Statins may be useful in diabetic foot ulceration treatment and prevention

Diabetic foot ulcers (DFUs) consist of an interaction of neuropathy, ischemia and infection. Neuropathy affects sensory, motor and autonomic pathways. Pathogenic factors for neuropathy include hyperglycemia, nonenzymatic glycosylation, oxidative stress, ischemic and hypoxic factors, nerve growth factor anomalies, activation of polyol pathway and immunologic abnormalities. All these factors are stated to contribute to microvascular disease and neural dysfunction. Peripheral neuropathy and ischemia combined with repetitive traumas can lead to diabetic foot ulceration. Fifteen percent of diabetic patients develop foot ulcers during their lifetime and nonhealing ulcers are responsible for 85% of nontraumatic lower extremity amputation. On the other hand, the treatment cost of foot disease in diabetic patients is estimated at $1 billion annually. When these conditions are considered, it is very important to design improved and novel strategies for treatment and prevention of diabetic foot disease. Lipid-lowering agents, such as statins, have been shown to prevent cardiovascular events in patients with diabetes. However, in addition, to preventing macrovascular diseases, statins may also be able to retard the progression of microvascular complications of diabetes. Statins alter the balance between vasodilatation and vasoconstriction in favor of vasodilatation by increasing nitric oxide (NO) synthesis, by downregulating endothelin 1 (ET-1) synthesis and reducing vascular response to angiotensin-2 (AT-2). These agents have been shown to augment cerebral blood flow by upregulating endothelial nitric oxide synthase (eNOs) and to reduce cerebral infarct size in a murine model of cerebral ischemia. In addition, recent in vivo and in vitro investigations have evidenced that statins have a favorable effect on diabetic peripheral neuropathy independent of its lipid-lowering effect by demonstrating restoration or preservation of microcirculation of the sciatic nerve. We hypothesized that statins can be useful for the prevention and treatment of diabetic foot. Possible mechanisms include the reduction of neuropathy and ischemia or through growth factors, the effectiveness of which has been shown for fracture healing in animal models.