An urea, arginine and carnosine based cream (Ureadin Rx Db ISDIN) shows greater efficacy in the treatment of severe xerosis of the feet in Type 2 diabetic patients in comparison with glycerol-based emollient cream. A randomized, assessor-blinded, controlled trial

Cutaneous complications are common in diabetes, with approximately 30% of patients experiencing some skin involvement during the course of their illness and these may also be an early indicator of undiagnosed diabetes[1]. In particular xerosis is a common skin disorder frequently observed in diabetic patients[2]. Skin xerosis and callous formation could be risk factors for diabetic ulcers developing[3]. An effective hydration of foot skin in diabetics is a relevant preventive strategy in order to maintain a healthy foot[4]. Emollient and moisturizer topical products are efficacious in repairing the epidermal barrier function and in ameliorating xerosis[5]. However few studies have been conducted in diabetic patients assessing wheter this treatment can help correct alterations in functional and mechanical properties of diabetic skin. Urea is considered an effective hydrating and emollient topical product[6]. Recent experimental data performed in human keratinocytes suggest that urea is not a simple emollient compound but it is able to improve cell differentiation increasing gene expression of transglutaminase, filaggrin, aquaporin, and loricrin, therefore improving keratinocytes differentiation[7]. Arginine is an important substrate for Nitric Oxide formation[8]. In diabetic skin a deficit in NO production has been demonstrated[9]. This reduction could be due to an enhanced arginine consumption linked to high arginase enzymatic activity[10]. Carnosine is able to interfere with advanced glycosylated end-products formation[11]. This action has been also demonstrated for urea[12]. Recently a topical cream product containing urea 5%, arginine and carnosine has been developed (Ureadin Rx Db, Isdin Spain). This formulation, from a theoretical point of view, is an interesting topical product with a composition particularly suitable for the specific treatment of the xerotic skin in diabetic patients. However, so far, not controlled clinical data are available particular with a head-to-head comparison design with standard topical emollient treatment. The aim of the present study was to evaluate the efficacy of topical urea (Ureadin Rx Db, ISDIN) containing also arginine and carnosine, in comparison with glycerol-based (15%) emollient topical product containing also vaseline (8%) (Dexeryl, Pierre Fabre ) in the treatment of xerotic skin in Type 2 diabetic patients.

A total of 78 patients were screened for inclusion in the study. A total of 40 patients, fulfilling inclusion and exclusion criteria were enrolled: 20 were randomised to UC and 20 to EC group. Table 1 shows the patients characteristics at baseline. Main characteristics at randomisation were similar in the two groups even if there werea significative differences in patients randomised to UC in comparison to EC group regarding age, duration of diabetes and baseline VAS scores mean values. All patients concluded the 4-week treatment period. Figure 1 shows the study flowchart. UC induced a significantly greater hydration than the glycerol-based emollient cream: in UC group DASI score was reduced from 1.7 at baseline to 0.2 at week 4 ( p < 0.001; Wilcoxon test, a percentage reduction of 89%); in the EC group DASI score was reduced from 1.9 to 1.0 at week 4, a 47% percentage reduction in comparison with baseline values. After 4 weeks, compared with the control group, mean DASI score in UC treated group was significantly lower (0.2 vs. 1.0; p = 0.048, unpaired T-test) (Figure 2). Median values of DASI score were 1.5 in UC group and 2 in EC at baseline. At week 4 median DASI scores were 0 for UC group and 1 in EC group, respectively (p = 0.0005 Mann–Whitney test). Mean VAS score significantly improved in both groups during treatment. Mean VAS score at the end of treatment period was significantly higher in UC group in comparison with the control group (9.8 vs. 8.2; p = 0.05, unpaired T-Test) (Figure 3). Median values of VAS score were 6 in UC group and 7 in EC at baseline. At week 4 median VAS scores were 10 for UC group and 9 in EC group, respectively(p = 0.0001 Mann–Whitney test). Mean Itching score (IS) at baseline were 8.5 in UC and 9.3 in EC group. At week 4, mean IS increased significantly (P = 0.05, Wilcoxon test) in UC to 9.9 in comparison to baseline. In EC group mean IS score was 9.7 at week 4. No differences were observed in the two groups at week 4 (Figure 4).

Diabetes mellitus induces many pathophysiologic changes in the skin[16]. Diabetes also induces increase in the dermis of advanced glycosylation end products (AGEs), which may be responsible for some skin changes in persons with elevated blood sugars[17]. Xerosis (with prevalence higher than 40%) with pruritus and scleroderma-like skin changes are the most commonly observed cutaneous manifestations of this common disease[18]. Xerosis of the diabetic foot could promote ulceration through the development of fissures and hyperkeratosis. Its treatment is therefore important and must be implemented early on. Skin xerosis is commonly treated with the repeated use of emollients and moisturizers[19]. Their use is based on sound evidence of the importance of maintaining the skin's water content. Emollient products could vary in term of beneficial effects on the skin[20]. Recent data have shown that topical urea can act not only as a simple hydrating molecule but in addition it could be able to improve cell differentiation of keratinocytes. In a randomized placebo controlled trial Garrigue[21] et al. have shown that topical urea 5% is able to improve xerosis in the diabetic foot by 61% after 4 weeks of treatment. In our study we compared urea, arginine and carnosine topical product with a standard treatment reference (Dexeryl). Reduction of xerosis score observed in our trial was 90% in the UC group. This clinical effect could be due to the particular composition of UC. Urea and carnosine could favourably interfere with formation and accumulation of advanced glycated end-products[22]. Topical urea is able to increase the synthesis of aquaporin in keratinocytes therefore increasing the hydration of the skin[6]. Arginine supplementation improves microcirculation in diabetes[23]. Therefore UC composition could have a strong rational as an “active” emollient for the treatment of skin xerosis observed in diabetic patients.

Our study has shown that application of urea 5% associated with arginine and carnosine cream increase skin hydration and alleviate the condition of skin dryness in Type 2 diabetic patients in comparison with a control glycerol-based emollient product. Some limitations should be considered in evaluating our results. First this study was not double-blind. The main difficulty in performing a double-blind trial in this setting was linked to the different formulations and texture of the study products. Therefore we decided to perform an assessor-blinded evaluation of the primary endpoint of the study. A second limitation of our study is that we have evaluated as primary endpoint a subjective clinical assessment parameters (DASI score and the VAS) instead of an instrumental objective variable. However the main therapeutic goal of emollient treatment in diabetes is to obtain an increase in hydration of the skin clinically evaluable. Further studies are necessary to evaluate if the treatment with this topical product could be associated with improvement in microcirculation and/or modification of skin structure in diabetes.