Risk factors for diabetic foot complications in type 2 diabetes-A systematic review.

INTRODUCTION

Diabetes mellitus is one of the major health concerns of the 21st century. The number of patients with diabetes has been increasing steadily for the past three decades, and this increase will probably continue throughout the next decades: from an estimated 463 million patients between the age of 18 and 99 years affected in 2019 to an estimation of 700 million people in the same age group affected in 2045 worldwide. Diabetes accounts for approximately 4.2 million deaths annually and causes a tremendous financial burden on healthcare systems: in 2019, the global health care costs for diabetes totalled 760 billion US dollars for patients in the age group between 18 and 99 years. 1 , 2

Patients with diabetes face a high risk of developing serious adverse health conditions that shorten the life expectancy, lower the quality of life and increase medical care costs. 1 , 3 The diabetic foot (DF) syndrome is a serious diabetic late complication strongly related to diabetic neuropathy and peripheral artery disease. Tissue necrosis can result in a need for lower extremity amputation (LEA). 1 According to the International Working Group on the Diabetic Foot (IWGDF), DF is defined as: ‘Infection, ulceration, or destruction of tissues of the foot of a person with currently or previously diagnosed diabetes mellitus, usually accompanied by neuropathy and/or peripheral arterial disease in the lower extremity’. 4

Around 25% of all patients with diabetes develop foot complications during their course of disease. 5 The condition constitutes a major cause for hospital admissions in people with diabetes, accounting for nearly 70% of all amputations conducted in the United States in 1997. 1 , 6 , 7 Moreover, diabetic foot ulcers (FU) and amputations make up the most expensive diabetic late complication in terms of hospital costs. 8 In the year after the first FU, the health expenditures for patients with diabetes with FUs are five times higher than for those without FUs and almost three times higher in the subsequent years. In 2007, one‐third of all costs for diabetes were linked solely to foot complications. 9 Patients with diabetes suffering from FUs reveal a 10‐20 times higher risk for amputation than subjects without diabetes, 10 and FUs are further associated with a higher mortality risk compared to those patients without foot complications. 11 Approximately 1% of all patients with diabetes have to undergo lower limb amputation in high‐income countries, with the percentage being higher in low‐ and middle‐income countries. 1 In addition, patients with a history of DF complications carry a higher risk of subsequent re‐ulcerations. 12

DF conditions, especially with severe complications and the need for amputations, are one of the most serious and preventable diabetic late complications. Besides the efforts made on conducting regular foot examinations and the progress on risk classification systems, both prevention and early detection methods must be improved. 13 , 14 A further necessary aspect in the prevention would be the identification of risk factor profiles allowing to identify patients at high risk for foot disease.

A large number of articles have been published on this matter, however, with a large heterogeneity in the conducted studies and large differences in their quality. In contrast to more recent reviews on other aspects of the diabetic foot such as management and costs of this late complication, 15 , 16 only few reviews have been published on the associated risk factors, with the last publication in 2012. 17 Both the presentation of results and the number of published articles since the last published review on risk factors for diabetic foot complications justify a most up‐to‐date systematic review, which was designed to identify and characterize the published risk factors associated with the DF in type 2 diabetes mellitus (T2DM), which comprises approximately 90%‐95% of all patients with diabetes. 18 The results of the review should on the one hand guide physicians, researchers, patients and other interested parties in the identification of patients at high risk of developing DF complications and on the other hand identify risk factors that can serve as starting points to be tackled in order to reduce this risk.

MATERIALS AND METHODS

The protocol of this systematic review was developed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses: The PRISMA statement. 19 To assure a comprehensive overview of the current literature, the databases MEDLINE, EMBASE, Cochrane, CINAHL, LISTA and Academic Search Elite were searched. The following approach was used: variations of terms for diabetes and also for foot or amputation or ulcer had to be included in the title of a publication, while, in addition, a variation of a term for risk or predictor had to be included in the abstract. The Boolean search term was chosen as follows: “(diab* OR T2DM):ti AND (foot OR amputation OR ulcer*):ti AND (risk* OR predict* OR determ* OR incidence):ab”.

The following inclusion and exclusion criteria were defined for the evaluation of the articles: Only studies conducted in human subjects were included.Only studies published in English language were included.Diabetes and the outcome of interest (eg FU or LEA) had to be clearly defined.The subject population had to consist of patients suffering from T2DM.If the subject population was a mixed population with diabetes, the proportion of patients with T2DM had to be at least 75%.The studies had to be at least of observational nature including a control group, that is patients with diabetes who developed foot complications had to be compared to patients with diabetes who did not.Only studies on the first development of foot complications were included, which led to the exclusion of studies investigating recurrent complications or subsequent events after a first DF development.To assure a minimum level of quality, the patient population had to consist of at least 100 subjects.The risk factors had to be analysed in a multivariate model adjusted at least for age as a covariate.

Only studies conducted in human subjects were included.

Only studies published in English language were included.

Diabetes and the outcome of interest (eg FU or LEA) had to be clearly defined.

The subject population had to consist of patients suffering from T2DM.

If the subject population was a mixed population with diabetes, the proportion of patients with T2DM had to be at least 75%.

The studies had to be at least of observational nature including a control group, that is patients with diabetes who developed foot complications had to be compared to patients with diabetes who did not.

Only studies on the first development of foot complications were included, which led to the exclusion of studies investigating recurrent complications or subsequent events after a first DF development.

To assure a minimum level of quality, the patient population had to consist of at least 100 subjects.

The risk factors had to be analysed in a multivariate model adjusted at least for age as a covariate.

The search included publications published up until August 2019 when the database searches were performed. Repeating the search at time of submission in July 2020 identified no additional articles, which would warrant inclusion in this review. After removing duplicates and triplicates, all remaining publications were included in a screening of the abstracts and subsequently screening of the full articles. The initial screening was performed by the first author; ambiguous cases were discussed and decided with the corresponding author. In these steps, studies that did not fit the aforementioned inclusion and exclusion criteria were removed from further analysis (see Figure 1). The reference sections of included studies were checked in order to identify potential studies, which had been missed earlier and are relevant. Furthermore, if more than one publication analysed data from the same study or database, it was checked whether the subpopulations and/or risk factors differed between the publications, and only if this was the case, more than one publication was included from the same source of data. Otherwise, the most recent publication would have been included. After the final number of eligible studies has been identified, the publications were summarized in line with the approach published by Drinkwater et al, who performed a well‐structured, comprehensive, and easily understandable systematic review on risk factors for cataract in patients with T2DM. 20 Due to the large clinical and methodological diversity of the included studies (concerning, eg patient populations, outcomes and study designs), the conduction of a systematic review was more reasonable than the performance of a meta‐analysis. 21 Important characteristics and data from the eligible studies were brought together in tabular forms. The information entered included author and year of study, country, study design, study name, patient characteristics (sample size, number of events, baseline age at study entry, proportion of T2DM, proportion of female patients, diabetes duration at time of development of outcome, follow‐up time), potential conflicts of interest, methods and limitations, results from multivariate analyses as well as the covariates included in the models. The quality of included studies was assessed using the Newcastle‐Ottawa Quality Assessment Forms for Cohort Studies and Case‐Control Studies, 22 with a median follow‐up time of 3 years chosen to be sufficient for outcome question 2 in case of cohort studies. The risk of bias was assessed for each included publication using the Cochrane handbook guidelines. 23 In the following sections, for reporting effects for a specific potential risk factor we use the wording positive or negative association or relationship synonymously for statistically significant effects only. In addition, we use the notation consistent association if only positive effects and null effects or only negative effects and null effects have been reported and inconsistent association if both positive and negative effects have been reported.

CONSORT diagram of literature search. Note: Indicated numbers for exclusion criteria represent the minimum number of articles. Articles were not evaluated for each criterion but were discarded as soon as one of the exclusion criteria was met

RESULTS

Six databases were searched to retrieve all relevant literature on risk factors for the initial development of DF conditions. 9,476 publications were identified by predefined search terms. After removal of 4,583 duplicates and triplicates and 388 publications not written in English language, 4,505 references remained and were assessed for eligibility via screening of title, abstract and/or full text. A final number of 31 articles were included in the analysis (see Figure 1). 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 The screening of the reference sections of these publications did not reveal any further articles meeting all specified inclusion and exclusion criteria, thus justifying the predefined search terms. The final sample comprised eleven cross‐sectional and twenty longitudinal studies. In the 31 articles, 28 different study populations were analysed, with two articles each from the Kaiser Permanente Northern Carolina Diabetes Registry (US), 30 , 44 the Diabetes Care in General Practice (DCGP) study (Denmark) 28 , 29 and the Taiwan National Health Insurance Research Database (NHIRD, Taiwan). 41 , 45 However, in all three cases, different subpopulations were included in the studies, and different risk factors were analysed in each of the publications. Therefore, all of the articles were considered for the systematic review. Associations between risk factors and the particular outcomes were given as the summary measures relative risk (RR), odds ratio (OR) or hazard ratio (HR).

The characteristics of all 31 articles, which were published between 1995 and 2019, are shown in Table 1. Six studies were performed in China, 32 , 33 , 36 , 39 , 51 , 54 five in the United States, 30 , 34 , 44 , 49 , 52 three in Taiwan, 41 , 45 , 46 two in the UK, 26 , 35 Denmark 28 , 29 and Saudi Arabia, 25 , 37 and one study each in Australia, 27 Austria, 40 Finland, 48 Ghana, 43 Italy, 47 New Zealand, 42 Pakistan, 53 Republic of Nauru 38 and Singapore. 50 In addition, two multinational studies were included, one of which was conducted in Europe (UK, Switzerland, Germany, Poland, Croatia), East Asia (Hong Kong, Japan), the United States and Cuba, 31 while the other one recruited subjects at sites across the UK, the United States and Canada. 24 The sample sizes ranged from the lower bound for inclusion (100 subjects) 47 up to more than 1.3 million subjects. 45 While, in 17 studies, only subjects with T2DM were included, the proportion of subjects with T2DM in a mixed diabetic study population was at least 75% in eight studies. In six studies, the patient population was not further defined concerning the proportions of subjects with T1DM and T2DM. While, in most publications, the gender was distributed rather evenly, one study was performed on the US National Veterans Health Administration (VHA) database, in which the proportion of female patients was as low as 2.6%. 52 The mean duration of diabetes ranged from 3.7 years 38 to more than 13 years 25 , 28 in the different patient populations; however, this value was not stated in nine of the 31 articles. 24 , 26 , 34 , 41 , 45 , 47 , 48 , 50 , 52 The mean follow‐up time in longitudinal studies varied between one year 24 , 39 and 13 years. 44

Characteristics of studies: Values for baseline age, diabetes duration and follow‐up time are given as mean, mean ± standard deviation or the range in parentheses, if not stated otherwise

At 6‐year follow‐up: 5.7 years

at 14‐year follow‐up:

13.9 years

DF: 28

LEA: 45

DF: 49.1

LEA: 48.7

Newly diagnosed: 33.1%

1‐3 years: 24.6%

4‐6 years: 18.8%

7‐10 years: 13.2%

>10 years: 10.3%

<5:26.7%

5‐10:23.3%

10.1‐20:31.6%

>20:18.4%

At baseline: 1,333;

at follow‐up after 1 year:

687

Abbreviations: DF, diabetic foot; IQR, interquartile range; LEA, lower extremity amputation; PY, person‐years; RCT, randomized controlled trial; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; UK, United Kingdom; USA, United States of America; WHO, World Health Organization.

First author is codirector of QResearch and director of ClinRisk (a company that offers a software to implement clinical risk algorithms within clinical computer systems); the co‐author is a statistician at ClinRisk.

The methodological aspects and the corresponding limitations of the particular studies are summarized in Table 2. There were large variations concerning the definition of T2DM, ranging from criteria defined by the American Diabetes Association or the World Health Organization (WHO) to identification of patients with diabetes from charts or records via search for relevant diagnostic codes. In some publications, diabetes was assessed via self‐reported questionnaires. There were four main different outcomes: any diabetic foot (any DF), FU, LEA and Charcot arthropathy (CA). In some publications, also foot gangrene (FG) was assessed in addition. 25 , 31 , 37 The outcomes were defined differently, ranging from WHO definition to individual classifications. The assessment of the outcome was in most cases performed via foot examination or via searches in medical records for relevant diagnostic procedure codes. The limitations of the included studies are discussed in Table 2. Most common limitations were missing patient characteristic data and the fact that cross‐sectional studies do not allow for the assessment of a causal relationship between risk factors and outcome. Furthermore, in many of the studies analysing LEA as end‐point, previous foot problems of patients have not been assessed. This did not allow a judgement on the novelty of foot conditions and assessment if initial development of foot conditions was evaluated.

Methods and limitations of included studies

Abbreviations: ADA, American Diabetes Criteria; CA, Charcot arthropathy; DF, diabetic foot; FG, foot gangrene; FU, foot ulceration; GP, general practitioner; ICD, International Statistical Classification of Diseases and Related Health Problems; IWGDF, International Working Group on the Diabetic Foot: LEA, lower extremity amputation; NOMESCO, Nordic Medico‐Statistical Committee; OHA, oral hypoglycaemic agent; OPCS, Office of Population Censuses and Surveys; PAD, peripheral arterial disease; PN, peripheral neuropathy; PVD, peripheral vascular disease; RCT, randomized controlled trial; T2DM, type 2 diabetes mellitus; WHO, World Health Organization.

Table 3 shows the results of the individual studies including the published summary measures, and—if stated—the corresponding confidence intervals and p‐values. In addition to the results of the multivariate analyses, the covariates included in the analyses are listed.

Outcomes and results of included studies

stat. sign.: age (HR 0.957), PN (1.050), VPT (1.056);

not stat. sign.: type of diabetes, ethnicity, economic status, duration of diabetes

stat. sign.: age (≥45 y: OR 3.81 [95% CI: 2.22‐6.54], P < .0001), male gender (1.92 [1.49‐2.48], P < .0001), PN (7.20 [4.84‐10.71], P < .0001), duration of diabetes (≥10 y: 2.50 [1.66‐3.77], P < .0001), insulin use (3.98 [3.02‐5.23], P < .0001), retinopathy (1.84 [1.43‐2.35], P < .0001), poor glycaemic control (1.49 [1.12‐1.98], P = .006);

not stat. sign.: Charcot joint, PVD, nephropathy, cerebral vascular disease, coronary heart disease, hypertension, smoking

stat. sign.: social deprivation (highest quintile of deprivation compared to lowest quintile) (OR 1.77 [95% CI: 1.45‐2.14], P < .0001)

in T2DM only: increased deprivation per quintile (1.13 [1.09‐1.16], P < .0001);

not stat. sign.: increased deprivation per quintile in patients with T1DM

Risk factors for active FU at baseline:

stat. sign.: intermittent claudication (OR 17.24 [95% CI 3.66‐81.23), P < .001), duration of diabetes (per increase of 5 y: 1.58 [1.12‐2.23], P = .009), PN (15.84 [1.95‐128.81], P = .010), antihypertensive therapy (11.16 [1.13‐95.44], P = .028)

not stat. sign.: age, exercise, diabetes treatment, microalbuminuria, PVD, history of vascular bypass

Risk factors for hospitalization for FU during follow‐up:

stat. significant: retinopathy (OR 3.86 [95% CI 2.26‐6.59], P < .001), cerebrovascular disease (3.76 [1.97‐7.19], P < .001), intermittent claudication (2.77 [1.52‐5.04], P = .001), PN (2.24 [1.35‐3.71), P = .002), HbA1c (for a 1% increase: 1.22 [1.07‐1.40], P = .003), alcohol consumption (for 1 standard drink/day increase: 1.16 [1.05‐1.27], P = .003), decreased eGFR (2.12 [1.30‐3.51], P = .004), PVD (1.85 [1.10‐3.13], P = .021), pulse pressure (for a 5 mmHg increase: 1.07 [1.00‐1.14], P = .038);

not stat. sign.: duration of diabetes, fasting plasma glucose, diabetes treatment, systolic blood pressure, albuminuria, history of vascular bypass

For end‐point active ulcer at baseline: age, exercise, duration of diabetes, diabetes treatment, antihypertensive therapy, PN, intermittent claudication, PVD, history of vascular bypass

For end‐point hospitalization for FU during follow‐up: duration of diabetes, alcohol consumption, fasting plasma glucose, HbA1c, diabetes treatment, systolic blood pressure, pulse pressure, albuminuria, nephropathy, retinopathy, PN, intermittent claudication, PVD, cerebrovascular disease, history of vascular bypass

Risk factors for FU at baseline:

stat. sign.: male gender (OR 2.45 [95% CI 1.01‐5.98], P < .05), PN (2.51 [1.30‐4.85], P < .01), retinopathy (6.21 [2.13‐18.10], P < .001), PVD (3.22 [1.46‐7.13], P < .01);

not stat. sign.: age, impaired vision or blindness, microalbuminuria, proteinuria, stroke, myocardial infarction, angina/ischaemic heart disease, mental disorder

Risk factors for FU at 6‐year follow‐up:

stat. sign.: PN (2.72 [1.24‐5.96], P < .05), PVD (2.84 [1.10‐7.37], P < .05), myocardial infarction (4.36 [1.60‐11.91], P < .01);

not stat. sign.: age, gender, retinopathy, impaired vision or blindness, microalbuminuria, proteinuria, stroke, angina/ischaemic heart disease, heart failure, cancer, mental disorder

Risk factors for FU at 14‐year follow‐up:

stat. sign.: PN (5.60 [1.98‐15.88], P <.01), PVD (5.15 [1.59‐16.74], P < .01), myocardial infarction (3.40 [1.07‐10.81], P < .05), heart failure (4.76 [1.40‐16.15], P < .05);

not stat. sign.: age, gender, retinopathy, impaired vision or blindness, microalbuminuria, proteinuria, stroke, angina/ischaemic heart disease, mental disorder

Risk factors for any amputation during follow‐up: male gender (HR 2.40 [95% CI 1.31‐4.41], P < .01), PN (2.09 [1.19‐3.69], P < .05), retinopathy (6.42 [2.59‐15.90], P < .001), impaired vision or blindness (6.92 [2.35‐20.38], P < .001), microalbuminuria (2.11 [1.21‐3.67], P < .01), PVD (3.43 [1.65‐7.12], P < .001), myocardial infarction (2.79 [1.01‐7.75], P < .05);

not stat. sign.: age, proteinuria, stroke, angina/ischaemic heart disease, heart failure, cancer, mental disorder

Risk factors for FU at 6‐year follow‐up:

stat. sign.: patient's motivation reported by GP (poor vs very good: OR 12.37 [95% CI 1.22‐25.23], P < .05), patient's own effort reported by GP (poor vs good: 6.24 [2.16‐18.01], P < .05);

not stat. sign.: patient‐reported effort, influence of life circumstances as reported by GP

Risk factors for any amputation during 13‐year follow‐up:

stat. sign.: patient's own effort reported by GP (poor vs good: HR 4.17 [95% CI 1.67‐10.45], P < .01), life circumstances as reported by GP (none in particular vs good: 2.96 [1.07‐8.22], P < .05; poor vs good: 2.60 [1.03‐6.54], P < .05);

not stat. sign.: patient's motivation reported by GP, patient‐reported effort

stat. sign.: triglycerides (150‐199 vs < 150 mg/dL: HR 1.29 [95% CI 1.07‐1.55]; 200‐499 vs < 150 mg/dL: 1.40 [1.19‐1.65]; >500 vs < 150 mg/dL: 1.65 [1.22‐2.24]), LDL (>160 vs < 100 mg/dL: 1.30 [1.03‐1.64]), HDL (>60 vs < 40 mg/dL: 1.37 [1.02‐1.84]), male gender (1.59 [1.33‐1.90]), ethnicity (Asian vs white: 0.51 [0.39‐0.69]), duration of diabetes (10‐19 vs < 10 y: 1.94 [1.65‐2.28], >20 vs < 10 y: 2.38 [1.96‐2.88]), diabetes therapy (T2DM on insulin vs diet only: 2.41 [1.88‐3.10], T2DM on oral OHA vs diet only: 1.62 [1.28‐2.05]), BMI (obese vs normal weight: 0.80 [0.65‐0.98]), height (2nd vs 1st quartile: 1.43 [1.09‐1.86], 3rd vs 1st quartile: 1.34 [1.01‐1.77], 4th vs 1st quartile: 1.98 [1.48‐2.66]), hypertension (1.51 [1.27‐1.78]), PN (2.60 [2.23‐3.04]), retinopathy (1.85 [1.15‐2.98]), heart attack (1.27 [1.06‐1.52]), stroke (1.97 [1.55‐2.50]), end‐stage renal disease (4.29 [3.06‐6.03]);

not stat. sign.: LDL (100‐129 and 130‐159 both vs < 100 mg/dL), HDL (40‐59 vs < 40 mg/dL), age, ethnicity (African American, Hispanic, Mixed/Other, all vs White), HbA1C, statin medication, fibrate/niacin medication, smoking, BMI (underweight and overweight, both vs normal weight)

stat. sign.: indirect bilirubin (≥ 6 μmol/l vs < 6 μmol/l: OR 0.75 [95% CI 0.57‐0.98], P = .029);

not stat. sign.: total bilirubin, direct bilirubin

stat. sign.: VEGF‐A (lower 1st tertile vs upper 3rd tertile: OR 1.76 [95% CI 1.01‐3.07], analysed as continuous variable per 10‐unit increase: 0.93 [0.88‐0.97]), PlGF (lower 1st tertile 1 vs upper 3rd tertile: 2.36 [1.34‐4.15], analysed as continuous variable per 5‐unit increase: 0.96 [0.94‐0.99]);

not stat. sign.: VEGF‐A (middle 2nd tertile vs upper 3rd tertile), PlGF (middle 2nd tertile vs upper 3rd tertile)

Risk factors for FU:

stat. sign.: age (for every year increase: OR 0.991 [95% CI 0.985‐0.997], P = .003), retinopathy (1.357 [1.154‐1.595], P < .001), PN (3.441 [2.94‐4.027], P < .001), hypertension (2.265 [1.586‐3.237], P < .001), PVD (4.309 [3.668‐5.062], P < .001), coronary artery disease (1.388 [1.178‐1.635], P << .001], chronic kidney disease (1.824 [1.541‐2.158], P < .001);

not stat. sign.: number of HbA1cs drawn, most recent BMI

Risk factors associated with CA:

stat. sign.: age (for every year increase: 0.964 [0.938‐0.99], P = .008), hypertension (2.571 [1.213‐4.131], P = .018), PN (1.233 [1.035‐3.038], P = .049);

not stat. sign.: number of HbA1cs drawn, most recent BMI, retinopathy, PVD, coronary artery disease, chronic kidney disease

stat. sign.: metformin (HR 0.70 [95% CI 0.64‐0.77]), insulin (1.64 [1.41‐1.91]) (HR for each diabetes drug group is compared with no prescription of that particular medicine);

not stat. sign.: glitazones, gliptins, sulphonylureas, other OHA

stat. sign.: skin autofluorescence (OR 2.55 [95% CI 1.10‐5.91], P = .03), triglycerides (0.31 [0.13‐0.74], P < .01), BUN (1.22 [1.02‐1.46], P = .03), right ABI (0.001 [0.000‐0.04], P < .01), C‐reactive protein (1.02 [1.001‐1.03], P = .03);

not stat. sign.: duration of diabetes, age, left ABI, HDL, creatinine, LDL, VPT

risk factors associated with FU, FG and/or LEA: nationality (non‐Saudi vs Saudi: OR 2.47 [95% CI 1.39‐4.38], P = .002), PN (3.21 [1.69‐6.10], P < .0001), PVD (2.80 [1.56‐5.01], P < .001), duration of diabetes (10.1‐20 y vs < 5 y: 3.70 [1.26‐10.84]; >20 y vs < 5 y: 3.60 [1.09‐11.89]);

not stat. sign.: gender, age, inulin use, OHA use, clopidogrel use, duration of diabetes (5‐10 y vs < 5 y), haemoglobin (125‐138 g/l, 138‐149 g/l, ≥149 g/l, all vs < 125 g/l)

stat. sign.: fasting plasma glucose (per 1mmol/l increment: RR 1.26 [95% CI 1.14‐1.38], P < .001), diabetes duration (per year increase: 1.15 [1.07‐1.23], P < .001), female gender (0.34 [0.18‐0.83], P = .015), systolic blood pressure (per 10 mmHg: 0.78 [0.76‐0.80], P = .010);

not stat. sign.: age, BMI, total plasma cholesterol, fasting plasma triglycerides, mean daily alcohol intake, smoking

Risk factors associated with FU at baseline:

stat. sign.: male gender (OR 2.062 [95% CI 1.323‐3.215], P = .001), smoking (1.597 [1.057‐2.411], P = .026), location (city vs rural: 2.234 [1.515‐3.293], P < .0001), retinopathy (1.781 [1.234‐2.569], P = .002), ABI < 0.9 (5.452 [3.489‐8.519], P < .0001), intermittent claudication (5.216 [2.763‐9.848), P < .0001), diabetes therapy (insulin vs OHA: 4.205 [2.247‐7.869], P < .0001; OHA and insulin vs OHA: 2.526 [1.323‐4.824], P = .005), BMI (0.927 [0.883‐0.927], P = .002), HDL (per unit increase: 0.238 [0.134‐0.423], P < .0001), haemoglobin (per unit increase: 0.976 [0.970‐0.985], P < .0001), postprandial blood glucose (0.940 [0.908‐0.972], P < .0001);

not stat. sign.: age, living alone (yes/no), occupation, hypertension, PN, PVD, nephropathy, cataracts, duration of diabetes, HbA1c, fasting plasma glucose, bilirubin, creatinine, cholesterol, triglyceride, albumin, WBC

Risk factors associated with FU at follow‐up:

stat. sign.: HDL (OR 0.427 [95% CI 0.228‐0.799], P = .008), nephropathy (2.320 [1.449‐3.714], P < .0001), diabetes therapy (insulin vs OHA: 3.136 [1.357‐7.251], P = .008; OHA and insulin vs OHA: 2.629 [1.125‐6.148], P = .026);

not stat. sign.: all other factors also analysed at baseline

stat. sign.: elevated VPT (RR 25.4 [95% CI 3.1‐205], P = .0024), mean plantar pressure (6.3 [1.2‐32.7], P = .0291), daily alcohol intake (5.1 [1.1‐24.0], P = .0404), mediasclerosis (0.07 [0.01‐0.6], P = .0174);

not stat. sign.: age, diabetes duration, body weight, OHA therapy, insulin use, history of angiography, flatfoot deformity, hallux valgus, oxford shoes, varicosis, dry skin, skeletal abnormalities, HbA1c, triglycerides, stage of peroneal nerve conduction velocity, diastolic blood pressure

stat. sign.: age at T2DM onset (HR 1.024 [95% CI 1.013‐1.035]), male gender (1.643 [1.237‐2.183]), heart failure (2.134 [1.445‐3.151]), hypertension (0.674 [0.496‐0.915]), coronary artery disease (0.705 [0.502‐0.988]), hyperlipidaemia (0.361 [0.269‐0.486]), retinopathy (2.067 [1.118‐3.821]), PN (2.338 [1.617‐3.38]), peripheral arterial occlusive disease (4.134 [2.717‐6.289]);

not stat. sign.: chronic kidney disease, atrial fibrillation, stroke, nephropathy

stat. sign.: ethnicity (East Asian vs European/other: HR 0.23 [95% CI 0.10‐0.56], P < .001; Indian vs European/other: 0.48 [0.27‐0.83], P < .001; Maori vs European/other: 1.61 [1.35‐1.93], P < .001), age at onset (per 10 y: 1.52 [1.42‐1.63], P < .001), female gender (0.72 [0.60‐0.87], P < .001), diabetes duration (per year: 1.19 [1.17‐1.22], P < .001), smoking status (ex‐smoker vs nonsmoker: 1.26 [1.09‐1.47], P = .003; current smoker vs nonsmoker: 1.63 [1.35‐1.97], P < .001), height (per 10 cm: 1.35 [1.23‐1.48], P < .001), systolic BP (per 10 mmHg: 0.69 [0.53‐0.89], P = .005; squared: 1.01 [1.01‐1.02], P = .001), HbA1c (per 10 mmol/mol: 1.27 [1.24‐1.31], P < .001), total/HDL‐cholesterol ratio (1.05 [1.02‐1.09], P = .007);

not stat. sign.: ethnicity (Pacific vs European/other), weight, BMI

stat. sign.: age (per 10‐year increase: HR 1.11 [95% CI 1.06‐1.22], P < .001), male gender (3.50 [2.88‐5.23], P < .001), type of diabetes (T2DM vs T1DM: 8.21 [2.58‐1.07], P < .001), BMI (each 5kg/m 2 increase: 3.2 [2.51‐7.25], P < .001), HbA1c (per % increase: 1.11 [1.05‐1.25], P = .03), hypertension (1.14 [1.12‐3.21], P < .001), PN (6.56 [6.21‐8.52], P < .001), PVD (7.73 [4.39‐9.53], P < .001);

not stat. sign.: duration of diabetes, dyslipidaemia, nephropathy

stat. sign.: glucose score (OR 1.75 [1.37‐2.24]), systolic blood pressure (per 1 mm Hg: 1.02 [1.01‐1.04]), retinopathy (3.68 [1.78‐7.62]), PN (4.05 [2.01‐8.17]), stroke (2.70 [1.27‐5.75]);

not stat. sign.: duration of diabetes, type of diabetes, BMI, treatment (insulin and OHA, both vs diet only), ethnicity (black and other, both vs white), total cholesterol, smoking status (never or ex‐smoker vs current smoker), myocardial infarction

stat. sign.: age (5 age groups [35‐45, 45‐55, 55‐65, 65‐75, >75 y] compared to < 35 y: each HR ≥ 1.73, each P < .0001), male gender (HR 1.83 [95% CI 1.756‐1.916], P < .0001), salary (8 salary groups [insured dependents, ≤15,840; 15,841‐22,800; 22,801‐28,800; 28,801‐36,300; 36,301‐45,800; 45,801‐57,800; 57,801‐72,800] compared to > 72,801: each HR ≥ 4.67, each P < .0009), low income status (3.69 [3.387‐4.028), P < .0001), diabetic complications (different number of complications [1, 2, 3, 4, ≥5] compared to no complications: each HR ≥ 1.68, each P < .0001, city household income (middle vs high: 1.12 [1.066‐1.178], P < .0001), degree of urbanization (urbanization divided into 8 levels; all levels compared with highest level of urbanization: each HR ≥ 1.26; each P < .0001), attending clinic for regular care is not a metabolic disease clinic (1.47 [1.362‐1.591], P < .0001), ownership of hospital for regular care (nonprofit vs public: 1.16 [1.085‐1.248], P < .0001), not attending preventive programme ‘P4P Care’ (3.46 [3.187‐3.758], P < .0001);

not stat. sign.: household income (low vs high), ownership of hospital for regular care (private vs public)

stat. sign.: age (10‐year increment: OR 1.19 [95% CI 1.10‐1.28], P < .01), type of diabetes (1.67 [1.24‐2.25), P < .01), duration of diabetes (10‐year increment: 1.78 [1.65‐1.93], P < .01), smoking status (ex‐smoker vs never smoker: 1.33[1.05‐1.69], P < .05), hypertension (1.34 [1.15‐1.57], P < .01), body height (10‐cm increment: 1.16 [1.03‐1.32], P < .05);

stat. sign. risk factors studied in subset of 9,295 subjects: fasting plasma glucose (0.6 mmol/l increment: 1.12 [1.04‐1.21], P < .01);

not stat. sign.: gender, smoking status (current vs never smoked), dyslipidaemia (yes vs no; and unknown vs no)

stat. sign.: hypertension (OR 21.27 [95% CI 4.09‐110.62], P = .0001), dyslipidaemia (6.07 [1.43‐25.66], P = .014), BMI (1.17 [1.02‐1.34], P = .019), pulse wave velocity (2.26 [1.36‐3.75], P = .002), reactive hyperaemia index (0.01 [0.001‐0.185], P = .002);

not stat. sign.: age, systolic blood pressure, aortic augmentation index, cognitive function (Mini‐Mental State Examination)

stat. sign.: major depression compared to no depression (HR 2.00 [95% CI 1.24‐3.25]);

not stat. sign.: minor depression compared to no depression

stat. sign.: age ≥ 65 (OR 0.8 [95% CI 0.71‐0.89], P < .001), female gender (0.79 [0.71‐0.87], P < .001), year of discharge (2007 vs 2004:0.72 [0.60‐0.87], P = .001; 2008 vs 2004:0.58 [0.48‐0.70], P < .001; 2009 vs 2004:0.40 [0.34‐0.49], P < .001), ethnicity (Malay vs Chinese: 1.55 [1.35‐1.77], P < .001), renal disease (3.18 [2.84‐3.56], P < .001);

not stat. sign.: year of discharge (2005 vs 2004; 2006 vs 2004), ethnicity (India vs Chinese; Other vs Chinese)

stat. sign. in female patients: uric acid (for every 1‐μmol/L increment: OR 1.004 [95% CI 1.001‐1.008], P < .05; quintile 5 vs quintile 1:4.727 [1.357‐16.468], P < .05);

not stat. sign.: uric acid (quintiles 2, 3, 4, each vs quintile 1 [lowest concentration of uric acid])

stat. sign.: age (OR 1.027 [95% CI 1.003‐1.051], P = .025), duration of diabetes (1.063 [1.027‐1.100], P = .001), PN (23.926 [5.41‐105.6], P = .001), PVD (0.267 [0.143‐0.532], P = .001), HbA1c (6.187 [4.646‐8.239], P = .001);

not stat. sign.: gender, BMI

stat. sign.: serum cystatin C (OR 4.828 [95% CI 1.711‐13.620], P = .003), coronary artery disease (3.566 [1.470‐8.648], P = .005), insulin use (2.605 [1.258‐5.394], P = .01), difference between supine and sitting transcutaneous oxygen pressure (1.076 [1.032‐1.122], P = .001), hypertension (1.021 [1.003‐1.039], P = .023);

not stat. sign.: age, diastolic blood pressure, haemoglobin, creatinine, calcium, albumin, triglycerides, HDL, proteinuria, microalbuminuria, ABI, transcutaneous oxygen pressure (in sitting position, in supine position)

Abbreviations: ABI, ankle‐brachial index; ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; BP, blood pressure; BUN, blood urea nitrogen; CA, Charcot arthropathy; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; DF, diabetic foot; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; FG, foot gangrene; FU, foot ulceration; GGT, gamma‐glutamyl transferase; GP, general practitioner; HbA1c, haemoglobin A1c; HDL, high‐density lipoprotein; HR, hazard ratio, LDL, low‐density lipoprotein; LEA, lower extremity amputation; mmHg, millimetres of mercury; OHA, oral hypoglycaemic agent; OR, odds ratio, PlGF, placenta growth factor; PN, peripheral neuropathy; PVD, peripheral vascular disease; RR, risk ratio; stat. sign., statistically significant; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; VEGF‐A, vascular endothelial growth factor A; VPT, vibration perception threshold; WBC, white blood cell count.

The findings of the single publications were brought together in Table 4 to build an overview of the associations that have been shown for the single risk factors across all included publications. In total, the relationship between 79 different risk factors and the five previously defined outcomes has been studied. Apart from male gender, peripheral neuropathy (PN), retinopathy, nephropathy, poor glycaemic control, insulin use, duration of diabetes, smoking and height, for all of which a positive association with the outcome of interest was shown, the results for the other risk factors showed higher discordances. A total of 41 risk factors were each analysed in one study only.

Risk factor associations oversight

Abbreviations: BMI, body mass index; CA, Charcot arthropathy; CAD, coronary artery disease; CVD, cardiovascular disease; DF, diabetic foot; FU, foot ulceration; HbA1c, haemoglobin A1c; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; LEA, lower extremity amputation; OHA, oral hypoglycaemic agent; PlGF, placenta growth factor; PN, peripheral neuropathy; PVD, peripheral vascular disease; stat. sign., statistically significant; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; VEGF‐A, vascular endothelial growth factor; VPT, vibration perception threshold; WBC, white blood cell count.

The assessment of the quality of the included studies using the Newcastle‐Ottawa Quality Assessment Forms for Cohort Studies and Case‐Control Studies yielded results ranging from six to nine out of nine possible stars. Table 5 depicts the risk of bias in the included studies as assessed using the Cochrane handbook guidelines. Although, in a number of cases, some aspects could not be assessed, none of the included studies showed a risk of bias in more than one category.

Risk of various bias in included studies

Abbreviations: DF, diabetic foot; FU, foot ulceration; GP, general practitioner; LEA, lower extremity amputation; N/A, not assessable; PN, peripheral neuropathy. Colors represent low (green), high (red) and unclear/not assessable (grey) risk of bias.

DISCUSSION

This systematic review was performed to create a list of the associated risk factors for DF analysed in the literature and to combine the published results. The most frequently assessed variables were age, gender, duration of diabetes, hypertension and PN, followed by peripheral vascular disease (PVD), glycaemic control, BMI or weight and nephropathy. Of the 79 variables that were assessed, the following ones were shown to have a positive association with the outcome of interest in at least three publications (with no publications indicating a negative association): male gender, poor glycaemic control, PN, retinopathy and nephropathy, insulin use, duration of diabetes, smoking and height. Using the Newcastle‐Ottawa Assessment Forms, we confirmed the overall good quality of the studies included in this systematic review, although design problems could have affected the results on specific potential risk factors, as discussed in the following chapters on groups of risk factors.

Gender

One of the risk factors for which the highest consistency was retrieved was male gender. Although the prevalence of diabetes in general and especially the one of DF complications is slightly higher for men compared to women, 55 the effect has been shown to be even more pronounced in 11 out of 14 studies that analysed male gender as a potential risk factors for DF conditions: all of those studies showed a risk ratio of at least 1.5 for male patients with diabetes compared to female patients with diabetes. 25 , 28 , 30 , 38 , 39 , 41 , 42 , 43 , 45 , 48 , 50 In three cross‐sectional studies, no significant association was detected between gender and DF. 37 , 46 , 53

Peripheral neuropathy, retinopathy and nephropathy

A similarly strong association with DF was published for PN and retinopathy as well as for nephropathy. A possible explanation for this result could be due to a common physiological origin: diabetic late complications are classified into macrovascular and microvascular diseases, the latter arising from damage of small blood vessels and leading to retinopathies, nephropathies and neuropathies, a crucial prerequisite for DF conditions. 1 , 3 , 56 For PN, a positive relationship with the respective outcome was detected in twelve out of fourteen studies that analysed this association, with risk ratios ranging from 1.05 to 25.4. 24 , 25 , 27 , 28 , 30 , 34 , 40 , 41 , 43 , 44 , 47 , 53 In only two studies, no association was shown. 36 , 39 However, while one of those two studies was a cross‐sectional study that did not detect a relationship between elevated vibration perception threshold, an indication of PN, and FU, 36 the other one observed the patients for a follow‐up time of only one year in order to assess the development of FU, a time period that might probably be too short to detect long‐term complications in a comprehensive manner. 39 In eight studies that assessed the potential association of retinopathy with DF, a consistently positive relationship was shown. 25 , 27 , 28 , 30 , 34 , 39 , 41 , 44 The only limitation in this agreement is that Dekker et al could show this positive association only when analysing the outcome FU but did not detect an association between retinopathy and the outcome CA. 34 For nephropathy, a positive relationship was shown in six out of nine studies, 27 , 30 , 34 , 39 , 50 , 52 while the other three did not detect an association. 25 , 41 , 43

Glycaemic control

Although a strong positive relationship with poor glycaemic control would be logical for all late complications of diabetes, discrepancies were shown in the results regarding HbA1c values, fasting or postprandial blood and plasma glucose concentrations: for HbA1c, a positive association was shown in six studies, 25 , 27 , 42 , 43 , 44 , 53 while, in four studies, no association could be detected. 30 , 37 , 39 , 40 In those that detected a positive association, the risk ratios ranged from values close to one (eg Sarfo et al showed a hazard ratio of 1.11 per one unit (%) increase of HbA1c 43 ) to odds ratios larger than six. 53 In addition, of the four studies that analysed fasting blood glucose, only two showed a positive relationship, 38 , 46 while two other studies did not find any association. 27 , 39 Postprandial glucose was only assessed as a potential risk factors in one study, in which a positive association with the outcome FU was identified. Notably, the study group that described this association between postprandial glucose and FU could not find any association of HbA1c and fasting blood glucose with FU. 39 When comparing the study characteristics of the articles that showed varying results concerning the relationship between glycaemic control and DF, there is no notable heterogeneity concerning study design, population sizes or other characteristics that could explain the differences in the results.

Age and duration of disease

With being examined in 21 studies, age was the risk factor for which a potential relationship with DF was analysed the most. However, the results are highly inconsistent: while eight studies showed a positive relationship with the respective outcomes, 25 , 41 , 42 , 43 , 45 , 46 , 48 , 53 a negative relationship and therefore a protective effect of patients’ age were shown in three studies. 24 , 34 , 50 In addition to that, ten studies could not detect an association between the patients’ age and the presence of foot complications. 27 , 28 , 30 , 36 , 37 , 38 , 39 , 40 , 47 , 54 Differences between the study characteristics that could explain these contradictory results could not be retrieved. The eight studies showing a positive relationship analysed different end‐points with one study analysing any DF, 25 one study analysing FU 53 and six studies analysing LEA. 41 , 42 , 43 , 45 , 46 , 48 Even the three studies that showed a negative relationship analysed different outcomes: while Abbott et al detected a statistically significant negative relationship with the outcome FU (HR 0.957 for each year of age), 24 Yang et al analysed the outcome LEA (OR 0.8 associated with age ≥ 65 years) 50 and Dekker et al detected a protective effect of age with the outcomes FU (OR 0.991 for every year increase) and CA (OR 0.964 for every year increase). 34 Therefore, although age was stated to be an important risk factor for the development of T2DM itself, 57 this might not be necessarily the case when analysing foot complications. The crucial factor for the DF might not be the patients’ age per se, but rather the duration living with the disease, a factor that of course correlates with the patients’ age in many cases. This hypothesis is strengthened by the fact that studies, in which the relationship between the duration of diabetes and foot complications was assessed, showed a consistently positive association, even after adjusting for age. This association was reported in eight publications, 25 , 27 , 30 , 37 , 42 , 46 , 48 , 53 while six groups could not detect a statistically significant relationship. 24 , 36 , 39 , 40 , 43 , 44 Similar results for the development of DF depending on the duration of diabetes have already been highlighted by Monteiro‐Soares et al 17

Diabetes treatment

When looking at the studies that analysed diabetes treatment and its potential association with foot complications, the picture on a possible influence of insulin use is rather consistent: five out of nine studies detected a positive relationship between insulin and foot complications, 25 , 30 , 35 , 39 , 54 and no study showed a negative association. For the use of oral hypoglycaemic agents (OHA), the picture is less consistent: while, in one study, a protective effect was shown with metformin use, 35 no association was detected with other OHA in several studies. 30 , 35 , 37 , 40 , 44 However, these results have to be interpreted with caution since insulin use is associated with patients showing more severe courses of disease and whose blood glucose levels could not be controlled by lifestyle changes or the use of OHA such as metformin. 58 , 59 , 60 Besides that, it might be hypothesized that patient groups from earlier years have not been treated according to current treatment guidelines and might have received insulin treatment at earlier time points during their course of their disease.

Hypertension and dyslipidaemia

Since physiological anomalies such as hypertension and dyslipidaemia are quite common in T2DM, 18 , 61 a positive association of hypertension with late complications such as DF conditions might be hypothesized. For hypertension, the majority of studies, namely eight out of 14 that analysed this association, showed a positive relationship. 27 , 30 , 34 , 43 , 44 , 46 , 47 , 54 However, in two studies, a protective effect of high levels of blood pressure was described. 38 , 41 While one of those studies was a rather small retrospective cohort study with 375 patients, in which neither the mean duration of diabetes nor the follow‐up time was given, 38 the other study was a large prospective cohort study analysing more than 45,000 subjects. However, also for the latter study, the patients’ duration of disease and the follow‐up time were not stated, and the validity of the results can therefore not be fully assessed. 41

Dyslipidaemia is often associated with T2DM: when glucose cannot be metabolized by the cells, fats are mobilized, leading to high levels of fatty acids in the bloodstream. 61 However, it seems that dyslipidaemia is not associated with DF conditions: of four studies that analysed this potential risk factor, a positive association of dyslipidaemia with FU was only found in one cross‐sectional case‐control study, 47 while, in another study, a protective effect for LEA was shown with hyperlipidaemia. 41 Two further studies identified no association with the outcome of interest. 43 , 46 In addition, the three studies that analysed the effect of increased cholesterol levels at study entry consistently showed no effect. 38 , 39 , 44 For aberrant levels of HDL‐ and LDL‐cholesterol, the results of the studies are highly inconsistent: while, for low levels of HDL‐cholesterol, two studies showed a positive relationship, 39 , 42 one study found a negative one 30 and two studies found no association. 36 , 54 For increased levels of LDL‐cholesterol, one study showed a positive association with the outcome LEA, 30 but two studies detected no association. 36 , 54 For high levels of triglycerides, only one out of six studies identified a positive relationship of triglyceride levels >150 mg/dL and LEA. 30 In contrast, Hu et al showed a negative relationship and therefore a protective effect of high levels of triglycerides. 36 Although aberrant levels of lipids and hypertension play an important role in the development of T2DM and late complications such as macrovascular damage that can result in myocardial infarction, PVD or stroke, 3 , 56 , 62 it has to be considered that in some articles, it was not possible to distinguish between the diagnosis of dyslipidaemia and/or hypertension and current blood values which can reach normal levels after proper therapy. Therefore, results on dyslipidaemia and/or hypertension as potential risk factors, especially protective results, must be interpreted with caution.

Obesity, physical activity and height

Although obesity and lack of physical activity are two of the major risk factors for the development of T2DM 18 , 63 and the biggest part of T2DM might even be attributed to obesity, 64 those factors do not seem to play a crucial role in the development of DF complications: out of 10 studies that evaluated the association of BMI or weight, 30 , 34 , 38 , 39 , 40 , 42 , 43 , 44 , 47 , 53 only two identified a positive relationship with the outcome, 43 , 47 while one study showed a negative association. 39 Another study showed a negative association of obese versus normal weight, while no association was found for over‐ and underweight versus normal weight. 30 In six studies, no association was shown. 34 , 38 , 40 , 42 , 44 , 53 Exercise was only analysed as a risk factor in one study, in which no association was shown with the outcome FU. 27 Notably, the analysis of a possible association between height and DF complications led to consistent results over three studies, in all of which a positive association was shown with the outcome LEA. 30 , 42 , 46 This might be due to the fact that a taller body implies larger levels of pressure on the limbs or due to neuropathy depending on the length of nerve fibres with longer fibres being more affected than shorter ones. 65 While Callaghan et al and Robinson et al found height to be significantly associated with LEA even after adjusting for BMI, 30 , 42 Tseng et al did not adjust for BMI. 46

Peripheral vascular disease and cardiovascular disease

Since T2DM is a metabolic syndrome that increases the risk of heart disease and stroke, 63 , 66 and more severe courses of disease are in general associated with more late complications, it might be hypothesized that the presence of any DF disease might correlate with patients’ history of PVD and CVD. Concerning history of PVD and its association with DF conditions, there was high consistency: in seven out of 11 studies, a positive relationship was shown. 27 , 28 , 36 , 37 , 39 , 41 , 43 However, Younis et al found a negative relationship and therefore a protective effect of history of PVD. 53 In another study, a retrospective cohort study on more than 22,000 patients, a positive relationship was detected with the outcome FU, but not with the outcome CA. 34 In two further studies conducted by Al‐Rubeaan et al and Zhao et al, no association was detected. 25 , 54 Interestingly, one of those two studies, a cross‐sectional cohort study on 411 subjects conducted by Zhao et al, was the only one of three studies analysing the effect of CVD, that showed a positive relationship for this potential risk factor. 54 Besides that, a prospective cohort study on more than 45,000 patients in Taiwan showed a protective effect which might be explained by the fact that patients diagnosed with CVD usually receive medical treatment such as drugs against hypertension, antiplatelet therapy or lipid‐lowering therapy, thus preventing peripheral arterial insufficiency. 41 In addition, no effect between CVD and any DF was again stated by Al‐Rubeaan et al. 25 From a physiological point of view, the protective effect is not expected, since not only PN, but also the damage of blood vessels, which should be advanced in patients with history of PVD and CVD, enhances DF damage, leading to potential necrosis of tissue and the need for amputation. 1

CONCLUSION

An important distinction can be made between amenable and nonamenable risk factors: while nonamenable risk factors such as gender, height or duration of disease cannot be changed by the patient and/or the physician, amenable factors are the ones that can be tackled by patients and their physicians in order to reduce the risk for DF complications. The most important amenable risk factors identified by this most up‐to‐date systematic review are glycaemic control and smoking. Those factors could serve to prevent the development of DF complications and especially the potential for limb amputations, thereby increasing the quality of life of patients with T2DM. Due to the high personal and financial burden associated with DF and the large heterogeneity among included studies, additional longitudinal studies in large patient populations are necessary to identify more modifiable risk factors that can be used in the prediction and prevention of DF complications.

CONFLICTS OF INTEREST

None declared.

AUTHOR CONTRIBUTION

SR developed the protocol, conducted the literature search and wrote the first draft of the manuscript. WO was involved in study design, screening of relevant articles, design of result tables and writing the article. ML contributed her clinical expertise to writing the introduction, results and discussion section. All authors have read and approved the final manuscript.

ETHICAL APPROVAL

The study was conducted in accordance with the Declaration of Helsinki and approved by the Research Committee for Scientific Ethical Questions at UMIT University.