Predictors of improvement and progression of diabetic polyneuropathy following treatment with α-lipoic acid for 4 years in the NATHAN 1 trial
Introduction
About one third of all patients with diabetes are affected by diabetic sensorimotor polyneuropathy (DSPN) which has a major impact on morbidity and mortality (Ziegler, Papanas, Vinik, & Shaw, 2014). Neuropathic sensory deficits such as reduced touch and vibration perception are independent predictors of mortality (Coppini, Bowtell, Weng, Young, & Sönksen, 2000), cardiac death or nonfatal myocardial infarction (Young et al., 2009), incident cardiovascular disease (CVD) events (Brownrigg et al., 2014), and lower-limb amputation (Rajamani et al., 2009). On the other hand, history of myocardial infarction and CVD and the underlying risk factors such as obesity, hypertension, and hyperlipidemia may predict the risk of developing DSPN (Forrest et al., 1997, Sands et al., 1997, Tesfaye et al., 2005, Wiggin et al., 2009, Ylitalo et al., 2011, Ziegler et al., 2008, Ziegler et al., 2009).
Effective causal treatment of DSPN remains challenging for the physician. The Diabetes Control and Complications Trial/Epidemiology 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 et al., 2014, The Diabetes Control and Complications Trial Research Group, 1993). In contrast, there is no clear evidence that intensive diabetes therapy or a target-driven intensified intervention aimed at multiple risk cardiovascular factors favorably influence the development or progression of DSPN and CAN in type 2 diabetic subjects (Boussageon et al., 2011, Charles et al., 2011, Charles et al., 2013, Gaede et al., 2008, Sandbæk et al., 2014). In fact, self-reported history of neuropathy was a significant predictor for increased mortality in patients with type 2 diabetes allocated to a very intensive diabetes therapy aimed at HbA1c < 6.0% in the ACCORD trial (Calles-Escandón 2010). On the other hand, near-normoglycemia is difficult to achieve in a considerable number of individuals with diabetes. Thus, there is an unmet need for disease-modifying treatments considering the pathogenetic mechanisms contributing to DSPN. Since diabetic neuropathy is closely linked to CVD and both oxidative stress and vascular dysfunction play a paramount pathogenetic role (Nishikawa et al., 2000, Ziegler, Buchholz, et al., 2015), agents that reduce oxidative stress such as α-lipoic acid (ALA) and those ameliorating vascular dysfunction and promote vasodilatation such as ACE inhibitors have been evaluated in clinical trials showing improvement of DSPN and CAN (Malik et al., 1998, Papanas and Ziegler, 2014, Ruggenenti et al., 2011).
The efficacy and safety of ALA have been assessed in several controlled clinical trials and meta-analyses (Papanas & Ziegler, 2014). In the NATHAN 1 trial, we evaluated the efficacy and safety of α-lipoic acid over 4 years in patients with mild-to-moderate DSPN (Ziegler et al., 2011). The primary outcome measure was a composite score including the Neuropathy Impairment Score of the lower limbs and 7 nerve function tests (NIS-LL + 7 tests). Primary analysis showed no significant difference between the groups for the changes in NIS-LL + 7 tests from baseline to 4 years (p = 0.105). The lack of improvement in the composite score was predominantly due to the fact that nerve conduction deficits in the placebo-treated group did 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), respectively. The changes in nerve conduction and quantitative sensory testing did not differ between both groups after 4 years (Ziegler et al., 2011).
Based on the epidemiological and clinical evidence, here we hypothesized that CVD and its underlying risk factors which are frequently encountered in type 2 diabetic patients and the concomitant pharmacotherapy could modify the effect of ALA on neuropathy outcomes. Thus, in the present post-hoc analysis of the NATHAN 1 study, we aimed to determine the baseline factors that may predict effect of ALA on neuropathic impairments and cardiac autonomic function focusing on CVD and its risk factors such as obesity and hypertension as well as concomitant medication.
Section snippets
Study population and methods
The NATHAN (Neurological Assessment of Thioctic Acid in Diabetic Neuropathy) 1 trial was a multicenter (36 centers in USA, Canada, and Europe), randomized, double-blind, placebo-controlled, two-arm, 1:1 allocation ratio, parallel-group clinical trial using film-coated tablets containing ALA 600 mg qd (Thioctacid® HR, MEDA Pharma GmbH & Co. KG, Bad Homburg, Germany) or matching placebo tablets in diabetic patients with mild-to-moderate polyneuropathy. Approvals were obtained from the local ethics
Results
The changes in NIS-LL from baseline to 4 years in the different baseline subcategories and treatment groups are shown in Table 2. The numerically highest (more than − 1 point) mean improvements in NIS-LL during ALA treatment were observed in the baseline subcategories with BMI < 30 kg/m2, type 1 diabetes, clinically relevant smoking (yes), and ACE inhibitor treatment (yes), while the highest (more than 1 point) incremental mean NIS-LL (progression) during placebo treatment was noted for the
Discussion
The results of this post-hoc analysis of the NATHAN 1 trial demonstrate that improvement and prevention of progression of neuropathic impairments after 4 years of treatment with ALA were predicted by normal values of modifiable cardiovascular risk factors such as BMI and blood pressure, but on the other hand also by a higher burden due to CVD, diabetes, and neuropathy, suggesting that optimal control of CVD risk factors could contribute to improved efficacy of ALA in diabetic polyneuropathy. In
Author contributions
DZ, PAL, RF, HT, and AIV contributed to the study design. DZ, PAL, RF, HT, and AIV participated in the acquisition and interpretation of the data. DZ contributed to data analysis. DZ wrote the manuscript, PAL, RF, HT, and AIV reviewed the manuscript. DZ is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Acknowledgements
The authors wish to thank Dr. Hans Christian Kuhl, Biometrics Department, MEDA Pharma GmbH & Co. KG, for statistical analyses, Dr. Alexander Strom for drawing the figures, and all investigators, subinvestigators, and volunteers participating in this trial. This work was sponsored by MEDA Pharma GmbH & Co. KG, Bad Homburg, Germany.
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Conflict of interest: DZ received honoraria for speaking and consulting activities from MEDA Pharma. HT is employee of MEDA Pharma.
ClinicalTrials.gov Identifier: NCT00977483