Treatment and Prevention of Diabetic Neuropathy

Diabetic peripheral neuropathy affects sensory, autonomic, and motor neurons of the peripheral nervous system in individuals with type 1 or type 2 diabetes.[1] Diabetic neuropathy is evident in about 60% of patients diagnosed with diabetes and is the most common and troublesome complication of the disease.[2,3] Diabetic neuropathy is the most common form of neuropathy in developed countries and is responsible for 50-70% of nontraumatic lower-limb amputations.[4] From 2000-2001, about 82,000 nontraumatic lower-limb amputations were performed each year among people with diabetes in the US.[5] Hyperglycemia is the primary risk factor for severity of diabetic neuropathy and possibly for the progression of neuropathy.[4,5] Treatment and prevention of neuropathy begins with achieving glycemic control. Once neuropathy is diagnosed, pharmacologic therapy can be initiated with the goals of both reducing symptoms and preventing the progression of neuropathy.[4] The intent of this article is to summarize available information concerning the treatment and prevention of diabetic peripheral neuropathy.

Treatment of diabetic neuropathy

The treatment of diabetic neuropathy may be viewed as having 3 components: primary prevention, symptom management, and disease modification.[1] The results from the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that intensive therapy can significantly reduce or delay the development of neuropathy and other complications in patients with type 1 and type 2 diabetes, respectively.[7],[8] Development of safe, effective disease-modifying agents targeting the underlying pathologies has been difficult (see Future Treatments, below), but remains a critical focus of secondary intervention and offers hope for future therapies.[1]

Sensorimotor Neuropathy

Small-fiber nerve dysfunction usually occurs early in the course of the disease and often is present without objective signs or evidence of nerve damage.[4,9] It is manifested by lower limb pain and hyperalgesia followed by the loss of thermal sensitivity and reduced pinprick sensation.[4,10] Spontaneous episodes of pain can be severe and debilitating. Several pharmacologic agents have been clinically evaluated to help reduce these painful sensations. Currently available treatment options are directed toward symptom relief and should be managed to achieve a balance between relief and treatment-limiting side effects.[11,12]Table 1. outlines the advantages and disadvantages of each treatment option.

Table 1. Advantages and disadvantages of symptomatic treatments for small-fiber neuropathy

NE = norepinephrine, 5-HT = serotonin, DA = dopamine, VAS = visual analog scale, $$ = high expense of drug therapy, § = not approved by the FDA as a treatment for symptoms of diabetic neuropathy.

Large-fiber neuropathies involve sensory or motor nerves or both and signs tend to predominate over symptoms.[4,21] Large fibers are myelinated, rapid–conducting fibers stretching the length of the body from the toes to the medulla oblongata. These fibers are generally affected first due to their length. They are readily represented in the electromyograph allowing for subclinical abnormalities in nerve function to be detected.[4] Often patients will complain of floors feeling “strange” while walking, or the inability to turn pages in a book.[4] If sensory nerves are affected, then pain management can also be achieved with the agents listed in Table 1. Patients with large-fiber neuropathy are often uncoordinated and ataxic; therapy should be designed to help achieve muscle strength and improved coordination and balance.[4] Table 2 illustrates several management options.

Table 2. Management of large-fiber neuropathies[4]

Autonomic neuropathy

Involvement of the autonomic nervous system can occur as early as the first year after diagnosis of diabetes, resulting in major manifestations of cardiovascular, gastrointestinal, and genitourinary system dysfunction.[22]

Cardiovascular autonomic neuropathy

Cardiovascular autonomic neuropathy (CAN) is a common form of autonomic neuropathy, causing abnormalities in heart rate control and central and peripheral vascular dynamics. CAN occurs in approximately 17% of patients with type 1 diabetes and 22% of patients with type 2 diabetes.[22] Common clinical signs of CAN include resting tachycardia, exercise intolerance, and orthostatic hypotension. Early identification of CAN is essential to permit timely initiation of therapy to decrease the risk of further complications, including myocardial infarction. In a review of several epidemiological studies among individuals diagnosed with diabetes, it was shown that the 5-year mortality rate was 5 times higher in patients experiencing symptoms of CAN compared to individuals without CAN.[22] Results from the DCCT show that intensive glycemic treatment can prevent the development of abnormal heart rate variability and slow the deterioration of autonomic dysfunction over time in individuals with type 1 diabetes.[23] Treatment of CAN should commence with intensive glycemic therapy to achieve near-normal glucose levels. Current accepted treatment options for symptomatic relief of CAN are illustrated in Table 3.

Table 3. Treatment options for symptomatic relief of CAN[4,22,24]

§ = not approved by the FDA as a treatment of diabetic autonomic neuropathy

Gastrointestinal autonomic neuropathy

Diabetic autonomic neuropathy can impair both gastric acid secretion and gastrointestinal motility, causing gastroparesis, and is detectable in 50% of patients with long-standing diabetes.[22] Several common manifestations of GI autonomic neuropathy include: gastroesophageal reflux disease (GERD), diarrhea, constipation, nausea and vomiting, early satiety, cramping, bloating, and epigastric pain. Achieving glycemic control is the primary treatment for diabetic GI autonomic neuropathy.[22] Hyperglycemia has been shown to negatively affect gastric contractions and GI emptying; controlling blood sugar improves gastric motor dysfunction.[1] Nonpharmacologic treatments should be directed at dietary changes emphasizing the consumption of multiple, small meals and decreasing fat content. Fiber intake should also be increased in patients not at risk for developing bezoars from gastroparesis. Pharmacologic therapy consists of prokinetic agents, antidiarrheals, and antibiotics. These agents are listed in Table 4.

Table 4. Pharmacologic treatments options for GI autonomic neuropathy[1,24]

§ = not approved by the FDA as a treatment of diabetic autonomic neuropathy

Genitourinary autonomic neuropathy

Erectile dysfunction (ED) occurs in 35-75% of men with diabetes and tends to occur at an earlier age than it does in the general population.[22]The initiation of penile erection is directed by the autonomic nervous system.[1] Women with diabetes may experience decreased libido as a result of vaginal dryness and pain during intercourse. Female diabetic sexual dysfunction has not been adequately studied and treatment focuses on relieving painful symptoms associated with vaginal dryness with the use of water-based lubricants. Neurogenic bladder (cystopathy) may also be caused by autonomic neuropathy, resulting in the inability to sense bladder fullness or initiate micturition, resulting in urinary retention, bladder enlargement, and incontinence. Neurogenic bladder generally does not respond well to pharmacologic treatments. Bethanechol (10-30 mg 3 times daily) and doxazosin may reduce urinary retention, but may not induce complete bladder voiding, which increases the risk of urinary tract infections.[1] Abdominal massage techniques such as Crede’s method can be used to initiate micturition to start the flow of urine; however, catheterization may eventually be necessary.[1],[24] Table 5 summarizes the available pharmacologic treatment options used to treat erectile dysfunction in men. All 3 phosphosdiesterase-5 inhibitors appear to be equivalent in efficacy for the treatment of diabetes-related sexual dysfunction.[27] Note that several medications commonly prescribed for patients with diabetes may cause erectile dysfunction.[24]

Table 5.Pharmacologic treatment options for erectile dysfunction[1]

Future treatments

Aldose reductase inhibitors have been investigated as potential pathogenetic therapies for diabetic neuropathy for many years. Aldose reductase, the first enzyme of the polyol pathway, is thought to play a role in initiating the metabolic damage to peripheral nerves during hyperglycemia. Only 1 agent in this drug class, epalrestat,[32] is currently marketed. This drug is available in Japan, but not in the US or Europe. Other aldose reductase inhibitors currently in clinical trials include fidarestat, AS-3201, and ranirestat.[12,33,34]

Ruboxistaurin mesylate (LY333531) is a selective protein kinase C β (PKC β) inhibitor currently in phase 3 clinical trials for the treatment of diabetic neuropathy. PKC β is thought to mediate several enzymatic signaling systems associated with diabetic neuropathic dysfunction; therefore, inhibition might result in decreased progression of diabetic neuropathy.[35] Improvements in symptoms for treated patients were observed in a 1-year trial.[36] Improvements in vibratory detection threshold (a measure of large-fiber function) were observed in a subset of patients with early diabetic peripheral neuropathy.[38]

Accumulating evidence supports the use of antioxidants in the pathogenetic and symptomatic treatment of diabetic neuropathy.[21] A meta-analysis of 4 trials (ALADIN I, ALADIN III, SYDNEY, NATHAN II) including 1,258 patients receiving alpha-lipoic acid or placebo reported a significant improvement in positive sensory symptoms of polyneuropathy with alpha-lipoic acid.[37]

Prevention

First and foremost, prevention of diabetic neuropathy begins with glycemic control. In each of the various forms of neuropathy, severity directly correlates to blood glucose levels in type 1 and type 2 diabetes.[21] The DCCT showed that intensive treatment of hyperglycemia (achieving A1C levels <7%) can reduce the prevalence of diabetic neuropathy by 50%.[38] Clinical studies have determined that a stepwise progressive management program controlling hyperglycemia, blood pressure, and lipids can reduce the likelihood of developing autonomic neuropathy.[4]

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