Growth factors for treating diabetic foot ulcers

What are diabetic foot ulcers?

People who suffer from diabetes mellitus (usually referred to as ‘diabetes’) can develop wounds (ulcers) on their feet and ankles. These diabetic foot ulcers can take a long time to heal, and affect quality of life for people with diabetes. In some people, failure of these ulcers to heal can contribute to the need for some level of amputation on the foot. Any treatments that encourage diabetic foot ulcers to heal will be valuable.

What are growth factors?

Growth factors are substances that occur naturally in the body. They promote growth of new cells and healing of wounds. Treatment of diabetic foot ulcers with growth factors may improve the healing of ulcers.

The purpose of this review

This Cochrane review tried to identify the benefits and harms of treating diabetic foot ulcers with growth factors in addition to providing standard care (i.e. pressure relief, removal of dead tissue from the wound, infection control and application of dressings).

Findings of this review

The review authors searched the medical literature up to 3 March 2015, and identified 28 relevant medical trials, with a total of 2365 participants. The trials were performed in ten different countries, generally in out-patient settings. All the trials had low numbers of participants, which makes potential overestimation of benefits and underestimation of harms more likely. Half of the trials were sponsored by the pharmaceutical industry that produces these growth factors.

The trials tested 11 different types of growth factor, usually by applying them to the ulcer surface. Growth factors had no effect on the risk of having one toe or more amputated when compared with either another growth factor, or placebo (inactive fake medicine), or standard care alone (evidence from four trials). However, when compared with placebo or no growth factor, growth factors seemed to make complete healing of ulcers (wound closure) more likely to occur (evidence from 12 trials).

Shortcomings of the trials included in this review

None of the trials reported data on participants’ quality of life. Harms caused by treatments were poorly reported, so the safety profile of growth factors remains unclear.

It is clear that more trials are required to assess the benefits and harms of growth factors in the treatment of diabetic foot ulcers. These trials should be well-designed, conducted by independent researchers (not industry-sponsored), and have large numbers of participants. They should report outcomes that are of interest to patients, such as: how many of the participants’ ulcers healed, and how long the healing took; any level of amputation in the foot; quality of life; ulcer-free days following treatment; and harms caused by treatment, including whether there are any potential cancer risks.

Authors' conclusions: 

This Cochrane systematic review analysed a heterogeneous group of trials that assessed 11 different growth factors for diabetic foot ulcers. We found evidence suggesting that growth factors may increase the likelihood that people will have complete healing of foot ulcers in people with diabetes. However, this conclusion is based on randomised clinical trials with high risk of systematic errors (bias). Assessment of the quality of the available evidence (GRADE) showed that further trials investigating the effect of growth factors are needed before firm conclusions can be drawn. The safety profiles of the growth factors are unclear. Future trials should be conducted according to SPIRIT statement and reported according to the CONSORT statement by independent investigators and using the Foundation of Patient-Centered Outcomes Research recommendations.

Read the full abstract...
Background: 

Foot ulcers are a major complication of diabetes mellitus, often leading to amputation. Growth factors derived from blood platelets, endothelium, or macrophages could potentially be an important treatment for these wounds but they may also confer risks.

Objectives: 

To assess the benefits and harms of growth factors for foot ulcers in patients with type 1 or type 2 diabetes mellitus.

Search strategy: 

In March 2015 we searched the Cochrane Wounds Group Specialised Register, The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Ovid MEDLINE, Ovid MEDLINE (In-Process & Other Non-Indexed Citations, Ovid EMBASE and EBSCO CINAHL. There were no restrictions with respect to language, date of publication or study setting.

Selection criteria: 

Randomised clinical trials in any setting, recruiting people with type 1 or type 2 diabetes mellitus diagnosed with a foot ulcer. Trials were eligible for inclusion if they compared a growth factor plus standard care (e.g., antibiotic therapy, debridement, wound dressings) versus placebo or no growth factor plus standard care, or compared different growth factors against each other. We considered lower limb amputation (minimum of one toe), complete healing of the foot ulcer, and time to complete healing of the diabetic foot ulcer as the primary outcomes.

Data collection and analysis: 

Independently, we selected randomised clinical trials, assessed risk of bias, and extracted data in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I2 statistic. We subjected our analyses to both fixed-effect and random-effects model analyses.

Main results: 

We identified 28 randomised clinical trials involving 2365 participants. The cause of foot ulcer (neurologic, vascular, or combined) was poorly defined in all trials. The trials were conducted in ten countries. The trials assessed 11 growth factors in 30 comparisons: platelet-derived wound healing formula, autologous growth factor, allogeneic platelet-derived growth factor, transforming growth factor β2, arginine-glycine-aspartic acid peptide matrix, recombinant human platelet-derived growth factor (becaplermin), recombinant human epidermal growth factor, recombinant human basic fibroblast growth factor, recombinant human vascular endothelial growth factor, recombinant human lactoferrin, and recombinant human acidic fibroblast growth factor. Topical intervention was the most frequent route of administration. All the trials were underpowered and had a high risk of bias. Pharmaceutical industry sponsored 50% of the trials.

Any growth factor compared with placebo or no growth factor increased the number of participants with complete wound healing (345/657 (52.51%) versus 167/482 (34.64%); RR 1.51, 95% CI 1.31 to 1.73; I2 = 51%, 12 trials; low quality evidence). The result is mainly based on platelet-derived wound healing formula (36/56 (64.28%) versus 7/27 (25.92%); RR 2.45, 95% 1.27 to 4.74; I2 = 0%, two trials), and recombinant human platelet-derived growth factor (becaplermin) (205/428 (47.89%) versus 109/335 (32.53%); RR 1.47, 95% CI 1.23 to 1.76, I2= 74%, five trials).

In terms of lower limb amputation (minimum of one toe), there was no clear evidence of a difference between any growth factor and placebo or no growth factor (19/150 (12.66%) versus 12/69 (17.39%); RR 0.74, 95% CI 0.39 to 1.39; I2 = 0%, two trials; very low quality evidence). One trial involving 55 participants showed no clear evidence of a difference between recombinant human vascular endothelial growth factor and placebo in terms of ulcer-free days following treatment for diabetic foot ulcers (RR 0.64, 95% CI 0.14 to 2.94; P value 0.56, low quality of evidence)

Although 11 trials reported time to complete healing of the foot ulcers in people with diabetes , meta-analysis was not possible for this outcome due to the unique comparisons within each trial, failure to report data, and high number of withdrawals. Data on quality of life were not reported. Growth factors showed an increasing risk of overall adverse event rate compared with compared with placebo or no growth factor (255/498 (51.20%) versus 169/332 (50.90%); RR 0.83; 95% CI 0.72 to 0.96; I2 = 48%; eight trials; low quality evidence). Overall, safety data were poorly reported and adverse events may have been underestimated.

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