Cumulative risk of diabetic foot complications in risk groups of type 1 and type 2 diabetes: Real-world evidence from a 22-year follow-up study

Abstract

The International Working Group on the Diabetic Foot (IWGDF) recommends annual foot screening for low-risk individuals of diabetic foot ulcers (DFUs), with screening frequency increasing with an increased risk.¹ These screening intervals are largely based on expert opinion, owing to limited supporting evidence.¹ Annual screening intervals for diabetic retinopathy, once similarly recommended, were revised, and extended for low-risk individuals upon evaluation of progression risks.²

It is relevant to consider if foot screening intervals for individuals at very low-risk (IWGDF risk category = 0)¹ of diabetic foot complications (DFCs) may be extended beyond a year. A prerequisite for this guideline revision would be ascertaining the risk of DFCs. Hence, we aimed to estimate the cumulative risk (CR) of DFCs in risk groups of type 1 (T1D) and type 2 diabetes (T2D), using a simple risk-stratification rule. Based on the IWGDF 4-level risk-stratification system,¹ our study combines categories 1–2 into a single ‘high-risk’ group and uses two clinically-relevant risk factors.

A total of 14 609 individuals (6279 with type 1 diabetes and 8330 with type 2 diabetes) were included in the study with a total follow-up time of 135 143 person-years (from risk-stratification method 1). At baseline, 56.4% of the T1D population was at low risk, as compared to 27.3% of the T2D population. The median age was 34.9 years (Q1, Q3: 25.0, 45.1) and 50.9 years (Q1, Q3: 37.7, 61.5) in the T1D low- and high-risk groups, respectively, while it was 52.4 years (Q1, Q3: 43.8, 60.1) and 63.6 years (Q1, Q3: 55.5, 71.6) in the T2D low- and high-risk groups, respectively. Tables S2 and S3 show detailed baseline population characteristics.

During the follow-up period, a total of 613 events (478 DFUs and 135 LEAs) and 961 events (763 DFUs and 198 LEAs) were recorded in the T1D and T2D populations, respectively. From 2000 to 2020, there was a decline in the incidence of DFCs in high-risk men and women with T1D and T2D, whereas for the T2D low-risk groups, we find a threefold increase from 2000 to 2011, which slightly decreases after 2017 (Figures S1, S2 and Tables S4 and S5). Based on risk-stratification method 1, the 3-year CR of DFCs was 0.20% (95% CI 0.13%–0.30%) and 3.92% (95% CI 3.62%–4.27%) in the T1D low- and high-risk groups, respectively. Similarly, the 3-year CR of DFCs in the T2D low-risk group was 0.39% (95% CI 0.26%–0.58%), while in T2D high-risk group, it was 4.31% (95% CI 4.01%–4.62%). Based on risk-stratification methods, Tables 1 and S6 present yearly CR of DFCs, while Figures 1 and S3 illustrate unadjusted IR of DFCs in T1D and T2D.

Our main finding is that for many people living with diabetes, the risk for DFC is very low and thus screening intervals could be prolonged. A strength of this study is the detailed registration of LOPS and foot pulse in a large cohort of individuals with an extensive follow-up period. Some study limitations are as follows: Firstly, since DFC was included as a composite outcome, specific risk estimates for individual outcomes of DFUs and LEAs were unavailable. This was done due to the low no. of LEAs (<3) in the T1D low-risk group, which could not have been reported. Therefore, outcomes in the low-risk group were predominantly DFUs, while outcomes in the high-risk group were a combination of DFUs and LEAs. Hence, it may be inferred that the T1D low-risk group is not at significant risk for LEA. Secondly, since DFUs are poorly reported in the DNPR, the possibility that some individuals at baseline may have prevalent DFUs cannot be entirely rejected.⁶ However, the under-reporting of DFUs in the DNPR was overcome by using detailed DFU data from the SDCC electronic health records, where all individuals screened in the foot clinic are given an applicable diagnosis code. Some individuals at SDCC with minor DFUs might have been underreported if they were not screened in the foot clinic, but these numbers are assumed to be negligible since all major DFUs are screened and reported.

Conducting foot screenings in individuals with diabetes is important to prevent DFCs through early interventions, education, and proper footwear. The IWGDF 2023 guidelines-recommended yearly foot screenings for low-risk groups may be relevant in some clinical settings. However, the large difference observed in CR of DFCs between risk groups of T1D and T2D populations in our study serves as an initial guide to propose that foot screening intervals for individuals at low risk of DFCs are extended beyond 1 year in Denmark and comparable healthcare settings.

Previous studies conducted in Danish populations^{7, 8} found that the IR of LEA increase with age and DM duration, which is consistent with our findings. This supports the generalizability of our results, as we observe the same trends as seen in previous studies with different populations, including less complicated T2D. Additionally, it provides an argument for using age as a factor in risk stratification.

The risk of DFCs is expected to be the same for the T1D population across Denmark; while it is expected to be the same or lower for the T2D population followed in general practice, where a higher proportion of low-risk individuals are treated. There was no notable difference between the CR estimated by risk-stratification methods 1 and 2. We speculate that the increase in IR from 2000 until 2011 observed in T2D low-risk groups might have been driven by the increased registration of DFCs in these groups at SDCC. These results may not be generalizable to populations in dissimilar healthcare settings, but this concept may be applied broadly to evaluate risk and consider local screening intervals.

These results would hence, support that foot screening intervals for low-risk groups of DFCs are extended beyond 1 year in comparable healthcare settings. Additionally, comprehensive risk prediction models like the Steno T1 Risk Engine⁹ incorporating additional predictors, such as smoking, hypertension, and blood glucose, could provide more precise risk profiles for DFCs in individuals with T1D and T2D.

A.A. contributed to the study design, formal analysis, writing the initial draft and editing the manuscript. P.F.R. contributed to study conceptualisation, study design, formal analysis, supervision of the work and reviewed and edited the manuscript. A.H. contributed to study conceptualisation, study design, formal analysis and reviewed and edited the manuscript. C.S.H. contributed to study conceptualisation, study design, and reviewed and edited the manuscript. V.K. contributed to the study design and reviewed and edited the manuscript. F.P. and A.R. contributed to study conceptualisation, and reviewed and edited the manuscript. P.R. and T.S.A. contributed to study conceptualisation, supervision of the work and reviewed and edited the manuscript. A.A. and T.S.A. are the guarantors of this study and take responsibility for the integrity of the data and the accuracy of the data analysis.

This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 101073533 (DIALECT: Diabetes Lower Extremity Complications Research and Training Network in Foot Ulcer and Amputation Prevention). A.H. is supported by a Data Science Emerging Investigator grant (no. NNF22OC0076725) by the Novo Nordisk Foundation. T.S.A. was supported by the Novo Nordisk Foundation Grant (NNF23OC0084081; Map D-Foot). P.F.R. was supported by a research grant from the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation, grant number NNF17SA0031406. A.A. was supported by a travel grant from the European Association for the Study of Diabetes (EASD) for attending their 60th Annual Meeting where some results from the current manuscript were presented as a short oral presentation.

P.R. has served as consultant on advisory boards for Astra Zeneca, Abbott, Bayer, Novartis, Boehringer Ingelheim, Gilead and Sanofi (honoraria to his institution); has received unrestricted grants (to his institution) from Astra Zeneca, Bayer, and Novo Nordisk; and grants from Bayer, Novo Nordisk and Lexicon pharmaceuticals (study medication to investigator initiated study). T.S.A. and P.F.R. own stocks with Novo Nordisk A/s. No other potential conflicts of interest were reported by the other authors. The funding bodies played no role in study design, data management, analysis, interpretation or writing of the manuscript.