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C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n
Oral Treatment With -Lipoic Acid
Improves Symptomatic Diabetic
The SYDNEY 2 trial
pain and is responsible for both substan-tial morbidity and increased mortality (1–4). Neuropathic pain affects 16% of OBJECTIVE — The aim of this trial was to evaluate the effects of ␣-lipoic acid (ALA) on
diabetic patients (5) and exerts a substan- positive sensory symptoms and neuropathic deficits in diabetic patients with distal symmetric tial impact on the quality of life, particu- larly by causing interference of sleep and RESEARCH DESIGN AND METHODS — In this multicenter, randomized, double-
enjoyment of life (6). Pain is a subjective blind, placebo-controlled trial, 181 diabetic patients in Russia and Israel received once-daily oral doses of 600 mg (n ϭ 45) (ALA600), 1,200 mg (n ϭ 47) (ALA1200), and 1,800 mg (ALA1800) of ALA (n ϭ 46) or placebo (n ϭ 43) for 5 weeks after a 1-week placebo run-in period. The primary outcome measure was the change from baseline of the Total Symptom Score (TSS), including stabbing pain, burning pain, paresthesia, and asleep numbness of the feet. Secondary end points included individual symptoms of TSS, Neuropathy Symptoms and Change (NSC) score, Neuropathy Impairment Score (NIS), and patients’ global assessment of efficacy.
nisms of DSP (8), several therapeutic ap-proaches have been developed including RESULTS — Mean TSS did not differ significantly at baseline among the treatment groups and
on average decreased by 4.9 points (51%) in ALA600, 4.5 (48%) in ALA1200, and 4.7 (52%) in
antioxidants such as ␣-lipoic acid (ALA) ALA1800 compared with 2.9 points (32%) in the placebo group (all P Ͻ 0.05 vs. placebo). The corresponding response rates (Ն50% reduction in TSS) were 62, 50, 56, and 26%, respectively.
Significant improvements favoring all three ALA groups were also noted for stabbing and burn- signed to favorably influence the underly- ing pain, the NSC score, and the patients’ global assessment of efficacy. The NIS was numerically reduced. Safety analysis showed a dose-dependent increase in nausea, vomiting, and vertigo.
solely to relieve pain. It is likely that in theforeseeable future, near normoglycemia CONCLUSIONS — Oral treatment with ALA for 5 weeks improved neuropathic symptoms
will not be achievable in the majority of and deficits in patients with DSP. An oral dose of 600 mg once daily appears to provide the pounds could offer the advantage of being Diabetes Care 29:2365–2370, 2006
effective despite persistent hyperglycemia.
1,258 diabetic patients with symptomaticDSP from four randomized clinical trials(14) including the first Symptomatic Dia- ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● From the 1German Diabetes Clinic, German Diabetes Center, Leibniz Institute at the Heinrich Heine Uni- versity, Du¨sseldorf, Germany; the 2Russian Medical Academy for Advanced Studies, Moscow, Russia; the3Neurology Clinic, Moscow Medical Academy, Moscow, Russia; the 4Department of Neurology, Mayo 600 mg i.v. as a daily infusion for 3 weeks Clinic, Rochester, Minnesota; the 5Federal Center for Diabetic Foot, Moscow, Russia; 6MEDA Pharma, Bad Homburg, Germany; and 7Hadassah University, Jerusalem, Israel.
to a clinically meaningful degree. This ef- Address correspondence and reprint requests to Prof. Dan Ziegler, MD, FRCPE, Deutsche Diabetes- Klinik, Deutsches Diabetes-Zentrum, Leibniz-Institut an der Heinrich-Heine-Universita¨t, Auf’m Hen-nekamp 65, 40225 Du¨sseldorf, Germany. E-mail:
of neuropathic deficits, assuming a poten- Received for publication 12 June 2006 and accepted in revised form 26 July 2006.
tial of the drug to favorably influence the Abbreviations: ALA, ␣-lipoic acid; DSP, distal symmetric polyneuropathy; NIS, Neuropathy Impairment
Score; NSC, Neuropathy Symptoms and Change; TSS, Total Symptom Score.
from a small oral pilot study (ORPIL) us- D. Z., A.A., A.B., P.J.D., I.G., P.A.L., N.Y., I.R., and M.N. received honoraria for speaking activities and A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion DOI: 10.2337/dc06-1216. Clinical trial reg. no. NCT00328601,
2006 by the American Diabetes Association.
have not yet been established. Therefore, The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. DIABETES CARE, VOLUME 29, NUMBER 11, NOVEMBER 2006 ␣-Lipoic acid in diabetic polyneuropathy
response trial using ALA (600, 1,200, and ripheral vascular disease severe enough to ble), and stage 3 (disabling neuropathy).
after a 1-week placebo run-in period.
ulcers or limb ischemia; significant he-patic or renal disease, antioxidant ther- RESEARCH DESIGN AND
METHODS — The SYDNEY 2 trial
blood pressure and heart rate after 3 min ␥-linolenic acid– containing substances of sitting, body weight, and standard lab- multicenter trial using three oral doses of Primary outcome measure. The pri-
the comparison of the changes in TSS from baseline to the end of treatment among the stabbing pain, burning pain, paresthesia, effects but no treatment-center interactions.
start of study treatment, and after 1, 2, 3, 4, and 5 weeks of treatment. All other pa- meaningful response to treatment. For all screening and at the end of the study.
efficacy variables, the analyses of the in- Secondary outcome measures. The
tention-to-treat population were primary.
three centers in Russia. All patients were plied with the baseline as covariate. In the for 1 week (single-blind run-in phase).
sessment as previously described (15).
5), the last value carried forward principle action, each time point was analyzed anal- (0 ϭ normal to 4 ϭ paralyzed), reflexes (0 ϭ normal to 2 ϭ absent with reinforce- because, in previous studies, no plateau in c e n t e r - a d j u s t e d C o c h r a n - M a n t e l - dality) of the index finger and great toe and is scored for both sides of the body.
a slower onset of efficacy was assumed for confirmatory analysis. The level of signif- Inclusion criteria at the screening visit icance (two sided) was set at ␣ ϭ 0.05.
1–19; sensation, questions 20 –29; and tes (type 1 or 2) defined by American Di- RESULTS — Of the 227 patients
and latency of the sural nerve) were per- patic or renal disease. Thus, 187 patients score for lower limbs (NIS[LL]) Ն2 points, prick test absent or decreased. At the ran- domization visit after the 1-week run-in, subjects had to comply with all of the fol- lowing criteria: TSS Ն5 points; TSS range efficacy was rated by the patient as very trial. Most patients (12) discontinued be- good/good, satisfactory, or insufficient.
cause of adverse events: 1 in the placebo al. (17,18): stage 0 (no neuropathy), stage last 3 months, sufficient compliance 85– plete the trial because of lack of efficacy; DIABETES CARE, VOLUME 29, NUMBER 11, NOVEMBER 2006 Ziegler and Associates
Table 1—Clinical characteristics in the intention-to-treat population
Treatment with oral antidiabetic agents (%) Data means Ϯ SD unless otherwise indicated. *Smoker within the last 2 years.
compared with the placebo arm (all P Ͻ the changes in mean TSS at any of the time 0.05) (Table 2). No significant differences tients are shown in Table 1. As a sign of pared with 26% after placebo (P Ͻ 0.05).
ment with oral antidiabetic agents (P ϭ 0.018) and BMI (P ϭ 0.036, Table 1).
blind period of the trial are illustrated in and NIS[LL] at screening and their changes Table 3. There were no significant differ- line TSS and its individual subscores.
groups versus placebo at weeks 2–5 (P Ͻ After 5 weeks of treatment, a significant placebo at week 1 (P Ͻ 0.05).
scores for stabbing/lancinating and burn- Table 2—Baseline levels and changes from baseline (negative values correspond to improvement) in the TSS and its individual subscores after
5 weeks of treatment (last value carried forward)

Data are means Ϯ SD. *P Ͻ 0.05 vs. placebo.
DIABETES CARE, VOLUME 29, NUMBER 11, NOVEMBER 2006 -Lipoic acid in diabetic polyneuropathy
the ALA1800 group (P Ͻ 0.05 for all ALAdoses vs. placebo).
verse events were 9 (21%) in the placebogroup, 12 (27%) in the ALA600 group(P ϭ 0.53 vs. placebo), 20 (43%) in theALA1200 group (P ϭ 0.03 vs. placebo),and 25 (54%) in the ALA1800 group (P ϭ0.001 vs. placebo). The rates of treat-ment-emergent adverse events in WorldHealth Organization preferred terms(Ͼ10% in any group) increased with es-calating doses and were nausea 0, 6(13%), 10 (21%), and 22 (48%) (P Ͻ 0.05for all ALA groups vs. placebo); vomiting0, 1 (2%), 2 (4%), and 12 (26%) (P Ͻ0.05 for ALA1800 vs. placebo); vertigo 0,2 (4%), 2 (4%), and 5 (11%), respectively(P ϭ 0.056 for ALA1800 vs. placebo).
CONCLUSIONS — The results of the
Figure 1—Mean TSS levels on a weekly basis during the placebo run-in and the randomized double-blind period of the trial. *P Ͻ 0.05 for ALA600, ALA 1200, and ALA1800 vs. placebo; **P Ͻ 0.05 for ALA1800 vs. placebo. proved the positive sensory symptomsscored by the TSS in diabetic patients cebo group (all P Ͻ 0.05, except for NSC with DSP. This overall effect was not dose number in ALA1800: P ϭ 0.08). For the with placebo (P ϭ 0.09) were noted. No dependent, as there were no differences in ment was noted in ALA1200 (P Ͻ 0.05) ALA1800 versus placebo (P ϭ 0.055). Re- garding the changes in NIS[LL], a trend for good/good, satisfactory, and insufficient ALA600 group (P ϭ 0.07 vs. placebo).
paresthesia and numbness was observed.
the placebo group, 62, 27, and 11% for the and placebo (P Ͻ 0.05) and a borderline Table 3—Screening levels and changes from screening in NSC scores, NIS, and NIS͓LL͔ after 5 weeks of treatment (last value carried forward)
Data are means Ϯ SD. Negative values correspond to improvement. *P Ͻ 0.05, †P ϭ 0.08, ‡P ϭ 0.055, §P ϭ 0.07, and ʈP ϭ 0.09 (each vs. placebo).
DIABETES CARE, VOLUME 29, NUMBER 11, NOVEMBER 2006 Ziegler and Associates
formulation. The coefficient of variation Diabetes Association. Diabetes Care 28: (R. Hermann, unpublished observations).
related to increased mortality in diabeticpatients: a survival analysis using an ac- celerated failure time model. J Clin Epide- A c i d i n E n d o t h e l i a l D y s f u n c t i o n that a response of at least 50% reduction definition, the response rates were 50 – drome resulted in a significant increase in betes. Diabet Med 21:976 –982, 2004 vasodilation of the brachial artery by 44 dose of oral ALA q.d. is 2.7. Whether the 6. Galer BS, Gianas A, Jensen MP: Painful placebo treatment after 4 weeks. This ef- description, and quality of life. Diabetes 7. Finnerup NB, Otto M, McQuay HJ, Jensen our finding that neuropathic deficits such proposal. Pain 118:289 –305, 2005 tion via anti-inflammatory and antithrom- faye S: Vascular factors and metabolic in- infusion of 600 mg ALA exerts an acute ef- teractions in the pathogenesis of diabetic fect on microcirculation in patients with di- neuropathy. Diabetologia 44:1973–1988, impairment of nitric oxide–mediated vaso- 9. Ziegler D: Thioctic acid: a critical review dilation in diabetes has been attributed to of its effects in patients with symptomatic increased vascular oxidative stress. At this diabetic polyneuropathy. Treat Endocrinol point, acute infusion of ALA improved ni- that resulting from intravenous treatment 10. Tesfaye S: Symptomatic diabetic periph- dependent vasodilation in diabetic patients the PKC ␤ inhibitor ruboxistaurin: trial ously reported (14). It is notable that this design (Abstract). Diabetologia 48 (Suppl.
favorable safety profile for the low dose.
11. Bril V, Buchanan RA: Long-term effects of tinued the study, whereas with the higher function in patients with diabetic sensori- rates of gastrointestinal side effects, 600 motor polyneuropathy. Diabetes Care 29: 12. Vincent AM, Russell JW, Low P, Feldman EL: Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev 25:612– Acknowledgments — This study was sup-
13. Ziegler D, Sohr CGH, Nourooz-Zadeh J: many. In addition to the authors listed, thefollowing colleagues contributed equally to in relation to the severity of diabetic poly- the study: Natalia Chernikova, MD; Barbara neuropathy and autonomic neuropathy.
ing 21 and 48%, respectively. The rate of Ellers-Lenz, Dipl.math.oec; Igor Strokov, MD; Diabetes Care 27:2178 –2183, 2004 Julio Wainstein, MD; and Hans J. Tritschler, 14. Ziegler D, Nowak H, Kempler P, Vargha reported in the ␣-Lipoic Acid in Diabetic dant ␣-lipoic acid: a meta-analysis. Diabet References
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23. Yorek MA, Coppey LJ, Gellett JS, David- the antioxidant thioctic acid (␣-lipoic son EP, Lund DD: Effect of fidarestat and 29. Haak ES, Usadel KH, Kohleisen M, Yilmaz ␣-lipoic acid on diabetes-induced epin- A, Kusterer K, Haak T: The effect of ␣-li- ropathy. Diabet Med 16:1040 –1043, eurial arteriole vascular dysfunction. Exp poic acid on the neurovascular reflex arc 17. Dyck PJ: Detection, characterization, and 24. Kunt T, Forst T, Wilhelm A, Tritschler H, sessed by capillary microscopy. Microvasc staging of polyneuropathy: assessed in di- abetics. Muscle Nerve 11:21–32, 1988 Zschaebitz A, Stofft E, Beyer J: ␣-Lipoic 30. Heitzer T, Finckh B, Albers S, Krohn K, 18. Dyck PJ, Karnes JL, O’Brien PC, Litchy Kohlschu¨tter A, Meinertz T: Beneficial ef- fects of ␣-lipoic acid and ascorbic acid ide-mediated vasodilation in diabetic pa- and staged severity. Neurology 42:1164 – products. Clin Sci (Lond) 96:75– 82, 1999 tients: relation to parameters of oxidative stress. Free Radic Biol Med 31:53– 61, 31. Reljanovic M, Reichel G, Rett K, Lobisch Nawroth PP: ␣-Lipoic acid decreases ox- M, Schuette K, Mo¨ller W, Tritschler H-J, perimental diabetic neuropathy. Diabetes uria. Free Radic Biol Med 22:1495–1500, with the antioxidant thioctic acid (␣-li- 26. Androne L, Gavan NA, Veresiu IA, Orasan Tritschler HJ: Effects of ␣-lipoic acid on R: In vivo effect of lipoic acid on lipid ized double blind placebo controlled trial (ALADIN II). Free Radic Res 31:171–179, interaction with essential fatty acids. Dia- neuropathy. In Vivo 14:327–330, 2000 21. Mitsui Y, Schmelzer JD, Zollman PJ, Mit- Meißner HP, Lobisch M, Schu¨tte K, Gries athy with the anti-oxidant ␣-lipoic acid: a nerve. J Neurol Sci 163:11–16, 1999 22. Coppey LJ, Gellett JS, Davidson EP, Dun- trolled trial (ALADIN Study). Diabetologia (ISLAND) study. Circulation 111:343– 33. Abbott CA, Vileikyte L, Williamson S, 28. Haak E, Usadel KH, Kusterer K, Amini P, locity, and vascular reactivity of epineur- fects of ␣-lipoic acid on microcirculation risk factors for diabetic neuropathic foot ial arterioles of the sciatic nerve. Diabetes in patients with peripheral diabetic neu- ulceration. Diabetes Care 21:1071–1075, ropathy. Exp Clin Endocrinol Diabetes 108: DIABETES CARE, VOLUME 29, NUMBER 11, NOVEMBER 2006


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