Diabetic peripheral neuropathy (DPN) is one of the major complications of diabetes mellitus, of which distal symmetric polyneuropathy (DSPN) is the most typical and major one, with a prevalence of about 30% in the diabetic population.1 DPN involves sensory and motor nerves and has a variety of manifestations. The importance of DPN is undeniable, but its prevention and treatment has always been a clinical challenge. In this article, we will review the current treatment of DPN from the perspective of evidence-based medicine, especially the current status of treatment for the pathological process of DPN. I. Pathophysiology of DPN The pathophysiology of DPN is complex, and it is generally believed that its development may be the result of a combination of metabolic disorders and circulatory disorders. On the one hand, hyperglycemia and dyslipidemia cause abnormal activation of intracellular polyols, hexosamine, glycosylation end products (AGEs) and protein kinase C (PKC) pathways, resulting in intracellular oxidative stress and inflammatory responses, which interact with each other and lead to impaired cellular function and eventually induce apoptosis; on the other hand, similar pathological damage to endothelial cells and circulatory disorders resulting in ischemia and hypoxia also aggravate the above reactions and directly affect the development of DPN. On the other hand, similar pathological damage to endothelial cells and ischemia and hypoxia caused by circulatory disorders can aggravate these reactions and directly affect the function and structure of nerve cells. In addition, the presence of insulin/C-peptide deficiency, low levels of related growth factors and disorders of n-6 essential fatty acid metabolism in diabetic patients also have an impact on the development of neuropathy. activation and other pathological processes are gradually recognized to also play an important role in diabetic neuropathy. Therefore, in DPN, controlling one factor alone is not sufficient to stop or reverse the development of DPN. The question currently faced is which of the many factors is the major one and at what point how to intervene to actually prevent or reverse the progression of DPN. Based on the increasing understanding of the pathophysiology of DPN, potential drugs have been developed with the aim of directly targeting the pathological changes in DPN. Strategies for the treatment of DPN The current treatment strategies for DPN include: (1) control of hyperglycemia and other controllable neuropathic risk factors, including hypertension, dyslipidemia and other cardiovascular risk factors; (2) symptomatic treatment; (3) etiological treatment; (4) treatment of diabetic foot and other related complications (3) glycemic control and risk factor control At present, the development of DPN is still irreversible, therefore The best strategy is to prevent its occurrence. The available evidence-based medical evidence suggests that strict glycemic control in early diabetic patients is an effective preventive measure.Callaghan et al,1 reviewed 17 randomized controlled clinical trials (RCTs) that looked at the effect of intensive glycemic control for at least 1 year on diabetic neuropathy over the last 20 years. Nine of the studies were for type 1 diabetes, and all but one showed that tighter glycemic control reduced the incidence of DPN. The largest of these, the American Diabetes Control and Complications Study (DCCT), showed, 3, that intensive insulin treatment for 5 years reduced the incidence of type 1 diabetic neuropathy by 60%. The other eight studies of intensive glycemic control in type 2 diabetes showed inconclusive results compared to type 1 diabetes. The UK Prospective Diabetes Study (UKPDS) showed4 that the incidence of impaired vibratory sensory thresholds was reduced in the intensive glycemic control group only at the 15-year follow-up, and did not differ from the control group at the previous 3, 6, and 12-year follow-ups. There was no significant reduction in the prevalence of DPN at the end of the trial in the 3 and 7-year Action Control Cardiovascular Risk Factors in Diabetes (ACCORD) studies,5 and the 5 and 6-year Veterans Affairs Diabetes Events Study (VADT),6 but there was no significant reduction in the prevalence of DPN at the end of the trial in the 4 studies that looked at the prevalence of impaired nerve conduction. However, of the 4 RCTs in which the observation of nerve conduction velocity or quantitative sensory testing was the observation, 3 eventually showed that tight glycemic control did significantly improve these objective indicators. Overall, the data from the current RCT support that intensive glycemic control improves type 2 diabetic neuropathy but has a relatively small effect on reducing its prevalence. This discrepancy between type 1 and type 2 diabetes may be due to differences in the studies themselves, as different studies used different evaluation criteria and treatment protocols, and different prevalence of DPN at baseline; on the other hand, it also suggests that the pathogenesis of type 2 diabetic neuropathy is more complex than that of type 1 diabetes, and therefore more difficult to treat and evaluate. The same study also tells us that there are still patients with DPN after strict glycemic control in both type 1 and type 2 diabetes, so in addition to controlling hyperglycemia, we should continue to look for other controllable risk factors to improve the prevention and treatment effect. Recent studies suggest us that in addition to age, disease duration and poor glycemic control, some traditional cardiovascular risk factors, such as hypertension, dyslipidemia, obesity and smoking, are closely related to the development of diabetic neuropathy.7-8 For example, Wiggin et al,9 found that hypertriglyceridemia is an independent risk factor for myelinated nerve fiber loss. These study data support us to consider some new prevention and control concepts, such as dyslipidemia, especially triglyceride abnormalities, may play an important role in the progression of DPN, suggesting that controlling triglycerides, etc. can help prevent the development of DPN, but the effect is to be verified in clinical trials. IV. Allopathic treatment of DPN The progress of allopathic treatment of DPN is mainly in the management of painful neuropathy, and its treatment is aimed at reducing pain and improving quality of life, which cannot really change the progression of neuropathy. Only allopathic treatment may control the development of neuropathy or even reverse its development. Especially in view of the current status of glycemic control in the diabetic population, i.e., most diabetic patients fail to achieve the glycemic target, it is particularly important to intervene in the pathophysiology of diabetic neuropathy itself and improve DPN in the high glucose state.10 There are few clinically available drugs that directly target the etiology of diabetic neuropathy, and most of them are still in animal testing or clinical trial stage. (i) Targeting intracellular metabolic abnormalities 1. Anti-oxidative stress: α-lipoic acid is a powerful antioxidant factor that can directly scavenge reactive oxygen species and free radicals. It has been used in the treatment of symptomatic neuropathy for more than 50 years. With the deeper understanding of the pathological changes of DPN, especially the establishment of the doctrine of oxidative stress, its therapeutic effect on DPN has received attention. The results of three recent meta-analyses have shown that intravenous application of α-lipoic acid at 600 mg per day for 3 weeks significantly improved DPN symptoms and nerve conduction velocity.11-13 Given its good safety profile, it is now one of the few therapeutic agents targeting the etiology of DPN. However, intravenous application is clearly not convenient for a chronic disease such as diabetes, and there are also questions about the interval between repeated applications and the safety of long-term application. Oral lipoic acid would be more convenient, and most recent clinical studies suggest some efficacy, but its clinical effects are less certain than those of intravenous medication. A recent 4-year clinical study, the NATHAN1 trial, showed that oral application of lipoic acid, 600 mg daily, did reduce and delay the development of nerve damage, although nerve conduction velocity was not improved.14 Therefore, whether intravenous or oral, more evidence-based medical evidence is needed for the treatment of DPN with alpha-lipoic acid. 2. aldose reductase inhibitors (ARIs): In response to the theory of abnormal polyol pathway in diabetic neuropathy, ARIs can theoretically inhibit the metabolism of glucose through polyol pathway in high glucose state and reduce the accumulation of intracellular sorbitol and fructose, thus improving neuropathy. To date, nine ARIs have been developed, some of which have been abandoned due to serious adverse effects or limited efficacy, some are still in clinical trials, and only epalrestat is currently being used in the clinic. Epalrestat was marketed in Japan in 1992, and clinical trials have been conducted mainly in Japan, including two RCTs (3 months and 3 years of treatment, respectively),15-16 and a large uncontrolled study.17 From the trial results, epalrestat has been shown to be effective in improving DPN symptoms and delaying the progression of DPN, and patients can tolerate long-term treatment. However, the current study data do not show that epalrestat can completely stop the progression of DPN. Also, epalrestat has only been used locally, mainly in Asia, and its widespread use in the population has not been recognized. New ARIs, including ranibistat and fidarestat, are currently in clinical trials. Fidarestat reduces sorbitol concentrations in diabetic patients, and preliminary RCT studies have shown that fidarestat improves neuropathy symptoms and severity scores, as well as electrophysiological parameters of the median and tibial nerves (e.g., F-wave latency, motor nerve conduction velocity). Clinical studies related to ranirestat have shown that it can improve motor nerve function in mild to moderate DPN. PKC inhibitors: Hyperglycemia causes increased production of intracellular triglycerides and activates PKC, which initiates a series of pathological changes. abnormal changes in PKC pathway mainly affect vascular endothelial cells, which increase vasoconstriction and capillary permeability, causing vascular endothelial cell proliferation and basement membrane thickening, resulting in neural ischemia and hypoxia. Therefore, PKC inhibitors are thought to correct the activation of PKC and improve neurovascular blood supply for therapeutic purposes. The main drug currently available is the oral PKC-β inhibitor ruboxistaurin, but RCT studies to date have yielded mixed results. A recent meta-analysis pooled 6 relevant RCTs, suggesting that it was effective in only some studies,18 so the therapeutic effect of ruboxistaurin on DPN is inconclusive. 4, aminohexose pathway inhibitor: Hyperglycemia causes activation of the aminohexose pathway, which leads to increased expression of fibrinogen activator inhibitor-1 (PAI-1) and transforming growth factor β1 (TGF-β1) and intracellular ROS activation by affecting transcription factor Sp1. Benfotiamine is a fat-soluble vitamin B1 derivative that has an inhibitory effect on the aminohexose pathway. Benfotiamine has been used clinically in the treatment of vitamin B1 deficiency and also in the treatment of neuritis. For the therapeutic effects of DPN, the 2007 BENDIP,19 along with the 2005 BEDIP study,20 showed that it improved DPN symptoms. However, the number of people in these trials was small and the efficacy was mainly evaluated by symptom scores. 5, AGE inhibitors (AGEIs): AGE and its receptor system (AGE-RAGE) can enhance oxidative stress, activate the nuclear factor (NF)-κB signaling pathway, stimulate the production of transforming growth factors, etc. In addition, the process of molecular rearrangement during AGE formation and AGE-RAGE interactions can also play an important role in DPN pathogenesis by increasing the production of reactive oxygen groups that are involved in oxidative stress injury through various mechanisms. Currently two AGEIs, aminoguanidine and N-benzoylmethylthiazole bromide, are only used in animal experiments and no clinical application data are available. The therapeutic effect of benfotiamine on DPN is thought to be achieved in part through inhibition of the AGE pathway. (ii) Targeting circulatory disorders Drugs to improve microcirculation: As a vascular complication of diabetes mellitus, ischemia and hypoxia caused by vascular endothelial damage and circulatory disorders are an important part of its pathophysiology, so it is reasonable to treat DPN by improving microcirculation. Currently available clinical drugs include prostaglandin E1 and angiotensin converting enzyme inhibitors (ACEI). Prostaglandin E1 is mainly used in vascular diseases, and its therapeutic effect on DPN has been shown to be effective in phase II clinical trials. In a small RCT study,21 patients were given 10 mg of prostaglandin E1 intravenously daily and showed significant improvement in symptoms and sensory thresholds after 4 weeks, but no change in nerve conduction velocity. ACEI was also shown to be effective only in phase II clinical trials. c-peptide increased endothelial nitric oxide synthase and Na+-K+ ATPase activity and improved blood flow to the neural circulation. In a preclinical RCT, C-peptide subcutaneous injection for 6 months improved sensory nerve function, 22 in early type 1 diabetic patients. Overall, this class of drugs may be effective in treating DPN, and there is a lack of sufficient evidence-based medical evidence. (iii) For nerve damage itself 1. Vitamin B12 and methylcobalamin: Vitamin B12 deficiency causes central and peripheral nerve dysfunction, and methylcobalamin is a vitamin B12 derivative. In vitro studies have shown that methylcobalamin can promote the synthesis of lecithin and myelin formation of neurons in cultured rat tissues, and is believed to promote the repair and regeneration of damaged peripheral nerves. Methylcobalamin is widely used in the treatment of DPN in China. However, it should be noted that from the perspective of evidence-based medicine, there are not many international RCTs applying methylcobalamin for DPN treatment, and high-quality large-scale RCTs are even rarer. A systematic review included seven RCTs of vitamin B12 for the treatment of diabetic neuropathy,23 of which three RCTs used vitamin B complexes and four used methylcobalamin. It found that either vitamin B complex or vitamin B12 alone relieved symptoms of diabetic neuropathy but provided relatively inferior improvement in electrophysiological examinations. Because of the poor quality of the seven RCTs, current evidence-based medical data are insufficient to confirm the therapeutic effects of vitamin B12 or methylcobalamin on DPN. 2. Growth factors: Reversing neuropathy by promoting nerve regeneration and repair has been the ultimate goal of DPN treatment. Growth factors, especially nerve growth factor, have been highly anticipated, but the results of clinical trials have been unsatisfactory. Recombinant human nerve growth factor, although shown to be effective in preliminary clinical trials, was not found to differ from controls in further multicenter, large-sample, prolonged RCT studies,24 while recombinant human brain-derived growth factor did not differ from controls in a small-sample RCT study,25 either. There are many other drugs developed for the pathophysiology of DPN, but they are not discussed in this article because they have not been used in the clinic or have just started clinical studies. V. Considerations on the current state of DPN etiology and future prospects Among the drugs currently available for the etiology of diabetic neuropathy, only lipoic acid has more evidence-based medical evidence to prove its effectiveness. Many other drugs, which have been shown to be effective in animal studies, have either been shown to be ineffective in clinical trials or have insufficient clinical evidence-based evidence. The reasons for this include: (1) The pathological mechanism of diabetic neuropathy is complex, with various factors acting at different levels and in different processes, and drug development often targets only one of these aspects, so its effect is often masked by other pathological processes and does not play a significant role. (2) Clinically, the improvement of diabetic neuropathy is extremely slow, with most type 1 diabetes requiring more than 1 year and most type 2 diabetes requiring more than 4 years to see results. And most of the current clinical trials are below 1 year, so negative results may occur. (3) There are no drugs or methods that can reverse the development of neuropathy, which is related to the difficult nature of regeneration after nerve damage. Once DPN occurs, it is difficult to reverse it, so early prevention is important, and should be started even in the early or prediabetic stage. This requires the detection and control of other risk factors, such as dyslipidemia, in addition to glycemic control, in order to improve the efficiency of prevention and treatment. However, it is not clear whether controlling other risk factors can really benefit as much as controlling blood glucose. Therefore, from the perspective of evidence-based medicine, it is necessary to design and conduct an RCT to control other risk factors to observe their effects on DPN. At the same time, there are few pharmacological tools available for the causative treatment of DPN, and their efficacy is poor, far from reversing the disease. In continuing to explore possible drugs and methods of allopathic treatment, firstly, it is recommended to adopt a combination of drugs targeting different mechanisms; secondly, clinical trials should be appropriately extended for a minimum of 1 year of observation. Because there are not many real high-quality RCTs that can guide the clinical practice well, the domestic treatment of DPN is heavily dependent on empirical treatment. There is an urgent need to carry out more high-quality RCTs, and in addition to the development of new drugs, it is necessary to explore combination therapy to screen out truly effective therapeutic drugs and methods.