3.3 Median MNCV
Nine trials[12–14,22,25,27,28,32,34] involving 646 patients measured the median MNCV. Heterogeneity was significant for the analysis (P < .00001, I 2 = 90%), the RE model was used. Compared with P monotherapy, median MNCV showed significant improvement in the M + P combination therapy group (MD 6.29, 95% CI 4.63–7.94, P < .00001) (Fig. 4A). On sensitivity analyses, after excluding the study reported by Li HJ, the I 2 value ranged from 90% to 71% and the overall effect ranged from 7.42 to 10.38. The subgroup with < 28 days of study duration showed moderate heterogeneity in median MNCV outcome (I 2 = 57%, P = .07).
3.4 Median SNCV
Nine trials[12–14,22,25,27,28,32,34] involving 646 patients measured the median SNCV. As shown in Figure 4B, the RE model was used because significant heterogeneity between studies for the 2 groups was observed (P < .00001, I 2 = 94%). Compared with P monotherapy, M + P combination therapy increased median SNCV significantly (MD 5.68, 95% CI 3.53–7.83, P < .00001). On sensitivity analyses, we found the I 2 value ranged from 89% to 95%, which indicated the result, was robust.
3.5 Peroneal MNCV
Eleven trials[12–14,22,24,25,27–29,32,34] involving 773 patients measured the peroneal MNCV. As shown in Figure 5A, the RE model was used because significant heterogeneity between studies for the two groups was observed (P < .00001, I 2 = 92%). Compared with P monotherapy, M + P combination therapy accelerated peroneal MNCV significantly (MD 5.36, 95% CI 3.86–6.87, P < .00001). The sensitivity analyses showed that the I 2 value ranged from 88% to 93% and the overall effect ranged from 6.07 to 7.60, which indicated the result was robust.
3.6 Peroneal SNCV
Eleven trials[12–14,22,24,25,27–29,32,34] involving 773 patients measured the peroneal SNCV. As shown in Figure 5B, the RE model was used because significant heterogeneity between studies for the 2 groups was observed (P < .00001, I 2 = 86%). Compared with P monotherapy, M + P combination therapy improved peroneal SNCV significantly (MD 4.62, 95% CI 3.48–5.75, P < .00001). On sensitivity analyses, we found the I 2 value ranged from 80% to 88%, which indicated the result, was robust.
Eight studies[12,14,24–26,28,29,31] reported the adverse events, there were no serious treatment-related side effects during the treatment period in both M + P combination therapy group and P monotherapy group. Only some mild adverse effects including facial blushing (4 cases),[12,14,25] local skin redness (3 cases), pain at the injection site (9 cases),[24,28] gastrointestinal discomfort (1 case), dizziness (4 cases),[14,25,29] abdominal distention (3 cases), limb burning (3 cases), anepithymia (2 cases), headache (2 cases)[25,28] and transient orthostatic hypotension (1 case) in M + P combination therapy group, and facial blushing (2 cases),[14,29] pain at the injection site (12 cases),[24,25,28,29] abdominal distention (1 case), limb burning (1 case), anepithymia (2 cases), headache (1 case), transient orthostatic hypotension (1 case), and dizziness (2 cases)[14,25] in P monotherapy group were reported. Because most studies did not report these side effects in detail, we were unable to analyze the rates of adverse events.
With the raised prevalence of diabetes, the occurrence of DPN increases significantly and has become a leading cause of diabetes-related disability. Sensory neuropathy is a principal form of DPN, whose pathological changes include demyelination of nerve fibers, axonal degeneration, cell hyperplasia, and then fading-away of myelinated fibers. Currently, DPN is believed to be closely related to various factors, including genetic predisposition, glucose toxicity, abnormal aldose reductase activity, oxidative stress.[5,35] Besides that, factors such as diabetic microangiopathy-induced hypoxic-ischemic neuronal death and altered hemodynamics, as well as disorder of intrinsic clotting, also play a vital role in the occurrence of DPN.[1,36] Therefore, regulating blood glucose homeostasis, improving the microcirculation of peripheral nerve endings, and suppressing oxidative stress are cures of DPN, moreover, significant treatment options for diabetic complications.
P, an efficient biological activator, induces vasodilation of blood vessels through activating intracelluar adenylate cyclase, enhances erythrocyte deformability, improves microcirculation disturbance, protects against ischemia-hypoxia injury in peripheral nerve tissue, and finally ameliorates the symptoms of peripheral nervous system involvement in the form of sensory impairment and diminished tendon jerks suggesting the presence of neuropathy. In addition, P can reactivate Na(+)-K(+)-ATPase at the surfaces of nerve cells, improve neuronal metabolism and inhibit oxidation of the plasma membrane of a cell,[10,37] all of which contribute to the improvements of DPN. It has been demonstrated that P significantly improve the clinical symptoms of DPN and increase the conduction velocity of sensory and motor fibres in human median, peroneal nerves.[10,11,38]
M, a vitamin B12 analog, is involved in methyl transfer reactions in vivo by methylation. M is distributed to organelles in axons of nerve cells easily after being absorbed into the body, promotes nucleic acid and protein synthesis, and axon regeneration.[39,40] It also can stimulate phosphatidylcholine synthesis to increase myelinogenesis, and then speed up the motor and sensory NCVs.[41,42] Additionally, M accelerates NCVs directly by improving blocked nerve impulse conduction and decreased neurotransmitter levels. Many studies suggested that M monotherapy or polytherapy with other drugs is an effective and safe therapy for patients with DPN.[25,44–46]
Our findings showed that, after P monotherapy and M + P combination therapy, DPN patients all had improvement in clinical symptoms and NCVs, while patients who received the later therapy showed significant higher-level improvement. Moreover, the results also indicated that synergistic potential existed in the course of combination therapy without severe adverse events. We executed subgroup and sensitivity analyses in order to minimize the influence of a particular study or an inferior study design. Results of subgroup analyses according to the study duration suggested that the efficacy and 4 NCVs benefits were seen in 2 subgroups (Table 2).
Our analysis also has several limitations that must be taken into consideration when interpreting the results. First, the sample size of 3 trials was small.[29,32,33] Second, a reporting bias existed in our meta-analysis, due to only the data from published trials were included and the unpublished statistically nonsignificant results were excluded, but it would be very difficult to gain access to data from the unpublished studies. Third, because this study was a study-level meta-analysis, individual patient data were not included in the analysis, thus, we could not adjust for patient-level confounders. In addition, the small-study effect, insufficient number of trials, and significant statistical heterogeneity may result in the asymmetry of funnel plot, which indicated the likelihood of publication bias.
In summary, this meta-analysis suggests that DPN patients with M + P combination therapy have significant higher-level improvement in clinical symptoms and NCVs compared with P monotherapy. Moreover, the results also indicate that no serious adverse events occur during M + P combination therapy. But, due to poor methodological quality of the studies included, strong and definitive recommendations cannot be made for patients with DPN and further large-scale, well-designed RCTs are urgently needed.
Investigation: De-Qi Jiang, Shi-Hua Zhao, Ming-Xing Li.
Methodology: Shi-Hua Zhao, Li-Lin Jiang, Yong Wang.
Writing – original draft: De-Qi Jiang.
Writing – review & editing: Yan Wang.
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Keywords:Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
diabetic peripheral neuropathy; efficacy; meta-analysis; methylcobalamin; nerve conduction velocity; prostaglandin E1