Advertisement

Diabetologia

, Volume 63, Issue 1, pp 49–64 | Cite as

Preventing foot ulceration in diabetes: systematic review and meta-analyses of RCT data

  • Fay CrawfordEmail author
  • Donald J. Nicolson
  • Aparna E. Amanna
  • Angela Martin
  • Saket Gupta
  • Graham P. Leese
  • Robert Heggie
  • Francesca M. Chappell
  • Heather H. McIntosh
Open Access
ARTICLE

Abstract

Aims/hypothesis

Foot ulceration is a serious complication for people with diabetes that results in high levels of morbidity for individuals and significant costs for health and social care systems. Nineteen systematic reviews of preventative interventions have been published, but none provides a reliable numerical summary of treatment effects. The aim of this study was to systematically review the evidence from RCTs and, where possible, conduct meta-analyses to make the best possible use of the currently available data.

Methods

We conducted a systematic review and meta-analysis of RCTs of preventative interventions for foot ulceration. OVID MEDLINE and EMBASE were searched to February 2019 and the Cochrane Central Register of Controlled Trials to October 2018. RCTs of interventions to prevent foot ulcers in people with diabetes who were free from foot ulceration at trial entry were included. Two independent reviewers read the full-text articles and extracted data. The quality of trial reporting was assessed using the Cochrane Risk of Bias tool. The primary outcome of foot ulceration was summarised using pooled relative risks in meta-analyses.

Results

Twenty-two RCTs of eight interventions were eligible for analysis. One trial of digital silicone devices (RR 0.07 [95% CI 0.01, 0.55]) and meta-analyses of dermal infrared thermometry (RR 0.41 [95% CI 0.19, 0.86]), complex interventions (RR 0.59 [95% CI 0.38, 0.90], and custom-made footwear and offloading insoles (RR 0.53 [95% CI 0.33, 0.85]) showed beneficial effects for these interventions.

Conclusions/interpretation

Four interventions were identified as being effective in preventing foot ulcers in people with diabetes, but uncertainty remains about what works and who is most likely to benefit.

Keywords

Diabetes Evidence-based healthcare Foot ulcer Meta-analysis Prevention Systematic review 

Introduction

Foot ulceration is a serious complication of diabetes that can result in high levels of morbidity for individuals and burdens health and social care systems with huge costs [1, 2]. Predicting those people most likely to develop a foot ulcer has been the subject of much research and the independent risk factors have been established [3, 4]. However, the value of prediction models to inform treatment decisions depends on the availability of effective interventions to modify risk [5].

As part of a wider research project to create a cost-effective, evidence-based pathway for assessing and managing the foot in diabetes, we conducted an overview of existing systematic reviews to synthesise the available evidence on treatment effects (PROSPERO registration: CRD42016052324). Although the overview identified 19 published reviews [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24], it failed to provide reliable numerical summaries of effects because of limitations of the reviews in scope, overlap and quality [25]. A comprehensive review of RCTs was required to enable us to make the best possible use of the data currently available and re-explore the possibility of performing meta-analyses.

Methods

Our aim was to systematically review data from RCTs of interventions used to prevent foot ulcerations in diabetes, and to conduct meta-analyses to obtain pooled estimates of their effects. We included data from RCTs only, as this is the only method of clinical evaluation that controls for known, unknown and unmeasured confounding.

The protocol can be viewed at www.journalslibrary.nihr.ac.uk/programmes/hta/1517101.

Eligibility criteria

Trials were permitted to include people of any age with a diagnosis of type 1 or type 2 diabetes, with or without a history of ulceration, but free from foot ulceration at trial entry.

Simple interventions (e.g. education aimed at individuals with diabetes or physicians, or the provision of footwear) and complex interventions (where several interventions were provided together) were eligible for inclusion. Standard care or active treatment were eligible as comparators.

Outcomes

Primary outcomes

We were primarily interested in foot ulcers (incident, primary and recurrent) reported as binary outcomes (present/absent). These could be defined, for example, as ‘a full-thickness skin defect that requires more than 14 days to heal’ [26] or according to a system of ulcer classification [27]. Primary outcomes were the absolute numbers of incident primary ulcers and of incident recurrent ulcers.

Secondary outcomes

In reports where foot ulceration was the primary outcome we also sought data on amputation (minor: involving the foot [intrinsic to the foot]; or major: involving the foot and leg); mortality; gangrene; infection; adverse events; harms; time to ulceration; quality of life (measured using the EuroQol five-dimensions questionnaire or the six- or 12-item Short Forms); timing of screening; self-care; hospital admissions; psychological (knowledge/behaviour); and adherence to therapy.

Searches

We searched OVID MEDLINE (see electronic supplementary material [ESM] Table 1) and OVID EMBASE (from inception to February 2019) and the Cochrane Central Register of Controlled Trials (to October 2018) for eligible RCTs, without language restrictions. ClinicalTrials.gov was searched for ongoing clinical trials (search date: 21 February 2019).

Trial selection and data extraction

One reviewer screened all titles and abstracts and a 10% random sample was checked by a second reviewer. Two reviewers working independently screened full-text articles and extracted data (D. J. Nicholson, and either F. Crawford or A. E. Amanna) about the included populations, including the risk classification, interventions, comparators and outcomes. For each trial we extracted absolute numbers on an intention-to-treat basis, where the numbers randomised to each group were available, and calculated RRs and 95% CIs. Where reports lacked information or clarity, we contacted the trial authors. Non-English language reports were translated.

Risk of bias (quality) assessment

We assessed the quality of trial reporting using the Cochrane Risk of Bias tool [28]. The five domains we assessed were: random sequence generation, allocation concealment, blinding of assessors to the outcome, incomplete outcome data and selective reporting [28]. We also noted whether an a priori sample size calculation was reported [29].

Data analysis

Absolute numbers were extracted and RRs and 95% CIs were calculated. Where it made clinical and statistical sense to pool the data, we undertook meta-analyses with trial data weighted according to the inverse variance method and assessed heterogeneity using the I2 statistic [28]. Analyses were conducted using R version 3.4.2 (https://cran.r-project.org).

Results

From 10,488 studies, 22 RCTs met our eligibility criteria [30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51]. A flow diagram showing the flow of information throughout the process of screening and selecting studies for inclusion in the review is presented in Fig. 1 and the characteristics of the included trials are described in Table 1. Table 1 also incorporates the results from the risk of bias assessment; only five of the 22 trials [36, 39, 42, 46, 50] were judged to be at low risk of bias.
Fig. 1

Flow diagram of study selection

Table 1

Characteristics of included trials

Author

Population characteristics

Details of experimental and control interventions

Standard care

Outcomes (unit of analysis) Length of follow-up

Risk of biasa

Education

Monami 2015 [34]

n = 121 (I = 61, C = 60)

Male: 60%

Mean age: 71 years

Previous ulcers: 11%

T2DM: 100%

Mean diabetes duration: 15 years

Ulcer risk: high

Participants defined as ‘high risk’ if neuropathy diagnosed, previous diabetic foot ulcer or foot abnormalities

Intervention: brief educational programme

2 h programme provided by a physician (for 15 min) and nurse (for 105 min) to groups of five to seven participants: 30 min face-to-face lesson on risk factors for foot ulcers and 90 min interactive session with practical exercises on behaviours for reducing risk

Control: brief leaflet and standard care

All participants had previously received standard multidisciplinary education for diabetes (with a structured group programme at diagnosis or first contact, and follow-up meetings every 2 years)

Ulcers (n), amputation (n), mortality (n), knowledge score, time spent for intervention and ulcer care in control group (min per participant)

Follow-up: 6 months

Sequence generation: +

Allocation concealment: +

Assessor blinding to outcome data: –

Incomplete data addressed: –

Selective reporting: +

Sample size calculated: +

Annersten Gershater 2011 [35]

n = 131 (I = 61, C = 70)

Male: 73%

Mean age: 64 years

Previous ulcers: 100%

T2DM: 67%

Mean diabetes duration: NR

Ulcer risk: high (IWGDF)

Intervention: group session of foot care education from a registered diabetes nurse

Oral and written instructions on self-care based on IWGDF guidelines

1× 60 min plus standard care

Control: standard information, oral and written instructions on self-care based on IWGDF guidelines

Routine care from staff

Adjusted shoes for indoor and outdoor use and individually fitted insoles

Ulcers (n), cause of ulcers (stress, trauma, other), location of ulcers (big toe or other, plantar, other including heel)

Follow-up: 6 months

Sequence generation: +

Allocation concealment: +

Assessor blinding to outcome data: –

Incomplete data addressed: +

Selective reporting: +

Sample size calculated: +

Lincoln 2008 [36]

n = 172 (I = 87, C = 85)

Male: 67%

Mean age: NR

Previous ulcers: 100%

T2DM: 77%

Mean diabetes duration: NR

Ulcer risk: high (10 g monofilament, Neurotip, VPT ≥25 V)

Intervention: 1 h structured foot care education session provided by the researcher in participants’ own homes

Control: standard care and the same foot care leaflets as the intervention group

Regular podiatry and suitable orthoses when appropriate

Overall medical care followed national UK clinical guidelines

Ulcers (n), amputations (n), quality of life (DFS-SF), mood (HADS, HADS-anxiety, HADS-depression), protective foot care behaviours (NAFF)

Follow-up: 6 and 12 months

Sequence generation: +

Allocation concealment: +

Assessor blinding to outcome data: +

Incomplete data addressed: +

Selective reporting: +

Sample size calculated: +

Dermal infrared thermometry

Armstrong 2007 [37]

n = 225 (I = NR, C = NR)

Male: 96%

Mean age: 69 years

Previous ulcers: unclear

T2DM: 100%

Mean diabetes duration: 13 years

Ulcer risk: IWGDF risk group 2/3

Intervention: infrared thermometry and a complex intervention provided by attending physicians

Control: a complex intervention only

Footwear, education and professional foot care

Ulcers (n, %), rate of ulcer (HR), temperature difference at ulcer site (survival curve)

Follow-up: 18 months

Sequence generation: +

Allocation concealment: +

Assessor blinding to outcome data: +

Incomplete data addressed: +

Selective reporting: ?

Sample size calculated: +

Lavery 2004 [38]

n = 85 (I = 41, C = 44)

Male: 49%

Mean age: 55 years

Previous ulcers: 41%

T2DM: NR

Mean diabetes duration: 14 years

Ulcer risk: IWGDF risk group 2/3

Intervention: infrared thermometry and a complex intervention provided by treating physician (evaluation), nurse case manager (contact) and podiatrist (follow-up)

Control: complex intervention; foot evaluation by a podiatrist every 10–12 weeks, therapeutic footwear, diabetic foot education

Footwear, education and professional foot care

Foot complications: ulcers, Charcot foot, infection and amputation (n)

Quality of life: pre- and post-physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, mental health (SF-36 scores)

Follow-up: 6 months

Sequence generation: ?

Allocation concealment: ?

Assessor blinding to outcome data: +

Incomplete data addressed: +

Selective reporting: +

Sample size calculated: –

Lavery 2007 [39]

n = 173 (I1 = 59, I2 = 56, C = 58)

Male: 54%

Mean age: 65 years

Previous ulcers: 100%

T2DM: 95%

Mean diabetes duration: 13 years

Ulcer risk: high (10 g monofilament, VPT ≥25 V, palpation of pulses, Doppler, ankle brachial index ≥0.07)

Infrared thermometry and a complex intervention; study nurse for contact, treating physician for foot evaluations, podiatrist for assessing shoes/insoles

I1: enhanced care with infrared thermometry

I2: structured care with a structured daily foot self-inspection

Control: standard care

Lower-extremity evaluation, education programme, therapeutic insoles and footwear

All participants received a pedometer to record their daily activity in a log book

Participants were told to inspect their feet daily and to contact a nurse if necessary

Foot ulcers (n), foot trauma, fracture, death, osteomyelitis, time to ulceration (days)

Follow-up: 15 months

Sequence generation: +

Allocation concealment: +

Assessor blinding to outcome data: +

Incomplete data addressed: +

Selective reporting: +

Sample size calculated: +

Skafjeld 2015 [40]

n = 41 (I = 21, C = 20)

Male: 56%

Mean age: 58 years

Previous ulcers: 100%

T2DM: 71%

Mean diabetes duration: 18 years

Ulcer risk: IWGDF risk group 3

Intervention: foot skin temperature monitoring, theory-based counselling provided by study nurse, contact study nurse if increase in temperature for >2 days

Control: standard care

Foot care and recording observations daily, customised footwear

Ulcer (n), increased skin temperature (°C), customised footwear worn (h/day), contacts with study nurse

Follow-up: 12 months

Sequence generation: +

Allocation concealment: ?

Assessor blinding to outcome data: +

Incomplete data addressed: +

Selective reporting: +

Sample size calculated: –

Complex interventions

Cisneros 2010 [41]

n = 53 (I = 30, C = 23)

Male: 62%

Mean age: 62 years

Previous ulcers: 28%

T2DM: 96%

Mean diabetes duration: 14.5 years

Ulcer risk: IWGDF risk group (I/C) 1 (6/10), 2 (15/7), 3 (3/3) or 4 (6/3)

Intervention: complex intervention

Therapeutic education in groups of eight, 4× 90 min provided by researcher, two pairs of protective shoes, testing for neuropathy

Control: information on regular foot care and footwear use according to spontaneous demand during individual consultations with the researcher

Routine care from staff, instructions on foot care when requested, testing for neuropathy

Ulcer occurrence (n), ulcer recurrence (n), time to foot ulceration (survival time – quarterly evaluations)

Follow-up: 24 months

Ulcerations were noted to occur more frequently in those at high risk

Sequence generation: ?

Allocation concealment: ?

Assessor blinding to outcome data: +

Incomplete data addressed: ?

Selective reporting: +

Sample size calculated: –

LeMaster 2008 [42]

n = 79 (I = 41, C = 38)

Male: 51%

Mean age: 66 years

Previous ulcers: 42%

T2DM: 94%

Mean diabetes duration: 11 years

Ulcer risk: moderate or high risk

Intervention: complex intervention

Part 1 (1–3 months): physical therapist led exercises to strengthen lower-extremity muscles and promote balance over eight sessions

Part 2 (4–12 months): increase in moderately intense activity by 50% over 12 months among community-dwelling participants

Provided by physical therapist and study nurse

Control: standard care

Foot-related self-care skill education, daily foot examination

Usual medical care from their own healthcare providers

Participants were referred to orthotists or podiatrists for therapeutic footwear at enrolment

Foot ulcer rates (lesions/lesion episode, full-thickness ulcer/ulcer episode, weight-bearing full-thickness plantar ulcer/ulcer episode) (n)

Step activity, person-years at risk

Follow-up: 12 months

Sequence generation: +

Allocation concealment: +

Assessor blinding to outcome data: +

Selective reporting: +

Incomplete data addressed: +

Sample size calculated: +

Liang 2012 [43]

n = 62 (I = 31, C = 31)

Male: 56%

Mean age: 56 years

Previous ulcers: 0%

T2DM: 87%

Mean diabetes duration: 11 years

Ulcer risk: ADA risk category 1/2/3

High risk, n = 100%

Intervention: complex intervention

Foot care kit containing foot care cream, 10 g monofilament, thermometer to measure water temperature for washing feet, alcohol cotton pieces and a mirror

Daily foot care and diabetes education classes provided by a diabetes nurse-led multidisciplinary team (three endocrinologists, four nurses and one dietitian)

Control: standard care

Conventional care alone according to ADA standards; medication adjustment, foot assessment and 2 h of education about diabetes foot care

Ulcers (n, %), amputation (n, %), HbA1c (%), diabetes knowledge, foot care behaviour

Follow-up: 24 months

Sequence generation: ?

Allocation concealment: ?

Assessor blinding to outcome data: ?

Selective reporting: ?

Incomplete data addressed: +

Sample size calculated: –

Litzelman 1993 [44]

n = 396 (I = 191, C = 205)

Male: 19%

Mean age: 60 years

Previous ulcers: NR

T2DM: 100%

Mean diabetes duration: 10 years

Ulcer risk: NR

Intervention: participant education sessions, self-foot care, reinforced through telephone follow-up (2 weeks) and postcard reminder (1 and 3 months)

Informational flow sheets on foot-related risk factors for amputation in individuals with diabetes

Prompts for healthcare providers to: (1) ask that participants remove their footwear; (2) perform foot examinations; and (3) provide foot care education

Provided by nurse clinicians

Control: care as usual plus standard care

1 year after the initial assessment, all participants underwent a repeated history and physical examination performed by nurse clinicians blind to participants’ randomised treatment

Participant outcomes: participant behaviour (scale)

Behaviour of healthcare provider (%)

Physical findings (ulcers, physical examination, dry/cracked skin, corns, calluses, ingrown nails, fungal infections, improperly trimmed nails, foot/leg cellulitis, leg deformity, sensory examination) (%)

Follow-up: 12 months

Sequence generation: ?

Allocation concealment: ?

Assessor blinding to outcome data: +

Selective reporting: +

Incomplete data addressed: ?

Sample size calculated: –

McCabe 1998 [45]

n = 1997 randomised (I = 997, C = 1000)

Male: 53%

Mean age: 60 years

Previous ulcers: unclear

T2DM: 80%

Mean diabetes duration: NR

Ulcer risk: low, moderate, high

Ankle brachial index ≤0.75, history of foot ulcers = high risk

Intervention: primary foot screening examination with a biothesiometer and palpation of pedal pulses

Foot pressures, subcutaneous oxygen levels, ankle brachial indices and X rays, weekly diabetic foot clinic for high-risk participants

Provided by general diabetic outpatient clinic

Control: participants were silently tagged and continued to attend the general outpatient clinic, but received no additional care

Participants were advised to inspect and wash their feet daily, avoid constricting clothing and footwear, wear prescribed footwear at all times and contact the clinic whenever they thought it necessary

Participant outcomes: ulcers (n), ulcer progressing to amputation (%)

Process outcomes: screening cost (£), compliance with follow-up/treatment (%)

Follow-up: 24 months

Sequence generation: ?

Allocation concealment: ?

Assessor blinding to outcome data: ?

Selective reporting: +

Incomplete data addressed: +

Sample size calculated: –

Custom-made footwear and offloading

Bus 2013 [46]

n = 171 (I = 85, C = 86)

Male: 82.5%

Mean age: 62 years

Previous ulcers: 100%

T2DM: 71%

Mean diabetes duration: 17 years

Ulcer risk: high (assessed with 10 g monofilament and vibration perception plus pedis tests)

Intervention: custom-made footwear, of which the offloading properties were improved and subsequently preserved based on in-shoe plantar pressure measurement and analysis

A local specialist provided the footwear and a local orthopaedic shoe technician manufactured the footwear

Control: custom-made footwear that did not undergo improvement based on in-shoe pressure measurement (i.e. usual care)

Each participant received written and verbal instructions on foot care and on proper use of footwear

All footwear in both study groups was evaluated at delivery and at 3 month follow-up visits (pressure measurements, temperature monitor and activity monitor)

Ulcer recurrence (participants with ulcer, previous ulcer location, complicated foot ulcers); ulcer recurrence according to adherence and non-ulcerative lesions (all in n, %); in-shoe peak pressure, daily step count, adherence (mean ± SD)

Follow-up: 18 months

Sequence generation: +

Allocation concealment: +

Assessor blinding to outcome data: +

Incomplete data addressed: +

Selective reporting: +

Sample size calculated: +

Reiber 2002 [47]

n = 400 (I1 = 121, I2 = 119, C = 160)

Male: 77%

Mean age: 62 years

Previous foot ulcers or infection requiring antibiotics: 100%

T2DM: 93%

Mean diabetes duration:

<6 years: 33%

6–24 years: 11%

≥25 years: 56%

Ulcer risk: high (assessed by 10 g monofilament and presence of foot deformity)

Therapeutic shoes with two types of inserts and standard care; provided by the study pedorthist provided and evaluated by a panel of three foot care specialists

Intervention 1: three pairs of therapeutic shoes and customised medium-density cork inserts with a neoprene closed-cell cover

Intervention 2: three pairs of therapeutic shoes and prefabricated, tapered polyurethane inserts with a brushed nylon cover

Control: usual footwear and standard care

Participants continued to receive regular healthcare and foot care from the VA or GHC

A lightweight terry-cloth house slipper (Tru-Stitch Footwear, Malone, NY, USA) with no internal seam and a textured sole was designed for all participants to use to minimise differences in out-of-shoe exposure

Lesions and ulcers (ulcers, non-ulcerative, total, person-years of follow-up); incidence per person (n participants with ≥1 ulcer, cumulative incidence per person, RR); incidence per person-year (ulcer and ulcer episode, n; incidence, RR); pivotal events for ulcer episodes (shoe and non-shoe related) (all in n and 95% CI)

Follow-up: 24 months

The majority of ulcers developed in those with foot insensitivity

Sequence generation: +

Allocation concealment: ?

Assessor blinding to outcome data: +

Incomplete data addressed: +

Selective reporting: +

Sample size calculated: +

Rizzo 2012 [48]

n = 298 (I = 148, C = 150)

Male: NR

Mean age: 67 years

Previous ulcers: 20%

T2DM: 84%

Mean diabetes duration: 18 years

Ulcer risk: high (IWGDF risk group ≥2)

Intervention: orthoses and shoes, plus standard care

Screening by an experienced podologist; foot and current ulcer risk evaluated by a team of a diabetologist, podologist, and orthopaedic technician

Control: standard care

In-depth education on preventing ulceration, advice regarding footwear

Urgent consultation within 24 h if ulcers developed

Foot ulcer (participants n), new foot ulcers (n), cumulative incidence of ulcers and recurrences (3 and 5 years; χ2, % and p value), ulcer due to trauma or hyperpressure (n, %), VPT (mean ± SD), cost evaluation (€)

Follow-up: 12 months

Sequence generation: +

Allocation concealment: ?

Assessor blinding to outcome data: –

Incomplete data addressed: +

Selective reporting: +

Sample size calculated: –

Lavery 2012 [49]

n = 299 (I = 149, C = 150)

Male: 67%

Mean age: 70.5 years

Previous ulcers: 26.95%

T2DM: NR

Mean diabetes duration: 12.5 years

Ulcer risk: high (IWGDF risk group 2/3)

Intervention: shear-reducing insole and complex intervention

Concerns addressed by study nurse, evaluation conducted by a physician

Control: standard care

Foot and lower-extremity evaluation by a physician every 10–12 weeks, education programme focused on foot complications and self-care practices

Therapeutic shoes and standard insoles

Contact with study nurse if concerned

Ulcers (n, %), footwear compliance (4, 4–8, 8–12, 12–16 h/day; n, %), time to ulcer (HR)

Follow-up: 18 months

Sequence generation: ?

Allocation concealment: ?

Assessor blinding to outcome data: +

Incomplete data addressed: +

Selective reporting: +

Sample size calculated: +

Ulbrecht 2014 [50]

n = 150 (I = 79, C = 71)

Male: 68%

Mean age: 59.5 years

Previous ulcers: 100%

T2DM: NR

Mean diabetes duration: NR

Ulcer risk: high (inability to feel 10 g monofilament, high plantar pressure, ankle brachial index)

Intervention: bespoke orthoses with offloading properties, provided by study coordinators (clinicians)

Control: three different manufacturers’ orthoses plus three pairs of identical orthoses to be rotated while using the primary study footwear according to a written rotation protocol, changing the numbered orthoses in a set rotation every month; also offered one of two types of footwear models

Education on self-care behaviours with all participants, with a focus on wearing the study shoes for all steps taken and on examining the feet daily to note and report problems

Educational brochure to reinforce advice

Ulcers (n, %), peak barefoot plantar pressure vs lesion (ulcer, non-ulcerative, no lesion; kPa)

Questionnaires for quality of life (scaled to 100), foot self-care (0–1), fear of falling (scale to 100), participant satisfaction (five-point Likert scale)

Follow-up: 1, 3 and 6 weeks, then every 3 months for another 15 months (potential 16.5 months)

Sequence generation: +

Allocation concealment: +

Assessor blinding to outcome data: +

Incomplete data addressed: +

Selective reporting: +

Sample size calculated: +

Uccioli 1995 [51]

n = 69 (I = 33, C = 36)

Male: 62%

Mean age: 60 years

Previous ulcers: 100%

T2DM: 75%

Mean diabetes duration: 17 years

Ulcer risk: high (mean VPT ≥25 V)

Intervention: therapeutic shoes with custom insoles specially designed for individuals with diabetes (Podiabetes by Burrato Italy)

Control: participants were free to wear ordinary shoes or their own non-therapeutic shoes unless clearly dangerous

All participants received the same educational guidelines on foot care and general information on the importance of appropriate footwear (i.e. proper size, durability and sole)

Ulcer relapses (n, %), cumulative incidence of relapse (multiple regression analysis), ulcer relapse between groups (χ2, %, p value), ulcer-free time, peripheral neuropathy (VPT, peripheral vascular disease), ankle brachial index (mean ± SD), use of therapeutic shoes

Follow-up: 12 months

Sequence generation: ?

Allocation concealment: ?

Assessor blinding to outcome data: ?

Incomplete data addressed: +

Selective reporting: +

Sample size calculated: –

Digital silicone devices

Scirè 2009 [32]

n = 167 (I = 89, C = 78)

Male: NR

Mean age: 56.5 years

Previous ulcers: unclear

T2DM: 88%

Mean diabetes duration: 16 years

Ulcer risk: high (VPT ≥25 V)

Intervention: digital silicone orthoses (Podikon, Epitech, Saccolongo, Italy) and regular care at the diabetic foot clinic

Control: no orthoses, but regular care at the diabetic foot clinic

Callus management; soft insole and extra-deep shoe

Ulcers (%), hyperkeratosis (plantar, dorsal, interdigital; %), skin hardness (%)

Stable deformities (%)

Podobarometric evaluationb (pre- and post-evaluation in mean ± SD)

Follow-up: 3 months

Sequence generation: +

Allocation concealment: ?

Assessor blinding to outcome data: +

Incomplete data addressed: +

Selective reporting: +

Sample size calculated: –

Antifungal nail lacquer

Armstrong 2005 [30]

n = 70 (I = 34, C = 36)

Male: 97%

Mean age: 70 years

Previous ulcer: 57%

T2DM: NR

Mean diabetes duration: 12 years

Ulcer risk: high (IWGDF risk group 2/3)

Intervention: antifungal treatment (ciclopirox 8%) and self-management (daily inspection)

Control: self-management (daily inspection)

A staff podiatrist examined each participant at recruitment

A clinician familiar with the care and status of participants staffed a foot hotline 24 h/day

Preventative care programme and telephone support

Ulcers, unexpected visits, missed appointments, tinea pedis/ hyperkeratosis at start and end of study (%)

Follow-up: 12 months

Sequence generation: +

Allocation concealment: ?

Assessor blinding to outcome data: ?

Incomplete data addressed: +

Selective reporting: +

Sample size calculated: –

Elastic compression stockings

Belcaro 1992 [31]

n = 160 (I = 80, C = 80)

Male: 50%

Mean age: 53 years

Previous ulcers: none

T2DM: NR

Mean diabetes duration: 15 years

Ulcer risk: microangiopathy measured with laser Doppler, VPT also measured

Intervention: knee elastic stockings with compression at the ankle of 25 mmHg, worn for at least 6 h/day while active and/or working

Control: no stockings

NR

Ulcers (n, %), number of limbs (n)

Deterioration of microcirculation

Supine resting flux (mean ± SD)

Venoarteriolar response (median and range)

Follow-up: 48 months

Sequence generation: ?

Allocation concealment: –

Assessor blinding to outcome data: –

Incomplete data addressed: +

Selective reporting: +

Sample size calculated: –

Podiatric care

Plank 2003 [33]

n = 91 (I = 47, C = 44)

Male: 56%

Mean age: 65 years

Previous ulcers: 100%

T2DM: 93%

Mean diabetes duration: 16 years

Ulcer risk: high (reduced sensation assessed by 128 Hz tuning fork, 5.07 monofilament)

Intervention: chiropodist care and standard care

Control: chiropodist care and standard care according to participant preference

Instruction on the possible benefits of regular chiropody care and the aim of the study

Ulcers (feet and participants), death, amputation (n, %).

Follow-up: 12 months

Sequence generation: +

Allocation concealment: +

Assessor blinding to outcome data: ?

Incomplete data addressed: +

Selective reporting: +

Sample size calculated: –

aRisk of bias: low (+), uncertain (?) or high (–)

bIncludes total surface of the foot (cm2), average weight-bearing pressure (kPa), weight distribution compared with the total (%), weight distribution compared with the rear foot (%), static maximum peak pressure (kPa) and dynamic maximum peak pressure (kPa)

C, control; DFS-SF, Diabetic Foot Scale-Short Form; GHC, Group Health Co-operative; HADS, Hospital Anxiety and Depression Scale; I, intervention; IWGDF, International Working Group on the Diabetic Foot; NAFF, Nottingham Assessment of Functional Footcare; NR, not reported; T2DM, type 2 diabetes mellitus; VA, Veterans Affairs; VPT, vibration perception threshold

Overall, the included trials assessed eight different types of interventions to prevent foot ulceration, which we grouped as follows: (1) education alone (three trials) [34, 35, 36]; (2) dermal infrared thermometry (four trials) [37, 38, 39, 40]; (3) complex interventions (five trials) [41, 42, 43, 44, 45]; (4) custom-made footwear and offloading insoles (six trials) [46, 47, 48, 49, 50, 51]; (5) digital silicone device (one trial) [32]; (6) antifungal treatment (one trial) [30]; (7) elastic compression stockings (one trial) [31]; and (8) podiatric care (one trial) [33].

Education alone

Three RCTs evaluated single-session education interventions of varying length and content for people at high risk of foot ulceration [34, 35, 36].

Meta-analysis

(n = 423) (Fig. 2a) showed no statistically significant difference in the incidence of foot ulceration at 6 months compared with standard care and advice (RR 1.04 [95% CI 0.54, 1.97]) [34, 35, 36]. The quality of the included trials was variable, with only one trial [36] judged to be at low risk of bias across all domains. Other sources of potential bias arose from one trial [34] being stopped early and another [35] reporting an interim analysis before target recruitment was reached [52].
Fig. 2

Forest plots of foot ulcers in people receiving standard care vs (a) education alone, (b) dermal infrared thermometry, (c) complex interventions and (d) custom-made footwear and offloading

Secondary outcomes

Two trials of education interventions reported data on amputation [34, 36], mortality [34], knowledge [34], behaviour [36] and/or quality of life [36]. No amputations were recorded for participants in either arm at 6 months’ follow-up in one trial [34]. The other trial reported 3/85 amputations in the intervention arm vs 0/85 in the control arm at 6 months, and no difference (n = 9 in both arms) at 12 months [36].

One trial [34] reported that two participants, one in each arm, had died by 6 months. In the same trial, a statistically significant difference in knowledge (as measured by the Patient Interpretation of Neuropathy knowledge score) was observed in the intervention arm [34].

One trial [36] reported on quality of life and found no differences between the two arms on the Diabetic Foot Scale, but higher scores for those in the education arm on the Nottingham Assessment of Functional Footcare questionnaire, which assesses behaviour, compared with the control group.

Dermal infrared thermometry

Four RCTs involving 468 participants with diabetes were identified [37, 38, 39, 40]. In one trial [37], the numbers of participants randomised to either dermal infrared thermometry or standard care were not known, and so an RR and 95% CI could not be calculated.

Meta-analysis

A pooled analysis of data from three RCTs (n = 243) [38, 39, 40] found that dermal infrared thermometry reduced the number of foot ulcers in people with a history of foot ulceration (RR 0.41 [95% CI 0.19, 0.86]) (Fig. 2b). Outcomes were collected between 6 and 15 months. The quality of these trials was variable, with only one trial [39] judged to be at low risk of bias across all domains.

Secondary outcomes

Trials of dermal thermometry variously reported on amputation following infection [37], quality of life (36-item Short Form [SF-36]) [37], adherence to therapy [38, 39] and time to ulceration [39, 40].

In one trial, amputations following infections occurred in 0/41 participants in the intervention group vs 2/44 in the comparator group [38]. In the same trial there was no statistically significant difference in quality of life measured using SF-36 in any category or in the overall score [38].

Two trials [39, 40] found no statistically significant difference between the dermal thermometry group and the comparator group in the time that prescribed footwear and insoles were worn, as measured using a self-report questionnaire containing an ordinal scale of <4 to >12 h/day. The time to ulceration was statistically significantly longer in the dermal thermometry treatment group compared with standard care in one trial [39] but not in another [40].

Complex interventions

Five RCTs evaluated the effects of complex interventions (i.e. integrated combinations of patient- or physician-level interventions and structural interventions) on the development of a foot ulcer [41, 42, 43, 44, 45].

Meta-analysis

A pooled analysis of data from five RCTs (n = 2587) showed that complex interventions statistically significantly reduced the number of foot ulcers (RR 0.59 [95% CI 0.38, 0.90]) at 1 or 2 year follow-up (Fig. 2c), with little evidence of statistical heterogeneity (I2 = 10%; Fig. 2c) despite the variety of interventions tested. However, with the exception of one trial [42], all had a high risk of bias and the validity of these data may be compromised. One trial gave no information about the participants’ risk category [44], while three included people with no history of foot ulceration [41,43]. One trial included people who were at low/moderate or high risk of developing a foot ulcer, found that 75% of ulcers occurred in people with higher levels of risk; for the highest risk category (category 4), 2/6 individuals in the intervention group and 2/3 individuals in the comparator group developed foot ulcers [41].

None of the individual trial results reached statistical significance and only one [42] reported an a priori sample size calculation; however, one trial [45] recruited everyone attending the foot care service.

Secondary outcomes

Amputation [43, 45], time to ulceration [41] and/or knowledge [43] were reported in three trials. In one trial [43] amputations occurred only in the control arm (2/31 vs 0/31 in the intervention arm), and in a second trial [45] there were fewer amputations in the intervention group (one major and six minor amputations) compared with the control group (12 major and 13 minor) [45]. The time to ulceration was shorter in the control group vs the intervention group in one trial, but this did not reach statistical significance [41].

In one trial participants’ knowledge about foot care, as measured using a diabetes knowledge questionnaire, was statistically significantly better in the intervention group compared with the control group [43].

Custom-made footwear and offloading insoles

Six RCTs evaluated custom-made footwear and offloading insoles [46, 47, 48, 49, 50, 51].

Meta-analysis

A pooled estimate of data from six trials showed a beneficial association for custom-made footwear and offloading insoles on reducing the development of foot ulcers (pooled RR 0.53 [95% CI 0.33, 0.85]; Fig. 2d) for outcomes collected at 12–24 months in 1387 people, of whom 464 had no history of foot ulceration. There was evidence of considerable statistical heterogeneity (I2 = 78%), which we explored using baseline risk of ulceration in a subgroup analysis (Fig. 3). This pooled analysis of four trials [46, 47, 50, 51], all of which excluded people with no history of foot ulceration, failed to detect a statistically significant difference (RR 0.71 [95% CI 0.47, 1.06]). The six trials were of variable quality, with only two [46, 50] having a low risk of bias across all five domains.
Fig. 3

Subgroup analysis. Forest plot of foot ulcers in people with a history of foot ulceration receiving custom-made footwear and offloading vs standard care

Secondary outcomes

Adherence [46, 48, 49] and/or cost [48] data were reported in four trials. One trial measured adherence using a temperature-based monitor placed inside the shoe, and found that 35/85 participants in the intervention group and 42/86 in the control group adhered to wearing their allocated footwear [46]. The trial authors conducted a subgroup analysis in participants who wore their allocated footwear, which showed a statistically greater reduction in ulcer recurrence in the intervention group; however, the analysis using data from the entire trial population failed to detect a beneficial association. A second trial of custom-made footwear and offloading insoles measured adherence using a self-reported physical activity questionnaire, and found that footwear and insole use was high in the groups who received cork inserts (83%) and prefabricated insoles (86%) [47]. A third trial measured participant compliance with footwear using self-reports of the number of hours per day that the shoes were worn. There were no statistically significant differences between each group in the number of people who wore the shoes for less than 4 h per day (23/149 vs 16/150), 4–8 h (77/149 vs 83/150), 8–12 h (38/149 vs 46/150) and 12–16 h (10/149 vs 6/150) [49].

Cost data collected in one trial published in 2012 found the cost of supplying footwear and insoles to be €675 per person per year [48].

Digital silicone devices

In one RCT of digital silicone devices [32], 167 participants with peripheral neuropathy, as defined by a vibration perception threshold of >25 V measured using a biothesiometer, and toe deformities (clawed toes, hallux valgus, interdigital lesions) were randomised to receive a bespoke silicone digital orthotic (n = 89) or standard care (n = 78). The number of ulcers was statistically significantly lower in the intervention group (RR 0.07 [95% CI 0.01, 0.55]) at 3 month follow-up. This trial had a low risk of bias in all domains except for allocation concealment, which was unclear.

Antifungal treatment

In a trial of antifungal nail lacquer, participants in the intervention group (n = 34) received advice to inspect their feet daily and apply ciclopirox 8% to their toenails [30]. The control group (n = 36) received advice about daily foot inspections. A history of foot ulcers was reported by 57% of participants. After 12 months there were two ulcerations in each group (RR 1.06 [95% CI 0.19, 5.76]). The risk of bias was unclear in two domains: allocation concealment and blinding of the outcome assessor.

Elastic compression stockings

An RCT of elastic stockings randomly allocated 160 people with no history of foot ulceration to either knee-length elastic stockings worn for 6 h/day or standard care [31]. There were three ulcers in the intervention group and ten in the control group, a difference that was not statistically significant (RR 0.37 [95% CI 0.11, 1.02]). The trial had a high or unclear risk of bias in the domains of sequence generation, allocation concealment and assessor blinding.

Secondary outcomes

Thirteen limbs were reported as lost during the 48 month trial; 3/74 in the intervention arm and 10/75 in the control arm.

Podiatric care

One trial compared free chiropody care (n = 47) with no chiropody care (n = 44) for people all at high risk of foot ulceration [33]. Those receiving free chiropody were recommended to seek care at least once per month. The control group could seek chiropody if they were willing to pay for it, and their standard care included advice on the possible benefits of regular chiropody. There was no statistically significant difference in the number of ulcerations in the two groups (RR 0.67 [95% CI 0.43, 1.05]). This trial had a low risk of bias in all domains except assessor blinding to outcome data, which was unclear.

Secondary outcomes

There were 2/47 amputations in the intervention arm vs 1/44 in the control arm. Deaths were recorded as 2/47 in the intervention arm vs 4/44 in the control arm [33].

Data for other secondary outcomes of interest, such as gangrene, self-care, hospital admissions, timing of screening and adverse events or harms, were absent from the trial reports.

Ongoing trials

The search for ongoing trials of foot ulcer prevention in diabetes from the ClinicalTrials.gov website found 24 studies being conducted worldwide. The stated interventions in these studies are: physiotherapy (n = 1), skin temperature (n = 6), hygiene (n = 1), offloading insoles (n = 10), risk stratification (n = 2), PET-CT (n = 1), amniotic tissue (n = 1) and unclear (n = 2). The list of these studies can be obtained from the corresponding author.

Discussion

The purpose of this systematic review was to evaluate the evidence base and obtain summary statistics for preventative interventions for foot ulceration in diabetes to create a cost-effective, evidence-based care pathway. The meta-analyses of dermal infrared thermometry, complex interventions and therapeutic footwear with offloading insoles suggest that these interventions can help prevent foot ulceration in people with diabetes.

The meta-analysis of data from RCTs of dermal infrared thermometry in people with a history of foot ulceration and a moderate to high risk of ulceration indicates that this is a promising intervention deserving of further evaluation in randomised trials with larger participant samples, and we note from our search of the ClinicalTrials.gov trial registry that new trials are currently underway. If foot ulcer prevention can be confirmed in large, well-conducted trials, this form of self-monitoring could relieve pressure on healthcare systems. However, advising individuals to abstain from all weight-bearing activities when foot temperatures rise by more than 4°C may prove challenging, and poor adherence might diminish any benefit in a real-world context outside of a trial setting.

Specialist foot care, of the type evaluated in the included trials of complex interventions, is considered a marker of good-quality diabetes service delivery and it is intuitively correct to suppose it leads to improved outcomes. While a statistically significant reduction in foot ulcers was apparent in our meta-analysis, such an effect was not evident in any single trial. This does support the suggestion of others that very large sample sizes may be needed for trials of this nature [53]. Surprisingly, there was a low level of statistical heterogeneity in the pooled data, despite quite marked differences in the clinical care provided in the intervention arms of the trials and the participation of people with three different levels of ulcer risk.

Our review did not identify any trials of complex interventions that reflect the composition of multidisciplinary foot services as recommended in clinical guidelines [54, 55, 56]. These influential documents advise the involvement of diabetologists, podiatrists, vascular surgeons, diabetes specialist nurses and orthotists as the core team in a diabetes foot care service, but patient outcomes from such healthcare service arrangements have not been evaluated in RCTs. An evaluation of outcomes from people at different levels of ulceration risk who receive care in specialist foot care settings would be worthwhile.

The true value of therapeutic footwear and offloading insoles in preventing foot ulcers has been obscured by contradictory trial results and poor interpretation of data in systematic reviews; two larger trials involving only those with a history of foot ulcers both failed to detect evidence of effectiveness [46, 47], and visual inspection of our analyses of pooled data from all six trials shows greatest beneficial effect in those where the majority of participants were considered to be at high or moderate risk but had not experienced a foot ulcer [48, 49], albeit only one reached statistical significance [48]. Our subgroup analysis of data from four trials of participants with a history of foot ulceration found no statistically significant difference in the number of recurrent ulcers between the custom footwear and control groups.

This observation calls into question the conclusions of other systematic reviews evaluating footwear and insoles in the prevention of foot ulcers [6, 17, 24]. The most recent included randomised and non-randomised data and adopted a consensus approach to the analysis. The reviewers concluded that: ‘The evidence base to support the use of specific self-management and footwear interventions for the prevention of recurrent plantar foot ulcers is quite strong, but…is practically non-existent for the prevention of a first foot ulcer and non-plantar foot ulcer’ [24]. An individual participant data analysis using data from these six trials together with data from the ten ongoing studies of offloading insoles identified by our search of the ClinicalTrials.gov database could permit subgroup analyses to explore the value of footwear and offloading insoles in people with different baseline risks, and potentially resolve these ongoing uncertainties.

The marked reduction in ulcerations reported with the use of a dermal silicone device by individuals at high risk of ulceration is encouraging [32]. These devices are simple to make at the chair-side and easy for wearers to keep clean. Although they are a type of offloading intervention, we did not include these data in the meta-analysis of footwear and offloading insoles because they differ substantially in that they are only worn around the toes.

Three separate small trials [30, 31, 33] evaluating, respectively, the effects of a daily application of a fungal nail lacquer (ciclopirox 8%) with daily foot inspections, the use of elastic compression stockings and podiatry all failed to show a reduction in foot ulcers, possibly as a result of small sample sizes.

Strengths and limitations of this review

We have comprehensively reviewed a body of evidence from RCTs and made the fullest use of the data currently available to derive best estimates of treatment effects to inform a wider piece of work. In so doing we have highlighted uncertainties, gaps and limitations in the existing evidence base to inform practice, generated new research hypotheses and added value to this area of research.

The weaknesses of this review arise from the potential biases identified in many of the trial reports, especially for complex interventions, which may have produced unreliable results. Previous authors of systematic reviews have cited a lack of similarity between studies [13], lack of standardisation in terminology, prescription, manufacture and material properties of interventions [16], heterogeneity in study designs, methodology and participant populations [18], and differences in participant demographics [22] as reasons for not conducting meta-analyses, and we are aware of the potential limitations in the pooled analyses that we present here, both in the number and quality of trials. We have tried to produce conservative, less biased summary measures by adopting an intention-to-treat approach and a random-effects model. We acknowledge criticisms about the use of the latter [57], but believe the insights gleaned and the generation of new research hypotheses justifies our decision to pool data [58].

Conclusions

Our analyses found evidence of beneficial effects for four types of interventions used to prevent foot ulcers in people with diabetes, but considerable uncertainty remains about what works and who is most likely to benefit. Attention should be given to recommendations for the conduct of trials of interventions for the foot in diabetes, and researchers conducting future trials should endeavour to complete the trial to target recruitment as informed by an a priori sample size calculation [29, 59].

Notes

Acknowledgements

We thank M. Smith (NHS Fife librarian) and our public partner W. Morrison (Dunfermline, UK) for their help and enthusiasm during the project. We also thank the following for their kind replies to our requests for clarification and additional information about their trials: D. G. Armstrong (University of Southern California, Los Angeles, CA, USA), L. Cisernos (Universidad Federal de Minas Gerais, Brazil), C. Chan (University of Alberta, Edmonton, AB, Canada), J. Everett (University of Calgary, AB, Canada), M. Gershater (Malmö University, Sweden), T. Kelechi (Medical University of South Carolina, Charleston, SC, USA), L. Lavery (University of Texas, Austin, TX, USA), D. Litzelman (Indiana University, Bloomington, IN, USA), S. Morgan (University of Washington, Seattle, WA, USA) and A. Piaggesi (University of Pisa, Italy). We appreciate the help received from two anonymous journal referees for their insightful comments and suggestions for improving our manuscript.

Members of the wider project team who were not directly involved in this research were: K. Gray (R&D Department, NHS Fife), D. Weller (Department of General Practice, University of Edinburgh), J. Brittenden (Institute of Cardiovascular and Medical Sciences, University of Glasgow), J. Lewsey and N. Hawkins (both Health Economics and Health Technology Assessment [HEHTA], Institute of Health and Wellbeing, University of Glasgow).

Contribution statement

All authors made substantial contributions to the concept or design of the work or the acquisition, analysis or interpretation of data for the work and have drafted the manuscript critically and approved the final version. FC, FMC and HHM are the guarantors of this research and accept full responsibility for the work and/or the conduct of the study, had access to the data and controlled the decision to publish.

Funding

This systematic review was funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme (HTA project: 15/171/01) as part of a wider project. The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2019_5020_MOESM1_ESM.pdf (408 kb)
ESM (PDF 407 kb)

References

  1. 1.
    Kerr M (2017) Diabetic foot care in England: an economic study. Diabetes UK, LondonGoogle Scholar
  2. 2.
    Kerr M, Barron E, Chadwick P et al (2019) The cost of diabetic foot ulcers and amputations to the National Health Service in England. Diabet Med 36(8):995–1002PubMedGoogle Scholar
  3. 3.
    Crawford F, Cezard G, Chappell FM, on behalf of the PODUS group (2018) The development and validation of a multivariable prognostic model to predict foot ulceration in diabetes using a systematic review and individual patient data meta-analyses. Diabet Med 35(11):1480–1493PubMedGoogle Scholar
  4. 4.
    Monteiro-Soares M, Ribas R, Pereira da Silva C et al (2017) Diabetic foot ulceration development risk classifications’ validation: a multicentre prospective cohort study. Diabetes Res Clin Pract 127:105–114PubMedGoogle Scholar
  5. 5.
    Steyerberg EW (2009) Clinical prediction models: a practical approach to development, validation, and updating. Springer, New YorkGoogle Scholar
  6. 6.
    Arad Y, Fonseca V, Peters A, Vinik A (2011) Beyond the monofilament for the insensate diabetic foot: a systematic review of randomized trials to prevent the occurrence of plantar foot ulcers in patients with diabetes. Diabetes Care 34(4):1041–1046PubMedPubMedCentralGoogle Scholar
  7. 7.
    Binning J, Woodburn J, Bus SA, Barn R (2019) Motivational interviewing to improve adherence behaviours for the prevention of diabetic foot ulceration. Diabetes Metab Res Rev 35(2):e3105PubMedGoogle Scholar
  8. 8.
    Dorresteijn JA, Kriegsman DM, Assendelft WJ, Valk GD (2012) Patient education for preventing diabetic foot ulceration. Cochrane Database Syst Rev, Issue 10, Art. no.: CD001488.  https://doi.org/10.1002/14651858.CD001488.pub4
  9. 9.
    He JD, Zhang L, Liu L, Zhu YJ (2013) Intensive versus routine education on diabetes mellitus for prevention diabetic foot ulcer: a systematic review. Chinese J Evid Based Med 13(12):1470–1474Google Scholar
  10. 10.
    Hoogeveen RC, Dorresteijn JA, Kriegsman DM, Valk GD (2015) Complex interventions for preventing diabetic foot ulceration. Cochrane Database Syst Rev, Issue 8, Art. no.: CD007610Google Scholar
  11. 11.
    Kaltenthaler E, Morrell CJ, Booth A, Akehurst RL (1998) The prevention and treatment of diabetic foot ulcers: a review of clinical effectiveness studies. J Clin Effect 3(3):99–104Google Scholar
  12. 12.
    Mason J, O’Keeffe C, McIntosh A, Hutchinson A, Booth A, Young RJ (1999) A systematic review of foot ulcer in patients with type 2 diabetes mellitus. I: Prevention. Diabet Med 16(10):801–812PubMedGoogle Scholar
  13. 13.
    O’Meara S, Cullum N, Majid M, Sheldon T (2000) Systematic reviews of wound care management: (3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration. Health Technol Assess 4(21):1–237PubMedGoogle Scholar
  14. 14.
    Spencer SA (2000) Pressure relieving interventions for preventing and treating diabetic foot ulcers. Cochrane Database Syst Rev, Issue 3, Art. no. CD002302.  https://doi.org/10.1002/14651858.CD002302
  15. 15.
    Buckley CM, Perry IJ, Bradley CP, Kearney PM (2013) Does contact with a podiatrist prevent the occurrence of a lower extremity amputation in people with diabetes? A systematic review and meta-analysis. BMJ Open 3(5):pii: e002331Google Scholar
  16. 16.
    Bus SA, Valk GD, van Deursen RW et al (2008) The effectiveness of footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in diabetes: a systematic review. Diabetes Metab Res Rev 24(Suppl 1):S162–S180PubMedGoogle Scholar
  17. 17.
    Bus SA, van Deursen RW, Armstrong DG, Lewis JE, Caravaggi CF, Cavanagh PR on behalf of the International Working Group on the Diabetic Foot (IWGDF) (2015) Footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in patients with diabetes: a systematic review. Diabetes Metab Res Rev 32(Suppl 1):99–118Google Scholar
  18. 18.
    Healy A, Naemi R, Chockalingam N (2013) The effectiveness of footwear as an intervention to prevent or to reduce biomechanical risk factors associated with diabetic foot ulceration: a systematic review. J Diabetes Complicat 27(4):391–400PubMedGoogle Scholar
  19. 19.
    Heuch L, Streak Gomersall J (2016) Effectiveness of offloading methods in preventing primary diabetic foot ulcers in adults with diabetes: a systematic review. JBI Database System Rev Implement Rep 14(7):236–265PubMedGoogle Scholar
  20. 20.
    Maciejewski ML, Reiber GE, Smith DG, Wallace C, Hayes S, Boyko EJ (2004) Effectiveness of diabetic therapeutic footwear in preventing reulceration. Diabetes Care 27(7):1774–1782PubMedGoogle Scholar
  21. 21.
    Mayfield JA, Sugarman JR (2000) The use of the Semmes-Weinstein monofilament and other threshold tests for preventing foot ulceration and amputation in persons with diabetes. J Fam Pract 49(11 Suppl):S17–S29PubMedGoogle Scholar
  22. 22.
    Paton J, Bruce G, Jones R, Stenhouse E (2011) Effectiveness of insoles used for the prevention of ulceration in the neuropathic diabetic foot: a systematic review. J Diabetes Complicat 25(1):52–62PubMedGoogle Scholar
  23. 23.
    Ahmad Sharoni SK, Minhat HS, Mohd Zulkefli NA, Baharom A (2016) Health education programmes to improve foot self-care practices and foot problems among older people with diabetes: a systematic review. Int J Older People Nursing 11(3):214–239Google Scholar
  24. 24.
    van Netten JJ, Price PE, Lavery LA et al (2016) Prevention of foot ulcers in the at-risk patient with diabetes: a systematic review. Diabetes Metab Res Rev 32(Suppl 1):84–98PubMedGoogle Scholar
  25. 25.
    Ballard M, Montgomery P (2017) Risk of bias in overviews of review: a scoping review of methodological guidance and four-item checklist. Res Synth Methods 8(1):92–108PubMedGoogle Scholar
  26. 26.
    Boyko EJ, Ahroni JH, Stensel V, Forsberg RC, Davignon DR, Smith DG (1999) A prospective study of risk factors for diabetic foot ulcer: the Seattle Diabetic Foot Study. Diabetes Care 22(7):1036–1042PubMedGoogle Scholar
  27. 27.
    Frykberg RG (2002) Diabetic foot ulcers: pathogenesis and management. Am Fam Physician 66(9):1655–1662PubMedGoogle Scholar
  28. 28.
    Higgins JPT, Green S (eds) (2011) Cochrane handbook for systematic reviews of interventions 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available from www.Cochrane-handbook.org
  29. 29.
    Jeffcoate WJ, Bus SA, Game FL, Hinchliffe RJ, Price PE, Schaper NC (2016) Reporting standards of studies and papers on the prevention and management of foot ulcers in diabetes: required details and markers of good quality. Lancet Diabetes Endocrinol 4(9):781–788PubMedGoogle Scholar
  30. 30.
    Armstrong DG, Holtz K, Wu S (2005) Can the use of a topical antifungal nail lacquer reduce risk for diabetic foot ulceration? Results from a randomised controlled pilot study. Int Wound J 2(2):166–170PubMedGoogle Scholar
  31. 31.
    Belcaro G, Laurora G, Cesarone MR, Pomante P (1992) Elastic stockings in diabetic microangiopathy. Long term clinical and microcirculatory evaluation. Vasa 21(2):193–197PubMedGoogle Scholar
  32. 32.
    Scirè V, Leporati E, Teobaldi I, Nobili LA, Rizzo L, Piaggesi A (2009) Effectiveness and safety of using Podikon digital silicone padding in the primary prevention of neuropathic lesions in the forefoot of diabetic patients. J Am Podiatr Med Assoc 99(1):28–34PubMedGoogle Scholar
  33. 33.
    Plank J, Haas W, Rakovac I et al (2003) Evaluation of the impact of chiropodist care in the secondary prevention of foot ulcerations in diabetic subjects. Diabetes Care 26(6):1691–1695PubMedGoogle Scholar
  34. 34.
    Monami M, Zannoni S, Gaias M, Nreu B, Marchionni N, Mannucci E (2015) Effects of a short educational program for the prevention of foot ulcers in high-risk patients: a randomized controlled trial. Int J Endocrinol 2015:615680PubMedPubMedCentralGoogle Scholar
  35. 35.
    Annersten Gershater M, Pilhammar E, Apelqvist J, Alm-Roijer C (2011) Patient education for the prevention of diabetic foot ulcers: interim analysis of a randomised controlled trial due to morbidity and mortality of participants. Eur Diabetes Nurs 8(3):102b–107bGoogle Scholar
  36. 36.
    Lincoln NB, Radford KA, Game FL, Jeffcoate WJ (2008) Education for secondary prevention of foot ulcers in people with diabetes: a randomised controlled trial. Diabetologia 51(11):1954–1961PubMedGoogle Scholar
  37. 37.
    Armstrong DG, Holtz-Neiderer K, Wendel C, Mohler MJ, Kimbriel HR, Lavery LA (2007) Skin temperature monitoring reduces the risk for diabetic foot ulceration in high-risk patients. Am J Med 120(12):1042–1046PubMedGoogle Scholar
  38. 38.
    Lavery LA (2004) Home monitoring of skin temperatures to prevent ulcerations. Diabetes Care 27(11):2642–2647PubMedGoogle Scholar
  39. 39.
    Lavery LA, Higgins KR, Lanctot DR et al (2007) Preventing diabetic foot ulcer recurrence in high-risk patients: use of temperature monitoring as a self-assessment tool. Diabetes Care 30(1):14–20PubMedGoogle Scholar
  40. 40.
    Skafjeld A, Iversen MM, Holme I, Ribu L, Hvaal K, Kilhovd BK (2015) A pilot study testing the feasibility of skin temperature monitoring to reduce recurrent foot ulcers in patients with diabetes—a randomized controlled trial. BMC Endocr Disord 15:55PubMedPubMedCentralGoogle Scholar
  41. 41.
    Cisneros LL (2010) Evaluation of a neuropathic ulcers prevention program for patients with diabetes. Rev Bras Fisioter 14(1):31–37PubMedGoogle Scholar
  42. 42.
    LeMaster JW, Mueller MJ, Reiber GE, Mehr DR, Madsen RW, Conn VS (2008) Effect of weight-bearing activity on foot ulcer incidence in people with diabetic peripheral neuropathy: feet first randomized controlled trial. Phys Ther 88(11):1385–1398PubMedGoogle Scholar
  43. 43.
    Liang R, Dai X, Zuojie L, Zhou A, Meijuan C (2012) Two-year foot care program for minority patients with type 2 diabetes mellitus of Zhuang tribe in Guangxi, China. Can J Diabetes 36(1):15–18Google Scholar
  44. 44.
    Litzelman DK, Slemenda CW, Langefeld CD et al (1993) Reduction of lower extremity clinical abnormalities in patients with non-insulin-dependent diabetes mellitus: a randomized, controlled trial. Ann Intern Med 119(1):36–41PubMedGoogle Scholar
  45. 45.
    McCabe CJ, Stevenson RC, Dolan AM (1998) Evaluation of a diabetic foot screening and protection programme. Diabet Med 15(1):80–84PubMedGoogle Scholar
  46. 46.
    Bus SA, Waaijman R, Arts M et al (2013) Effect of custom-made footwear on foot ulcer recurrence in diabetes: a multicenter randomized controlled trial. Diabetes Care 36(12):4109–4116PubMedPubMedCentralGoogle Scholar
  47. 47.
    Reiber GE, Smith DG, Wallace C et al (2002) Effect of therapeutic footwear on foot reulceration in patients with diabetes: a randomized controlled trial. JAMA 287(19):2552–2558PubMedGoogle Scholar
  48. 48.
    Rizzo L, Tedeschi A, Fallani E et al (2012) Custom-made orthesis and shoes in a structured follow-up program reduces the incidence of neuropathic ulcers in high-risk diabetic foot patients. Int J Low Extrem Wounds 11(1):59–64PubMedGoogle Scholar
  49. 49.
    Lavery LA, Lafontaine J, Higgins KR, Lanctot DR, Constantinides G (2012) Shear-reducing insoles to prevent foot ulceration in high-risk diabetic patients. Adv Skin Wound Care 25(11):519–524PubMedGoogle Scholar
  50. 50.
    Ulbrecht JS, Hurley T, Mauger DT, Cavanagh PR (2014) Prevention of recurrent foot ulcers with plantar pressure-based in-shoe orthoses: the CareFUL prevention multicenter randomized controlled trial. Diabetes Care 37(7):1982–1989PubMedPubMedCentralGoogle Scholar
  51. 51.
    Uccioli L, Faglia E, Monticone G et al (1995) Manufactured shoes in the prevention of diabetic foot ulcers. Diabetes Care 18(10):1376–1378PubMedGoogle Scholar
  52. 52.
    Pocock S (1992) When to stop a clinical trial. BMJ 305(6847):235–240PubMedPubMedCentralGoogle Scholar
  53. 53.
    Jeffcoate WJ (2011) Stratification of foot risk predicts the incidence of new foot disease, but do we yet know that the adoption of routine screening reduces it? Diabetologia 54(5):991–993PubMedGoogle Scholar
  54. 54.
    SIGN (2010; updated 2017) SIGN 116: management of diabetes: a national clinical guideline. Available from www.sign.ac.uk/assets/sign116.pdf. Accessed 5 June 2019
  55. 55.
    National Institute for Health and Care Excellence (2015) Diabetic foot problems: prevention and management. Available from www.nice.org.uk/guidance/ng19/resources/diabetic-foot-problems-prevention-and-management-pdf-1837279828933. Accessed 6 June 2019
  56. 56.
    IWGDF (2019) IWGDF guidelines on the prevention and management of diabetic foot disease. Available from https://iwgdfguidelines.org/wp-content/uploads/2019/05/IWGDF-Guidelines-2019.pdf. Accessed 5 June 2019
  57. 57.
    Kirkwood BR, Sterne JAC (2003) Essential medical statistics, 2nd edn. Blackwell Science, OxfordGoogle Scholar
  58. 58.
    Freemantle N, Wood J, Crawford F (1998) Evidence into practice, experimentation and quasi experimentation: are the methods up to the task? J Epidemiol Community Health 52(2):75–81PubMedPubMedCentralGoogle Scholar
  59. 59.
    Jeffcoate WJ, Vileikyte L, Boyko EJ, Armstrong DG, Boutlon AJM (2018) Current challenges and opportunities in the prevention and management of diabetic foot ulcers. Diabetes Care 41(4):645–652PubMedGoogle Scholar

Copyright information

© The Author(s) 2019

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Fay Crawford
    • 1
    • 2
    Email author
  • Donald J. Nicolson
    • 1
  • Aparna E. Amanna
    • 1
  • Angela Martin
    • 1
  • Saket Gupta
    • 1
  • Graham P. Leese
    • 3
  • Robert Heggie
    • 4
  • Francesca M. Chappell
    • 5
  • Heather H. McIntosh
    • 6
  1. 1.NHS FifeQueen Margaret HospitalDunfermlineUK
  2. 2.School of MedicineUniversity of St AndrewsFifeUK
  3. 3.NHS TaysideDundeeUK
  4. 4.Health Economics and Health Technology Assessment (HEHTA) Institute of Health and Wellbeing College of Medical, Veterinary and Life SciencesUniversity of GlasgowGlasgowUK
  5. 5.The Centre for Clinical Brain Sciences (CCBS) Neuroimaging SciencesUniversity of EdinburghEdinburghUK
  6. 6.Healthcare Improvement ScotlandGlasgowUK

Personalised recommendations