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A Prospective, Randomized, Controlled Double-Blind Study of a Moisturizer for Xerosis of the Feet in Patients with Diabetes
The loss of moisture from the stratum corneum and intercellular matrix leads to dry skin, or xerosis. Clinically dry skin appears rough, uneven, and cracked. Raised or uplifted skin edges (scaling), desquamation (flaking), chapping, and pruritus may be present. A person who has a decrease or loss of function of the sweat glands on the plantar surface of the foot will experience xerosis of the feet.
Xerosis of the feet is a skin condition found in all age groups but can be aggravated by certain conditions. The incidence of xerosis increases with age, exposure to dry environmental conditions, and physiological changes that alter circulatory supply to the lower extremities. People with diabetes have a high incidence of xerosis of the feet, especially on the heels. While assessing for predictors of foot lesions in patients with diabetes, one study found that 82.1% of their patients had skin with dryness, cracks, or fissures.1 An unpublished survey of 105 consecutive patients with diabetes conducted by one of the authors revealed that 75% had clinical manifestation of dry skin. Dry skin often leads to cracks and fissures, which can serve as a portal of entry for bacteria. These cracks and fissures are associated with an increased risk of cellulitis and foot ulceration2,3 that, if left unchecked, can eventually lead to amputation. The importance of examining patients' feet and offering instruction in preventive foot care by physicians and diabetes educators is often overlooked.
Xerosis can be controlled with moisturizers. The common ingredients often found in these products are urea and lactic acid; both are natural moisturizers. Urea was found to be a potent skin humidifier and descaling agent, particularly in 10% concentration.4 Urea-containing moisturizers work by decreasing transepidermal water loss.5 The lactic acid in moisturizers is in the form of alpha hydroxy acid (AHA). Alpha hydroxy acid is an exfoliating agent of the epidermis that sloughs off the dry skin cells and promotes the new growth of skin. Lactic acid also serves as a good humectant, retaining water in the stratum corneum; it also increases the extensibility and elasticity of the stratum corneum protein.6 Kempers et al7 found moisturizers containing AHA lead to significantly greater improvement in xerosis than non-AHA containing moisturizing lotion. However, at high concentrations, AHA may cause skin irritation and redness. Many over-the-counter moisturizers containing either urea or lactic acid are available. A moisturizer containing ammonium lactate 12% (Lac-Hydrin™, Westwood-Squibb Pharmaceuticals Inc., Buffalo, NY) has been approved by the FDA for treatment of dry, scaly skin and is available by prescription only. Carmol™ (Doak Dermatologics, Fairfield, NJ) is also available by prescription in creams with 10%, 20%, or 40% urea. Several studies demonstrate the efficacy of some moisturizers,8-11 but none of the published studies involved the feet of patients with diabetes.
The purpose of this study was to evaluate the safety and efficacy of a moisturizer containing 4% lactic acid and 10% urea in the treatment of severe xerosis of the feet in patients with type 1 or type 2 diabetes.
Study Design
A prospective, randomized, controlled double-blind study design was used to compare the treatment of xerosis with a moisturizer containing 10% urea and 4% lactic acid in an emulsion base to a moisturizer containing the emulsion base only.
Patients. The study was conducted at the Diabetes Care Center at Baptist Hospital in Miami, Fla. and the Joslin-Beth Israel Deaconess Foot Center in Boston, Mass. Institutional Review Board approval and written patient consent were obtained in both clinical centers. To be included, patients had to be 18 years of age or older with type 1 or type 2 diabetes and moderate-to-severe xerosis in both feet. The main exclusion criteria included history of ichthyosis vulgaris, use of any topical steroids or moisturizers on the feet in the previous 2 weeks, known hypersensitivity to creams used in the study, presence of acute skin disease or infection such as erysipelas and vasculitis, presence of foot ulcer associated with cellulitis or deep tissue infection, and evidence of gangrene on the feet. Patients who had participated in a clinical study with a moisturizing product within the previous 4 weeks or who had a history of poor compliance with medical treatment also were excluded. The patients served as their own control - one foot was to receive the test cream and the other was to receive the vehicle cream.
All patients received a diary sheet to record weekly evaluations of the xerosis on each foot. They were asked to rate whether the xerosis had improved, stayed the same, or became worse. A section for comments was provided if the patients wanted to provide any of their own opinions.
Study products. The two study products were a test cream and vehicle. The test cream (Atrac-Tain® cream, Coloplast Corporation, Marietta, Ga.) contained 10% urea and 4% lactic acid in a nongreasy emulsion base. The vehicle was the nongreasy emulsion base, similar in texture, color, and odor without the urea and lactic acid. The test and vehicle creams were provided to patients in a box containing 10 bags marked day 1 to day 10. Each bag contained two small tubes marked with a color-coded label for the left or right foot. One tube contained the test cream and the other contained the vehicle cream. The sponsor randomized these tubes before sending them to the participating centers.
Baseline evaluation and assessments. Patients who met eligibility criteria were enrolled and had their feet examined. Xerosis was evaluated using a nine-point Xerosis Assessment Scale (XAS) (see Table 1).12 This scale is used clinically by many healthcare providers, including the authors, to assess xerosis. Photographs of each corresponding grading scale were available for the investigators to assist in the evaluation.
The presence of any foot ulcer was evaluated using the Wagner grading system.13 Photographs were taken of each foot. Patients were instructed to wash their feet daily for 2 weeks with the nonmoisturizing soap provided to them. They also were instructed not to use a moisturizer during this wash out period. Patients returned after 2 weeks to have their feet examined and eligibility criteria re-evaluated. Testing was started for patients who still met eligibility criteria. Each subject was given a box containing the previously randomized cream and vehicle. Patients were instructed to apply the creams to the appropriate foot, as marked on the tubes, twice daily. The investigator applied the creams at the initial visit to demonstrate proper technique. Patients were instructed to use care not to mix up the tubes and advised to either use a different hand to apply cream to each foot or to wash their hands in between applications. Latex or nonlatex gloves were provided to patients at their request.
Follow-up evaluation. Patients returned weekly for 4 weeks to have the xerosis on their feet assessed. The extra bags of cream in each box were to allow for a difference of plus or minus 2 days for return visits. At each weekly visit, the feet were examined by the same investigator at each site. Each investigator was provided with the same visual guide for the xerosis scale. Assessments were done using the nine-point XAS, photographs of both feet were taken, and a new box of cream provided. Any comments regarding the study creams were recorded in the diary sheet, along with the progress of the treatment and any adverse events. The investigator applied the cream at each follow-up visit to reinforce proper technique. At the end of week 4, patients had their feet examined and all progress recorded. They were not given a new box of creams and were asked to eliminate the use of creams for the next 2 weeks.
Final evaluation. After 2 weeks of not using any creams, patients returned to have their feet assessed for regression of xerosis. Photographs were taken of both feet.
Statistical analysis. The Wilcoxon Rank Sum Test, a nonparametric procedure, was used for statistical technique. This test was selected because the XAS yields ordinal data. The program used for analysis was StatView®, an SAS format. Two comparisons were made - one between each weekly XAS grade and the patients' entry level XAS grade and the second between each weekly XAS grade of the test cream and the XAS grade of the vehicle. Data are presented as mean ± SD.
Results
Forty patients were enrolled in the study, 22 males and 18 females, with a mean age of 62 ± 11 years. The average diabetes duration for these patients was 12.4 ± 11.8 years. Their average body weight was 99.3 ± 24.6 kilograms. Thirty patients completed the study and are included in the statistical analysis, five did not meet criteria for xerosis, four dropped out after screening, and one was excluded because of onychomycosis.
Efficacy assessment. The xerosis gradings for both the test cream and the vehicle at each visit are shown in Table 1. As expected, no significant difference in xerosis was found between the two feet at the beginning of the study. Feet that received the test cream and feet that received the vehicle showed significant improvement in xerosis grading by the end of the study. However, feet that received the test cream showed significantly greater (P <0.01) improvement in xerosis grading compared to feet that had received the vehicle. Improvement was noted at all points during the study. Additionally, feet that received the test cream regressed significantly less (P <0.05) after 2 weeks of not using any creams.
Foot ulcers. Two patients had a Wagner grade 1 superficial ulcer on one or both of their feet and 28 patients did not have any ulcer (Wagner grade 0) at the start of the study. Among these 28 patients, 16 were at high risk of developing foot ulcers and 12 were at low risk of developing foot ulcers as assessed by the investigators. None of the patients developed new ulcers during the study.
Diary sheet. All patients completed the diary sheets. Nineteen patients did not make any additional comments and five stated that both their feet felt better. Five patients stated that one foot felt and looked better (the feet that they indicated as feeling better were found at the end of the study to be the ones to which the test moisturizer was applied). One subject thought that both the test cream and the vehicle were better than the product used before entering the study.
Adverse events. No serious adverse events related to the cream occurred in this study and no significant differences were found between the safety of the test product and the vehicle.
Discussion
The main objective of this study was to evaluate the efficacy of the test cream containing 10% urea and 4% lactic acid in the feet of diabetic patients with moderate-to-severe xerosis. Results showed that while the emulsion base alone can improve xerosis if used daily, the test cream provided significantly greater improvement in xerosis of the studied population. The difference in improvement was apparent even after 1 week of daily application. The difference in the grading scores widened as the study progressed and was greatest at the end of the study period (see Table 2). The test cream also showed a longer-lasting effect. After discontinuing use of any cream for 2 weeks, feet that had the test cream applied regressed less than feet that had the emulsion base applied.
Xerosis is very common in the feet of patients with diabetes, especially in type 2 diabetes. Autonomic neuropathy may play a role in xerosis of patients who have diabetes. Aging has been shown to be another factor in xerosis.14-16 Aging and longer duration of diabetes have been found to be closely associated with the presence of xerosis.17 Unfortunately, many healthcare providers still do not look at the feet of diabetic patients. Examining the feet of diabetic patients at every encounter is imperative. The most effective method to prevent diabetic foot complications is to have patients remove their shoes and socks so the healthcare provider can examine their feet at every visit.18 When, upon examining the feet, evidence of xerosis is found, healthcare providers should recommend a moisturizer to keep the skin moist and soft. Regular use of moisturizer also may play a role in the prevention of contact dermatitis.19
The current study showed that using a moisturizer on a daily basis improves xerosis in feet of patients with diabetes. This is important because untreated xerosis can lead to cracks and fissures with subsequent violation of the skin barrier to bacteria. The heel is an area where cracks and fissures often occur in xerotic feet. Ulceration and infection at the heel can be very difficult to manage and potentially lead to major amputation. Some of the patients in this study presented with heels having moderately deep fissures. The test cream healed these fissures after a few weeks of usage (see Figure 1). Compliance with treatment is another consideration: Even though applying moisturizer to the feet appears to be a simple thing to do, 25% of the patients failed to apply the cream daily and did not complete the study. Compliance rate in clinical practice may be much lower.
Moist, elastic skin, resulting from using a moisturizer, can help prevent further foot complications. Areas of dry, thick skin in the plantar aspect of the foot can raise pressure in that area.20 Callus formation is the result of the body's protective response to areas of high pressure. Unfortunately, this protective mechanism can become a vicious cycle. An area of dry skin or high pressure causes the body to develop callus, increasing pressure to that area; the body's response to this increased pressure is to build even more callus. High foot pressures have been associated with high risk of developing foot ulcers in patients who have diabetes21; in addition, high plantar foot pressure has a high specificity for predicting the development of foot ulceration.22 Though not well studied, the sheer force in the feet also may be a risk factor for developing a foot ulcer. The soft, elastic skin may reduce pathological shear force; thereby, preventing ulceration.
Conclusion
Xerosis in the feet of people with diabetes can be controlled with consistent application of moisturizer. Healthcare providers should routinely inspect the feet of patients with diabetes and encourage them to use moisturizers daily. Several currently available moisturizers contain either lactic acid or urea. The test cream in this study that contains both lactic acid and urea was found to be safe and effective in controlling xerosis in the feet of people with diabetes.
Acknowledgments
This study was supported by an educational grant from Coloplast Corporation, Skin Care Division, North Mankato, Minn. Stephen E. Bohnenblust EdD, Professor, Department of Health Science, Minnesota State University, Mankato, MN, performed the statistical analysis.
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