Diabetic Foot Ulcers

Progress Stalled in Diabetic Foot Ulcers; Major Unmet Need

Veronica Hackethal, MD
September 24, 2014

The development of new treatments for diabetic foot ulcers has stalled for the past 2 decades, and novel, effective methods of tackling this debilitating condition are greatly needed, according to a recent review published in the August issue of Advances in Therapy.

"Diabetic foot ulcers are a very, very expensive problem that seriously affects the quality of life of diabetic patients," commented lead author Aristidis Veves, MD, professor of surgery and research director of the Joslin-Beth Israel Deaconess Foot Center and of the Microcirculation Lab at Harvard Medical School, Boston, Massachusetts. For decades, Dr. Veves's group has researched nonhealing wounds in diabetic patients
"The number of cases of foot ulcerations and amputations has been the same over the past 10 to 15 years. It is a major problem, with major unmet needs and lack of progress over the past 2 decades," he stressed.
Even with the current treatments available, about 1 in 4 patients with diabetic ulcers will require a foot amputation, he added.

"The best thing is to try to prevent diabetic foot ulcers from developing [in the first place] with patient education, appropriate footwear, and regular care," Dr. Veves explained.
The main principles for the standard care of diabetic foot ulcers are "the same" as they were 20 years ago, he says, and include debridement, pressure offloading, infection management, and revascularization.
"Once diabetic foot ulcers develop, the problem requires aggressive care by a multidisciplinary team of podiatrists, vascular surgeons, infectious disease, endocrinologists, and so on," he notes.

Standard of Care is Backbone of Treatment
One issue that remains challenging is developing effective wound dressings for diabetic foot ulcers, Dr. Veves explains. Many types exist, but there is not much evidence to show that any one is better than any other.
Only 3 products have been approved by the Food and Drug Administration (FDA) for the treatment of diabetic foot ulcers. These include 2 bioengineered skin-care products, Apligraf and Dermagraft (Organogenesis), but these are expensive, according to Dr. Veves. Apligraf is made of cultured cells from neonatal foreskin and Dermagraft is derived from human neonatal dermal fibroblasts.

In a limited number of trials, the best these products do is heal about half of ulcers, he noted.
Becaplermin (Regranex, Smith & Nephew) is the only FDA-approved growth factor for treating diabetic foot ulcers. It has been on the market since 1998. Although "widely used," 12-week healing rates hover around 34%. In addition, the FDA has placed a boxed safety warning on the product pointing to the increased risk for cancer mortality associated with use of Regranex.

Other adjunctive treatments include oxygen therapy, negative-pressure wound therapy, electrical stimulation, and shockwave therapy. Although some research has suggested benefits with these methods, results are conflicting and larger clinical trials are needed.

Products currently in clinical trials that appear promising include germicides, living-skin equivalents, and acellular dermal matrices, according to Dr. Veves. A phase 3 clinical trial is currently under way for the angiotensin analog NorLeu3-A(1-7) (active pharmaceutical ingredient in DSC 127, Derma Sciences). Results to date have suggested that topical application of this agent could help speed healing in patients with diabetic foot ulcers.
Future potential therapies include stem cell-based therapies, topical neuropeptides, delivery of gene-encoding growth factors via viral vectors, and cytokine inhibition. Larger-scale clinical studies of all these methods are also needed.
"So many products have failed, so it makes it difficult to predict what will work. We definitely need new products that will improve the efficacy [of healing] and, if possible, reduce the cost.…There is not enough research in this area," Dr. Veves says.

And he added, "The main point is that all these advanced treatments — which are quite expensive — are adjuncts to standard care (offloading, debridement). If you're not providing standard care, these treatments will not work."

Amputation May Sometimes Be the Best Option
Another expert, Paul J. Kim, DPM, associate professor in the department of plastic surgery and director of research at the center for wound healing at Georgetown University School of Medicine, Washington, DC, who was not involved in this review, says: "The diversity of treatment options for diabetic foot is indicative of the lack of a single approach that is clearly superior to another."

And reflecting Dr. Veves's sentiment about the lack of progress in developing effective treatments, Dr. Kim outlined 3 emerging trends in wound care for diabetic patients.
"The first is to acknowledging that quality of life, not just percentage of wound closure, is an important outcome for wound interventions," he said.
"The second is that wounds have correlates to soft-tissue malignant tumors. Surgical excision should be considered as a viable option rather than maintenance debridement," he emphasized.
"Finally, amputation should not necessarily be viewed as a negative outcome or complication, but perhaps as the best option for some patients."

The authors have reported no relevant financial relationships. Dr. Kim reports no relevant financial relationships.

http://www.medscape.com/viewarticle/832239