Increased Risk of Cognitive Impairment in Patients With Diabetes Is Associated With Metformin

Abstract

OBJECTIVETo investigate the associations of metformin, serum vitamin B12, calcium supplements, and cognitive impairment in patients with diabetes.RESEARCH DESIGN AND METHODSParticipants were recruited from the Primary Research in Memory (PRIME) clinics study, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, and the Barwon region of southeastern Australia. Patients with Alzheimer disease (AD) (n = 480) or mild cognitive impairment (n = 187) and those who were cognitively intact (n = 687) were included; patients with stroke or with neurodegenerative diseases other than AD were excluded. Subgroup analyses were performed for participants who had either type 2 diabetes (n = 104) or impaired glucose tolerance (n = 22).RESULTSParticipants with diabetes (n = 126) had worse cognitive performance than participants who did not have diabetes (n = 1,228; adjusted odds ratio 1.51 [95% CI 1.03–2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05–4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B12, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19–0.92]).CONCLUSIONSMetformin use was associated with impaired cognitive performance. Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B12 and calcium use on cognition in older people with diabetes who are taking metformin.

Response to Comment on Moore et al. Increased Risk of Cognitive Impairment in Patients With Diabetes Is Associated With Metformin. Diabetes Care 2013;36:2981–2987

“…We thank Goodarzi (1) for his interest in our work (2) and recognize that we agree with most of the criticisms leveled at our study. Indeed, most of the points raised were acknowledged in our original work.…”

Metformin Treatment and Homocysteine: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…This malabsorption ultimately leads to a reduction of serum Vitamin B 12 [41][42][43][44][45]. Hence, some researchers were calling attention to the monitoring of Vitamin B 12 concentration in the diabetic patients treated with metformin, and suggested Vitamin B 12 supplementation could be considered in patients with Vitamin B 12 deficiency [3,46,47], although some authors still doubt the clinical significance of this reduction [48,49]. A recent clinical trial suggested that the metformin-associated reduction of the serum Vitamin B 12 was due to the increased transportation and utility of Vitamin B 12 by cells stimulated by metformin [50].…”

Metformin: od mehanizmov delovanja do napredne klinične uporabe

“…Stopnja znižanja ravni vitamina B12 je odvisna od skupnega odmerka (95). Klinični pomen opisane spremembe je sicer še vedno stvar razprave; vsaj nekatere raziskave pa so pokazale, da bi lahko nižja koncentracija vitamina B12, povzročena z metforminom, vodila tudi razvoj v megaloblastne anemije (96), kognitivnega upada in napredovanja diabetične periferne nevropatije (97). Zaradi velikih zalog vitamina B12 se pomanjkanje izrazi šele po večletni uporabi metformina.…”