Supplements · Metabolic & Cardiometabolic
metformin causes vitamin B12 deficiency
In plain terms: Does metformin cause vitamin B12 deficiency?
Strong support Supplements 🔬 Includes disconfirming
Part of: 💊 metformin
RefutedContestedStrong support
consensus score 0.82
Yes — long-term metformin lowers serum B12 and raises risk of biochemical deficiency in a dose- and duration-dependent way, confirmed by both the DPPOS and a placebo-controlled RCT plus meta-analyses; clinically overt deficiency is less common but real.
📅 Last reviewed: 2026-07-15 ⓘ
Evidence ladder
How far up the ladder this claim has climbed. A high consensus on a low rung means "consistent so far," not "proven in people."
Top evidence so far: All trials, pooled (Meta-analysis)
MechanismIn-vitroAnimalObservationalRCTMeta-analysis
How the studies fall
16 support 0 contradict 3 tested null 1 mixed · 20 sources, 15 independent groups
What the evidence shows
Long-term metformin lowers serum vitamin B12 and raises biochemical deficiency in proportion to dose and duration: in UK Biobank, 6 to 13 percent of users depending on CUBN genotype against about 1 percent of the unexposed, and beyond five years the odds roughly tripled. Clinically overt deficiency is much rarer, and pooled randomised rates are low.
The evidence (20)
| Source | Grade | Stance | Quality | Finding |
|---|---|---|---|---|
| Tahir EA, Ahmed MG, Al Swayah MB, Elsayed SM, Alnoaimi FA, Hegazy AM, Abdelalim NS, Diab RA 2026 · Endocrinology, diabetes & metabolism | meta-analysis | mixed | low | 5 studies; RCT B12-deficiency pooled rate 1.4% [CI -0.012,0.040]; observational pooled 18.7% [CI -0.212,0.586], I2=88%; B12 decline at 6/12mo not stat/clin significant (p>0.05) |
| Baldwin FD, Bedair KF, Jorgensen AL, Green L, Asiimwe IG, Palmer CNA, Campbell A, Hayward C, Pan Q, Shu S, Li JH, Diabetes Prevention Program (DPP) Research Group, Pearson ER, Pirmohamed M, Carr DF 2026 · Diabetologia | observational | supports | high | UK Biobank GWAS; B12 deficiency baseline (no metformin) 0.84-1.20% vs metformin-exposed 6.02%(GG)/7.96%(GA)/12.84%(AA) CUBN rs1801222; time-to-10%-deficient 21yr(GG) vs 11yr(AA) |
| Rangare V, Nagwanshi J, Raghuwanshi K 2026 · Cureus | observational | supports | low | n=170 T2DM; metformin >5yr independent predictor of B12 deficiency, adjusted OR 2.85 (95% CI 1.32-6.12); concomitant pantoprazole also independent |
| Bissar L, Alghamdi MK, Alwajeeh S, Hefni L 2026 · Curr Diabetes Rev | observational | tested-null | moderate | Retrospective single-centre record review, 246 T2DM patients (Jeddah); deficiency = B12 <145 pmol/L. Underpowered trend: deficiency in 7.7% of metformin users vs 4.8% of non-users, 'not statistically significant (p=0.571)'. Same direction on levels: median B12 296 vs 382 pg/mL, p=0.001. Group sizes and adjustment not in abstract. |
| Iwańska A, Goncerz D, Ahmed M, Aoun R, Kozioł-Kozakowska A, Szczudlik E, Stępniewska A, Wójcik M, Starzyk JB 2026 · European journal of pediatrics | observational | supports | moderate | Children with obesity, n=500, 12% on metformin; metformin users had significantly lower B12 (398 vs 410 pg/mL, p=0.043); no non-metformin severity correlation |
| Chapman LE, Darling AL, Brown JE 2016 · Diabetes Metab | meta-analysis | supports | moderate | Meta-analysis: metformin associated with reduced serum B12, with dose and duration as risk modifiers. |
| Kakarlapudi Y, Kondabolu SK, Tehseen Z, Khemani V, J SK, Nousherwani MD, Saleem F, Abdelhameed AN 2022 · Cureus | observational | supports | moderate | Cross-sectional/cohort: higher B12 deficiency prevalence and peripheral neuropathy in metformin-treated T2D; smaller, lower-quality but concordant. |
| Out M, Top WMC, Lehert P, Schalkwijk CA, Stehouwer CDA, Kooy A 2018 · Diabetes Obes Metab | RCT | tested-null | moderate | HOME negative control: metformin did NOT lower vitamin D (no effect), showing the B12 finding is specific rather than a generic nutrient artifact. |
| Out M, Kooy A, Lehert P, Schalkwijk CA, Stehouwer CDA 2018 · J Diabetes Complications | RCT | supports | moderate | HOME post-hoc: metformin raised methylmalonic acid (functional B12 marker), confirming the deficiency is metabolically real, not just a transport artifact. |
| Niafar M, Hai F, Porhomayon J, Nader ND 2015 · Intern Emerg Med | meta-analysis | supports | moderate | Meta-analysis: metformin use significantly associated with lower B12 and higher deficiency risk in T2D across studies. |
| Wakode S, Gour R, Lokhande SL, Singhai A, Wakode A, Bharshankar R, Singh J, Sukumar MS 2026 · Cureus | observational | supports | moderate | Prospective, n=52 newly diagnosed T2DM, metformin monotherapy 6mo: B12 506.7->485.0 pg/mL (p<0.001); homocysteine and MMA rose in parallel |
| Bhadade R, Dongare N, Harde M, deSouza R, Patel A 2026 · The Journal of the Association of Physicians of India | observational | supports | moderate | n=180 (90 cases/90 cohabiting non-metformin controls); B12 206.66 vs 301.44 pg/mL (p<0.001); deficiency 40.0% vs 11.1%, OR 5.33 (95% CI 2.44-11.65) |
| Feingold KR, Adler RA, Ahmed SF, Anawalt B, Blackman MR, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hamilton E, Hofland J, Jan de Beur S, Kalra S, Kaltsas G, Kapoor N, Kim M, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Muzumdar R, Purnell J, Rey R, Sahay R, Shah AS, Sperling MA, Stratakis CA, Trence DL, Wilson DP, Feingold KR 2014 · Prescrire Int | meta-analysis | supports | moderate | Review notes metformin sometimes causes B12 deficiency leading to macrocytic anemia or peripheral neuropathy. |
| Ali HO, Agwu E, Ali MA, Jama YM, Ahmed AH, Yusuf MAM, Araye AA, Osobow IM, Sandeyl AA, Ahmed ZA, Onyanga N, Nor FI, Mohamed AH, Karshe AH, Hirsi AM, Mohamed AA, Jayte M 2026 · Diabetes, metabolic syndrome and obesity : targets and therapy | observational | supports | moderate | n=257 Ugandan T2DM on metformin; deficiency 10.1%; duration >=10yr AOR 3.94 (95% CI 1.34-11.56); dose 2000mg AOR 4.32 (95% CI 1.47-12.67) |
| Aroda VR, Edelstein SL, Goldberg RB, Knowler WC, Marcovina SM, Orchard TJ, Bray GA, Schade DS, Temprosa MG, White NH, Crandall JP, Diabetes Prevention Program Research Group 2016 · J Clin Endocrinol Metab | RCT | supports | high | DPPOS: long-term metformin increased risk of B12 deficiency vs placebo (HR rising with duration), with anemia and neuropathy signals; landmark prevention-cohort confirmation. |
| Ballal A, Vidyasagar S, Acharya V, Amrutha Sukumar C 2025 · Clinical medicine insights. Endocrinology and diabetes | observational | supports | moderate | Prospective cross-sectional; statistically significant association between metformin use and B12 deficiency; mean duration to deficiency onset 13.6 years |
| de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, Verburg J, Donker AJ, Stehouwer CD 2010 · BMJ | RCT | supports | high | HOME placebo-controlled RCT (4.3y): metformin lowered B12 by ~19% and raised risk of B12 deficiency (OR ~3), establishing causality not just association. |
| Yang W, Cai X, Wu H, Ji L 2019 · J Diabetes | RCT | supports | moderate | HOME-trial analysis: metformin associated with lower B12, more deficiency, and links to anemia and peripheral neuropathy; reinforces clinical sequelae. |
| Rubbani A, Khalid D, Nadeem S, Jamali AG, Rizvi SAB, Rabbani A, Sahitia S, Asfand Yar M, Albatrawi AAM, Abdul-Latif MM 2025 · Cureus | meta-analysis | tested-null | low | Meta-analysis links long-term metformin to iron-deficiency anemia and oxidative stress, noting associated B12 depletion. |
| Tillemans MPH, Giezen TJ, Egberts TCG, J Kalisvaart K 2026 · BMC geriatrics | observational | supports | moderate | n=7132 hospitalized elderly; metformin use independently associated with B12 deficiency, adjusted OR 2.5 (95% CI 1.7-3.6), dose-dependent |
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