Journal of Diabetes and Its Complications Xxx (2015) Xxx–Xxx

Journal of Diabetes and Its Complications xxx (2015) xxx–xxx

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Journal of Diabetes and Its Complications

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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). fl fi itant pharmacotherapy could modify the effect of ALA on neuropathy The in uence of baseline variables on the ef cacy of ALA vs. fi b outcomes. Thus, in the present post-hoc analysis of the NATHAN 1 placebo was analyzed in subgroups of patients strati ed by age ( 55 ≥ b ≥ study, we aimed to determine the baseline factors that may predict or 55 years), resting heart rate ( 76 or 76 bpm), and neuropathy ≤ N effect of ALA on neuropathic impairments and cardiac autonomic duration ( 3or 3 years) using the median as a cut-off, diabetes fi b ≥ function focusing on CVD and its risk factors such as obesity and duration de ned as short-term and long-term ( 10 or 10 years), fi hypertension as well as concomitant medication. HbA1c de ned as good control and unsatisfactory control of glycemia (b7.0 or ≥7.0%), sex, diabetes type, DSPN stage (stage 1: asymptom- 2. Subjects, materials and methods atic neuropathy or stage 2a: symptomatic neuropathy with preserved ability to walk on heels), retinopathy (yes/no), nephropathy (yes/no), fi “ 2.1. Study population and methods hypertension (yes/no), CVD de ned by the organ class cardiovascu- lar” as classified by medical history by the investigating physician and The NATHAN (Neurological Assessment of Thioctic Acid in Diabetic recorded in the case record forms (yes/no), insulin treatment (yes/ Neuropathy) 1 trial was a multicenter (36 centers in USA, Canada, and no), oral antidiabetic drugs (yes/no), ATC codes: C09: ACE inhibitors, Europe), randomized, double-blind, placebo-controlled, two-arm, 1:1 angiotensin II antagonists (yes/no), C10: lipid modifying agents (yes/ α allocation ratio, parallel-group clinical trial using film-coated tablets no), C02/C03/C07/C08: blockers and others, diuretics, ß blocking containing ALA 600 mg qd (Thioctacid® HR, MEDA Pharma GmbH & agents, calcium channel blockers (yes/no), N02/N03/N06: analgesics, fl Co. KG, Bad Homburg, Germany) or matching placebo tablets in antiepileptics, antidepressants (yes/no), M01: anti-in ammatory and diabetic patients with mild-to-moderate polyneuropathy. Approvals anti-rheumatic products (yes/no). were obtained from the local ethics committees of all participating centers.The trial design and results have been previously reported 2.2. Statistical analysis (Ziegler et al., 2011). The present analysis was based on the original cohorts that Data are expressed as mean ± SD for changes from baseline were treated with ALA (n = 233) or received placebo (n = 227). (Table 2). All analyses were conducted on an intention-to-treat (ITT) The demographic variables and outcome measures at baseline in basis. The treatment effect was analyzed within each subgroup, both groups are shown in Table 1 (Ziegler et al., 2011). Efficacy accepting that the power would only be moderate. However, measures included the NIS-LL, NIS-LL and 7 nerve function tests subgroups with strong treatment effects were expected to show (NIS-LL + 7 tests), vibration detection threshold (VDT), peroneal signals within the available sample size. Subgroup definitions

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 D. Ziegler et al. / Journal of Diabetes and Its Complications xxx (2015) xxx–xxx 3

Table 2 Changes in the Neuropathy Impairment Score of the lower limbs (NIS-LL) from baseline to 4 years in the different subcategories and treatment groups.

n α-Lipoic acidΔNIS-LL (points) n PlaceboΔNIS-LL (points)

Age: ≥55 years 114 −0.49 ± 3.82 118 1.15 ± 4.53 b55 years 105 −0.18 ± 5.12 92 −0.48 ± 4.30 Sex: male 143 −0.58 ± 3.91 141 0.33 ± 4.31 female 76 0.12 ± 5.39 69 0.64 ± 4.87 BMI: ≥30 kg/m2 90 0.63 ± 4.50 84 0.56 ± 3.78 b30 kg/m2 129 −1.02 ± 4.36 126 0.35 ± 4.92 Heart rate: ≥76 bpm 119 −0.68 ± 4.15 100 0.03 ± 3.84 b76 bpm 100 0.06 ± 4.84 110 0.80 ± 5.00 Systolic blood pressure: ≥140 mmHg 91 −0.01 ± 4.83 84 0.12 ± 4.79 b140 mmHg 128 −0.57 ± 4.22 126 0.64 ± 4.29 Diastolic blood pressure: ≥90 mmHg 47 0.05 ± 5.65 37 −0.15 ± 4.26 b90 mmHg 172 −0.45 ± 4.12 173 0.56 ± 4.54 Smoking: yes (clinically relevant) 20 −1.88 ± 3.42 24 1.02 ± 4.00 no (clinically irrelevant) 199 −0.19 ± 4.55 186 0.36 ± 4.56 History of CVD: yes 128 −0.38 ± 4.57 129 0.38 ± 4.91 no 91 −0.29 ± 4.38 81 0.51 ± 3.75 Type 1 diabetes 61 −1.05 ± 4.72 43 0.53 ± 5.83 Type 2 diabetes 158 −0.07 ± 4.37 167 0.41 ± 4.10 Diabetes duration: ≥10 years 145 −0.41 ± 4.53 134 0.60 ± 4.88 b10 years 74 −0.20 ± 4.42 76 0.13 ± 3.73 Hba1c: ≥7% 189 −0.41 ± 4.52 166 0.37 ± 4.77 b7% 30 0.08 ± 4.30 44 0.68 ± 3.29 Insulin treatment: yes 128 −0.45 ± 4.63 114 0.39 ± 4.83 no 91 −0.19 ± 4.29 96 0.49 ± 4.08 Oral antidiabetic drugs: yes 87 −0.13 ± 4.28 90 0.38 ± 4.11 no 132 −0.48 ± 4.62 120 0.47 ± 4.77 DSPN duration: N3 years 111 −0.38 ± 4.64 106 1.22 ± 4.92 ≤3 years 108 −0.30 ± 4.34 104 −0.37 ± 3.87 DSPN Stage 1 26 −0.71 ± 5.40 22 −0.48 ± 4.38 DSPN Stage 2a 193 −0.29 ± 4.36 188 0.54 ± 4.50 NIS-LL non-responder: yes 53 5.24 ± 3.85 73 4.84 ± 3.86 no 166 −2.12 ± 2.95 137 −1.92 ± 2.67 ACE inhibitors: yes 23 −2.09 ± 3.60 26 0.37 ± 4.14 no 196 −0.14 ± 4.54 184 0.44 ± 4.55 Other antihypertensive drugs: yes 22 −0.20 ± 4.13 24 1.58 ± 7.02 no 197 −0.36 ± 4.53 186 0.28 ± 4.06 ATC code N02, N03, N06: yes 31 −0.40 ± 3.72 20 −0.50 ± 4.20 no 188 −0.33 ± 4.60 190 0.53 ± 4.52

CVD: cardiovascular disease, DSPN: diabetic sensorimotor polyneuropathy, ATC: Anatomical Therapeutic Chemical, N02: analgesics, N03: antiepileptics, N06: psychoanaleptics. Values are mean ± SD.

resulting in smaller groups than n = 20 were not considered in the subcategories with BMI b 30 kg/m2, type 1 diabetes, clinically relevant present analysis. For all efficacy measures, changes from baseline to smoking (yes), and ACE inhibitor treatment (yes), while the highest study end (4 years) were evaluated. Within each subgroup, a baseline (more than 1 point) incremental mean NIS-LL (progression) during adjusted ANCOVA with fixed effects for center and treatment was placebo treatment was noted for the subcategories with age ≥55 years, performed (estimation method: restricted maximum likelihood DSPN duration N3 years, clinically relevant smoking (yes), antihyper- [REML], degrees of freedom: Kenward Rogers). Treatment differences tensive drugs other than ACE inhibitors (yes). However, the subcate- were estimated by difference of LS-means within each subgroup and gories with clinically relevant smoking, ACE inhibitor treatment (yes), 95% confidence intervals (CI) were calculated. All variables were and other antihypertensive drugs (yes) comprised only 20–31 subjects, coded in the same direction whereby positive treatment differences as did the subcategories with ATC code drug classes N02, N03, N06 (yes) indicate better efficacy of ALA compared to placebo treatment. and DSPN stage 1. The definition of NIS-LL non-response resulted in a Non-responders (progressors) were defined as an increase in NIS-LL marked mean increase in NIS-LL from baseline to 4 years by 5.24 points ≥2 points from baseline to 4 years. In the non-responder analysis of in the ALA treated group and by 4.84 points in the placebo group, while treatment effects in the various subcategories odds ratios (OR) with the number of non-responders in the placebo treated group was higher 95% CIs were calculated, with OR b 1 indicating a smaller chance for than in the ALA treated group. ALA treated participants than placebo treated participants to be a Fig. 1 shows the forest plots with LS-means estimates and 95% CI non-responder. The significance level was set to α = 0.05. If a CI does representing the differences in treatment effects between ALA and not cross zero for LS-means estimates or 1 for ORs, the result is placebo over 4 years on the NIS-LL within the subcategories related to regarded as statistically significant. To maintain clarity, only statisti- cardiovascular risk/disease (Fig. 1A) and diabetes and neuropathy cally significant (p b 0.05) and borderline significant (p b 0.06) (Fig. 1B) and baseline predictors of improvement in HRDB (Fig. 1C). LS-means estimates and ORs with 95% CIs are presented in the figures. Significant improvement of NIS-LL in the ALA treated group compared to placebo after 4 years was observed for the baseline subgroups with 3. Results age ≥55 years, BMI b 30 kg/m2, male sex, diastolic blood pressure b90 mmHg, CVD history, treatment with OADs, insulin treatment, The changes in NIS-LL from baseline to 4 years in the different neuropathy duration N3 years, DSPN stage 2a, and ATC code for drug baseline subcategories and treatment groups are shown in Table 2. classes N02, N03, N06 (no). Borderline significance was achieved for The numerically highest (more than −1 point) mean improvements the subgroups with systolic blood pressure b140 mmHg (p = 0.053), in NIS-LL during ALA treatment were observed in the baseline diabetes duration ≥10 years (p = 0.051), and HbA1c ≥7% (p =

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 4 D. Ziegler et al. / Journal of Diabetes and Its Complications xxx (2015) xxx–xxx

Fig. 1. LS-means estimates with 95% confidence intervals (CI) of the differences in treatment effects between ALA and placebo over 4 years on the Neuropathy Impairment Score of the Lower Limbs(NIS-LL)withinthesubcategoriesrelatedtocardiovascularrisk/disease (A) and diabetes and neuropathy (B) and baseline predictors of improvement in heart rate deep breathing (HRDB) (C). Open circles: subgroups achieving significance (p b 0.05) or borderline significance (p b 0.06) in favor of ALA, black circles: subgroups not achieving statistical significance.

0.054). Improvement in HRDB over 4 years in the ALA treated group 2 diabetes, diabetes duration ≥10 years, treatment with OADs, insulin compared to placebo was predicted by treatment with OADs, insulin, treatment, and neuropathy duration N3 years. Borderline significance and ACE inhibitors at baseline. was achieved for the subgroups with HbA1c ≥7% (p = 0.056) and Fig. 2 illustrates the odds ratios (OR) with 95% confidence intervals DSPN stage 2a (p = 0.053). representing the differences in treatment effects between ALA and No consistent predictors of treatment effects over 4 years could be placebo over 4 years with respect to NIS-LL progression (non-re- identified for the remaining efficacy measures including the compos- sponse) for the subgroups related to cardiovascular risk/disease ite score NIS-LL + 7 tests, VDT, peroneal MNCV, sural SNAP (Fig. 2A) as well as diabetes and neuropathy (Fig. 2B). Baseline amplitude, CDT, and HP 0.5–5.0 (data not shown). subgroups which predicted the prevention of NIS-LL progression (non-response) in the ALA treated group compared to placebo after 4. Discussion 4 years included age ≥55 years, BMI b 30 kg/m2, male sex, systolic blood pressure b140 mmHg diastolic blood pressure b90 mmHg, The results of this post-hoc analysis of the NATHAN 1 trial heart rate b76 bpm, CVD history, no clinically relevant smoking, type demonstrate that improvement and prevention of progression of

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 D. Ziegler et al. / Journal of Diabetes and Its Complications xxx (2015) xxx–xxx 5

Fig. 2. Odds ratios (OR) with 95% confidence intervals for baseline predictors of prevention of progression (non-response) in the Neuropathy Impairment Score of the Lower Limbs (NIS-LL) related to cardiovascular risk/disease (A) and diabetes and neuropathy (B) in the ALA treated group compared to placebo over 4 years. Open circles: subgroups achieving significance (p b 0.05) or borderline significance (p b 0.06) in favor of ALA, black circles: subgroups not achieving statistical significance.

neuropathic impairments after 4 years of treatment with ALA were cardiovascular risk factors such as hypertension, obesity, and smoking predicted by normal values of modifiable cardiovascular risk factors should be appropriately controlled to achieve an optimal ALA effect on such as BMI and blood pressure, but on the other hand also by a higher neuropathic impairments, but on the other hand, the drug is also burden due to CVD, diabetes, and neuropathy, suggesting that optimal particularly effective in patients who already developed more severe control of CVD risk factors could contribute to improved efficacy of stages of diabetes, neuropathy, and CVD. ALA in diabetic polyneuropathy. In contrast, improvement in cardiac Comorbidities are common among diabetic patients in clinical autonomic function was predicted by ACE inhibitor treatment, practice. In a large cohort of diabetic patients receiving pharmaco- indicating that agents known to improve HRV may favorably therapy for neuropathic pain, 89.5% reported comorbidities, including modulate the effect of ALA on cardiac autonomic function. hypertension (70.5%), hyperlipidemia (39.2%), and macrovascular In the NATHAN 1 trial, we previously demonstrated that after complications (37.0%) (Ziegler, Schneider, Boess, Berggren, & Birklein, 4 years of treatment both NIS and NIS-LL improved on ALA and 2014). Hypertension is a major CVD risk factor associated with DSPN worsened on placebo (Ziegler et al., 2011). Response analysis of (Kim et al., 2014), and increased echocardiographic left ventricular clinically meaningful improvement and progression in these scores mass predicts the development of DSPN in type 2 diabetic subjects after 4 years revealed that the percentages of clinical responders (Cardoso & Salles, 2008). According to a recent statement from the (decrease in NIS or NIS-LL by ≥2 points) were higher, while at the American Heart Association and American Diabetes Association same time those of non-responders (increase in NIS or NIS-LL by ≥2 (ADA) on prevention of CVD in adults with type 2 diabetes, for most points) were lower on ALA as compared with placebo. This difference individuals a blood pressure target b140/90 mmHg is appropriate was statistically significant for both NIS (p = 0.013) and NIS-LL (p = (Fox et al., 2015). Regarding glycemic control, the ADA considers 0.025) (Ziegler et al., 2011). The present analysis extends beyond HbA1c levels b7% a reasonable treatment goal for many non-pregnant these previous findings by showing that ALA may improve neuro- adults. More stringent HbA1c goals (b6.5%) are suggested for selected pathic impairments particularly in elderly insulin-treated patients individual patients, if this can be achieved without significant with history of CVD in whom weight and blood pressure are well hypoglycemia or other adverse effects of treatment (American controlled. On the other hand, the drug may also be more effective in Diabetes Association, 2015). According to the National Health and those with longer duration of diabetes and neuropathy as well as Nutrition Examination Surveys (NHANES) 2007 to 2012, among HbA1c levels ≥7%. The reasons for this apparent dichotomy are adults with diagnosed diabetes, 36% did not meet individualized unclear, but the practical implications are obvious. On the one hand, HbA1c targets (mean HbA1c level 7.3%) (Ali, Bullard, Gregg, & Del Rio,

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 6 D. Ziegler et al. / Journal of Diabetes and Its Complications xxx (2015) xxx–xxx

2014). Thus, ALA may be particularly suitable for elderly patients with Hyperlipidemia as another important CVD risk factor was not type 2 diabetes and CVD who cannot meet individualized HbA1c assessed, and the vast majority of participants did not receive statins. targets. A major strength of this analysis is that it includes extensive clinical Dyck et al. (2007) assessed the factors influencing DSPN endpoints and neurophysiological phenotyping of the relatively large original in placebo-treated diabetic patients participating in the NATHAN 1 cohort enrolled in the longest controlled trial ever published in the trial, two 1-year clinical trials, and an epidemiologic cohort. They field diabetic neuropathy. suggested that demonstrating neuropathy progression in controlled In conclusion, we demonstrated that both improvement and trials of DSPN is more likely when patients with developing rather prevention of progression of neuropathic impairments after 4 years of than established DSPN are selected and type 1 diabetic patients are treatment with α -lipoic acid on the one hand were associated with preferentially recruited, because there is less variability of normal test normal baseline blood pressure and weight, but on the other hand results due to their younger age. In contrast, our analysis shows that were predicted by a higher burden owing to age, diabetes, after 4 years of treatment with ALA, neuropathic impairments were neuropathy, and history of CVD. Moreover, improvement in cardiac more favorably improved in older subjects with stage 2a rather than autonomic function was linked to treatment with ACE inhibitors stage 1 DSPN. The reason for this discrepancy could be that Dyck et al. suggesting that treatment with agents known to improve HRV may (2007) assessed only placebo-treated participants, while the present favorably modulate the effect of ALA on cardiac autonomic function. analysis focused primarily on the effect size of ALA treatment. Our Thus, the drug may be particularly suitable for the elderly patient with data showing that higher age was associated with a better neuropathy a history of CVD and ACE inhibitor treatment and both more severe outcome on ALA is in line with a recent meta-analysis of 200 publicly diabetes and neuropathy who cannot meet individualized glycemic available randomized clinical trials of pharmacologic treatments for targets. neuropathic pain showing that standardized effect size was greater in subjects with higher mean age (Dworkin et al., 2013). Author contributions Our finding suggesting that ALA treatment improved cardiac autonomic function in patients treated with ACE inhibitors at baseline DZ, PAL, RF, HT, and AIV contributed to the study design. DZ, PAL, is of interest particularly against the background that HRV as a RF, HT, and AIV participated in the acquisition and interpretation of secondary endpoint remained unchanged after 4 years of ALA the data. DZ contributed to data analysis. DZ wrote the manuscript, treatment in the NATHAN 1 trial (Ziegler et al., 2011). Reduced HRV PAL, RF, HT, and AIV reviewed the manuscript. DZ is the guarantor of indicating CAN is a serious complication of diabetes associated with an this work and, as such, had full access to all the data in the study and increased risk of mortality, exercise intolerance, and, presumably, takes responsibility for the integrity of the data and the accuracy of increased incidence of silent myocardial infarction and ischemia the data analysis. (Young et al., 2009; Ziegler et al., 2015). Treatment with the ACE inhibitor quinapril and angiotensin II receptor blocker (ARB) losartan Acknowledgements administered as monotherapy or in combination for 1 year augment- ed vagal activity and reduced sympathetic predominance in diabetic The authors wish to thank Dr. Hans Christian Kuhl, Biometrics patients (Athyros et al., 1998). In the DEKAN study, we previously Department, MEDA Pharma GmbH & Co. KG, for statistical analyses, demonstrated that treatment with ALA using an oral dose of 800 mg/ Dr. Alexander Strom for drawing the figures, and all investigators, day for 4 months improved vagal activity in type 2 diabetic patients subinvestigators, and volunteers participating in this trial. This (Ziegler et al., 1997). It is possible that favorable modulation of work was sponsored by MEDA Pharma GmbH & Co. KG, Bad autonomic tone toward enhancing parasympathetic activity and Homburg, Germany. reducing sympathetic drive by these drugs could be translated into reduction of cardiovascular endpoints in diabetic subjects. Previous References studies have also demonstrated improvement in DSPN following treatment with ACE inhibitors and ARBs. In a controlled trial including Ali, M. K., Bullard, K. M., Gregg, E. W., & Del Rio, C. (2014). A cascade of care for diabetes in the United States: Visualizing the gaps. Annals of Internal Medicine, 161, 681–689. subjects with both type 1 and type 2 diabetes, treatment with the ACE American Diabetes Association (2015). 6. Glycemic targets. Diabetes Care, 38(Suppl. 1), inhibitor trandolapril for 1 year lowered the progression of electro- S33–S40. physiological parameters of DSPN, and also lowered systolic blood Athyros, V. G., Didangelos, T. P., Karamitsos, D. T., Papageorgiou, A. A., Boudoulas, H., & Kontopoulos, A. G. (1998). 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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 D. Ziegler et al. / Journal of Diabetes and Its Complications xxx (2015) xxx–xxx 7

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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