1. INTRODUCTION

      Diabetic foot ulcer (DFU) is the destruction of skin and tissues of the foot in patients with diabetes, usually accompanied by neuropathy and/or peripheral artery disease (PAD).1 It is estimated that the global prevalence was 6.3% in a meta-analysis published in 2017, with great variety between different countries.2 As the population of diabetes continues to increase, the number of patients with DFU is projected to increase greatly. DFU is associated with significant morbidity and mortality and can lead to increased hospitalization and lower limb amputation. 3

      A previous meta-analysis by Saluja et al. in 20204 examined 11 studies that measured the association of DFU and mortality. It showed that DFU was associated with an increased risk of all-cause mortality (risk ratio [RR] 2.45, 95% confidence interval[CI] 1.85-2.85).4 Another meta-analysis by Rathnayake et al. in 20205 evaluated the prognosis of patients with DFU after amputation. The results showed that the weighted mean of mortality at 1, 3 and 5 years was 13.62%, 30.25% and 50.55%, respectively.5 However, there were no studies that investigated the global mortality of DFU. Furthermore, the risk factors of mortality for patients with DFU were not fully evaluated.

      An improved understanding of mortality in a global view is critical for policy decisions. It can also raise the awareness of DFU among patients, their families and healthcare professionals. In this study, we conducted a systematic review and meta-analysis of all available studies to assess the long-term survival rates of DFU in a global view. In addition, the associated risk factors of mortality in patients with DFU will also be evaluated.

2. METHODS

      This systematic review and meta-analysis were reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses and the Meta-analysis of Observational Studies in Epidemiology reporting guidelines. The systematic review was registered on PROSPERO (CRD42022325099).

2.1 Search strategy and selection criteria

      A systematic search of databases (Medline, Embase, Scopus, Web of Science, Cochrane Library, China Science and Technology Journal Database [CQVIP], China National Knowledge Infrastructure, the Chinese Biomedical Literature Database [SinoMed] and Wanfang Data) was conducted to identify eligible articles published from 1 January 2011 to 31 July 2022. The search terms were ‘diabetic foot’ OR ‘diabetic feet’ OR ‘diabetic foot ulcer’ OR ‘diabetic foot complication’ AND ‘mortality’ OR ‘death’. Endnote X9 (Clarivate) was used to manage citations.

      Inclusion criteria were observational studies that reported the long-term mortality (> 1 year) of patients with DFU. Only studies that used the Kaplan–Meier curve to describe the survival of DFU or studies that reported one result of the 1-, 3- or 5-year mortality were included. Studies were excluded if the language of the publication was other than English and Chinese. Animal studies, reviews, congress abstracts, editorials, letters and comments were also not considered. Two investigators (LC and SS) independently selected studies. Discrepancies in the selection of studies and data extraction were resolved by consensus or following discussions with XR. References of the included articles were also reviewed to identify potentially relevant articles. If two studies had the same population source, the study with a larger sample size would be included. For case-control studies, only the data of DFU would be extracted.

      In addition, only studies that had Kaplan–Meier survival curves, from which data could be extracted, were included in the quantitative synthesis of Kaplan–Meier survival. Studies that only reported annual data would be used in combination with the aforementioned studies to pool the aggregate data-based survival.

2.2 Data extraction

      Data were extracted by three reviewers based on a prespecified protocol (LC, SS and YG). The characteristics of the study included the authors’ names, publication year, nationality and region. The countries were grouped into six regions (Africa, America, South-East Asia, Europe, Eastern Mediterranean and Western Pacific) based on the World Health Organization. The survival rates of DFU were either extracted from the literature or extracted from the Kaplan–Meier curve. The GetData Graph Digitizer (version 2.2) was used to digitize the Kaplan–Meier curves. Combined with the numbers at risk or the number that survived at the end of follow-up, patient data of each study were reconstructed according to the method introduced by Tierney et al.6

2.3 Risk of bias assessment

      Risk of non-randomized studies of interventions was used to assess the risk of bias.7 Because the studies included in this review did not test a specific intervention, the domains ‘classification of interventions’ and ‘deviation from intended intervention’ were rated as not applicable.

2.4 Statistical analysis

      The primary outcome was the long-term survival of DFU. The reconstructed patient data from the Kaplan–Meier survival curves of individual studies were pooled using a random effect model. The pooled Kaplan–Meier-based survival was estimated at different time points with 95% CIs to assess the primary outcome. An aggregate data metaanalysis from all available studies was also pooled. The causes of death were summarized from several studies. For studies that reported the comparison of survival stratified by age, sex, PAD, peripheral neuropathy, chronic kidney disease (CKD), end-stage renal disease (ESRD), amputation and cardiovascular disease, the hazard ratio (HR) and 95% CIs were pooled to analyse the impact of these factors on survival. Sensitivity analysis (leave one out) was performed to assess the robustness of the pooled effects. When 10 or more trials were included, we used a funnel plot and Egger's test to assess the possibility of publication bias. All statistical analyses were performed with R (version 4.2.1). The packages ‘metaSurvival’ and ‘meta’ were used in the analysis. P values of less than .05 were considered to be statistically significant.

3 RESULTS

      A total of 4538 records published from 1 January 2011 to 31 July 2022 were identified by systematic search, and 4182 records were screened after removal of duplicates. Figure 1 shows the flowchart of the study selection. We identified 34 studies that reported mortality of DFU (Figure 1, Table S1).

      A total of 124 376 patients, with 51 386 deaths, from 16 countries in five regions of the world (America, South-East Asia, Europe, Eastern Mediterranean and Western Pacific) were included in this study, with no data available for Africa. The Western Pacific and Europe published the most studies (Figure 2). Male gender accounted for the majority of the patients with DFU (58%), even excluding the study that included only veterans (98% males).8 The average age ranged from 57 to 71 years. Twelve studies reported the mean duration of diabetes before the onset of DFU. The mean duration of diabetes was very long, ranging from 11 to 19 years.

      The result of assessment of risk of bias is presented in Table S2. Twenty-three studies9-31 had a low risk of bias, and five studies32-36 had a moderate risk of bias. Six studies were identified as having a serious risk of bias. The studies by Aragon-Sánchez et al. 37 and Piaggesi et al.38 included only patients that underwent surgical treatment. The studies by Brennan et al.8 included a specific population of veterans with type 2 diabetes. The studies by Roth-Albin et al.39 and Al-Rubeaan et al.40 had a high loss of follow-up (> 20%). And the study by Troisi et al.41 only included patients who underwent peripheral angiography.

3.1 Mortality

      Kaplan–Meier was used to describe the survival of DFU in 28 of the included studies.9,10,12-21,23-25,27,29-38,40,41 Of these studies, the number at risk and survival proportions could be estimated in 27 studies.9,10,12-21,23-25,27,29-31,33-38,40,41 The pooled 1-, 3-, 5- and 10-year Kaplan–Meier-based survival rates, including 21 171 patients, were 86.9% (95% CI 82.6%-91.5%), 66.9% (95% CI 59.3%-75.6%), 50.9% (95% CI 42.0%-61.7%) and 23.1% (95% CI 15.2%-34.9%), respectively. A pooled Kaplan–Meier curve was plotted to show the overall survival (Figure 3).

      Aggregate data-based survival was pooled from all available studies, including Kaplan–Meier-based survival data estimated from the aforementioned 27 studies and data extracted from the articles that only reported annual mortality.11,22,26,28,32,39 Six studies only reported 1-year survival.11,22,26,28,32,39 Of these, one study reported 3-year survival32 and two studies reported 5-year survival.26,32 As a result, the pooled 1-, 3- and 5-year overall survival rates were 87.7%(95% CI 84.9%-90.4%), 68.6% (95% CI 62.4%-74.8%) and 63.1% (95%CI 57.6%-68.7%), respectively. There was significant heterogeneity (I 2 = 99%) (Figure S1A–C). Sensitivity analysis revealed that the pooled 1-, 3- and 5-year survival was similar after omitting any one of the studies included (Figure S2A–C).

      Another study including 66 323 patients, which enrolled a specific population of veterans with type 2 diabetes in the United States, showed that the overall 1-, 2- and 5-year survival rates were 80.8%, 69.0% and 28.6%, respectively.8

      We also pooled the 1-, 3- and 5-year survival of DFU by region (America, South-East Asia, Europe, Eastern Mediterranean and Western Pacific). Twelve studies came from the Western Pacific, while 14 studies were from Europe. Other regions included a small number of studies. The Europe and the Western Pacific regions had the lowest 1-year survival (85.3% and 88.4%, respectively) and lowest 5-year survival (56.6% and 65.2%, respectively) in the aggregate data-based meta-analysis (Table S3). Kaplan–Meier-based survival of Europe and the Western Pacific had similar results (Europe: 84.3% at 1 year, 61.3% at 3 years and 45.5% at 5 years; Western Pacific: 87.3% at 1 year, 66.7% at 3 years and 48.8% at 5 years).

3.2 Causes of death

      Eleven studies reported the causes of death in patients with DFU. 10,21,23-25,29,30,34,39,42,43 Of the 1637 deaths, cardiovascular diseases, including cerebrovascular diseases, accounted for nearly half (46.6%, 95% CI 33.5%-59.7%) (Figure 4A).10,21,23-25,29,30,34,39,42,43 Infection was the second most common cause of death, with a pooled proportion of 24.8% (95% CI 16.0%-33.5%) (Figure 4B).10,23- 25,30,34,42,43 The reported infections included sepsis, respiratory infection and foot infection. Cancer deaths accounted for 5.8% (95% CI 3.3%- 8.4%) (Figure 4C).23,25,30,34,42,43

3.3 Risk factors for mortality in patients with DFU

      Next, we assessed the HR of important risk factors for mortality in patients with DFU such as age, sex, PAD, peripheral neuropathy, CKD, amputation and cardiovascular disease. Of the 11 studies that analysed the impact of age on the mortality of patients with DFU, eight reported the HR and 95% CI per additional year. 16,18,21,24,30,32,33,35 The pooled HR for every 1-year increase of age was 1.054 (95% CI 1.045-1.063, P < .001). There was mild heterogeneity (I 2 = 33%) (Figure S3). The sensitivity analysis showed that the result was robust after omitting any one of the studies (Figure S4). The other three studies showed that the HRs and 95% CIs of mortality for older age (≥ 60, ≥ 65 and ≥ 70 years) were 1.95 (95% CI 0.74-5.16), 1.85 (95% CI 1.79-1.92) and 2.01 (95% CI 1.60-2.53), respectively. 15,26,31

      Nine studies reported the effect of gender on mortality. 16,18,21,23,26,30,37,40,44 The study by lacopi et al.44 was a secondary analysis of the same population in the study performed by Piaggesi et al.38 The pooled HR showed that there was no difference in mortality between the two genders (HR 1.124, 95% CI 0.832-1.519, P = .447) (Figure S5). There was significant heterogeneity (I 2 = 81%). However, in the sensitivity analysis, after omitting the study by Aragon-Sánchez, 37 the mortality became higher in men than in women (HR 1.257, 95% CI 1.037-1.524, P = .020, I 2 = 75%) (Figure S6).

      In 10 articles, patients with DFU were stratified by PAD. 14,15,17,21,23,24,26,32,33,35 The pooled HR was 1.882 (95% CI 1.592-2.225, P < .001). There was moderate heterogeneity (I 2 = 74%) (Figure 5A). This result revealed that the mortality of DFU with PAD was 88% higher than that of patients without PAD. The sensitivity analysis revealed that the heterogeneity was reduced after omitting the study by Rubio et al.21 (I 2 = 45.1%). However, the pooled HR did not change much (HR 1.810, 95% CI 1.505-2.177, P < .001) (Figure S7). In addition, another article also showed that the mortality of patients with PAD was much higher than that of patients without PAD (11% vs. 1.1%, P < .001).45 Notably, the definition of PAD varied among studies. In the studies conducted by Pena et al.14 and Amadou et al.,35 PAD was diagnosed with transcutaneous oxygen pressure less than 30 mmHg, while another study by Fagher and Löndahl combined the ankle-brachial index (ABI) with transcutaneous oxygen pressure to diagnose PAD.33

      Next, we investigated whether, in the patients without PAD,patients with neuropathy had higher mortality than patients without neuropathy. A study by Paisey et al.46 revealed that neuropathy (clinically diagnosed as the loss of protective sensation and symptoms) did not affect survival.

      In 13 articles9,17,18,21,23-26,32,36,37,40,41 that investigated the impact of CKD on mortality, three articles merely analysed mortality in patients with ESRD or on dialysis.9,17,41 The pooled HR of mortality for CKD was 1.535 (95% CI 1.227-1.919, P < .001). There was significant heterogeneity (I 2 = 88%) (Figure 5B). Although heterogeneity did not decrease obviously, the pooled HR was stable after omitting any one of the included studies (Figure S8). Furthermore, the pooled HR of mortality for ESRD was 3.586 (95% CI 1.333-9.643, P < .001,I 2 = 97%) (Figure 5B). The heterogeneity of HR for ESRD disappeared after omitting the study by Lo et al.17 in the sensitivity analysis (I 2 = 0%). There was still high mortality of ESRD, with a pooled HR of 5.924 (95% CI 4.297-8.167, P < .001) (Figure S9).

      In four articles, the impact of amputation on mortality of patients with DFU was assessed.16,17,32,40 The pooled HR was 2.415 (95% CI 1.323-4.408, P = .004, I 2 = 73%) (Figure 5C). The sensitivity analysis showed that the heterogeneity disappeared after omitting the study by Vuorlaakso et al.32 (I 2 = 7.9%), and the mortality was still higher in patients with amputation, with a pooled HR of 1.719 (95% CI 1.393-2.122, P < .001) (Figure S10). Notably, three studies studied major amputation, while the other did not clarify the type of amputation (major or minor).40

      Thirteen studies assessed the impact of cardiovascular disease history on mortality.8,9,15-18,21,24,27,32,33,36,40 The pooled HR was 1.449 (95% CI 1.276-1.645, P < .001, I 2 = 74.9%) (Figure 5D). In sensitivity analysis, the pooled HR was stable after omitting any one of the included studies (Figure S11).

      There were only two studies that analysed the association between ethnicity and mortality. The study by Jeyaraman et al. revealed that indigenous ethnicity had a higher mortality risk (univariate HR 1.45, 95% CI 1.10-1.92), and the effect disappeared in the multivariate analysis (HR 0.65, 95% CI 0.097-4.42).24 The study by Brennan et al. revealed that Black had a similar mortality risk to White (HR 0.97, 95% CI 0.92-1.01), while other races had a lower mortality risk (HR 0.92, 95% CI 0.87-0.97) than White.8

3.4 Publication bias

      The funnel plot of aggregate data-based survival (1 year) in Figure S12 revealed that there was publication bias. Publication bias was shown with Egger's test of the funnel plot asymmetry (P = .003).

4 DISCUSSION

      In this systematic review and meta-analysis, we quantified the mortality rate of DFU involving 124 376 patients in 34 studies from 16 countries around the world. The results suggested that the Kaplan–Meier-based survival rates were 86.9% at 1 year, 66.9% at 3 years and 50.9% at 5 years. Similar results were revealed in the aggregate data meta-analysis. Cardiovascular diseases and infections were the two leading causes of death. Older age, PAD, CKD (particularly ESRD), amputation and a history of cardiovascular disease were associated with higher mortality. Because there were no data on global mortality for DFU in the past, this study provides a basis for policy decisions and the management of DFU.

      It has been well recognized that DFU is associated with excess death. 4 This meta-analysis quantified the concrete magnitude of mortality for DFU worldwide. We used two methods to calculate the survival of DFU. First, the survival was estimated from the pooled Kaplan–Meier curve, and then we also performed the aggregate meta-analysis to assess the 1-, 3- and 5-year mortality. The results of the two methods were consistent, with the second method having slightly higher survival. It was probable that, when calculating mortality rates, some studies that reported annual mortality rather than Kaplan–Meier curves did not account for the loss of follow-up.

      The mortality of DFU varied greatly among the world's regions. We found that Europe and Western Pacific had the lowest 1- and 5-year survival in the aggregate data meta-analysis. The Kaplan–Meier meta-analysis revealed similar mortality in these two regions. Europe and the Western Pacific had the most sophisticated strategies for the diagnosis and management of DFU. The researchers in these regions published the greatest number of articles. The estimated mortality might be closer to the true mortality. The comparatively high survival in other areas might be related to the low publication rate with a low representation. 

      In this meta-analysis, we found that cardiovascular diseases accounted for nearly 50% of all deaths. It is well known that cardiovascular diseases, principally ischaemic heart disease and stroke, are the leading causes of death worldwide.47 According to the World Health Organization, nearly 32% of all global deaths are attributed to cardiovascular diseases. The high proportion of death from cardiovascular diseases in patients with DFU is consistent with the findings in the general population and the diabetes population.47,48 Aggressive management of cardiovascular risk factors could significantly reduce the mortality of patients with DFU.49 Thus aggressive measures should be taken to detect and manage cardiovascular diseases and associated risk factors.

      Infections, not merely foot infections, were found to be the second leading cause of death. Although infections were reported to be one of the most frequent causes of death in patients with DFU,50 the prevention, detection and management of infections has not received much attention in clinical practice. Moreover, it has received little attention in the published guidelines worldwide. Therefore, infection prevention and control should become more common measures in guideline development and clinical practice.

      Patients with PAD had a higher mortality rate than those without PAD in the general population. A previous meta-analysis by the ABI Collaboration showed that ABI was inversely associated with mortality in a dose-dependent pattern.51 However, PAD was largely underdiagnosed and hence undertreated, possibly because it was largely asymptomatic. 52 In this meta-analysis, the mortality of PAD in patients with DFU was still higher than that of patients without PAD.

      The contribution of peripheral neuropathy on survival in patients with DFU and no PAD is inconclusive. A study by Paisey et al46 revealed that neuropathy (clinically diagnosed as loss of protective sensation and symptoms) did not affect survival in patients with DFU and without PAD. However, one study revealed that peripheral neuropathy was associated with an increased risk of death, irrespective of diabetes.53 Cardiovascular autonomic neuropathy was significantly associated with mortality. 54-56 Thus further studies should be performed to evaluate the impact of neuropathy on mortality in patients with DFU. In this meta-analysis, we found that patients with CKD had increased mortality. For DFU patients with ESRD, the mortality rate was three times higher than that of patients without ESRD. It was estimated that up to 40% of people with diabetes would develop CKD.57,58 A study by Afkarian et al. found that for patients with type 2 diabetes, most of the excess all-cause and cardiovascular mortality was concentrated in patients with CKD.59 Thus the association between CKD and mortality was consistent between diabetes and DFU.

      Diabetes is the leading cause of non-traumatic amputation.60 A study by Hoffstad et al. showed that individuals with diabetes and amputation had a higher risk of death (HR 3.02, 95% CI 2.90-3.14) than those without amputation.61 In this meta-analysis, we found that amputation significantly increased mortality in patients with DFU. Of note, amputations were usually performed at an advanced stage of diseases, such as severe ischaemia, gangrene, severe infection and chronic non-healing foot ulcer. Many individuals receiving this procedure also had other medical conditions, such as PAD and CKD. Whether amputation itself is associated with increased mortality is uncertain. However, walking ability was associated with higher survival after amputation (5-year survival of 68% vs. 30%).62 Thus limb salvage or regaining walking ability after amputation appears critical to reducing mortality.

      The results of this meta-analysis have important implications for clinical practice. First, the lifetime incidence of DFU was high, ranging from 19% to 34%.63 The high mortality of DFU raised the importance of preventing foot ulcers. Second, because cardiovascular diseases are the leading cause of death, more attention should be paid to the management of cardiovascular diseases and risk factors. Third, health practitioners and policymakers should also pay more attention to the prevention, timely detection and management of various infections, including pulmonary and foot infections. Fourth, the high mortality in patients with DFUs and CKD, especially ESRD, indicates that further interventional measures, such as sodium-glucose co-transporter-2 inhibitors and finerenone,64 should be designated to reduce the risk or to slow the progression of CKD, thereby reducing cardiovascular disease and mortality.

      Notably, there was significant heterogeneity among studies. The heterogeneity might result from population diversity. The population in different studies came from hospitals, podiatric clinics, community primary health centres or the national registry of foot ulcers. There was also great diversity in patients enrolling. Some studies only included patients with first-onset foot ulcer, while others enrolled patients regardless of a previous history of foot ulcer. The severity of foot ulcer varied greatly. Patients in some studies had milder foot ulcer, while others had more severe ones. Besides, the diversity of treatments in different countries, and even in different regions of the same country, might also contribute to differences in mortality.

      There were limitations in this meta-analysis. The wide heterogeneity of studies might bias the findings of this systematic review. Second, most studies came from high-income countries in Europe and the Western Pacific regions. There were no data on Africa. Additional evidence from unrepresented regions might contribute to a more comprehensive understanding of mortality around the world. Third, we analysed the risk factors of mortality for patients with DFU. However, only some studies reported the HRs of these factors. Thus there might be publication bias. Fourth, the studies included were limited to English and Chinese language publications.

      In summary, we quantified mortality worldwide and summarized risk factors for death in patients with DFU. These findings have important implications for policy and practice. Screening and management of cardiovascular diseases and risk factors should remain important aspects of health promotion policies. The prevention and control of infection and CKD should be taken into consideration in policymaking and clinical practice. Further studies should be performed to examine whether aggressive interventional measures could reduce the risk of death from DFU.

ACKNOWLEDGEMENTS

      This study was partially supported by the Science and Technology Bureau of Sichuan Province (grant no. 2021JDKP0040), West China Nursing Discipline Development Special Fund Project, Sichuan University (grant no. HXHL20005) and the 1.3.5 Project for disciplines of excellence, West China Hospital, Sichuan University (grant no. ZYGD18025).

CONFLICT OF INTEREST

The authors declare that they have no competing interests.

AUTHOR CONTRIBUTIONS

LC and XR conceived and designed the study. LC and SS screened and identified eligible studies. LC, SS and YG extracted data from eligible studies. LC and YG performed the statistical analysis. LC drafted the initial manuscript. All authors provided critical comments on the manuscript and have access to the data. All authors approved the final version of the manuscript.

DATA AVAILABILITY STATEMENT

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

AVAILABILITY OF DATA AND MATERIALS

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

ORCID

Xingwu Ran https://orcid.org/0000-0002-6634-1241

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SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

How to cite this article: Chen L, Sun S, Gao Y, Ran X. Global mortality of diabetic foot ulcer: A systematic review and metaanalysis of observational studies. Diabetes Obes Metab. 2022;1‐10. doi:10.1111/dom.14840

This article is excerpted from the Diabetes Obes Metab. 2022;1–10. by Wound World.