Cross-sectional studycited by the Tayebat archivefull text checked A-ODD-05 in-depth review
Metformin and B12 in US survey
Association of biochemical B₁₂ deficiency with metformin therapy and vitamin B₁₂ supplements: the National Health and Nutrition Examination Survey, 1999-2006.
Overview
Reinstatler L et al.. Diabetes Care 2012 · PMID 22179958 · DOI 10.2337/dc11-1582
5.8% of metformin users had B12 deficiency vs 2.4% of other diabetics.
Does the study support the specific claim? Yes · Methodological quality: moderate
Plain-language summary
Study explained simply
- What did the researchers want to find out?
B12 deficiency prevalence with metformin; effect of supplements
- How was the study done?
Cross-sectional survey (NHANES)
- How many people, animals or samples were studied?
8,488 (1,621 with T2D + 6,867 without); US adults >=50 with/without type 2 diabetes
- What was actually found?
aOR 2.92.
- How large was the observed effect?
aOR 2.92 (1.26-6.78)
- What do the results mean in everyday life?
Consistent B12 effect.
- What are the study's limitations?
Snapshot survey (no time sequence); no duration-response; smoking/alcohol not adjusted; small inconsistencies between abstract and results; blood levels only.
- What does it say about Elawady's specific claim?
Supports C-ODD-07.
- Do the results apply to Germany and Europe?
US data.
- What can explicitly not be concluded from this study?
Causation alone.
Scientific in-depth review
1. Full reference
- Authors
- Reinstatler L, Qi YP, Williamson RS, Garn JV, Oakley GP
- Journal
- Diabetes Care
- Year
- 2012
- Identifier
- PMID 22179958 DOI 10.2337/dc11-1582 · PMC3263877
- Verification
- verified – PubMed E-utilities efetch, 2026-10-25
- Retracted
- no
- Corrections
- none
- Extent checked
- full text
- Conflicts of interest and funding
Supported by private donations to the Rollins School of Public Health, Emory University; no other potential conflicts of interest reported.
2. Research question
B12 deficiency prevalence with metformin; effect of supplements
3. Study design and population
- Study design
- Cross-sectional study – Cross-sectional analysis of the nationally representative NHANES 1999-2006 (survey-weighted prevalence, polytomous logistic regression).
- Population
US non-institutionalised adults >=50 years; type 2 diabetes defined as physician diagnosis after age 30 without insulin within 1 year. Excluded: HIV, high creatinine, prescription B12 injections, prediabetes, pregnancy, type 1 diabetes, metformin users without diabetes.
- Country
USA
- Period
1999-2006
- Sample size
8,488: 575 with type 2 diabetes using metformin, 1,046 with type 2 diabetes not using metformin, 6,867 without diabetes.
- Inclusion and exclusion criteria
As described in the abstract; details not available in abstract.
4. Methods and endpoints
- Exposure / intervention
Current metformin use (prescription questionnaire; median duration 5 years); supplemental B12 intake categories (0, >0-6, >6-25, >25 ug/day).
- Comparator
Type 2 diabetes without metformin; no diabetes.
- Endpoints
Biochemical B12 deficiency (serum B12 <=148 pmol/L) and borderline deficiency (>148-<=221 pmol/L).
- Statistical methods
Survey-weighted prevalence adjusted for age, race, sex; polytomous logistic regression adjusted for age, BMI, insulin and supplement use (alcohol and smoking not included, >60% missing); Fleiss attributable risk.
5. Actual results
- Results
Adjusted prevalence of deficiency: 5.8% (metformin) vs 2.2% (diabetes without metformin; abstract states 2.4%) vs 3.3% (no diabetes); borderline 16.2% vs 5.5% vs 8.8%. Geometric mean B12 317.5 vs 386.7 vs 350.8 pmol/L. Metformin vs no metformin (diabetes): adjusted OR deficiency 2.92 (95% CI 1.28-6.66 in results text; 1.26-6.78 in abstract); borderline 2.16 (1.22-3.85). No clear increase with duration of metformin use (4.1% <1 year, 8.1% >10 years; P=0.32). B12 supplements not associated with lower deficiency in metformin users (5.6% vs 5.3%), but >6 ug/day associated with 1.8% vs 14.1% for >0-6 ug (P trend 0.0273); in people without diabetes supplements associated with ~two-thirds lower deficiency (OR 0.26). 41% of deficient cases among people with diabetes attributable to metformin.
- Absolute risks
Prevalence of biochemical B12 deficiency 5.8% with metformin vs 2.2% without (diabetes) and 3.3% without diabetes.
- Authors' conclusion
Metformin therapy is associated with a higher prevalence of biochemical B12 deficiency; 2.4 ug/day (IOM) and 6 ug (multivitamins) may not be sufficient for metformin users; further research on supplementation and clinical outcomes needed.
6. Strengths
- Nationally representative sample with survey weights
- Detailed supplement dose information
- Two comparison groups
7. Weaknesses
- Cross-sectional; associations only, no temporality (authors)
- Only current metformin use; non-users may have stopped metformin (possibly because of low B12)
- No duration-response observed
- Smoking and alcohol not adjusted (>60% missing); undiagnosed diabetes and type misclassification
- Serum B12 alone defines deficiency (MMA unsuitable/missing); no clinical outcomes
- Internal inconsistencies between abstract and results (2.4% vs 2.2%; P values; CI 1.26-6.78 vs 1.28-6.66)
- Wide confidence interval for main OR
8. Risk of bias
- Orienting tool
- ROBINS-E
- Type of assessment
- structured assessment based on the full text by a single reviewer (no formal double review)
- Full formal assessment
- no
- Overall risk of bias
- some concerns
- Rationale
Single-reviewer ROBINS-E-oriented judgement from the full text; formal assessment needs two independent reviewers. Overall unchanged (some_concerns). Direction consistent with the de Jager RCT (A-ODD-04).
| Domain | Judgement | Rationale |
|---|---|---|
| Confounding | some concerns | Adjusted for age, BMI, insulin, supplements; smoking/alcohol, PPI use in final model not fully clear; diabetes duration differs between groups. |
| Exposure measurement | some concerns | Self-reported current medication; past use unknown. |
| Selection of participants | low | Population-based survey sample with weights. |
| Post-exposure interventions | not applicable | Cross-sectional design. |
| Missing data | some concerns | Large missingness for smoking/alcohol; MMA missing for one third. |
| Outcome measurement | low | Standardised laboratory serum B12. |
| Selection of reported result | some concerns | Discrepancies between abstract and results text. |
Full-text review (25 October 2026): Group sizes, borderline deficiency, geometric mean B12, duration analysis (no trend), supplement-dose findings, attributable fraction and funding (private donations, no COI) added; internal abstract/results discrepancies documented (2.4 vs 2.2%; CI); ROBINS-E domains added, overall unchanged.
9. Assessment of the statistical interpretation
About 3-fold higher odds of biochemical deficiency with metformin, imprecise (CI ~1.3-6.7), without duration-response; absolute difference ~3.6 percentage points. Cross-sectional design limits causal inference, but consistent with RCT evidence.
10. Relevance to the specific claim
Supports C-ODD-07.
11. Independent contrary findings
12. Transferability to Germany and Europe
US data.
13. Overall methodological judgement
Consistent with RCT.
| Multidimensional assessment | |
|---|---|
| Authenticity of the source | verified |
| Methodological quality | moderate |
| Risk of bias | some concerns |
| Precision of results | low |
| Directness | direct |
| Reproducibility | replicated |
| Consistency with the overall evidence | consistent |
| Regional transferability | high |
| Adequacy of the interpretation (by the archive) | correctly reported |
14. Open questions
None beyond those stated.
15. Linked fact checks
- Every major class of glucose-lowering drug (metformin, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 agonists) carries a documented signal of serious harm in the peer-reviewed literature. – Studies supporting the claim
- Long-term metformin lowers vitamin B12 and increases B12 deficiency (de Jager RCT: -19%, +7.2 percentage points deficiency over 4.3 years; DPPOS confirms). – Studies supporting the claim
Use by the Tayebat archive
Note: according to the archive, the studies were compiled by the archive operators. Whether Dr. Elawady himself cited this study is not established.
- What the archive says about the study
Listed in the archive bibliography for 'oral-diabetes-drugs' without its own interpretation; used as support for the claim that every drug class carries documented harm.
- A. What was actually studied?
B12 deficiency prevalence with metformin; effect of supplements
- B. What did the authors find?
aOR 2.92.
- C. What conclusions do the authors themselves draw?
Metformin associated with higher B12 deficiency; usual supplement doses may be insufficient.
- D. What does the archive derive from it?
Support for B12 harm.
- E. Is this derivation scientifically justified?
Justified.
- Adequacy of the interpretation (by the archive)
- correctly reported