Perspectives on Peripheral Neuropathy as a Consequence of Metformin-Induced Vitamin B12 Deficiency in T2DM

Table 1

Settings, designs, and results of studies that investigated the impact of metformin-induced low vitamin B12 on peripheral neuropathy in T2DM patients.

Study	Setting	Design	Results
Wile and Toth [15]	Neuromuscular clinic at a university hospital, Canada	Case-control study. Cases were T2DM patients on metformin with primary diagnosis of PN (59 participants). Controls were T2DM patients not taking metformin with primary diagnosis of PN (63 participants).	The metformin group had more severe PN (assessed by TCSS and NIS). Electrophysiological markers showed no significant difference between the two groups. Cumulative metformin dose showed a significant positive correlation with TCSS scores (rho = 0.80) and NIS scores (rho = 0.79).
Singh et al. [16]	Internal medicine clinic in a tertiary hospital, India	Cross-sectional study. Randomly selected T2DM patients were divided into metformin users (84 participants) and nonusers (52 participants).	The metformin group had more severe PN (assessed by TCSS). Cumulative metformin dose revealed a significant positive correlation with TCSS (rho = 0.53).
de Groot-Kamphuis et al. [17]	Secondary care outpatient diabetes clinic, the Netherlands	Cross-sectional study. Randomly selected T2DM patients were divided into metformin users (164 participants) and nonusers (134 participants).	Prevalence of neuropathy (obtained from records) was significantly lower in the metformin group.
Chen et al. [13]	Diabetes clinic of a tertiary hospital, UK	Cross-sectional study. Randomly selected T2DM patients were divided into metformin users (152 participants) and nonusers (50 participants).	All PN-assessing tools (monofilament, neurothesiometry, NTSS-6, and s-LANSS) showed no significant differences between the two groups.
Biemans et al. [18]	Four primary care centers, the Netherlands	Cross-sectional study. Metformin-treated T2DM patients were divided into the vitamin B12-deficient (126 participants) and normal (322 participants) groups.	There were no significant differences in PN (assessed by MNSI and extracted from records) between the two groups.
Russo et al. [19]	Diabetes clinic of a university hospital, Italy	Cross-sectional study. T2DM patients were divided into metformin users (124 participants) and nonusers (139 participants).	There was no significant difference in prevalence of PN between the two groups. PN was suspected based on abnormalities of certain evaluations and confirmed by NCVs.
Roy et al. [20]	Tertiary Hospital, India	Cross-sectional study. T2DM patients were divided into (1) the metformin group (35 participants), (2) the metformin + other antihyperglycemic group (20 participants), and (3) the nonmetformin group (35participants).	Neuropathy (assessed by NCVs) did not differ significantly between the groups.
Ahmed et al. [14]	Diabetes clinics of two tertiary hospitals, South Africa	Cross-sectional study. Metformin-treatedT2DM patients were divided into the vitamin B12-deficient (34 participants) and normal (87 participants) groups.	There was no difference in the presence of PN (assessed by NTSS-6) between the two groups. Levels of vitamin B12 and NTSS-6 scores were not correlated.

MNSI: Michigan Neuropathy Screening Instrument; NCVs: nerve conduction velocities; NIS: Neuropathy Impairment Score; NTSS-6: Neuropathy Total Symptom Score-6; PN: peripheral neuropathy; rho: Spearman’s rank correlation coefficient; s-LANSS: Self-administered Leeds Assessment of Neuropathic Symptoms and Signs; TCSS: Toronto Clinical Scoring System.