Vitamin B DPN Meta-Analysis
(2026)Objective
Evaluate whether vitamin B supplementation (mono- or combination) improves pain, clinical neuropathy scores, and nerve conduction parameters in adults with diabetic peripheral neuropathy (DPN).
Study Summary
• MNSI Examination improved (MD -0.39, 95% CI -0.66 to -0.12; I²=0%) but did not reach MCID of 0.5
• Sural sensory nerve improved: NCV +2.10 m/s (95% CI 0.35 to 3.86) and amplitude +0.88 µV (95% CI 0.08 to 1.67)
• Generic pain (NRS/VAS) unchanged (MD -0.44, 95% CI -1.77 to 0.89; I²=84.5%); disease-specific pain scale favored B (MD -3.06, 95% CI -5.61 to -0.51) but only 2 studies from same group
• Peroneal NCV/amplitude unchanged; tibial NCV paradoxically favored control (MD -1.23, 95% CI -2.37 to -0.09), driven by single benfotiamine trial in T1DM
• No serious adverse events attributable to vitamin B reported
Intervention
Vitamin B supplementation — B1 (thiamine, benfotiamine, sulbutiamine), B6 (pyridoxine), B9 (folate/L-methylfolate), B12 (cobalamin/methylcobalamin), or combinations; oral or parenteral routes.
Inclusion Criteria
Adults ≥18 y with diabetic peripheral neuropathy (T1DM or T2DM) diagnosed by validated clinical scales (NDS, MNSI, TSS), nerve conduction studies, or explicit author criteria; RCT design.
Study Design
Arms: Vitamin B (any form/dose/route, mono or combination) ± standard care vs placebo, no treatment/standard care, or active comparator.
Patients per Arm: 13 RCTs, 834 participants total (414 vitamin B, 420 control); individual trials 14–214 participants
Outcome
• MNSIE significant but sub-MCID (MD -0.39, 95% CI -0.66 to -0.12)
• Sural NCV +2.10 m/s (95% CI 0.35 to 3.86) and amplitude +0.88 µV (95% CI 0.08 to 1.67)
• NRS/VAS pain not significant (MD -0.44, 95% CI -1.77 to 0.89, I²=84.5%)
• Peroneal NCV/amplitude not significant; tibial NCV favored control (MD -1.23, 95% CI -2.37 to -0.09)
• Combination regimens showed larger numerical benefits than monotherapy (interaction p=0.039 for peroneal NCV only)
• Safety: no serious AEs attributable to B vitamins
Clinical Question
Does vitamin B supplementation (any form, dose, or route — as monotherapy or in combination) improve pain, clinical neuropathy scores, or nerve conduction parameters versus placebo/standard care in adults with diabetic peripheral neuropathy?
Bottom Line
In 13 RCTs (834 patients) with DPN, vitamin B improved MNSI clinical scores and sural sensory nerve conduction, but did not consistently reduce generic pain or motor nerve parameters; substantial heterogeneity and near-universal absence of baseline B-vitamin status data preclude routine recommendation, and combination regimens appear more promising than monotherapy.
Major Points
- 13 RCTs (834 participants; 414 vitamin B, 420 control) published 1981–2026 from Greece, Indonesia, USA, Iran, Germany, Malaysia, and Norway were pooled with random-effects meta-analysis (PRISMA 2020, RoB 2).
- MNSI Questionnaire improved with vitamin B (MD -1.44, 95% CI -2.48 to -0.39; 4 studies, n=233; I²=80.1%) and MNSI Examination improved (MD -0.39, 95% CI -0.66 to -0.12; 5 studies, n=284; I²=0%), though the MNSIE change did not reach the MCID of 0.5 points.
- Sural sensory nerve conduction velocity increased (MD 2.10 m/s, 95% CI 0.35–3.86; 5 studies, n=329; I²=0.6%) and sural amplitude increased (MD 0.88 µV, 95% CI 0.08–1.67; 5 studies, n=360; I²=52.7%) — the most consistent finding.
- Generic pain (NRS/VAS) showed no significant pooled effect (MD -0.44, 95% CI -1.77 to 0.89; 4 studies, n=321; I²=84.5%); disease-specific Pain Detect Questionnaire favored vitamin B (MD -3.06, 95% CI -5.61 to -0.51) but only 2 studies from same research group.
- Peroneal NCV (MD 0.09, 95% CI -2.04 to 2.22; I²=87.6%) and peroneal/tibial amplitudes were not significantly changed; tibial NCV paradoxically favored control (MD -1.23, 95% CI -2.37 to -0.09; I²=0%), driven by a single 24-month benfotiamine trial in T1DM (Fraser 2012).
- Combination B-vitamin regimens (n=4 studies) consistently produced numerically larger effects than monotherapy (n=9), but the interaction test was significant only for peroneal NCV (p=0.039); other outcomes remained non-significant.
- Risk of bias (RoB 2): low in 6/13 studies, some concerns in 5/13, high in 2/13, with randomization process and outcome measurement as the main sources of concern.
- Adverse events: only 4 of 13 trials reported AEs; no serious AEs attributable to vitamin B were reported; oral and IV B vitamins were generally well tolerated.
- Critical evidence gap: 11 of 13 trials did not measure baseline B-vitamin status and none stratified randomization by deficiency, likely diluting true treatment effects.
Study Design
- Study Type
- Systematic Review and Meta-Analysis of Randomized Controlled Trials
- Randomization
- No
- Blinding
- Not applicable (meta-analysis of RCTs; included RCTs ranged from open-label to double-blind)
- Sample Size
- 834
- Follow-up
- Included trial durations 0.28 months (5 IV injections over 9 days) to 24 months
- Centers
- Multiple (13 RCTs across ≥7 countries)
- Countries
- Greece, Indonesia, USA, Iran, Germany, Malaysia, Norway
Primary Outcome
Definition: MNSI Examination score (5 studies, n=284) — clinical neuropathy examination
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Reference group | Vitamin B supplementation | - (-0.66 to -0.12) | significant (favors vitamin B; I²=0%) |
Limitations & Criticisms
- Substantial heterogeneity for key outcomes: pain I²=84.5%, peroneal NCV I²=87.6%; pooled estimates presented narratively rather than as reliable summary estimates.
- Only 13 RCTs and most outcomes informed by 4–6 studies, limiting power for subgroup analyses and publication bias testing.
- 11 of 13 trials did not measure baseline B-vitamin status and no trial stratified randomization or reported effects by deficiency status — likely dilutes true treatment effect and is the most critical evidence gap.
- Two trials (Didangelos 2020, Farvid 2011) evaluated multi-component interventions containing non-B agents (superoxide dismutase, alpha-lipoic acid, acetyl-L-carnitine, minerals, vitamins C/E), preventing isolation of the vitamin B effect.
- Significant Pain Detect Questionnaire result derives from two studies by the same research group at the same institution using the same protocol — cannot be considered independently replicated.
- MNSIE improvement, while statistically significant, did not meet the established MCID of 0.5 points; MCIDs for other outcomes are either absent or not met.
- Unexpected tibial NCV result favoring control is entirely driven by one large precise study (Fraser 2012, 24-month benfotiamine monotherapy in T1DM) with zero heterogeneity.
- Prespecified subgroup analyses by dose, duration, route, and baseline status could not be performed due to insufficient studies per subgroup.
- 2 of 13 trials had high risk of bias and 5 had some concerns, potentially inflating effect estimates.
- Embase, Web of Science, and Scopus not searched due to institutional access limitations (search limited to PubMed, Cochrane, ClinicalTrials.gov plus reference screening of 8 systematic reviews).
Citation
J Clin Med. 2026;15(13):5156. doi:10.3390/jcm15135156