Intensive Glycemic Control For Diabetic Foot Ulcer Healing: A Multicenter Randomized Control Study (IN-GLOBE Study)

BURDEN OF DIABETIC FOOT According to International Diabetic Federation, there will be over 642 million people with diabetes in the world by 2040.Diabetic Foot Ulcer (DFU) is one of the most serious, most costly and at times life threatening complication of diabetes. The lifetime incidence of foot ulcer occurrence in diabetes is up to 25%. Both prevalence and incidence of DFU is higher in developing countries due to multitude of factors like poverty, poor sanitation & hygiene, barefoot walking, lack of education, poor healthcare access.

DFU related morbidity and hospitalization has shown a meteoric rise. One study showed that 20% of admissions in patients of diabetes were due to DFU. 56%of ulcers become infected and 1 in 5 of these will requiresome level of amputation.In addition, it has been projected that 15% of diabetic foot ulcers result in lowerextremity amputations and 85% of diabetic patientswho undergo lower extremity amputations had an ulcerprior to amputation.The 5-year relative mortality afterdiabetic foot ulcer is 48%, second only to lung cancer.

Multiple risk factors have been attributed to the development of DFU including male gender, duration of diabetes >10 years, older age, diminished vision, peripheral vascular disease, high BMI, sensory neuropathy, retinopathy, nephropathy, HbA1c, foot deformity, high plantar pressures, poor foot care habits, barefoot walking etc. From DCCT there exists robust evidence that strict glycemic control can decrease all diabetic related complications. There are other studies demonstrating improvements in neuropathy and peripheral vascular disease as a result of strict glycemic control. However, there is no specific evidence/intervention for DFU prevention.

IMPAIRED WOUND HEALING IN DIABETES Wound healing is impaired in diabetes at multiple stages. The defects are observed at both cellular and molecular levels. Extrinsic factors like mechanical stress, trauma and ischemia negatively influence the healing process. Hyperglycemia itself has been shown to have deleterious effect on wound healing through formation of advanced glycation end products (AGEs) & reactive oxygen species (ROS) which induce the production of inflammatory molecules (TNF-α, IL-1) and interfere with collagen synthesis. There is interference in collagen synthesis due to increased expression of matrix metalloproteinases.

CHALLENGES WITH RESEARCH IN THIS AREA With the clinical benchmarks set by major trials like UKPDS, it is often difficult for clinicians to ethically conduct any study investigating the effects of intensive versus conventional glycemic control. Even on demonstrating the clinical benefit involving intensive glycemic control, it is a difficult task to recruit as well as follow up subjects. Many diabetic patients are frail and have multiple co-morbidities that render them incapable of following such interventions. Intensive glycemic control makes these individuals prone to the detrimental effects of hypoglycemia. In a trial investigating the effect of hyperglycemia and intensive glycemic control on DFU healing, the authors faced many challenges in recruiting and allocating the patients. This trial was completed without any results.