**3.1 Treatments for diabetic peripheral neuropathy (DPN)**

Pharmacological treatment is used to control the painful sensation of DPN which manifested as numbness, burning, stabbing or excruciating or intractable pain. The U.S. Food and Drug Administration (FDA) has approved three drugs for the pain associated with DPN, namely, pregabalin, tapentadol and duloxetine. Besides that, analgesics such as tramadol, acetaminophen and opioids such as oxycodone also have been prescribed for pain associated with DPN. However, these drugs produced many sides effect such as constipation and nausea and had high tendency to be misused. Antidepressants such as amitriptyline, nortriptyline and venlafaxine have shown and efficacy in DPN management, but the doses in clinical trial are not reproducible in clinical practice [22].

Antioxidants such as Alpha-lipoic acid (ALA) have been shown to be a possible treatment agent for DPN by delaying or reversing nerve damage [23]. Treatments based on mesenchymal stem cell (MSC) generated from adipose tissue might potentially be regarded as possible DPN treatments. These medicines increase the production of pro-angiogenic, neuroprotective and anti-inflammatory substances, which improves the clinical presentation of the illness [24]. Biological treatment with lower doses of IL-6 also can help increase blood flow, reduce chronic inflammation, repair peripheral nerve fibre and restore DPN peripheral nerve function [25].

### **3.2 Treatments for peripheral vascular disease (PVD).**

In diabetic patients, a decrease in blood flow in both the microvascular (capillaries) and macrovascular (arteries and veins) systems, as well as a decrease in angiogenesis, raises the risk of ischemia. Tissue ischemia manifesting as dependent rubor with rest discomfort, ulceration or gangrene necessitates rapid examination for correctable artery occlusive disease in order to enhance perfusion and save limbs. In general, all patients with foot lesions and vascular testing revealing an ankle pressure of 100 mm Hg or toe pressure of 55 mm Hg should have arterial imaging investigations performed to identify occlusive lesions amenable to revascularisation such as open bypass or endovascular treatment [14]. In cases of common femoral artery occlusion, bypass is more successful and provides extended patency. Whereas, endovascular treatment similar to angioplasty in which a tiny balloon is inserted into a constricted portion of an artery and inflated to open the artery to enhance blood flow in the lower extremities [26]. Atherectomy is another method that uses a spinning cutting blade to remove atheroma. Diabetic patients must get multidisciplinary care, including medication for hypertension, hypercholesterolemia and bleeding, in order for these procedures to be effective [27].

#### **3.3 Relief of foot pressure**

The persistent and recurrent traumatism of the foot, as well as the use of inappropriate footwear, contributes to the development of a DFU. Both lower extremities should be inspected for skin trauma (redness, induration, oedema), ulceration, foot/ toe deformity and popliteal and ankle (posterior tibial, dorsalis pedis) pulses palpated. The education on precise foot care and suitable footwear must be stressed in the diabetic patient. Diabetic patients should be taught to self-examine their skin and feet on a regular basis, as well as be educated on skin care and footwear management [28].
