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Journal of Diabetes and Its Complications Xxx (2015) Xxx–Xxx Journal of Diabetes and Its Complications xxx (2015) xxx–xxx Contents lists available at ScienceDirect Journal of Diabetes and Its Complications journal homepage: www.jdcjournal.com Predictors of improvement and progression of diabetic polyneuropathy following treatment with α-lipoic acid for 4 years in the NATHAN 1 trial Dan Ziegler a,b,⁎, Phillip A. Low c, Roy Freeman d, Hans Tritschler e, Aaron I. Vinik f a Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany b Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany c Department of Neurology, Mayo Clinic, Rochester, MN, USA d Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA e MEDA Pharma GmbH & Co. KG, Bad Homburg, Germany f Department of Medicine, EVMS Strelitz Diabetes Research Center and Neuroendocrine Unit, Eastern Virginia Medical School, Norfolk, VA, USA article info abstract Article history: Aims: We aimed to analyze the impact of baseline factors on the efficacy of α-lipoic acid (ALA) over 4 years in Received 1 October 2015 the NATHAN 1 trial. Received in revised form 30 October 2015 Methods: This was a post-hoc analysis of the NATHAN 1 trial, a 4-year randomized study including 460 Accepted 31 October 2015 diabetic patients with mild-to-moderate polyneuropathy using ALA 600 mg qd or placebo. Amongst others, Available online xxxx efficacy measures were the Neuropathy Impairment Score of the lower limbs (NIS-LL) and heart rate during deep breathing (HRDB). Keywords: Results: Improvement and prevention of progression of NIS-LL (ΔNIS-LL ≥ 2 points) with ALA vs. placebo Diabetic polyneuropathy α-lipoic acid after 4 years was predicted by higher age, lower BMI, male sex, normal blood pressure, history of Neuropathic impairments cardiovascular disease (CVD), insulin treatment, longer duration of diabetes and neuropathy, and higher Autonomic function neuropathy stage. Participants treated with ALA who received ACE inhibitors showed a better outcome in Cardiovascular risk factors HRDB after 4 years. Conclusions: Better outcome in neuropathic impairments following 4-year treatment with α-lipoic acid was predicted by normal BMI and blood pressure and higher burden due to CVD, diabetes, and neuropathy, while improvement in cardiac autonomic function was predicted by ACE inhibitor treatment. Thus, optimal control of CVD risk factors could contribute to improved efficacy of α-lipoic acid in patients with higher disease burden. © 2015 Elsevier Inc. All rights reserved. 1. Introduction er-limb amputation (Rajamani et al., 2009). On the other hand, history of myocardial infarction and CVD and the underlying risk factors such About one third of all patients with diabetes are affected by as obesity, hypertension, and hyperlipidemia may predict the risk of diabetic sensorimotor polyneuropathy (DSPN) which has a major developing DSPN (Forrest, Maser, Pambianco, Becker, & Orchard, impact on morbidity and mortality (Ziegler, Papanas, Vinik, & Shaw, 1997; Sands, Shetterly, Franklin, & Hamman, 1997; Tesfaye et al., 2014). Neuropathic sensory deficits such as reduced touch and 2005; Wiggin et al., 2009; Ylitalo, Sowers, & Heeringa, 2011; Ziegler vibration perception are independent predictors of mortality et al., 2008; Ziegler et al., 2009). (Coppini, Bowtell, Weng, Young, & Sönksen, 2000), cardiac death or Effective causal treatment of DSPN remains challenging for the nonfatal myocardial infarction (Young et al., 2009), incident cardio- physician. The Diabetes Control and Complications Trial/Epidemiol- vascular disease (CVD) events (Brownrigg et al., 2014), and low- ogy of Diabetes Interventions and Complications (DCCT/EDIC) study demonstrated that intensive diabetes therapy in type 1 diabetic individual retards but not fully prevents the development of DSPN and cardiovascular autonomic neuropathy (CAN) (Martin, Albers, Pop- Conflict of interest: DZ received honoraria for speaking and consulting activities Busui, & DCCT/EDIC Research Group, 2014; The Diabetes Control and from MEDA Pharma. HT is employee of MEDA Pharma. Complications Trial Research Group, 1993). In contrast, there is no ClinicalTrials.gov Identifier: NCT00977483 clear evidence that intensive diabetes therapy or a target-driven ⁎ Corresponding author at: German Diabetes Center, Auf'm Hennekamp 65, 40225 fi Düsseldorf. Tel.: +49 211 33820; fax: +49 211 3382244. intensi ed intervention aimed at multiple risk cardiovascular factors E-mail address: [email protected] (D. Ziegler). favorably influence the development or progression of DSPN and CAN http://dx.doi.org/10.1016/j.jdiacomp.2015.10.018 1056-8727/$© 2015 Elsevier Inc. All rights reserved. Please cite this article as: Ziegler, D., et al., Predictors of improvement and progression of diabetic polyneuropathy following treatment with α-lipoic acid for 4 ..., Journal of Diabetes and Its Complications (2015), http://dx.doi.org/10.1016/j.jdiacomp.2015.10.018 2 D. Ziegler et al. / Journal of Diabetes and Its Complications xxx (2015) xxx–xxx in type 2 diabetic subjects (Boussageon et al., 2011; Charles et al., Table 1 ⁎ 2011; Charles et al., 2013; Gaede, Lund-Andersen, Parving, & Clinical characteristics of the intention-to-treat population at baseline. Pedersen, 2008; Sandbæk et al., 2014). In fact, self-reported history α-Lipoic acid Placebo P value of neuropathy was a significant predictor for increased mortality in n 230 224 patients with type 2 diabetes allocated to a very intensive diabetes Age (years) 53.3 ± 8.3 53.9 ± 7.6 0.3607 therapy aimed at HbA1c b6.0% in the ACCORD trial (Calles-Escandón Sex (% male) 66.1 67.0 0.8430 2010). On the other hand, near-normoglycemia is difficult to achieve BMI (kg/m2) 29.7 ± 6.1 29.8 ± 6.1 0.9226 in a considerable number of individuals with diabetes. Thus, there is Heart rate (bpm) 76.3 ± 12.3 74.6 ± 12.6 0.1603 TYPE 1/Type 2 Diabetes (%) 27.4/72.6 21.0/79.0 0.1111 an unmet need for disease-modifying treatments considering the Diabetes duration (years) 13.3 (0.8–56.1) 13.5 (0.9–46.7) 0.4190 pathogenetic mechanisms contributing to DSPN. Since diabetic Neuropathy duration (years) 3.0 (0.0–25.4) 3.2 (0.0–21.1) 0.2588 neuropathy is closely linked to CVD and both oxidative stress and Insulin treatment (%) 58.9 55.1 0.4170 vascular dysfunction play a paramount pathogenetic role (Nishikawa HbA1c (%) 8.9 ± 1.8 8.8 ± 1.9 0.6354 Fasting blood glucose (mmol/l) 11.1 ± 4.68 10.9 ± 4.26 0.6529 et al., 2000; Ziegler, Buchholz, Sohr, Nourooz-Zadeh, & Roden, 2015), Nephropathy (%) 11.7 12.0 0.5935 α agents that reduce oxidative stress such as -lipoic acid (ALA) and Retinopathy (%) 45.5 43.6 0.6833 those ameliorating vascular dysfunction and promote vasodilatation Neuropathy stage 1/stage 2a (%) 11.3/88.7 9.8/90.2 0.6074 such as ACE inhibitors have been evaluated in clinical trials showing NIS-LL + 7 (nds) 17.1 ± 8.4 16.8 ± 8.0 0.6740 improvement of DSPN and CAN (Malik et al., 1998; Papanas & Ziegler, NIS (points) 12.7 ± 8.6 12.2 ± 7.8 0.5062 NIS-LL (points) 9.8 ± 5.6 9.5 ± 5.3 0.6087 2014; Ruggenenti et al., 2011). Peroneal MNCV (m/s) 38.5 ± 5.03 38.1 ± 6.48 0.4957 The efficacy and safety of ALA have been assessed in several Sural SNAP (μV) 2.49 ± 3.38 2.43 ± 3.21 0.8387 controlled clinical trials and meta-analyses (Papanas & Ziegler, 2014). Vibration perception threshold (JND) 21.27 ± 3.18 21.21 ± 3.52 0.8393 In the NATHAN 1 trial, we evaluated the efficacy and safety of α-lipoic Cold detection threshold (JND) 17.86 ± 5.14 17.58 ± 5.33 0.5765 acid over 4 years in patients with mild-to-moderate DSPN (Ziegler Heart rate deep breathing (bpm) 7.26 ± 5.44 8.59 ± 6.59 0.0193 NSC weakness (number) 0.06 ± 0.30 0.03 ± 0.23 0.2353 et al., 2011). The primary outcome measure was a composite score NSC weakness (severity) 0.10 ± 0.56 0.04 ± 0.31 0.1613 including the Neuropathy Impairment Score of the lower limbs and 7 Total symptom score (points) 2.4 ± 1.9 2.6 ± 1.8 0.2752 nerve function tests (NIS-LL + 7 tests). Primary analysis showed no Data are mean ± SD, median (range), or % of patients. significant difference between the groups for the changes in NIS = Neuropathy Impairment Score, JND = just noticeable difference, LL = lower limbs, NIS-LL + 7 tests from baseline to 4 years (p = 0.105). The lack of MNCV = motor nerve conduction velocity, SNAP = sensory nerve action potential. ⁎ improvement in the composite score was predominantly due to the Published previously in Ziegler et al. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: The NATHAN 1 Trial. Diabetes Care fact that nerve conduction deficits in the placebo-treated group did 2011; 34: 2054–2060. Copyright 2011 by the American Diabetes Association. not progress. In contrast, improvement on ALA vs. placebo was noted for NIS (p = 0.028) and NIS-LL (p = 0.05). More patients showed a clinically meaningful response and fewer showed progression with ALA than with placebo for NIS (p = 0.013) and NIS-LL (p = 0.025), motor nerve conduction velocity (MNCV), sural sensory nerve action respectively. The changes in nerve conduction and quantitative potential (SNAP) amplitude, change in heart rate during deep sensory testing did not differ between both groups after 4 years breathing (HRDB), cooling detection threshold (CDT), and heat pain – (Ziegler et al., 2011). response slope (HP 0.5 5.0). A clinically meaningful progression fi ≥ Based on the epidemiological and clinical evidence, here we (non-response) was de ned as an increase in NIS-LL by 2 points over hypothesized that CVD and its underlying risk factors which are 4 years (Dyck, Davies, Litchy, & O'Brien, 1997; Peripheral Nerve frequently encountered in type 2 diabetic patients and the concom- Society, 1995).
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