Polyneuropathy in the diabetic patientupdate on pathogenesis and management
Dan Ziegler
German Diabetes Research Institute, Leibniz Institute at the Heinrich Heine University, Düsseldorf, Germany
Correspondence and offprint requests to: Professor Dan Ziegler, FRCP (Edin), Deutsches Diabetes-Forschungsinstitut an der Heinrich-Heine-Universität, Aufm Hennekamp 65, D-0225 Düsseldorf, Germany. Email: dan.ziegler{at}ddfi.uni-duesseldorf.de
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Clinical impact of diabetic polyneuropathy
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Distal symmetrical sensory or sensorimotor polyneuropathy (DSP) affects
30% of the hospital-based population and 20% of community-based samples of diabetic patients. The incidence of DSP is
2% per year. The most important aetiological factors that have been associated with DSP are poor glycaemic control, diabetes duration and height, with possible roles for hypertension, age, smoking, hypoinsulinaemia and dyslipidaemia [1]. Moreover, DSP is related to both lower extremity impairments such as diminished position sense and functional limitations such as walking ability. There is accumulating evidence suggesting that not only surrogate markers of microangiopathy such as albuminuria, but also those indicating the presence of polyneuropathy such as impaired nerve conduction velocity (NCV) and vibration perception threshold (VPT) predict mortality in diabetic patients [2,3]. Elevated VPT also predicts the development of neuropathic foot ulceration, one of the most common causes for hospital admission and lower limb amputations among diabetic patients [4]. Pain associated with diabetic neuropathy has a substantial impact on the quality of life, particularly interfering with sleep and enjoyment of life [5]. Chronic painful diabetic neuropathy is a long-term complication of diabetes and, hence, not infrequent in the diabetic patient with renal complications. An update on the current state of the art in this field is therefore of interest to the nephrologist.
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Pathogenetic mechanisms
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Recently performed experimental studies suggest a multifactorial pathogenesis of diabetic neuropathy. Most data have been generated in the diabetic rat model. Two approaches have contributed to elucidate the pathogenesis of diabetic neuropathy. The first is a better characterization of the pathophysiological, pathobiochemical and structural abnormalities that result in experimental diabetic neuropathy. The second approach is the performance of specific therapeutic interventions aimed to prevent the development of these alterations, to halt their progression or to induce their regression despite concomitant hyperglycaemia. At present, seven mechanisms are thought to contribute to the pathogenesis. In contrast to previous years, however, they are no longer regarded as being separate, but as resulting in a complex interplay giving rise to multiple interactions, e.g. between metabolic and vascular factors [6]: (i) increased flux through the polyol pathway that leads to accumulation of sorbitol and fructose, myo-inositol depletion and reduction in Na+-K+-ATPase activity; (ii) disturbances in n-6 essential fatty acid and prostaglandin metabolism which result in alterations of nerve membrane structure and microvascular and haemorrheological abnormalities; (iii) endoneurial microvascular deficits with subsequent ischaemia and hypoxia as well as generation of reactive oxygen species (oxidative stress) and the so-called hyperglycaemic pseudohypoxia; (iv) increased activity of protein kinase C ß (PKC ß); (v) deficits in neurotrophism leading to reduced expression and depletion of neurotrophic factors such as nerve growth factor (NGF), neurotrophin-3 and insulin-like growth factor, as well as alterations in axonal transport; (vi) accumulation of non-enzymatic advanced glycation end-products (AGEs) on nerve and/or vessel proteins, and (vii) immunological processes with autoantibodies to vagal nerve, sympathetic ganglia and adrenal medulla as well as inflammatory changes.
From the clinical point of view, it is important to note that, based on these pathogenetic mechanisms, therapeutic approaches could be derived, some of which have been evaluated in randomized clinical trials. These treatments include the inhibition of the increased flux through the polyol pathway by aldose reductase inhibitors (ARIs), correction of the deficits in essential fatty acids and disturbances of prostanoid metabolism by substitution of
-linolenic acid contained in evening primrose oil, administration of antioxidants (
-lipoic acid) to reduce the enhanced formation of reactive oxygen species that induce increased oxidative stress, improvement of reduced endoneurial blood flow and resulting hypoxia by vasodilating agents such as angiotensin-converting enzyme inhibitors, prostaglandin analogues, a PKC ß inhibitor, C-peptide, neurotrophic support by administration of recombinant human NGF, inhibition of non-enzymatic glycation and formation of AGEs by aminoguanidine, and immunosuppressive treatment.
Since in the foreseeable future normoglycaemia will not be achievable in the majority of diabetic patients, the advantage of the aforementioned treatment approaches is that they may exert their effects despite prevailing hyperglycaemia. Experimental studies of low-dose combined drug treatment suggest enhanced drug efficacy mediated by facilitatory interactions between drugs. In the future, combinations of drugs that produce synergistic effects could be a therapeutic option.
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Treatment based on pathogenetic concepts
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Aldose reductase inhibitors (ARIs)
An increased flux through the polyol pathway resulting in multiple biochemical abnormalities in the diabetic nerve is thought to play a major role in the pathogenesis of diabetic neuropathy. ARIs block the increased activity of aldose reductase, the rate-limiting enzyme that converts glucose to sorbitol. The first trials of ARIs in diabetic neuropathy were published 20 years ago. The various compounds that have been evaluated are alrestatin, sorbinil, ponalrestat, tolrestat, fidou restat, epalrestat, zopolrestat and zenarestat. Except for epalrestat which is marketed in Japan, none of these agents was licensed because of serious adverse events (sorbinil, tolrestat and zenarestat) or lack of efficacy (ponalrestat and zopolrestat). A meta-analysis of 13 clinical trials with ARIs revealed a marginal effect on peroneal motor NCV of 1.24 m/s and an even weaker effect on median motor NCV of 0.69 m/s after 1 year [7]. Data of 738 subjects from three trials with tolrestat showed a benefit equal to 1 m/s in a pooled analysis of NCV in all the nerves studied [8]. The following degrees of changes in motor and sensory NCV that are associated with a change in the neuropathy impairment score (NIS) of two points have been considered to be clinically meaningful in controlled clinical trials: median motor NCV, 2.5 m/s; ulnar motor NCV, 4.6 m/s; peroneal motor NCV, 2.2 m/s; median sensory NCV, 1.9 m/s; and sural sensory NCV, 5.6 m/s [9]. According to this suggestion, the changes in NCV obtained from the ARI trials cannot be considered so far to have achieved a meaningful treatment effect. In a 1 year phase II trial of zenarestat including 208 patients with diabetic polyneuropathy, a dose-dependent improvement in small myelinated fibre loss and peroneal NCV was observed [10], but subsequent large phase III trials of zenarestat had to be terminated prematurely due to a significant deterioration in renal function in some patients. Fidarestat (1 mg per day) has been shown to improve median nerve FCV and minimal latency as well as neuropathic symptoms after 1 year [11]. A recent 12 week study using doses up to 15 mg per day demonstrated improvement in six electrophysiological measures and vibration threshold in the big toe, measured using a calibrated C64 tuning fork [12]. Further trials of this compound currently are underway. Whether ARI treatment is associated with pain relief has not been well documented. In a 12 week controlled study including 196 patients, complete pain relief was noted in 48.6% of the patients receiving epalrestat compared with 22.6% of those on placebo [13].
Antioxidants (
-lipoic acid) and PARP inhibitors
There is accumulating evidence suggesting that free radical-mediated oxidative stress is implicated in the pathogenesis of diabetic neuropathy by inducing neurovascular defects that result in endoneurial hypoxia and subsequent nerve dysfunction [6]. In fact, one hypothesis suggests that hyperglycaemia-induced overproduction of superoxide by the mitochondrial electron transport chain is responsible for the increased polyol and hexosamine pathway flux, AGE formation, PKC activation and activation of the redox-sensitive proinflammatory transcription factor NF-
B [14]. The molecular mechanism for the overproduction of superoxide that activates these pathways is hyperglycaemia-induced inhibition of GAPDH. GAPDH is a multifunctional protein with diverse cytoplasmic, membrane and nuclear activities. Poly(ADP-ribosyl)ation of GAPDH is induced by poly(ADP-ribose) polymerase (PARP) which is activated by DNA strand breaks produced by mitochondrial superoxide overproduction [15]. Competitive PARP inhibitors have been shown recently to abolish the activation of PKC isoforms and NF-
B (PKC-dependent), hexosamine pathway flux, and AGE formation in endothelial cells [15]. PARP inhibitors also reversed experimental diabetic neuropathy [16], suggesting a future therapeutic potential in diabetic microvascular complications including neuropathy.
Antioxidant treatment with
-lipoic acid has been shown to prevent or ameliorate experimental diabetic neuropathy [17], thus providing a rationale for its potential use in diabetic patients. In Germany,
-lipoic acid has been licensed and used for treatment of symptomatic diabetic neuropathy for >20 years. Several randomized, placebo-controlled clinical trials have been published, suggesting the following. (i) According to a recent meta-analysis including 1258 patients, short-term treatment for 3 weeks using 600 mg of thioctic acid intravenously per day appears to reduce the main neuropathic symptoms including pain, paresthesias and numbness [18]. A 3-week pilot study of 1800 mg per day indicates that the therapeutic effect may be independent of the route of administration, but this needs to be confirmed in a larger sample size. (ii) A 3 week treatment also improves neuropathic deficits, and a subsequent oral treatment for 47 months tends to reduce neuropathic deficits and improves cardiac autonomic neuropathy. (iii) Preliminary data over 2 years indicate a possible long-term improvement in motor and sensory NCV in the lower limbs. (iv) Clinical and post-marketing surveillance studies have revealed a highly favourable safety profile of the drug [17]. A large multicentre trial is being conducted in North America and Europe to evaluate the effects of long-term treatment with
-lipoic acid over 4 years on the progression of diabetic polyneuropathy (NATHAN 1 study).
Vasodilators
Microvascular changes of the vasa nervorum and reduced endoneurial blood flow resulting in hypoxia are thought to be important factors in the pathogenesis of diabetic neuropathy [6]. Thus, there is a solid theoretical background to support treatment with vasodilating drugs. In a 1 year trial including 41 normotensive patients with mild neuropathy, several indices of NCV, but not neuropathic symptoms and deficits, were improved after 1 year of treatment with the ACE inhibitor trandolapril [19]. Further studies are clearly needed to define the therapeutic role of ACE inhibitors in diabetic neuropathy.
Nerve growth factor
NGF selectively promotes the survival, differentiation and maintenance of small fibre sensory and sympathetic neurons in the peripheral nervous system. It is expressed in the skin and other target tissues of responsive neuronal populations, binds to its high-affinity receptor (trk A) on nerve terminals, and exerts trophic effects after being retrogradely transported back to the neuronal perikaryon [20]. A 6 month phase II trial with recombinant human NGF (rhNGF) in 250 patients with symptomatic diabetic neuropathy showed an improvement of the sensory component of the neurological examination and both cooling detection and heat as pain threshold, but no effect on neuropathic symptoms [21]. In contrast, a subsequent large 12 month phase III trial failed to demonstrate a favourable effect of rhNGF on subjective or objective variables of diabetic neuropathy [22]. The reasons for the latter disappointing result could be the following: (i) DSP did not progress during the trial in the placebo group; (ii) the dose chosen may have been below the threshold to produce an effect; (iii) the most distal testing site (big toe) was selected for assessment where the most advanced neuropathic changes were expected, less susceptible to intervention than more proximal sites; (iv) the primary outcome measure [NIS at the lower limbs (NIS-LL)] is not sensitive to small fibre sensory dysfunction; (v) the drug did not get to the target tissue; and (vi) the manufacturing process for NGF has been altered after the phase II trial and prior to the phase III trial, leaving the possibility that the drug was not identical [22].
PKC ß inhibitor (ruboxistaurin)
Increased PKC activity, i.e. the activity of a family of serine-threonine kinases which regulate various vascular functions, including contractility, haemodynamics and cellular proliferation, has been implicated in the pathogenesis of diabetic complications including neuropathy [23]. Treatment with the PKC ß-selective inhibitor ruboxistaurin ameliorated several neuropathic deficits in experimental diabetic neuropathy. In a phase II study, doses of 32 or 64 mg ruboxistaurin per day ameliorated neuropathic symptoms and deficits, the changes of which were correlated with those of the clinical global impression after 1 year [24]. Phase III clinical trials with this agent are currently underway.
C-peptide
Recent studies suggest that C-peptide binds specifically to cell membrane-binding sites and augments skin microcirculation in type 1 diabetic patients possibly via an increase in both nitric oxide production and Na+/K+-ATPase activity. In experimental diabetic neuropathy, C-peptide administration prevented the NCV deficit, axonal atrophy, paranodal swelling as well as demyelination. It also produced an increase in Na+/K+-ATPase activity and phosphorylation of the insulin receptor. A pilot study showed an improvement in small fibre sensory and autonomic function in type 1 diabetic patients [25]. In a recent 3 month trial, sural sensory NCV and vibration perception were improved by subcutaneous C-peptide treatment, whereas no significant effect was detectable for cold or heat perception [26]. Phase IIb and phase III trials in diabetic neuropathy are needed to confirm these findings.
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New agents for treatment of painful diabetic neuropathy
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Antidepressants
Recently the rate of publications of controlled clinical trials demonstrating significant pain relief with several drugs has accelerated. Nevertheless, the symptomatic pharmacological treatment of chronic painful diabetic neuropathy remains a challenge. A survey of physicians experienced in treating neuropathic pain demonstrated that only a minority would rate results of analgesic treatment as excellent or good using antidepressants (40%), anticonvulsants (35%), opioids (30%) or simple analgesics (18%) [27]. For >30 years, psychotropic agents, among which antidepressants have been evaluated most extensively, constitute an important component in the treatment of chronic pain syndromes. Several authors consider the tricyclic antidepressants (TCAs) to be the drug treatment of choice for neuropathic pain. However, their use is limited by relatively high rates of adverse events and several contraindications. Thus, there is a need for agents that exert efficacy equal to or better than that achieved with TCAs but have a more favourable side effect profile. Because selective serotonin re-uptake inhibitors (SSRIs) have been found to be less effective than TCAs, recent interest has focused on antidepressants with dual selective inhibition of serotonin and noradrenaline, such as venlafaxine and duloxetine. In a 6 week trial among 244 patients the analgesic response rates were 56, 39 and 34% in patients given 150225 mg of venlafaxin, 75 mg of venlafaxin and placebo, respectively. Because patients with depression were excluded, the effect of venlafaxin (150225 mg) was attributed to an analgesic, rather than antidepressant, effect. The most common adverse events were tiredness and nausea [28]. Duloxetine was effective in reducing neuropathic pain in diabetic patients at doses of 60 and 120 mg/day in a 12 week trial [29]. The most frequent side effects included nausea, somnolence, dizziness and constipation each in
1028%. In a recent trial, venlafaxine was as effective as imipramine in reducing neuropathic pain, but tolerability was more favourable with venlafaxine [30]. Although duloxetine has not been formally compared with TCAs, the rates of adverse effects appear to be lower. Both venlafaxine and duloxetine have not yet been licensed for the treatment of neuropathic pain.
Anticonvulsants
Gabapentin is an anticonvulsant structurally related to
-aminobutyric acid, a neurotransmitter that plays a role in pain transmission and modulation. The exact mechanisms of action of this drug in neuropathic pain are not fully elucidated. Among others, they involve an interaction with the system L-amino acid transporter and high affinity binding to the
2-
subunit of voltage-activated calcium channels. In an 8 week multicentre dose escalation trial including 165 diabetic patients with painful neuropathy, 60% of the patients on gabapentin (3600 mg/day achieved in 67%) had at least moderate pain relief compared with 33% on placebo. Dizziness and somnolence were the most frequent adverse events, each in
23% of the patients [31]. Pregabalin is another
2-
ligand with a 6-fold higher binding affinity than gabapentin. Two large phase III trials over 6 weeks have shown that pregabalin at doses of 300 and 600 mg/day was effective in painful diabetic neuropathy, with a number needed to treat for pain reduction of
50% between 3.3 and 4.2 [32].
Strong opioids for add-on treatment
Two recent trials over 4 and 6 weeks have demonstrated significant pain relief and improvement in quality of life following treatment with controlled-release oxycodone, a pure µ-agonist, in a dose range of 10100 mg (mean 40 mg)/day in patients with painful diabetic neuropathy whose pain was not controlled adequately on standard treatment with antidepressants and anticonvulsants, which were not discontinued throughout the trial [33,34]. As expected, adverse events were frequent and typical of opioid-related side effects. The results of these studies suggest that opioids should be included among the therapeutic options for painful diabetic neuropathy, provided that careful selection of patients unresponsive to standard treatments, regular monitoring, appropriate dose titration and management of side effects are ensured.
Non-pharmacological treatment
Because there is no entirely satisfactory pharmacotherapy of painful diabetic neuropathy, non-pharmacological treatment options such as psychological support, transcutaneous electrical nerve stimulation or physical measures (e.g. cold water immersion) have been tried. As for the pharmacological treatment, considerable efforts must also be made to develop effective non-pharmacological approaches. Recently, treatment with a monochromatic near-infrared medical device [35] and wearing of shoe insoles generating a static magnetic field (450 G) [36] have been shown to reduce neuropathic pain in diabetic patients. Further studies are needed to confirm these promising results.
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Conclusions
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Although considerable improvement in the quality of controlled trials has been achieved recently, no major breakthrough in slowing the progression of diabetic neuropathy in the long run has been achieved with drugs used on the basis of present pathogenetic concepts. Some of the newer drugs have shown promising results in phase II trials, which require confirmation from large phase III trials. There is general agreement that these trials should be of sufficient duration (35 years) and adequate size (n>500), include patients with mild rather than advanced neuropathy, and aim at clinically meaningful and reliable outcome measures, with high quality, rigorously controlled standards. It is also conceivable that drugs interfering with the pathogenesis of diabetic neuropathy may be most effective in terms of prevention, rather than intervention.
Major limiting factors in the treatment of painful diabetic neuropathy are still the paucity of adequately large, conclusive trials and the relatively high rates of adverse effects for several drug classes. Recent trials included adequately large patient samples, but the effect on pain was not superior to the tricyclic compounds which have been used for many years. Thus, individual tolerability remains a major aspect in any treatment decision. Almost no information is available from controlled trials on long-term analgesic efficacy and the use of drug combinations. Combination drug use or the addition of a new drug to a therapeutic regimen may lead to increased drug toxicity or decreased efficacy. Drug interactions should become more predictable, based on better knowledge of drugdrug inhibition and metabolism by specific cytochrome P450 enzymes. Drug combinations may also include those aimed at symptomatic pain relief and quality of life on the one hand, and improvement or slowing of the progression of the underlying neuropathic process on the other. Future trials should consider these aspects in order to optimize current treatment strategies in painful diabetic neuropathy.
Conflict of interest statement. The author has received honoraria for speaking activities from Viatris, Lilly, Ono, Sankyo and Pfizer.
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