t h e p r e s e n c e o f hy p e r t e n s i o n , a n d subjects of 0.83%. Few studies have described the prevalence of macrovascular and microvascular complications were DFD among subjects with diabetes mellitus. The meta-analyzes positively associated with DFD. As expected, peripheral artery and systematic reviews done by Lazzarini et al. (5) and Zhang disease and diabetic neuropathy were associated with increased et al. (6) reported a prevalence of DFD of 4.7% (95% CI: 0.2– risk for DFD in the fully itemized model. These associations 11.9%) and 6.3% (95% CI: 5.4-7.3%), respectively. Both studies were even stronger in models merging conditions under described a significant variability in the prevalence from one Frontiers in Endocrinology 04 frontiersin.org Bundó et al. 10.3389/fendo.2022.1024904 TABLE 1 Clinical characteristics of the study subjects. Variable Patients without DFD Patients with DFD Total (N=390989) (N=3277) (N=394266) Age, mean, years 70.3 (12.5) 74.0 (12.0) 70.3 (12.5) Age ≥75 years, n (%) 146757(37.5) 1628 (49.7) 148385 (37.6) Sex (male), n (%) 214618 (54.9) 2090 (63.8) 216708 (55.0) Current Smoker, n (%) 55553 (14.4) 507 (15.6) 56060 (14.4) “Low risk” alcohol use, n (%) 90533 (34.9) 649 (28.4) 91182 (34.8) “At risk” alcohol use, n (%) 3294 (1.27) 41 (1.79) 3335 (1.27) Diabetes duration, mean (SD), years, 10.2 (6.55) 13.4 (7.35) 10.2 (6.57) Body mass index, mean (SD),kg/m2 30.0 (5.20) 30.1 (6.11) 30.0 (5.21) SBP, mean (SD), mmHg 133 (13.6) 132 (16.7) 133 (13.7) DBP, mean (SD), mmHg 75.1 (9.73) 71.8 (10.5) 75.1 (9.74) Comorbidities, n (%) Hypertension, 305581 (78.2) 3018 (92.1) 308599 (78.3) Hyperlipidaemia, 272111 (69.6) 2408 (73.5) 274519 (69.6) Ischemic heart disease 51252 (13.1) 771 (23.5) 52023 (13.2) Heart failure 28127 (7.19) 743 (22.7) 28870 (7.32) Cerebrovascular disease 38027 (9.73) 639 (19.5) 38666 (9.81) Peripheral arterial disease 28577 (7.31) 1575 (48.1) 30152 (7.65) Macrovascular complications 94340 (24.1) 2039 (62.2) 96379 (24.4) Diabetic neuropathy 24199 (6.19) 883 (26.9) 25082 (6.36) Diabetic retinopathy 39490 (10.1) 1186 (36.2) 40676 (10.3) Chronic kidney disease 122122 (31.2) 1956 (59.7) 124078 (31.5) Microvascular complications 64061 (16.4) 1666 (50.8) 65727 (16.7) Laboratory parameters HbA1c, mean, (SD), % 7.09 (1.29) 7.35 (1.54) 7.09 (1.29) HbA1c ≥ 8%, n (%) 56595 (18.84) 681 (27.7) 57276 (18.86) Total cholesterol (mg/dL), mean (SD) 182 (40.4) 164 (43.6) 182 (40.4) HDL cholesterol (mg/dL), mean (SD) 48.7 (12.7) 45.3 (13.3) 48.7 (12.7) LDL cholesterol (mg/dL), mean (SD) 103 (33.3) 91.1 (34.9) 103 (33.3) Triglycerides (mg/dL), mean (SD) 159 (104) 152 (97.9) 159 (104) Estimated glomerular filtration rate, mL/min/1.73m , mean 2 73.5 (18.4) 62.5 (23.5) 73.4 (18.5) (SD) DFD, diabetic foot disease; SD, standard deviation; HbA1c, glycosylate haemoglobin; SBP, systolic blood pressure; DPB, diastolic blood pressure. continent to another, and among the different regions where the ulcers of 1.93%, very similar to the figure found in Israel (15) studies were carried out. Their great limitation was the (1.2%) and in Taiwan (2%) (16). In Saudi Arabia, the overall heterogeneity among the data, even within the same country. prevalence of DFD was 3.3%, while the prevalence of foot ulcers, In Zhang’s study, the prevalence in Europe was 5.1%. Analyzing gangrene, and amputations were 2.05%, 0.19%, and 1.06%, the included studies, great methodological variability was respectively (17). These prevalences are higher compared to observed, most with a small number of patients included; those observed in our study. further, more than 66% of the studies were old, published In the current analysis, during 2018, a prevalence of 0.68% before 2010 (6). (2,687) of new episodes of diabetic ulcer were recorded. This A large amount of routinely collected health care data in percentage was lower if we compare this with the prevalence recent years allowed the performance of real clinical practice observed in a retrospective registry-based study (2.05%) from studies. Several studies have been published to determine the 65,534 Saudi diabetic patients during the 2000 and 2012 prevalence of DFD using different registry systems (databases). regardless of the type of diabetes (17). In a recent cross- These studies bring us closer to the reality of the health care area sectional study developed in the southern area of the studied. In Spain, Alonso et al. (14), in a study of diabetes-related metropolitan region of Barcelona, the point prevalence of foot complications in the Basque Country, found a prevalence of foot ulcers during a 2-month period in 2013 was 0.16% (18). That Frontiers in Endocrinology 05 frontiersin.org Bundó et al. 10.3389/fendo.2022.1024904 TABLE 2 Antidiabetic and other concomitant treatment. Patients without DFD (N=390989) Patients with DFD (N=3277) Total (N=394266) Antidiabetic treatment *, n (%) Diet and lifestyle only 90301 (23.1) 547 (16.7) 90848 (23.0) NIAD monotherapy 133538 (34.2) 653 (19.9) 134191 (34.0) Dual NIAD therapy 65360 (16.7) 399 (12.2) 65759 (16.7) Triple NIAD therapy 26592 (6.80) 146 (4.46) 26738 (6.78) Insulin alone 19612 (5.02) 599 (18.3) 20211 (5.13) Insulin in combination 55586 (14.2) 933 (28.5) 56519 (14.3) Other concomitant drugs**, n (%) Anticoagulants 24015 (6.14) 441 (13.5) 24456 (6.20) Antiplatelet agents 113289 (29.0) 1733 (52.9) 115022 (29.2) Antihypertensive 275630 (70.5) 2726 (83.2) 278356 (70.6) Lipid-lowering 206959 (52.9) 1881 (57.4) 208840 (53.0) Antibiotics 62926 (16.1) 1415 (43.2) 64341 (16.3) DFD: diabetic foot disease; NIAD: non-insulin antidiabetic drugs. *In the last three months. **In the last 12 months. study was not specifically designed to assess the prevalence of significant variation from one region to another, and in the case DFD, and included the recorded diagnostic codes of different of major lower-limb amputations, Catalonia is in an types of ulcers (including venous ulcers), without including intermediate situation among the different health care regions other forms of DFD, like those of our study (amputations, (20). The rate of amputations in Catalonia in 2016 among the osteomyelitis, Charcot disease). Additionally, that study did diabetic population aged between 45 and 74 years was 27.4 per not characterize subjects with diabetes. Furthermore, our study 10,000 people with diabetes (3). The results provided in our is more representative of the Catalonian population. Therefore, study are lower, suggesting a decrease in the number of episodes, our findings are hardly comparable to those of this recent as was the case for other countries (19); however, this finding study (18). will need to be confirmed in further studies. Regarding Charcot In our study population, there were 943 (0.24%) new foot disease, we could only identify 39 newly diagnosed patients episodes of amputations. According to a systematic review by (0.01%) in 2018. There are few published studies for comparison. Narres et al. (19), the incidence of lower-limb amputations in the In a retrospective hospital-based study, Fabric et al. (21) found diabetic population ranged from 78 to 704 per 100,000 people an annual incidence of 0.3%. with diabetes/year. Also, high variation exists for these Comparing diabetic patients with and without DFD in our procedures, from one country to another and even within the study, in the DFD group, there were more men, they were older, same country. In Spain, the incidence of amputations also shows with a longer diabetes duration, with a higher percentage of TABLE 3 DFD prevalence and DFD related variables. Total (N=394266) Patients with DFD*(N=3277) DFD, n (%) 3,277 (0.83) 3,277(100) Foot ulcers, n (%) 2687 (0.682) 2687 (82.0) Osteomyelitis, n (%) 220 (0.06) 220 (6.71) Gangrene, n (%) 261 (0.07) 261 (7.96) Charcot foot, n (%) 39 (0.01) 39 (1.19) Amputations, n (%) 943 (0.24) 943 (28.8) Major amputations, n (%) 168 (0.04) 168 (5.13) Minor amputations, n (%) 393 (0.1) 393 (12.0) Non-specific amputations, n (%) 596 (0.2) 596 (18.2) Previous history of DFD 10852 (2.75) 3105 (94.8) *Active episodes of DFD during 2018; DFD: diabetic foot disease. Frontiers in Endocrinology 06 frontiersin.org Bundó et al. 10.3389/fendo.2022.1024904 A B C D FIGURE 2 DFD and different comorbidities models (A) Fully itemized model; (B) Microvascular complications merged model; (C) Macrovascular complications merged model; (D) Microvascular and Macrovascular merged model BMI: body mass index; DFD: diabetic foot disease. smokers and patients with hypertension, and a higher of a general vascular failure (2, 23, 29). A previous history of a proportion of micro- and macrovascular complications. These DFD increases the risk 13-fold of a new DFD episode, which is in findings are in line with other similar studies. It is known that line with what has repeatedly described in multiple studies. the risk of ulcers and amputation increases with age (6, 14, 22), Our study has some limitations. Firstly, as in all studies duration of diabetes (6, 23), poor metabolic control (15, 23), and based on routinely collected healthcare data, the underreporting smoking (6), and are more prevalent in men (6, 23), but is yet to or missing data is quite frequent and is a clear limitation. Also, to be explained (6). In our analysis, only 7.31% of the patients prevent possible overestimation of the prevalence, only one without DFD had a recorded diagnosis of peripheral artery episode was recorded for each person with T2DM, the closest disease compared to 48.1% of those diagnosed with DFD. to the cut-off date. The multivariable models are descriptive and These results are similar to previous studies, and its presence do not predict the occurrence of DFD in 2018. On the other dramatically worsens the prognosis of these patients (24). It is hand, as strength, the large sample size provides valuable surprising that only 6.19% of patients without DFD and 26.9% of information and gives us an idea of the magnitude of the those who had an episode of DFD had a recorded diagnosis of problem in our country and primary health care facilities. peripheral neuropathy. This percentage is much lower than In conclusion, our real-world primary care database study in those previously reported by other authors (25). This is most Catalonia, Spain, shows a lower DFD prevalence than in other probably due to the already-described underreporting of this similar studies. In our study, type 2 diabetic subjects with DFD complication in primary care electronic health care records (26) were older, with longer duration of diabetes, had more micro- and it is in line with previously published similar studies with the and macro-vascular complications, and were more often treated same database (27, 28). with insulin and antiplatelet agents than those without DFD. Concerning the risk factors in the multivariable descriptive Further, a previous history of DFD was the stronger risk factor models, we observed strong associations of macrovascular and for a new episode of DFD in subjects with T2DM. Moreover, microvascular complications in patients with DFD. These interventions are needed in our primary health care settings in chronic complications are related with DFD as a consequence order to improve the DFD codification and detection. The strong Frontiers in Endocrinology 07 frontiersin.org Bundó et al. 10.3389/fendo.2022.1024904 A B FIGURE 3 DFD models for association with antidiabetic drugs or previous history of DFD (A) DFD model adjusted by antidiabetic treatment (B) Fully adjusted model for DFD considering the previous history of DFD DFD: diabetic foot disease. economic and social impact of DFD warrants future studies to were used under license. Requests to access these datasets should evaluate the risk factors related to occurrence and prognosis, be directed to Dr. Dı́dac Mauricio, didacmauricio@gmail.com. potentially increasing the knowledge of prevention and better treatment of this complex disease. Ethics statement Data availability statement The studies involving human participants were reviewed and approved by Primary Health Care University Research Institute The data analyzed in this study is subject to the following Jordi Gol (number 19/035-P). Written informed consent for licenses/restrictions: Restrictions apply to the availability of some participation was not required for this study in accordance with or all data generated or analyzed during this study because they the national legislation and the institutional requirements. Frontiers in Endocrinology 08 frontiersin.org Bundó et al. 10.3389/fendo.2022.1024904 Author contributions de Salud Carlos III Madrid, Spain, Generalitat de Catalunya. Peris 2016-2020. The Strategic Plan for Health Research and Conceptualization, MB. Methodology, MB, BV, DM, and JF- Innovation Barcelona, Spain. N. Software. Formal analysis, RP-T. Data curation, RP-T. JF-N has received advisory and/or speaking fees from Astra- Writing—original draft preparation, MB and BV. Writing— Zeneca, Ascensia, Boehringer Ingelheim, GSK, Lilly, MSD, review and editing, MB, BV, DM, JF-N, JL, MM-C, EJ, and Novartis, NovoNordisk, and Sanofi. He has received research XC. Supervision, DM. Project administration, BV. All authors grants to the institution from Astra-Zeneca, GSK, Lilly, MSD, contributed to the article and approved the submitted version. Novartis, NovoNordisk, Sanofi, and Boehringer. DM has received advisory and/or speaking fees from Almirall, Esteve, Ferrer, Janssen, Lilly, Menarini, MSD, NovoNordisk and Sanofi. Funding MB and JL have received advisory and speaking fees from MSD. EJ has received educational, sponsorship and speaker fees from This research received no external funding. The project has Astra Zeneca, Bayer, Lilly, Novonordisk and Sanofi. XC has received internal support, call: 8a Convocatòria d’Ajuts a received speaker’s bureau and advisory board honoraria from projectes de Institut Català de la Salut with SIDIAP financing AstraZeneca, Boehringer Ingelheim, Esteve, Lilly Diabetes, Novo code 4R18/187-1 and file number SIDIAP-18/7. Nordisk A/S, Roche, and Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that Acknowledgments could be construed as a potential conflict of interest. This work was realized thanks to the non-financial grants: 8th Call for SIDIAP from IDIAP Jordi Gol in 2018 and Fourth Publisher’s note call for Research Grants from the Northern Metropolitan Primary Care Directorate for the year 2020 from the Catalan All claims expressed in this article are solely those of the Institute of Health. authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or Conflict of interest claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. MM-C has received advisory and/or speaking fees from Astra-Zeneca, Bayer, Boehringer Ingelheim, GSK, Lilly, MSD, NOVARTIS, NovoNordisk, and Sanofi. He has received research Supplementary material grants to the institution from Astra-Zeneca, GSK, Lilly, MSD, Novartis, NovoNordisk, and Sanofi. He has received research The Supplementary Material for this article can be found grants from Institut Universitari d’Investigació en Atenció online at: https://www.frontiersin.org/articles/10.3389/ Primària Jordi Gol IDIAP Jordi Gol Barcelona, Spain, Instituto fendo.2022.1024904/full#supplementary-material References 1. Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their 6. Zhang P, Lu J, Jing Y, Tang S, Zhu D, Bi Y. Global epidemiology of diabetic recurrence. N Engl J Med (2017) 376:2367–75. doi: 10.1056/NEJMra1615439 foot ulceration: a systematic review and meta-analysis†. Ann Med (2017) 49:106– 2. Frykberg RG, Zgonis T, Armstrong DG, Driver VR, Giurini JM, Kravitz SR, 16. doi: 10.1080/07853890.2016.1231932 et al. Diabetic foot disorders: a clinical practice guideline. J Foot Ankle Surg (2006) 7. Aschner P. 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