Diabetic peripheral neuropathy in type 2 diabetes mellitus in Korea.

Diabetic peripheral neuropathy (DPN), a common and troublesome complication in patients with type 2 diabetes mellitus (T2DM), contributes to a higher risk of diabetic foot ulcer and lower limb amputation. These situations can negatively impact the quality of life of affected individuals. Despite its high prevalence and clinical importance, most diabetes mellitus patients not only do not recognize the presence of diabetic neuropathy, but also do not report their symptoms to physicians or other health care providers. Therefore, DPN is usually under diagnosed and undertreated. For early detection and appropriate intervention for DPN, a careful history, physical with neurologic examination, and prompt treatment are needed in T2DM patients.

INTRODUCTION

The prevalence of type 2 diabetes mellitus (T2DM) in Korea is estimated to be 7.3% (in those over 20 years of age), and it has increased about 5-fold over the past 30 years according to a report of the Korea National Health and Nutrition Examination Survey (KNHNES III, 2005) [1,2]. The number of patients with T2DM is expected to increase dramatically from about 3.2 million in 2011 (8.8% of the national population) to about 4.25 million (11.1%) by 2030 [3]. This enormous increase in the number of T2DM patients will inevitably be accompanied by chronic diabetic microvascular or macrovascular complications. Among the diabetic complications, diabetic peripheral neuropathy (DPN) is the most prevalent and troublesome complication in patients with diabetes mellitus (DM).

Diabetic neuropathy (DN), which may be focal or diffuse, is diagnosed when diabetic patients complain of symptoms and/or show signs of peripheral nerve dysfunction after the exclusion of other etiologies [4,5]. Chronic sensorimotor DPN is the most common form of DN [6,7]. Peripheral neuropathic pain in diabetic patients is defined as pain arising as a direct consequence of abnormalities in the peripheral somatosensory system in people with diabetes [8]. The symptoms can be present as severe numbness, paresthesia, or hyperesthesia, however, DPN may be asymptomatic in about 50% of patients [9]. As the DPN progresses, the painful symptoms usually disappear [10]. In addition, DPN is also associated with substantial morbidity, which includes not only a susceptibility to foot or ankle fractures and ischemic ulceration leading to lower-limb amputations, but also depression [11-13]. According to the Seattle Diabetic Foot Study, which included 749 diabetic patients, there were a number of findings that independently increase the risk for DM foot ulcer, including certain foot deformities, reduced foot arterial perfusion, and both sensory and autonomic neuropathy [14]. Diabetic patients with critical limb ischemia have high risks of lower limb amputation and death [15].

In addition to its influence on morbidity and mortality, painful symptoms in DPN have a significant detrimental impact on quality of life as the condition limits daily activities and interferes with sleep [16-18]. Considering the health-related economic viewpoint, diabetic foot disease significantly increases the health care costs in patients with DM. According to a retrospective study that analyzed insurance costs in the United States, the cost of care for patients with a foot ulcer is 5.4 times higher in the year after the first ulcer episode, but 2.8 times higher in the second year compared with that of diabetic patients without foot ulcers [19]. Therefore, early detection and prompt intervention for DPN must be performed for patients with T2DM.

PREVALENCE OF DPN IN KOREAN PATIENTS WITH T2DM

The prevalence of DPN is generally estimated to be 10% to 50% in patients with T2DM, and the incidence increases with age and duration of DM [17,18,20]. The reported prevalence of DN in Korea is variable, from 14.1% to 54.5% depending on the study population and the diagnostic method (Table 1) [21-24]. In the Diabcare-Asia 1998 study, which included 230 DM centers from 12 countries (n=24,317), the frequencies of retinopathy, microalbuminuria, and neuropathy were 21%, 39%, and 34%, respectively. The prevalence of those complications was significantly higher in those patients with higher hemoglobin A1c (HbA1c) levels [22]. A nationwide survey performed in 2006 by the Committee of the Korean Diabetes Association on the Epidemiology of Diabetes Mellitus (n=5,652) showed that the prevalence of DPN defined by neurologic symptoms or nerve conduction velocity abnormalities was 44.7%. This prevalence was higher than the prevalence of microalbuminuria or retinopathy [23]. In a prospective observational study among 508 Korean T2DM patients, diabetic foot disease occurred in 32 patients (6.3%), and the incidence of diabetic foot disease increased when peripheral neuropathy was present (odds ratio [OR], 2.949; 95% confidence interval [CI], 1.075 to 8.090) [24].

Table 1

Prevalence of diabetic neuropathy in patients with diabetes in Korea

From Won JC, Ko KS. Korean Clin Diabetes 2010;11:177-83, with permission [21].

NA, not available; NCV, nerve conduction velocity.

While chronic neuropathic pain is present in 13% to 26% of DM patients [25], it can be found not only in diabetic subjects, but also in impaired glucose tolerance (IGT) or impaired fasting glucose individuals [26]. According to a community-based cross-sectional study from the United Kingdom, chronic DPN is common and often severe but frequently unreported and therefore inadequately treated [18]. Interestingly, they showed that 12.5% of patients had never reported their symptoms to their doctors, and 39.3% never received treatment [18].

There are some studies about the relationships between DPN and other diabetic complications in Korean T2DM patients. Chung et al. [27] reported that the prevalence of cardiovascular disease (CVD) was higher in patients with DPN. In their multivariate analysis, DPN was independently associated with CVD (OR, 1.801; 95% CI, 1.009 to 3.214) in T2DM patients (n=1,041), with a 52.8% prevalence determined by neurophysiologically diagnosing peripheral polyneuropathy based on electroneuromyographic findings. A close relationship between peripheral sensory neuropathy and peripheral vascular disease was also reported independent of glucose level and other microvascular complications, in particular, retinopathy in T2DM [20,28]. Other studies showed a relationship between DPN and arterial stiffness or insulin resistance [29,30]. The association between cardiovascular risk factors and development of large-fiber nerve dysfunction, which was measured by vibration perception threshold, was reported in type 1 DM patients (n=1,407) in the EURODIAB Prospective Complication Study [31]. These findings suggest the importance of DPN as a cardiovascular risk factor.

PATHOGENESIS AND MECHANISM OF DPN

Hyperglycemia not only activates the sorbitol accumulation with a subsequent increase in cellular osmolarity, but it also shunts to the hexose pathway, producing oxidative stress and the formation of advanced glycation end products (Table 2) [11]. Damage to peripheral nerves results in hyperexcitability in the primary afferent nociceptors. This damage leads to hyperexcitability in central neurons and the generation of spontaneous impulses within the axons as well as the dorsal root ganglion of these peripheral nerves [32,33]. This mechanism is suggestive of an abnormality contributing to the pain in DPN.

Table 2

Pathogenesis of diabetic peripheral neuropathy

ROS, reactive oxidative stress; AGE, advanced glycation end product; FFA, free fatty acid; LDL, low density lipoprotein; ER stress, endoplasmic reticulum stress.

DIAGNOSIS OF DPN

The diagnosis of DPN usually depends on the subjective symptoms of neuropathy. Most of the clinical practice guidelines, including those from the Korean Diabetes Association, recommend that DPN screening should begin at the initial diagnosis of T2DM and should be performed at least annually thereafter [34-36]. The exclusion of non-diabetic causes of neuropathy, including alcoholism, vitamin B12 deficiency, endocrinopathies, vasculitides, heavy metal exposure, drug use, and malignancy, is important because these may account for 10% of the cases of neuropathy in people with DM [37].

Though the symptoms can exist without signs, the severity of painful symptoms can be reliably assessed by the visual analogue scale or the numerical rating scale (0, no pain; 10, worst possible pain). This latter assessment is most widely used in neuropathic pain assessment [5]. In addition, validated scales and questionnaires such as the Neuropathic Pain Symptoms Inventory, the Brief Pain Inventory, and the Neuropathic Pain Questionnaires are widely used (Table 3) [5]. However, the nerve conduction study remains the most reliable, accurate, and sensitive method to evaluate peripheral nerve function, and it has been adopted as the gold standard. This approach is not only time-consuming, expensive, and insensitive for the detection of small-fiber neuropathy, but also it is impractical to perform in an outpatient clinic setting. However, the Semmes-Weinstein monofilament (SWMF) test is simple to use as a screening tool to identify patients at risk for diabetic foot complication in the primary care setting [38,39]. The inability to sense the 10 g force pressure is considered as insensate and an independent predictor for higher risk of foot ulceration [40]. Lee et al. [38] considered the SWMF test as a useful screening tool for DPN. The nerve conduction study (NCS) was used as a gold standard to compare the sensitivity and the specificity of the SWMF test. The results were considered as abnormal if the patient could not perceive the 5.07/10 g SWMF at more than four of ten sites (37 T2DM outpatients). The sensitivity and the specificity at two sites (the third and fifth metatarsal head sites) were 93.1% and 100%, the same as at the ten sites. It is likely that the two-site SWMF test is a useful screening test for DPN as is the ten-site test. In a study of 126 diabetic patients, 41% complained of DPN symptoms, and SWMF and vibration perception were more impaired in patients with subjective sensory symptoms [39]. In 82 diabetic patients, the medial plantar sensory NCS provided a more sensitive diagnosis of DPN, even in patients with normal range measurements in the sural nerve [41]. The medial plantar sensory nerve action potential was abnormal in 46.7% of the symptomatic and 14.3% of the asymptomatic diabetic patients with normal routine NCS in this study [41]. The medial plantar sensory NCS may be helpful in the diagnosis of subclinical DPN in the asymptomatic diabetic patient. Compared to the single test, the combinations of tests have a greater than 87% sensitivity in detecting DPN [4].

Table 3

Diagnosis of diabetic peripheral neuropathy

SW monofilament, Semmes-Weinstein monofilament (SWMF); QOL, quality of life.

TREATMENT OF DPN

The aims of DPN treatment are to decrease the painful symptoms, to treat the specific pathogenic mechanism, and to prevent progression or subsequent complications. Treatment of the pain of DPN is mainly symptomatic management [42]. Most of all, strict diabetic control and correction of metabolic risk factors should be initiated. The lifestyle intervention that improves glycemic control and decreases blood pressure with lipid profiles improves both the painful neuropathic symptoms and the intra-epidermal nerve fiber density. These findings suggest that early diagnosis and prompt intervention may be of significant clinical benefit [32].

For pharmacological treatment, first line therapy consists of tricyclic antidepressants (TCA), duloxetine, pregabalin or oxycodone (Table 4) [36]. If the pain is not controlled with first-line therapy, second-line therapy or combination therapy can be used, for which the potential side effects and possible drug interactions must be considered. Topical treatment with a 5% lidocaine plaster or capsaicin is also considered.

Table 4

Pharmacologic treatment of diabetic peripheral neuropathy

NE, norepinephrine; BPH, benign prostatic hyperplasia.

aDuloxetine and pregabalin are only two Food and Drug Administration (FDA)-approved treatments of diabetic peripheral neuropathy.

Randomized controlled trials have been performed for the treatment of DPN in Korean patients with T2DM using alpha-lipoic acid, pregabalin, or tramadol/acetaminophen combination treatment. The neuropathic symptom score, assessed by the Total Symptom Score, was improved after intravenous alpha-lipoic acid treatment at a dose of 600 mg/day for 14 days in 19 T2DM patients compared to 13 control subjects (P<0.05) [43]. Open-label study with oral thioctic acid 600 mg once daily for 8 weeks (n=61) also improved DPN symptoms without serious adverse effects in Korean diabetic patients [44]. In an open, randomized, comparative study conducted in 163 T2DM subjects with DPN, tramadol/acetaminophen (Ultracet@) treatment (n=79) for 6 weeks was as effective as gabapentin (n=84) for the decrease of pain intensity, an increase in the quality of life, an increase in mood, and a decrease in sleep disturbance in the treatment of painful DN [45]. Ten weeks of pregabalin treatment for patients with neuropathic pain (DPN [type 1 or 2 diabetes, n=18], postherpetic neuralgia [n=146], or posttraumatic neuropathic pain [n=76]; n=162 pregabalin, n=78 placebo) showed a significant reduction in the Daily Pain Rating Scale score with improvement in anxiety and a decrease in sleep disturbance [46]. Despite the improvement in treatment modalities for chronic pain in recent years, patients with DPN still continue to be inadequately treated [47].

CONCLUSION

The dramatic increase in the prevalence of T2DM with its acute or chronic complications are a major health concern in Korea. Screening of high risk individuals, early detection, and proper management of DPN in patients with T2DM is urgently needed. Careful foot examination, active application of outpatient screening tools including the assessment of pedal pulses, and an organized diabetic foot-care program are needed.

Despite the improvement in treatment modalities for chronic pain in recent years, patients with DPN continue to be inadequately treated. Therefore, active pharmacologic treatment should be considered to relieve neuropathic pain and improve the quality of life in patients with T2DM.