Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial
de Jager et al. • BMJ
Key Finding
Metformin reduced B12 by 19% (P<0.001); B12 deficiency (<150 pmol/L) NNH 13.8 per 4.3 years; deficiency prevalence 9.9% metformin vs 2.7% placebo
Key Findings
- 1Metformin reduced B12 by 19% (95% CI −24% to −14%; P<0.001)
- 2B12 deficiency (<150 pmol/L): 9.9% metformin vs 2.7% placebo
- 3Number needed to harm for B12 deficiency: 13.8 per 4.3 years
- 4B12 deficiency associated with elevated homocysteine (23.7 vs 14.9 µmol/L)
Original title: “Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial”
Plain English Summary
Randomized placebo-controlled trial of 390 type 2 diabetic patients on insulin examining metformin effects on B12 over 4.3 years. Metformin reduced B12 by 19% with NNH 13.8 for deficiency.
In-Depth Analysis
Study Details
Authors: Jolien de Jager, Adriaan Kooy, Philippe Lehert, et al.
Journal: BMJ, 2010 May 20; 340:c2181
PMCID: PMC2874129
Key Statistics (from original paper)
Study Design
- •N = 390 type 2 diabetic patients receiving insulin
- •Randomized placebo-controlled trial
- •Follow-up: 4.3 years
Primary Outcomes (Metformin vs Placebo)
| Biomarker | Change | 95% CI | P-value |
|---|---|---|---|
| Vitamin B12 | −19% | −24% to −14% | <0.001 |
| Folate | −5% | −10% to −0.4% | 0.033 |
| Homocysteine | +5% | −1% to +11% | 0.091 |
B12 Deficiency (<150 pmol/L)
- •Metformin group: 9.9%
- •Placebo group: 2.7%
- •Absolute risk increase: 7.2 percentage points
- •Number needed to harm: 13.8 per 4.3 years
Low B12 (150-220 pmol/L)
- •Metformin group: 18.2%
- •Placebo group: 7.0%
- •Number needed to harm: 8.9 per 4.3 years
Homocysteine by B12 Status
- •Deficiency (<150 pmol/L): 23.7 µmol/L
- •Low (150-220 pmol/L): 18.1 µmol/L
- •Normal (>220 pmol/L): 14.9 µmol/L
Source: PMC full text (PMC2874129)
Paradigm Relevance
How this study applies to different clinical perspectives:
Standard Medical
RelevantConventional clinical guidelines used by most doctors
Why it matters:
Supports current recommendations for periodic B12 monitoring in long-term metformin users.
Research Consensus
RelevantCurrent scientific understanding, often ahead of guidelines
Why it matters:
Establishes clear dose-duration relationship; homocysteine elevation confirms functional significance.
Metabolic Optimization
RelevantProactive targets for optimal health, not just disease absence
Why it matters:
Strong evidence for proactive B12 monitoring and supplementation in all metformin users.
Study Details
- Type
- Randomized Controlled Trial
- Methodology
- N = 390 type 2 diabetic patients on insulin. Randomized placebo-controlled trial. Follow-up 4.3 years.
Evidence Quality
Grade A - RCT. PMC2874129. Strong evidence for metformin-B12 association.
Related Biomarkers
Calculate & Evaluate on Metabolicum
Original Source
DOI (Digital Object Identifier) is a permanent link to this publication. Unlike website URLs that can change, a DOI always resolves to the correct source.
Related Studies
Proton Pump Inhibitors, H2-Receptor Antagonists, Metformin, and Vitamin B-12 Deficiency: Clinical Implications
Miller JW • Advances in Nutrition • 2018
PPIs/H2RAs: HR 1.83 (95% CI 1.36-2.46) for B12 deficiency with ≥10 months use; Metformin: mean B12 reduction of -54 pmol/L (95% CI -81 to -26)
Clinical Guidelines for B12 Deficiency Recognition and Management
Langan RC, Goodbred AJ • Am Fam Physician • 2017
Neurological protection requires B12 levels above 500 pg/mL
Comprehensive Review of Vitamin B12 Deficiency
Stabler SP • N Engl J Med • 2013
MMA testing identifies tissue-level deficiency missed by serum B12