Recombinant Human Epidermal Growth Factor for Diabetic Foot Ulcer Healing: A Systematic Review and Meta-Analysis

Author: Lin Jin

Background

From 1980 to 2014, the prevalence of diabetes among adults aged 18 years and older has approximately doubled from 4.7% to 8.5%, and globally, the number of patients has almost quadrupled during this time period to an estimated 422 million people (1). Diabetic complications can arise if diabetes is improperly treated or left untreated. An example of a complication is diabetic foot ulcer (DFU), which is one of the most significant causes of amputation (2). Approximately 6% of all diabetic patients develop DFU annually (3), and they have a high risk of being infected, requiring hospital attention (4). Additionally, survival prognosis is low amongst patients with DFU, with 3-year cumulative mortality rate of 28% (3); Moreover, this rate almost doubles amongst diabetic patients with amputation (5). There is also a high economic cost associated with the treatment of DFUs owning to the long duration of the condition (6, 7), which often requires long-term hospitalization and results in loss of labour productivity (6). Therefore, DFU is rapidly becoming a growing public health challenge.

DFUs are the consequence from diabetes-related vascular disease and neuropathy (8). Hyperglycemia induces several cellular mechanisms and abnormalities metabolic, leading to the endothelial dysfunction and the consequent ischemia and increased risk of ulceration (9). Neuropathy causes the reduction in feeling in the foot (8). Therefore, diabetic patients often do not notice foot injury, which can lead to ulceration. Metabolic abnormalities from Diabetes can result in ischemia of the endoneurial microvascular circulation, which further deteriorates nerves (10).

Metabolic control, wound care, pressure relieving casts (11), debridement (12), pressure relief (13), and antibiotics are the rudimentary therapeutic interventions for the control of DFU. Growth factors, regarded as a relatively new therapy, function by activating growth and multiplication of cells while inducing protein production (14). These growth factors are regarded as ground-breaking technologies in the science and art of wound healing (15).

Epidermal growth factor was first isolated by Stanley Cohen from submaxillary glands of adult mice (16). It is a polypeptide that displaces strong mitogenic activity (17). Since its discovery, EGF has been isolated in human glands such as submandibular and parotid (18). It acts as an important regulator of cell growth, influencing both cell multiplication and differentiation, which can ultimately improve wound healing (19). Several randomized clinical trials (RCTs) have evaluated the efficacy of recombinant human epidermal growth factor (rhEGF) -related treatment versus control treatment in patients with DFUs. To our knowledge, however, only one systematic review of randomized clinical trials (RCTs) has been published summarizing specifically the efficacy of rhEGF for DFU healing (20). This review indicates that rhEGF has a high efficacy in treating DFUs by accelerating wound healing (20). However, it is not comprehensive as non-English publications were excluded (20). It did not include certain eligible RCTs that also meet the inclusion and exclusion criteria (21, 22). In addition, it is prone to the error – lack of rigorous assessment of bias risks.

Objective

In light of the absence of rigorous assessment and conclusive analysis about the efficacy of rhEGF for DFUs healing, we plan to conduct a systematic review and meta-analysis of RCTs evaluating the efficacy of rhEGF for DFUs healing. The proposed systematic review with a broad scope will aim to address the previously noted limitations, and provide up-to-date best available evidence through rigorous synthesis methods, including assessment of the quality of the evidence using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach.

Methods

Sources and searches:

The previous review of RCTs failed to include all eligible studies. Therefore, we plan to use the terms “diabetic foot ulcer”, “epidermal growth factor” and any relevant terms to perform search in Ovid MEDLINE, Ovid EMBASE, Ovid MEDLINE (In-Process & Other Non-Indexed Citations), EBSCO CINAHL and the Cochrane Central Register of Controlled Trials, to select eligible studies. We will further manually search the reference lists of the included studies in key journals in the field.

Study Selection:

Randomized clinical studies, reported in any languages and published in any dates, recruiting adults ( >18 years old) with type 1 or type 2 Diabetes diagnosed with foot ulcer. Generally, DFU is classified using Wagner-Meggit (table 1) or University of Texas classification (table 2); and the proposed review includes DFU patients with any ulcer grade based on the two classifications. Trials are eligible for inclusion if the intervention is either topical application and/or intralesional infiltration of rhEGF-based formulation with or without standard treatment, and if the intervention is compared with placebo, or standard treatment. Urogastrone, Heberpro-p, Citoprot-P and Herbermin are the brand names ofrhEGF-based formulation. Standard treatment includes metabolic control, antibiotic therapy, debridement, wound dressing, and pressure relief. We will select main outcomes (patient-important for decision-making) from the “Summary of finding table” which lists all relevant outcomes. After reviewing literature from primary studies, other relevant reviews, and clinical practice guidelines, we consider that any eligible studies should report at least one of the following primary outcomes, selected from the main outcomes: low limb amputation (at least one toe) rate, positive granulation response rate and time, complete wound healing rate and time, infection rate and/or ulcer recurrence rate. Main outcomes that are not selected will be taken as secondary outcomes. Exclusion criteria will apply to non-randomized control studies, e.g., case-control, cohort, case series, and other observational studies. Studies evaluating the efficacy of other types of growth factors for DFUs will be excluded.