Results
Twenty-two RCTs met the review eligibility criteria; the characteristics of the included trials are in , the risk-of-bias assessments are in , the process of selection is presented in Appendix 4, , and a flow diagram showing the flow of literature can be found in Appendix 5, . A list of excluded RCTs is in Table 45 in Appendix 4.
Characteristics of included RCTs
Risk of bias in included RCTs studies
Risk of bias
We identified eight separate interventions:
antifungal treatment
elastic compression stockings
digital silicone device
education alone
podiatric care
digital thermometry
complex interventions
custom-made footwear and offloading.
Antifungal treatment
One trial evaluating the effect of antifungal treatment was identified by our searches.102 Thirty-four participants in the intervention group received self-management advice (daily foot inspection) and antifungal nail lacquer (8% ciclopirax) for daily application, while 36 participants in the control group received only advice about foot self-inspection. Almost all patients (97%) were male; patients’ mean age was 70 years, and 57% had experienced previous foot ulcers. Their mean duration of diabetes mellitus was 12 years, but it was not reported how many had type 2 diabetes mellitus (T2DM). Standard care was reported to be a preventative care programme and telephone support, but the exact arrangements for this were unclear. At 12-month follow-up, there were two ulcerations in each group (RR 1.06, 95% CI 0.19 to 5.76). The concealment of the allocation and the blinding of the outcome assessor were unclear and the trial was rated as being at risk of selection and performance bias. No secondary outcomes were reported.
Elastic compression stockings
In one RCT evaluating the effect of elastic compression stockings,93 160 participants were randomised in equal numbers to the intervention or the control group for 48 months. Half of the trial participants were male; patients’ mean age was 53 years and none had a history of foot ulcers. Their mean duration of diabetes mellitus was 15 years, but the number with T2DM was not reported. The intervention group received knee-length elastic stockings with compression at the ankle of 25 mmHg, worn for at least 6 hours per day. There was a difference in the number of limbs that ulcerated in each group (three in the intervention group and 10 in the control group), but this did not reach statistical significance (RR 0.37, 95% CI 0.11 to 1.02). It was unclear how the random allocation was generated, and the nature of the intervention meant that it was not possible to blind patients to the allocation. The outcome assessment was not conducted by an investigator blinded to the random allocation, and the trial was judged to be at risk of selection bias and performance bias.
Secondary outcomes: elastic compression stockings
Thirteen amputations were reported during the 48-month trial: 3 out of 74 in the intervention arm and 10 out of 75 in the control arm.
Digital silicone device
One RCT evaluated the effect of digital silicone devices.97 One hundred and sixty-seven participants with forefoot deformities who were considered to be at high risk of ulceration, as defined by a VPT of ≥ 25 V, were recruited into the trial. Their mean age was 56.5 years but gender was not reported. Eighty-eight per cent had T2DM and their mean duration of diabetes mellitus was 16 years. Participants in the intervention arm (n = 89) received a bespoke silicone digital orthotic with a variety of therapeutic intents and densities depending on the characteristics of the deformity. The patients in the intervention group received instructions about maintaining the orthotic and were advised to wear it until the end of the follow-up period. The 78 people in the control arm received standard therapy, which comprised the same examinations and procedures as the intervention group, but silicone orthotics were not provided. Both groups also received an accommodating soft insole and an extra-deep shoe. Outcomes collected at 3 months showed a statistically significant difference in the numbers of foot ulcers, with the digital orthotic group experiencing a beneficial effect (RR 0.07, 95% CI 0.01 to 0.55). Concealment of the allocation was not possible because of the nature of the intervention, and the trial was at risk of selection bias. No secondary outcomes were reported.
Podiatric care
Plank et al.94 compared free chiropody care (n = 47) with no recommendation for chiropody care (n = 44) for 12 months. Fifty-six per cent of the 91 participants were male and their mean age was 65 years. All participants had a history of foot ulceration and were at high risk of another ulcer. Their mean duration of diabetes mellitus was 16 years, and 93% had T2DM. Those receiving free chiropody were recommended to seek care at least once per month. No recommendation was given to patients in the control group, but they could seek chiropody care if they were willing to pay for it. Standard care consisted of instructions on the possible benefits of regular chiropody care. It was unclear if both groups received standard care. There was no statistically significant difference in effect of number of foot ulcers (RR 0.67, 95% CI 0.43 to 1.05). In addition, there were fewer ulcerations in the intervention group (n =18) than in the control group (n = 25) but there were more amputations in the intervention group than in the control group (two vs. one, respectively). Fewer people died in the intervention group (n = 2) than in the control group (n = 4). It was not reported whether or not the outcome was assessed by an investigator who was blind to the allocation and, therefore, the trial data are at risk of performance bias.
Secondary outcomes: podiatric care
Two amputations occurred among 47 participants in the intervention arm and one amputation occurred among 44 participants in the control arm. Two people in the intervention arm died and four people in the control arm died.33
Data on 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.
Education alone
Three RCTs78–80 evaluated education alone.
One hundred and twenty-one people were followed up for 6 months.78 Most of the individuals were male (60%); participants’ mean age was 71 years, and almost 11% had a history of foot ulceration. All had T2DM and their mean duration of diabetes mellitus was 15 years. The 60 people in the intervention group received a 2-hour group education programme (in groups of 5–7 patients). This comprised 30-minute face-to-face lessons on risk factors for foot ulcers, instructions on how to check their feet regularly, and information on ulcers and other foot conditions. In an additional 90-minute interactive session, health-care professionals demonstrated practical actions that would reduce the risk of foot ulcers. The 60 people in the control arm received a leaflet with recommendations for preventing foot ulcers. People in both arms received a standard multidisciplinary general education about diabetes mellitus at diagnosis, but they did not receive foot-specific education. At the 6-month follow-up, no statistically significant beneficial effect was observed in the intervention group (RR 0.08, 95% CI 0.00 to 1.31). The trial quality was compromised by a lack of concealment of the random allocation schedule, lack of collection of outcomes by an independent investigator and incomplete outcome data.
The RCT by Gershater79 comprised 131 people who had previously received treatment for a foot ulcer in a diabetes specialist foot clinic. They were recruited after the ulcers had healed and most of them were men (73%); their mean age was 64 years. The majority had T2DM, but the overall mean duration of diabetes mellitus was not reported. Those in the intervention group (n = 61) received foot care education led by a diabetes specialist nurse, designed to improve participants’ confidence in managing their foot health. This consisted of one 60-minute group session with 2–5 participants of the same gender in each group. The group discussions took place in the diabetes foot clinic conference room and were facilitated by a diabetes specialist nurse. Participants could choose to adopt a set of predefined actions/goals.
The 70 people in the control arm received standard, oral and written instructions on self-care based on the International Consensus on the Diabetic Foot.118 Both arms received standard care, which comprised adjusted shoes and individually fitted insoles, and the recommendation for regular chiropody. All participants also received standard oral and written instructions on self-care provided by a diabetes specialist nurse. The trial quality was compromised by a lack of concealment of the random allocation schedule (selection bias) and lack of the collection of outcomes by an independent investigator (performance bias).
Lincoln et al.80 randomised 172 people (two-thirds of whom were male) who had previously had ulcers to an intervention or a control group. Eighty-seven people in the intervention arm received a single 1-hour structured foot care education session from a researcher at home. The session included an explanation of the main causes of foot ulcers and a foot examination to identify risk factors (deformity, ischaemia or neuropathy), and advice was reinforced with written information. Shoes and insoles were examined for suitability and participants were advised to contact the clinic immediately if any new or recurrent foot problem emerged. The control group (n = 85) received standard care, consisting of unstructured and opportunistic foot care and the same written information as given to the intervention group. Standard care included podiatry and suitable orthoses when appropriate. At the 12-month follow-up, there was no statistically significant difference in the number of patients with foot ulceration between the two groups (RR 1.00, 95% CI 0.70 to 1.44). All quality assessment items were judged to be at a low risk of bias.
Education alone: meta-analysis
A pooled estimate of the effect of education on the incidence of foot ulceration at 6 months found that foot ulceration was not statistically significantly reduced in three trials of 423 people with diabetes mellitus (RR 1.04, 95% CI 0.55 to 1.97) ().78–80 The heterogeneity (I2) was 54%.
Meta-analysis: education alone.
Secondary outcomes: education alone
Two trials of education interventions reported data on amputation,78,80 mortality,78 knowledge,78 behaviour80 and/or QoL.80 One trial78 reported no amputations in either of its arms after 6 months’ follow-up. The other trial80 reported three amputations among 85 participants in the intervention arm, compared with no amputations among the 85 participants in the control arm at 6 months; by 12 months there was no difference between the arms (nine amputations in both).
One trial78 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 with the Patient Interpretation of Neuropathy knowledge score) was observed in the intervention arm.78
One trial80 reported on QoL and found no differences between the two arms on the Diabetic Foot Scale, but scores on the Nottingham Assessment of Functional Footcare questionnaire, which assesses behaviour, were higher in the education arm than in the control arm.
Digital thermometry
Four RCTs87–89,120 involving 468 patients were identified by our searches.
Armstrong et al.89 followed up 225 people (approximately 69 years of age) for 18 months. Their mean duration of diabetes mellitus was 13 years, but the authors did not report how many had T2DM. The number of participants randomised to the intervention group or the control group is not known. The intervention was an infrared skin thermometer to measure temperatures on six sites on the foot twice per day. Patients were told that, if they recorded a temperature difference of > 4 °F between feet at the same site, they should contact the study co-ordinator and reduce activity until their temperature normalised. Patients also received standard care consisting of footwear, education and professional foot care. The control group also received standard care and were advised to contact the study co-ordinator if they had any foot abnormalities. Participants’ feet were also checked for any signs of irritation from shoes or signs of impending ulcer. The number of ulcers in the intervention and control groups was reported to be 5 and 14, respectively, but the absence of the denominators for each group prevents the calculation of an effect. The quality of the trial is compromised because there was no allocation concealment, and because of the incompleteness of data reporting (selection and attrition bias).
A second RCT (i.e Lavery et al.87) recruited 85 people (49% were male) with a mean age of 55 years. The mean duration of diabetes mellitus was 14 years, but it was not reported how many had T2DM. The participants were randomised to digital thermometry or standard care and followed up for 6 months. Forty-one participants received a hand-held infrared skin thermometer to measure the temperature at six predetermined sites on the sole of each foot in the morning and the evening. They received additional standard footwear, education and professional foot care, and were advised to contact a nurse case manager and to significantly reduce walking if they recorded a temperature difference of > 4 °F between feet at the same site. The control group received standard care footwear, education and professional foot care. No statistically significant difference was observed between the two groups (RR 0.15, 95% CI 0.02 to 1.19). There was a risk of bias from the generation and concealment of allocation being unclearly reported and there were incomplete outcome data. The method of generating the random sequence and the concealment of the allocation were both unclear and the trial data were at risk of selection bias.
The same authors (i.e. Lavery et al.88) conducted a three-arm trial over 15 months. Of the 173 participants, 54% were male; participants’ mean age was 65 years and all had a history of foot ulceration. Approximately 95% of participants had T2DM, and their mean duration of diabetes mellitus was 13 years. The 59 participants in the first intervention arm received standard care plus a digital infrared skin thermometer and were asked to measure the temperature on the sole of their foot in the morning and the evening and record this information in a logbook. The participants were advised to contact a nurse manager if the difference in temperature between feet was > 4 °F and to reduce their activity until their temperature normalised. A video was used to teach participants how to use the infrared thermometer. In the second intervention arm, 56 participants received standard therapy plus training to conduct a structured foot examination twice daily using a mirror (to identify redness, swelling, inflammation, etc.). These participants could also could contact a nurse if they detected any abnormalities.
The 58 participants in the control received standard care (including lower extremity evaluation by a physician every 8 weeks, an education programme focused on foot complications and inspection, and therapeutic insoles and footwear). A podiatrist replaced or repaired insoles or footwear if needed. There was also an education component provided by video, and the participants were told to inspect their feet daily and to contact a nurse if necessary. There was statistically a significant difference between the digital thermometry group and the standard care group (RR 0.29, 95% CI 0.11 to 0.73). This trial was at a low risk of bias in all four quality assessment items.
Skafjeld et al.120 followed up 41 participants (56% male; mean age of 58 years) for 12 months. All participants had previously had ulcers (71% had T2DM), and their mean duration of diabetes mellitus was 18 years. The 21 people randomised to the intervention group received a hand-held device with an infrared heat sensor to monitor their foot temperature. Participants recorded their daily physical activity using a step counter during the first week of the study, and throughout the study their recorded temperature at the same six places on the sole of each foot. Patients were advised that if the recorded skin temperature at the same spot differed by > 4 °F between their feet on 2 consecutive days they should contact the study nurse and reduce their physical activity until their temperature normalised. The control group of 20 participants received standard care, which involved inspecting their feet under the toes, below the toes and between the toes. Participants could contact the study nurse if they noticed changes in their feet, including a new ulcer. They were advised to always wear their customised footwear and consult their general practitioner if necessary. No statistically significant difference was observed in the number of ulcers between the intervention group and the control group (RR 0.67, 95% CI 0.32 to 1.41). Whether or not the allocation was concealed was not clear; in addition, the outcome data were incomplete and the trial data were at risk of selection and performance bias.
Digital thermometry: meta-analysis
A pooled analysis of data from three RCTs87,88,120 found that the use of digital infrared skin thermometry reduced the number of foot ulcers among 243 people with a history of foot ulceration (RR 0.41, 95% CI 0.19 to 0.86) (). An I2 of 33% was observed.
Meta-analysis: digital thermometry.
Secondary outcomes: digital thermometry
Trials of dermal thermometry variously reported on amputation following infection,89 QoL (assessed using the SF-36),37 adherence to therapy87,88 and time to ulceration.39,40
In one trial, amputations following infections were required in 0 out of 41 participants in the intervention group and in 2 out of 44 in the comparator group.38 In the same trial, there was no statistically significant difference in QoL measured using SF-36 in any category or in the overall score.87
Two trials88,120 found no statistically significant difference between the dermal thermometry group and the comparator group in the time for which prescribed footwear and insoles were worn, as measured using a self-report questionnaire with an ordinal scale of < 4 hours to > 12 hours per day. The time to ulceration was statistically significantly longer in the dermal thermometry treatment group than in the standard care group in one trial88 but not in another.120
Complex interventions
Five RCTs evaluated the effects of complex interventions on the development of foot ulcer.84,90–92,119
Cisneros90 recruited 53 participants (62% were male) with a mean age of 62 years, of whom 28% had previously had ulcers and 96% had T2DM. They had a mean duration of diabetes mellitus of 14.5 years. The 24-month intervention (n = 30) was a researcher-led preventative programme comprising therapeutic education (weekly group meetings) and the provision of two pairs of special protective shoes. The education component was delivered over four meetings, each lasting 90 minutes, in groups of up to eight participants; this addressed, with discussion, issues around the prevention of foot ulcers, inspection and foot hygiene, and the choice and use of footwear. Bespoke games were used as teaching aids to prompt individual reflection about lifestyle and diabetes mellitus, and there was a discussion at the end of each meeting between health professionals and individual patients. The pedagogical technique was based on communications and learning. Footwear was provided after completion of the educational programme, at the beginning of the study and after the fourth re-evaluation.
The control group (n = 23) received information on regular foot care and footwear use in response to demand during the individual consultations with the researcher. Both groups received standard care monitoring of their feet to survey the incidence and recurrence of neuropathic injury. Monofilament testing was performed using the monofilament Semmes–Weinstein 5.07 (10 g) to identify risk at three sites on the foot the (digital pulp of the hallux and the first and fifth metatarsal heads). All items in the quality assessment were unclear and the trial was possibly at risk from selection, performance, attrition and selective reporting bias.
A second RCT119 followed 79 participants (51% were male) with a mean age of 66 years for 12 months. It was reported that 42% of participants had previously had ulcers. The majority (94%) had T2DM, and their mean duration of diabetes mellitus was 11 years. Forty-one patients in the intervention received care in two parts. For the first 3 months, they worked with a physical therapist in exercise sessions to strengthen their lower extremity muscles and promote balance. In the second part, over 4–12 months, they increased their exercise activity by 50%. In addition, they received training in self-care and foot examination skills. The 38 participants in the control group were taught foot-related self-care skills, including daily foot examination, and could access their usual medical care from their own health-care providers. Every participant was referred to a local orthotist or podiatrist at enrolment and received therapeutic footwear to wear when weight bearing inside and outside the home. There was no statistically significant difference in the number of foot ulcers between the two groups (RR 0.19, 95% CI 0.02 to 1.52). All quality assessment items were rated as being at a low risk of bias.
A third RCT91 evaluating a complex intervention comprised 62 participants (56% were male) with a mean age of 56 years. Twenty-five per cent of participants had previously experienced an ulcer, and 87% were classified as having T2DM. On average, they had had diabetes mellitus for 11 years. Thirty-one participants in the intervention group received a foot care kit that contained nail clippers, foot care cream, a monofilament with 10-g pressure, a thermometer to measure the temperature of water for foot washing, alcohol cotton pieces and a mirror. They were shown how to use the kit and asked to carry out daily foot care, checking their feet every day with a mirror. Participants could attend diabetes education classes every 3–6 months and were followed up every month for 2 years by a nurse and an endocrinologist performing a foot examination. Both the control group and the intervention group received standard care consisting of medication adjustment, foot assessment and 2 hours of diabetes education. No statistically significant effect in the number of foot ulcers was evident (RR 0.07, 95% CI 0.00 to 1.12). All items in the quality assessment were unclear and the trial may be at risk from selection, performance, attrition and selective reporting bias.
In a fourth RCT92 evaluating a complex intervention, 396 participants were followed up for 12 months. Most of the participants were women (81%) and they had a mean age of 60 years; it was unclear whether or not they had previously experienced foot ulcers. Every patient had T2DM and had received a diagnosis at least 10 years before. The 191 patients in the intervention group received nurse-led patient education sessions involving one to four patients and covering appropriate foot care behaviours and footwear. Patients entered into a behavioural contract for desired self-foot care. A systems intervention was designed to prevent patient-specific risks using information flow sheets on foot-related risk factors for amputation in diabetic patients. Health-care providers used prompts to ask patients to remove their footwear and perform foot examinations, and patients were also given foot care education. Both groups received standard care, which consisted of a physical examination performed by nurse clinicians who were blind to patients’ randomised treatment. There was no statistically significant difference in the number of foot ulcers between the two groups (RR 0.47, 95% CI 0.20 to 1.12). All items in the quality assessment were judged to be unclear and the trial was possibly at risk from selection, performance, attrition and selective reporting bias.
In a RCT evaluating a complex intervention,84 the majority of the 2001 participants were male (53%) and the participants’ mean age was 60 years. It was not reported how many had previously had foot ulcers. Eighty per cent had T2DM, but their mean duration of diabetes mellitus was not reported. The 1001 participants in the intervention group received a foot risk assessment comprising testing of sensitivity to Semmes–Weinstein monofilaments, measurement of VPT using a biothesiometer and the palpation of pedal pulses. Those deemed to be at high risk of foot ulceration were invited to attend a weekly diabetic foot clinic, where they were provided with self-care advice, chiropody care and support hosiery and/or protective shoes. The 1000 participants in the control group continued to attend the general outpatient clinic and had ulcer and amputation outcomes collected but received no special care. The diabetes outpatient service advised those in the control group about the importance of daily foot inspection and washing, appropriate hosiery and footwear and making contact with the clinic whenever they deemed it necessary. No statistically significantly different effect in the number of foot ulcers was observed between the two groups (RR 0.69, 95% CI 0.41 to 1.15). Generation and concealment of allocation and blinding were unclear. Three items in the quality assessment were rated as unclear (apart from incomplete outcome data, which was rated as high risk) and the trial was rated as being at possible risk of selection, performance, attrition and selective reporting bias.
Complex interventions: meta-analysis
A pooled analysis of data from the 2587 people with diabetes mellitus in five RCTs showed that complex interventions statistically significantly reduced the number of foot ulcers in the intervention groups (pooled RR 0.59, 95% CI 0.38 to 0.90) (). The ulcer risk category of those who took part was not reported in three trials,84,92,119 but two trials included 44 patients who had not previously experienced a foot ulcer.90,91 Heterogeneity was found to be I2 10%; however, with the exception of one trial,119 the validity of these data may be affected by bias.
Meta-analysis: complex intervention.
Secondary outcomes: complex interventions
Amputation,84,91 time to ulceration90 and/or knowledge of foot care91 were reported in three trials. In one trial,91 amputations occurred only in the control arm (two among 31 participants, compared with none among the 31 participants in the intervention arm) and in a second trial84 there were fewer amputations in the intervention group (one major and six minor) than in the control group (12 major and 13 minor).84 The time to ulceration was shorter in the control group than in the intervention group in one trial, but this finding did not reach statistical significance.90
In one trial, participants’ knowledge of foot care (as measured using a diabetes knowledge questionnaire) was statistically significantly better in the intervention group than in the control group.91
Custom-made footwear and offloading
We identified six RCTs evaluating custom-made footwear and offloading devices.
Bus et al.99 recruited, and followed up for 18 months, 171 participants, most of whom were men (82.5%), with a mean age of 62 years. All had previously had ulcers. Nearly three-quarters (71%) of participants had T2DM, and their mean duration of diabetes mellitus was 17 years. Eighty-five people in the intervention arm received either custom-made footwear or semi-customised footwear with offloading properties improved, which was prescribed by a specialist in physical and rehabilitation medicine and manufactured by a local orthopaedic shoe technician. The custom-made shoes were created from a plaster-cast mould of the foot or from three-dimensional digital scans. Participants received orthoses made from either a cork base with added microcork and a mid-layer of ethylene vinyl acetate or a Plastazote leather. Participants were permitted to wear any additional custom-made footwear they owned at study entry or that was prescribed during follow-up. The 86 people in the control group wore footwear that was not improved based on in-shoe pressure measurement. Both groups received written and verbal instructions on foot care and on proper use of footwear as standard practice. No statistically significantly different effect was detected (RR 0.88, 95% CI 0.61 to 1.26). All four quality assessment items were judged to be at a low risk of bias.
A three-arm trial of footwear and orthoses86 recruited, and followed up for 24 months, 400 participants (77% were male) with a mean age of 62 years, all of whom had experienced a foot ulcer. The majority of participants (93%) had T2DM and the duration of diabetes mellitus was > 25 years in 56% of the trial population. Participants were randomly allocated to a group receiving three pairs of therapeutic shoes with medium-density cork inserts and a neoprene closed-cell cover or to a group receiving three pairs of therapeutic shoes with prefabricated, tapered polyurethane inserts and a brushed nylon cover or to the control group, who received usual footwear. All groups received standard professional foot care and a lightweight terry-cloth house slipper. There was no statistically significant difference in number of foot ulcers between those who received therapeutic shoes with either neoprene inserts or polyurethane inserts and the control group (RR 1.00, 95% CI 0.70 to 1.43). The reporting of concealment of allocation was unclear.
A third RCT, of footwear and pressure-relieving devices,96 included 298 participants, with a mean age of 67 years, of whom 20% had had a previous ulcer. The majority (84%) had T2DM, for a mean duration of 18 years. One hundred and forty-eight participants were randomised to the intervention group and received custom-made orthoses and shoes. Shoes were mostly semi-orthopaedic footwear, available on the open market, or craft-made orthopaedic shoes. Each patient also received additional education session about the need to wear the shoes and to inspect their feet daily. Patients could receive an urgent consultation within 24 hours if they developed a new foot ulcer. Follow-up took place every 3 months to assess the feet and the condition of the footwear. Standard care for 150 people in the control group comprised education to prevent foot ulcers and advice about footwear. A statistically significant difference between groups was observed (RR 0.30, 95% CI 0.18 to 0.49), with custom-made orthoses and shoes producing a beneficial effect. The concealment of allocation and outcome assessor blinding were unclear and the trial data are at risk of selection and performance bias.
A fourth RCT, of custom-made footwear and insoles,95 comprised 299 participants (67% were male and the mean age was 70.5 years). Twenty-five per cent had experienced a foot ulcer and, on average, they had had diabetes mellitus for 12.5 years, but the number with T2DM was not reported. The 149 participants in the intervention group received therapeutic shoes in which the standard insole had been replaced with an insole designed to reduce shear. The control group (n = 150) received the same brand of therapeutic shoes containing the standard insole. In both groups insoles were replaced every 4 months and the shoes were replaced once per year. Both groups also received standard care comprising a foot and lower extremity evaluation by a physician every 10–12 weeks and an educational video that focused on foot complications and self-care practices. The video addressed the aetiology of DFUs, risk factors, self-care practices and early warning signs of diabetic foot disease. Patients were to contact the study nurse if they identified an area of concern on their feet. After 18 months’ follow-up, no statistically significant difference in effect was detected (RR 0.30, 95% CI 0.08 to 1.08). The generation and concealment of allocation were unclearly reported, as was the completeness of the outcome data, and the validity of the trial data may be compromised by selection and reporting bias.
Uccioli et al.85 randomised 69 participants (62% were male and the mean age was 60 years). All participants had experienced a foot ulcer, 75% had T2DM, and the mean duration of diabetes mellitus of those recruited was 17 years. The period of follow-up was 12 months. The intervention arm comprised 33 people who received therapeutic shoes made from soft thermoformable leather with semirocker soles and custom-moulded insoles (which were of extra deep fit customised insoles and accommodate toe deformities) plus standard care. The 36 people in the control group were free to wear ordinary shoes, unless it was clearly dangerous for them to do so, and received only standard care, which comprised educational guidelines on foot care and general information about the importance of appropriate footwear. A statistically significant effect was observed (RR 0.47, 95% CI 0.25 to 0.87). Generation of the random allocation was judged to be at a high risk of bias, and concealment of allocation and blinding and completeness of the outcome data were unclear; consequently, the trial data may be at risk of selection, performance, attrition and reporting bias.
The sixth RCT98 randomised 150 participants (68% were male) with foot ulcers who had a mean age of 59.5 years. The number of participants with T2DM and the duration of diabetes mellitus were not reported. All participants were advised to remain in their healing devices or removable cast walkers until their foot ulcers healed and before shoes were dispensed at ≈7 weeks after randomisation. Seventy-nine people in the intervention group were randomised to receive bespoke orthoses with offloading properties to reduce pressure on the metatarsal heads. Modified using a computer-aided design process, the orthoses were milled from a block of ethylene vinyl acetate foam and covered with a polyurethane foam top cover. Seventy-one people in the control group received standard orthoses from three different manufacturers. Both groups were provided with extra-depth shoes from PW Minor (Batavia, NY, USA) but a different specification was required to accommodate the bespoke orthoses (DX2 as opposed to the extra-depth specification that was received by the control group). Study co-ordinators discussed self-care behaviour with all patients, focusing on wearing the study shoes for all steps taken and examining the feet daily to note and report problems to the study team. There was a statistically significant difference in effect at 15 months (RR 0.34, 95% CI 0.14 to 0.81). The risk of bias was low for all four quality assessment items.
Secondary outcomes: custom-made footwear and offloading
Adherence95,96,99 and/or cost96 data were reported in four trials. One trial measured adherence using a temperature-based monitor placed inside the shoe, and found that 35 out of 85 participants in the intervention group and 42 out of 86 participants in the control group adhered to wearing their allocated footwear.99 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 that received cork inserts (83%) and prefabricated insoles (86%).86 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 the groups in the number of people who wore the shoes for < 4 hours per day (23/149 vs. 16/150), 4–8 hours per day (77/149 vs. 83/150), 8–12 hours per day (38/149 vs. 46/150) or 12–16 hours per day (10/149 vs. 6/150).95
Cost data collected in one trial published in 2012 showed that supplying footwear and insoles cost €675 per person per year.96
Custom-made footwear and offloading: meta-analysis
A pooled estimate of data collected from trials evaluating custom-made footwear and offloading insoles showed a reduction in the number of foot ulcers (pooled RR 0.53, 95% CI 0.33 to 0.86) in 1387 people, of whom 464 had no history of foot ulceration; however, there was a high level of heterogeneity (I2 = 78%) possibly arising from variation in the construction of the shoes and insoles as well as the difference in risk ().
Meta-analysis: custom-made footwear and offloading.
Custom-made footwear and offloading: subgroup analyses
A subgroup analysis of data collected only from patients with a history of foot ulceration (n = 424) did not find a statistically significantly different effect in these patients (RR 0.71, 95% 0.47 to 1.06), and the degree of heterogeneity was I2 of 61% ( and ). Conversely, the RR of pooled data from two RCTs that included patients with no history of foot ulceration (n = 297) was 0.30 (95% 0.19 to 0.47) with I2 of 0%. It should be noted that many of the data in these analyses may be affected by biases emanating from the conduct of the trials, as only two trials were judged to be completely free of bias.98,99
Subgroup analysis: custom-made footwear and offloading in patients with a history of foot ulceration.
Subgroup analysis: custom-made footwear and offloading in patients with no history of foot ulceration.
shows the outcomes from the quality assessment process. Only 5 of the 23 trials were judged to be free of bias.
Ongoing randomised controlled trials
The searches for ongoing trials to prevent foot ulceration in diabetes mellitus from the ClinicalTrials.gov website found 24 studies being conducted worldwide, the details of which are presented in Appendix 4.
Discussion
The purpose of this SR was to evaluate the evidence base and obtain summary statistics for preventative interventions for foot ulceration in diabetes mellitus 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 mellitus.
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 under way. If foot ulcer prevention can be confirmed in large, well-conducted trials, this form of self-monitoring could relieve pressure on health-care systems; however, advising individuals to abstain from all weight-bearing activities when the difference in foot temperature exceeds 4 °F may prove challenging, and poor adherence might diminish any benefit in a real-world context outside 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 that this leads to improved outcomes. Although 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.13 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 inclusion 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.11,12 These influential documents advise that the core team in a diabetes foot care service should include diabetologists, podiatrists, vascular surgeons, diabetes specialist nurses and orthotists, but patient outcomes from such health-care service arrangements have not been evaluated in RCTs. An evaluation of outcomes for 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 SRs; two larger trials involving only those with a history of foot ulcers both failed to detect evidence of effectiveness,86,99 and visual inspection of our analyses of pooled data from all six trials found that the greatest beneficial effect was in trials in which the majority of participants were considered to be at high or moderate risk but had not experienced a foot ulcer,95,96 although the results reached statistical significance in only one trial.18 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-made footwear groups and the control groups.
This observation calls into question the conclusions of several SRs evaluating footwear and insoles for the prevention of foot ulcers.59,64,72 The most recent SR included randomised and non-randomised data and adopted a consensus approach to analysis. The reviewers concluded that there is strong evidence that footwear interventions prevent recurrent plantar foot ulcers but no evidence that they prevent a first foot ulcer.72 An individual participant data analysis using data from these six trials together with data from the 10 ongoing studies of offloading insoles identified by our search of the ClinicalTrials.gov database could allow for 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.97 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 these devices differ substantially in that they are worn only around the toes.
Three separate small trials evaluating the effects of daily application of an antifungal nail lacquer (ciclopirox 8%) plus daily foot inspections,89 the use of elastic compression stockings93 and podiatry94 all failed to show a reduction in foot ulcers, possibly as a result of small sample sizes.
The standard care arrangements in the control arms of the included trials trial varied greatly, and no coherent conclusions can be drawn about current clinical practice from the trial reports.
We have comprehensively reviewed a body of evidence from RCTs and made the fullest use of the data currently available to derive the 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 SRs have cited a lack of similarity between studies,49 a lack of standardisation in terminology, prescription, manufacture and material properties of interventions,65 heterogeneity in study designs, methodology and participant populations,66 and differences in participant demographics70 as reasons for not conducting meta-analyses, and we are aware of the potential limitations in the pooled analyses that we present here in both the number and the 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,52 but believe that the insights gleaned and the generation of new research hypotheses justify our decision to pool data. Our analyses found evidence of beneficial effects of four types of intervention to prevent foot ulcers in people with diabetes mellitus, 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 mellitus, and researchers conducting future trials should endeavour to complete the trial to target recruitment as informed by an a priori sample size calculation.103
