The most frequently recognized complication of diabetes, affecting more than 28 million people worldwide. All of them are at high risk for lower limb amputation.
Global Scourging Problem in Numbers
People With Diabetes
Risk for Developing DFU
People With Non-Healing DFUs
Number of Limb Amputation Each Year
The Diabetic Foot Problem
Complications of diabetes that affect the lower extremities are common, complex, and costly. Diabetic foot ulcer is the most frequently recognized complication. The U.S. prevalence of foot ulceration is around 13% in patients with diabetes, with a global average of 6.4%. The global annual incidence rate of foot ulceration is around 2% in diabetic patients, with annual incidence rate twice higher in the USA. It is estimated that about 25% of all diabetic patients have chronic wounds and are prone to develop a foot ulcer during their lifetime. Diabetic patients develop chronic ulcers of the lower legs due to inadequate blood flow and peripheral insensate neuropathy. Neuropathy is the critical risk factor for developing foot ulceration, and foot ulceration is the critical risk factor for foot infection and amputation. It is estimated that up to 50% of people with diabetes have neuropathy, up to 34% will develop a foot ulcer in their lifetime, and about 50% of those ulcers will become infected and 20% amputated. Of all amputations in diabetic patients, 85% are preceded by a foot ulceration which subsequently deteriorates to a severe gangrene or infection. Within three years, 55% of diabetic patients who have had a lower limb amputation will require a subsequent amputation. It has also been reported that 57% of diabetic patients may die within five years after amputation, and the risk for mortality of a diabetic patient with a foot ulcer is 2.5 times higher than that of a diabetic patient without a foot ulcer. Diabetic foot ulcers are a leading cause of hospitalization among diabetic patients, and result in significant reductions in quality of life. Of those who have a foot ulcer, 40% will experience another foot ulcer within a year, 60% within three years, and 65% within five years. As with cancer patients, those with foot ulcers aren’t healed, they are in remission. Thus, diabetic foot ulcers appear to cause considerable global disability burden.
According to the CDC’s (Centers for Disease Control) National Diabetes Statistics Report for 2020, about 34.2 million people, or 10.2% of the U.S. population, currently live with diabetes. By 2045, it is predicted that 50 million people in the USA will be diagnosed with diabetes. In 2019, about 1.4 million people experienced non-healing foot ulcers in USA. Individuals without diabetes and neuropathy feel the painful pressure point of an ulcer. However, a person with diabetic neuropathy will not feel the pain of an ulcer, and, just like someone might wear a hole in a shoe or a sock, these patients can literally wear a hole in their foot. In fact, when a foot ulcer is treated, it is often done without the use of anesthesia because a patient with a foot ulcer had lost the ability to sense pain in his feet. Therefore, when it comes to diabetes, what someone cannot feel can hurt him. Because of the silent nature of foot ulcers, they represent a big socio-economic problem that few people have heard of. People do not drop dead from a “foot attack” as they do from a heart attack, but they are dying from them all the same. Indeed, after an amputation, an individual may not get out of bed much in the following months, or even years, leading to overall health deterioration and, ultimately culminating in death from associated stroke or heart attack (Courtesy; David Armstrong).
The annual costs for treating complications of diabetic foot ulcers is higher than treating the five most common types of cancer. In the U.S., a total of $176 billion is spent annually on direct costs for diabetes care; as much as one third of this expenditure is foot ulcer-related. Yet too little is being done to solve the foot ulcer problem. Despite the devastating effect of foot ulcers and the massive costs they incur on the health care system, there is still no pharmaceutical product that accelerates a foot ulcer healing safely and cost-effectively. Diabetic foot ulcers have created an enormous economic and healthcare burden, which is worsening as the number of diabetic patients increases. In the USA, more than 100,000 non-traumatic lower limb amputations are done annually due to the presence of a foot ulcer, which account for 67% of all lower limb amputations. Assuming that the average cost of each amputation in the USA is around $60,000, the annual cost of all diabetes-related amputations is more than $6 billion. The cost of care for foot ulcers includes indirect costs to patients, their families, and society through lost income, disability, and decreased societal contributions. The combination of lost income and the cost of treating the 1.4 million U.S. citizens with a foot ulcer is exceeding $40 billion annually. Additionally, the psychosocial burden of a foot ulcer on a diabetic patient, his or her family, and society is intangible. The disability induced by a foot ulcer and the frequent hospitalizations to treat the ulcer can hamper a diabetic patient's ability to work, as well as cause poor quality of life because of dependency, social isolation, and depression.
Although the treatment methods and approaches and our understanding of the mechanisms of diabetic chronic wounds development and their management have improved, foot ulcers are still complicated chronic wounds problem which require lengthy therapy and treatment. The current management of a diabetic patient with a foot ulcer includes controlling blood glucose levels, and standard of care treatments that include cleansing, debridement, offloading, and infection control. Supplementary treatments to standard of care such as the application of bioengineered skin substitutes, use of negative pressure wound therapy, hyperbaric oxygen therapy, and ultrasound and extracorporeal shockwave therapy are expensive and do not always deliver the desired outcome. Strategies for foot ulcer care have evolved from passive dressings and skin grafts to biopharmaceutical approaches. Most innovation focuses on new materials and dressings which better clean and protect the wounded cutaneous tissues, or the development of products to stimulate wound healing using growth factors. Nonetheless, the efficacy of these innovations is limited because they target only one phase of the wound healing process. Additionally, excessive use of growth factor-containing products was found to increase the lifetime risk of patients developing cancer. For example, Regranex Gel (Becaplermin) is a topical platelet-derived growth factor formulation which was approved by the FDA in 1998 for treating neuropathic diabetic foot ulcer. Although it was efficacious, the FDA added a black box warning to its instructions for use and safety information in 2008, warning that repeated treatment with Regranex Gel is associated with an increased death rate from cancer. Since there is currently no safe and efficacious treatment for encouraging the healing of diabetic foot ulcers, more than 50% of all treated foot ulcers deteriorate and often lead to a digit or limb amputation to save the patient’s life. The insufficiency for a safe and cost-effective treatment which can hasten the healing of diabetic foot ulcers and reduce the related amputations rate and cost of treatments is an unmet medical need. Currently, there are no FDA-approved pharmaceuticals which promote the healing of a diabetic foot ulcer.