Twelve months of benfotiamine did not improve neuropathic outcomes in people with type 2 diabetes and symptomatic polyneuropathy: the BOND study
Aims: The BOND study sought to determine whether long-term treatment with benfotiamine could improve structural, functional and clinical measures of diabetic sensorimotor polyneuropathy (DSPN) in individuals with type 2 diabetes.
Methods: This randomised, double-blind, placebo-controlled, monocentre phase II trial enrolled 57 participants with mild-to-moderate symptomatic DSPN. Participants were assigned in a 1:1 ratio to receive benfotiamine 300 mg twice daily or matching placebo for 12 months.
The primary outcome was the change in corneal nerve fibre length (CNFL), measured using CCM, a validated, non-invasive marker of small fibre pathology and regeneration. Secondary outcomes included additional CCM parameters, intraepidermal nerve fibre density (IENFD), nerve conduction studies, quantitative sensory testing, cardiovascular autonomic function tests, sudomotor assessment, Neuropathy Symptom Score and quality-of-life measures. Circulating thiamine metabolites were measured to confirm pharmacodynamic activity and treatment adherence.
Results: Benfotiamine markedly increased circulating thiamine biomarkers, confirming systemic exposure. However, there was no significant difference between groups in the primary endpoint, with no improvement in CCM parameters over 12 months. There was no significant difference in IENFD between two groups. Large fibre function, quantitative sensory testing, autonomic measures, clinical scores and quality-of-life indices were similarly unchanged, aside from a non-significant trend in the Neuropathy Symptom Score. Treatment was well tolerated, with no relevant safety concerns.
Conclusions: In individuals with type 2 diabetes and established mild-to-moderate DSPN, 12 months of benfotiamine therapy did not induce measurable small fibre regeneration, functional improvement or clinically meaningful benefit compared with placebo.
Comments: A key strength of this study is the use of corneal confocal microscopy as the primary endpoint. Structural small fibre measures are rarely prioritised in neuropathy trials, and the agreeable skin biopsy findings support the results. Although benfotiamine increased circulating thiamine levels, this did not translate into structural recovery. Type 2 diabetic neuropathy arises from multiple interacting mechanisms, including metabolic, microvascular and inflammatory factors; targeting a single pathway is therefore unlikely to produce measurable regeneration, particularly in an unselected population. Participants were not recruited based on thiamine deficiency, and enhancement of transketolase activity alone may not be sufficient to achieve meaningful improvement in neuropathy. Methodologically, the sample size was based on effect estimates from observational data, which may have been optimistic given the slow progression of DSPN and the absence of placebo deterioration. Moreover, the wide range of secondary endpoints, while informative, may have reduced statistical power and complicated interpretation.
Maryam Ferdousi
Reference. Ziegler D, Sipola G, Strom A, Strassburger K, Jander L, Herder C, Knebel B, Reule C, Jaghutriz BA, Moreira Tupac Yupanqui AC, Icks A, Al-Hasani H, Roden M, Kuss O, Bönhof GJ. Effects of benfotiamine treatment over 12 months on morphometric, neurophysiological and clinical measures in type 2 diabetes patients with symptomatic polyneuropathy: a randomized, placebo-controlled, double-blind clinical trial (BOND study). BMJ Open Diabetes Res Care. 2026 Jan 22;14(1):e005773. doi: 10.1136/bmjdrc-2025-005773. PMID: 41571333; PMCID: PMC12829400.
