DPP IV Inhibition Facilitates Healing of Chronic Foot Ulcers in Type 2 Diabetes

Dipeptidyl Peptidase (DPP) IV Inhibition Facilitates Healing of Chronic Foot Ulcers in Patients With Type 2 Diabetes

A randomized versus placebo trial designed to evaluate the clinical and humoral effects of 4 months of vildagliptin on healing of chronic ulcers in type 2 diabetes.

The chronic foot ulcer is a leading cause of hospital admissions for people with diabetes in the developed world and is a major morbidity associated with diabetes, often leading to pain, suffering, and a poor quality of life for patients. Chronic diabetic foot ulcers are estimated to occur in 15% of all patients with diabetes and precede 84% of all diabetes-related lower-leg amputations.The pathophysiology of chronic diabetic ulcers is complex and still incompletely understood, the most important predisposing factors being diabetic neuropathy and vasculopathy. Both micro and macroangiopathy strongly contribute to development and delayed healing of diabetic wounds, through an impaired tissue feeding and response to ischemia. HIF-1α and VEGF, as well as the NO production from iNOS, may contribute to limitation of hypoxic injury by promoting angiogenesis and wound healing. Experimental and pathological studies suggest that suggest that he incretin hormone glucagon-like peptide-1 (GLP-1) may improves VEGF generation, and promote pancreatic islet viability through the up-regulation of HIF1α. Therefore, aim of this study is to evaluate the effect of the augmentation of GLP-1, by inhibitors of the dipeptidyl peptidase IV (DPP-4), such as vildagliptin, on HIF-1α, VEGF and iNOS in diabetic chronic ulcers.

In the placebo group, the dose of other concomitant hypoglycemic medication was changed to obtain a similar profile of metabolic parameters. All patients had diabetes and at least one full-thickness wound below the ankle for >3 months. All patients were examined weekly for the first 4 weeks (day 28) then every other week until day 120 or ulcer closure by any means. At each visit, tracings of the wound margins were made for computer planimetry to document changes in wound size, and photographs were taken for a visual record. All patients followed the regular treatment at the multidisciplinary diabetes foot clinic, included treatment of infection, debridement, off-loading, and metabolic control according to high international standards and standard good medical practice.

The experimental arm followed the same treatment of placebo group, but received also vildagliptin 50 mg per os b.i.d. for 4 months

50 mg per os b.i.d. for 4 months of treatment, added to the standard good medical practice.Plus Metformin and/or Sulfonylurea

Biopsy is performed from the periphery of the ulcer, before and after treatment with vildagliptin, in order to evaluate the above referred outcome. Optic microscopy is used to evaluate the epithelialization of the wound.

Biopsy is performed from the periphery of the ulcer, before and after treatment with vildagliptin, in order to evaluate the above referred outcome. Capillary density is measured using immunohistochemistry

The factor is assessed by immunoblot analysis (commercial kits). Arbitrary unit of measure are used to evaluate HIF-1α concentration. Higher values represent more factor.

The factor is assessed by immunoblot analysis (commercial kits).Arbitrary unit of measure are used to evaluate VEGF concentration. Higher values represent more factor.

The factor is assessed by immunoblot analysis (commercial kits). Arbitrary unit of measure are used to evaluate VEGF-R1 concentration. Higher values represent more factor.

The factor is assessed by immunoblot analysis (commercial kits). Arbitrary unit of measure are used to evaluate iNOS concentration. Higher values represent more factor.

Inclusion Criteria: Type 2 diabetes Oral hypoglycemic agents treatment Chronic foot ulcers Adequate blood circulation (perfusion) was assessed by a dorsum transcutaneous oxygen test >30 -mmHg, anklebrachial index values > 0.7 and < 1.2 with toe pressure > 30 mmHg, or Doppler arterial aveforms that were triphasic or biphasic at the ankle of the affected leg Written consensus Exclusion Criteria: Active Charcot disease Ulcers resulting from electrical, chemical, or radiation burns Collagen vascular disease Ulcer malignancy Untreated osteomyelitis, or cellulitis Ulcer treatment with normothermic or hyperbaric oxygen therapy Concomitant medications such as corticosteroids, immunosuppressive medications, or -chemotherapy Recombinant or autologous growth factor products Skin and dermal substitutes within 30 days of study start Use of any enzymatic debridement treatments Pregnant or nursing mothers

Marfella R, Sasso FC, Rizzo MR, Paolisso P, Barbieri M, Padovano V, Carbonara O, Gualdiero P, Petronella P, Ferraraccio F, Petrella A, Canonico R, Campitiello F, Della Corte A, Paolisso G, Canonico S. Dipeptidyl peptidase 4 inhibition may facilitate healing of chronic foot ulcers in patients with type 2 diabetes. Exp Diabetes Res. 2012;2012:892706. doi: 10.1155/2012/892706. Epub 2012 Nov 1.