Oral treatment with ALA for 5 weeks improved neuropathic symptoms and deficits in patients with DSP. An oral dose of 600 mg once daily appears to provide the optimum risk-to-benefit ratio.

OBJECTIVETo evaluate the efficacy and safety of α-lipoic acid (ALA) over 4 years in mild-to-moderate diabetic distal symmetric sensorimotor polyneuropathy (DSPN).RESEARCH DESIGN AND METHODSIn a multicenter randomized double-blind parallel-group trial, 460 diabetic patients with mild-to-moderate DSPN were randomly assigned to oral treatment with 600 mg ALA once daily (n = 233) or placebo (n = 227) for 4 years. Primary end point was a composite score (Neuropathy Impairment Score [NIS]–Lower Limbs [NIS-LL] and seven neurophysiologic tests). Secondary outcome measures included NIS, NIS-LL, nerve conduction, and quantitative sensory tests (QSTs).RESULTSChange in primary end point from baseline to 4 years showed no significant difference between treatment groups (P = 0.105). Change from baseline was significantly better with ALA than placebo for NIS (P = 0.028), NIS-LL (P = 0.05), and NIS-LL muscular weakness subscore (P = 0.045). More patients showed a clinically meaningful improvement and fewer showed progression of NIS (P = 0.013) and NIS-LL (P = 0.025) with ALA than with placebo. Nerve conduction and QST results did not significantly worsen with placebo. Global assessment of treatment tolerability and discontinuations due to lack of tolerability did not differ between the groups. The rates of serious adverse events were higher on ALA (38.1%) than on placebo (28.0%).CONCLUSIONSFour-year treatment with ALA in mild-to-moderate DSPN did not influence the primary composite end point but resulted in a clinically meaningful improvement and prevention of progression of neuropathic impairments and was well tolerated. Because the primary composite end point did not deteriorate significantly in placebo-treated subjects, secondary prevention of its progression by ALA according to the trial design was not feasible.

OBJECTIVE -Because ␣-lipoic acid (ALA), a potent antioxidant, prevents or improves nerve conduction attributes, endoneurial blood flow, and nerve (Na(ϩ) K(ϩ) ATPase activity in experimental diabetes and in humans and may improve positive neuropathic sensory symptoms, in this report we further assess the safety and efficacy of ALA on the Total Symptom Score (TSS), a measure of positive neuropathic sensory symptoms.RESEARCH DESIGN AND METHODS -Metabolically stable diabetic patients with symptomatic (stage 2) diabetic sensorimotor polyneuropathy (DSPN) were randomized to a parallel, double-blind study of ALA (600 mg) (n ϭ 60) or placebo (n ϭ 60) infused daily intravenously for 5 days/week for 14 treatments. The primary end point was change of the sum score of daily assessments of severity and duration of TSS. Secondary end points were sum scores of neuropathy signs (NIS), symptoms (NSC), attributes of nerve conduction, quantitative sensation tests (QSTs), and an autonomic test.RESULTS -At randomization, the groups were not significantly different by the criteria of metabolic control or neuropathic end points. After 14 treatments, the TSS of the ALA group had improved from baseline by an average of 5.7 points and the placebo group by an average of 1.8 points (P Ͻ 0.001). Statistically significant improvement from baseline of the ALA, as compared with the placebo group, was also found for each item of the TSS (lancinating and burning pain, asleep numbness and prickling), NIS, one attribute of nerve conduction, and global assessment of efficacy.CONCLUSIONS -Intravenous racemic ALA, a potent antioxidant, rapidly and to a significant and meaningful degree, improved such positive neuropathic sensory symptoms as pain and several other neuropathic end points. This improvement of symptoms was attributed to improved nerve pathophysiology, not to increased nerve fiber degeneration. Because of its safety profile and its effect on positive neuropathic sensory symptoms and other neuropathic end points, this drug appears to be a useful ancillary treatment for the symptoms of diabetic polyneuropathy. Diabetes Care 26:770 -776, 2003T he neuropathies associated with diabetes are heterogeneous (1). Perhaps the most common variety is diabetic sensorimotor polyneuropathy (DSPN), the disorder studied here. This variety appears to be caused by chronic hyperglycemia and associated metabolic derangements, damaging neurons (axons) or Schwann cells (or myelin) directly or indirectly by functional and structural alterations of microvessels or the blood nerve barrier. Inflammation, perhaps from immune mechanisms, may also be implicated in some cases (2).Recognizing that total hyperglycemic exposure may be the most important modifiable risk covariate for diabetic complications such as DSPN (3-8), why search for ancillary treatments in addition to rigorous glucose control? First, despite considerable effort to achieve near euglycemia (by frequent monitoring of plasma glucose, use of multiple injections of insulin, or use of insulin pumps), many ...

OBJECTIVE -Assessing clinimetric performance of diabetic sensorimotor polyneuropathy (DSPN) end points in single and multicenter trials.RESEARCH DESIGN AND METHODS -Assessed were placebo-treated patients with DSPN in the Viatris and Eli Lilly trials and an epidemiologic cohort.RESULTS -Test reproducibility in clinical trial cohorts (r I ϳ 0.7-0.85) approached that in the epidemiologic cohort (r I ϳ 0. 85-0.95). Associations between pairs of end points explained Ͻ10% of the variability of data (sometimes 15-35%), being higher in the epidemiologic cohort and the Viatris trial than in the Lilly trial. Most end points did not show monotonic worsening over 4 years. However, sural nerve amplitude and peroneal motor conduction velocity did. A nerve conduction score (⌺ 5 NC nds [5 attributes of nerve conduction expressed as normal deviates]) did not show monotonic worsening in established DSPN. In the epidemiologic cohort followed for 9.5 years, monotonic worsening of small magnitude occurred for sural amplitude, vibration detection threshold, and especially for composite quantitative sensation.CONCLUSIONS -The main reason why it is difficult to demonstrate monotonic worsening of neuropathic end points appears to be a very slow worsening of DSPN, a placebo effect for symptoms and signs, and measurement noise. Demonstrating disease progression in controlled trials of DSPN is more likely when 1) patients with developing rather than established DSPN are selected, 2) type 1 diabetic patients are preferentially recruited, 3) patients are selected who cannot or will not achieve ideal glycemic control, 4) end points chosen are known to show monotonic worsening, and 5) a restricted number of centers and expert examiners (trained, certified, using standard approaches, and reference values and interactive surveillance of tests) are used. Diabetes Care 30:2619-2625, 2007R igorous control of glycemia retards or ameliorates diabetic sensorimotor polyneuropathy (DSPN), but long and expensive trials are needed (1-4). No adjuvant treatment, in addition to glycemic control, has achieved sufficient efficacy, considering side effects, to obtain regulatory approval (e.g., by the Food and Drug Administration) (5-13). This contrasts to interventions ameliorating sensory symptoms of pain or autonomic symptoms (gastric atony, diarrhea, and sexual dysfunction) receiving approval (14 -20). Therefore, we ask, are controlled clinical trials of ancillary treatments doable, which end points should be used, and how long and rigorous do the trials need to be? Assuming that adjuvant efficacious treatments exist, why has it been so difficult to demonstrate efficacy? Possibilities are 1) interventions are not efficacious; 2) present diabetes care inhibits development of complications; 3) other diabetic complications (hypertension, hyperlipidemia, renal disease, and other) with possible adverse effects on DSPN (21) are now managed better; 4) the wrong kind, stage, or duration of DSPN is studied; 5) end points chosen are insufficiently sensitive, specific,...

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