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).
Original statement
أثبتت تجربة دي ياغر العشوائية المضبوطة هبوط فيتامين B12 المصلي 19% وزيادة نقصه المطلقة 7.2% خلال 4.3 سنوات (NNH = 13.8)، وأكدت متابعة DPPOS الـ 13 سنة الخطر التراكمي.
verbatim according to source. Translation by the project; the Arabic wording is authoritative.
Translation
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).
Origin
- Source status
- Archive editors
- Attribution
- Archive editors (not Elawady)
- Origin
- https://eltayebat.com/rule/oral-diabetes-drugs/
- Attribution uncertainty
- Editorial narrative and study selection written by the archive operators.
- Claimed mechanism
Reduced intestinal B12 absorption.
- Claimed health effect
B12 deficiency, raised homocysteine, possibly neuropathy and anaemia
- Population concerned
Long-term metformin users
- Geographic restriction by Elawady
none found
Scientific assessment
True – The statement is supported by robust evidence.
Certainty of evidence: high – Further research is very unlikely to change the assessment.
1. What was claimed?
Metformin causes B12 deficiency.
2. What is demonstrably correct?
de Jager: B12 -19% (95% CI -24 to -14%), absolute deficiency +7.2 percentage points, NNH 13.8 per 4.3 years (A-ODD-04). DPPOS: low B12 4.3 vs 2.3% at 5 years; low/borderline 20.3 vs 15.6% at 13 years; OR 1.13 per year of use; neuropathy more common in metformin users with low B12 (A-ODD-06). NHANES: 5.8 vs 2.4% deficiency (A-ODD-05). ADA 2026 recommends periodic B12 testing (I-ODD-16).
3. What is wrong or exaggerated?
Nothing in the numbers; but B12 deficiency is detectable and treatable and does not cancel metformin's benefits (I-ODD-01). In DPPOS low B12 at 13 years was not statistically significant for the strict cutoff (7.4 vs 5.4%, P=0.12) (A-ODD-06).
4. What remains unclear?
Clinical impact on neuropathy in the general metformin population.
5. Which studies support it?
A-ODD-04, A-ODD-05, A-ODD-06, I-ODD-16.
6. Which studies contradict it?
None.
7. What applies to Germany and Europe?
Same recommendation for monitoring in EU product information.
8. What is known about Egypt?
Egypt has one of the highest diabetes prevalences in the region; the same drug classes and insulins are used. Access barriers and cost may make advice to stop medication attractive, which increases the practical risk of this claim. No Egypt-specific evidence changes the assessment.
9. What practical conclusion is appropriate?
People on long-term metformin should have B12 checked periodically and treated if low, not stop metformin on their own.
Assessment details
- Rationale for certainty of evidence
Placebo-controlled RCT, long-term RCT follow-up and population survey consistently show the effect; guidelines recommend periodic B12 testing.
- Source quality
Archive editorial correctly quoting RCTs.
- Regional transferability
Universal.
- Individual exceptions
Risk rises with dose and duration.
- Regional scope of the claim
- general (biological/medical)
- Last reviewed
- 26 October 2026 provisional
Scientific evidence in detail
Scientifically well supported – The claim agrees with consistent, high-quality evidence.
Research question: Does long-term metformin lower vitamin B12 and increase B12 deficiency?
Research question in detail (PICO)
- Population
- Long-term metformin users with type 2 diabetes or prediabetes
- Intervention or exposure
- Metformin
- Comparison
- Placebo or non-use
- Geographic scope
- universal biology; regional data from Arab countries
- Outcomes
- Serum B12
- B12 deficiency
- Neuropathy, anaemia
Study results as reported by the authors. Our assessment follows below.
What speaks for the claim?
Metformin and vitamin B12
de Jager J et al.. BMJ 2010 · PMID 20488910 · DOI 10.1136/bmj.c2181 Randomised controlled trialfull text, structured risk-of-bias assessmentPlacebo-controlled RCT over 4.3 years.
- Actual result
- B12 -19% (-24 to -14%); deficiency +7.2 percentage points; NNH 13.8.
- Methodological quality
- high (RCT)
- Relevance
- direct
- Limitations
- Single trial in the Netherlands.
Metformin users have about twice the risk of low vitamin B12
Yang W et al.. J Diabetes 2019 · PMID 30615306 · DOI 10.1111/1753-0407.12900 Meta-analysisabstract checkednewly addedMeta-analysis of 31 studies.
- Actual result
- Deficiency RR 2.09 (1.49-2.93); B12 -63.7 pmol/L; no significant link with anaemia or neuropathy.
- Methodological quality
- moderate
- Relevance
- direct
- Limitations
- Heterogeneous, mostly observational.
What speaks against the claim?
No high-quality evidence against the claim was found.
What does the overall evidence say?
Editorial assessment based on the studies above – not itself a study result.
Which position is better supported?
Metformin lowers B12 and increases deficiency in a dose- and duration-dependent way; the remedy is periodic testing and supplementation, not stopping metformin.
Why some studies weigh more
RCT and long-term trial follow-up plus meta-analysis are consistent.
Is a causal relationship established? Yes, established Placebo-controlled RCT evidence.
Remaining uncertainty
Clinical consequences (neuropathy) in average users.
Justified conclusion
True.
Does this depend on the country?
- General biological effects
- Drug pharmacology and physiology are universal.
- Eating habits
- Low intake of animal foods (rich in B12) can add to the risk; diets that restrict meat or dairy should be considered.
- Origin of the food
- Not applicable.
- Contaminants
- Not applicable.
- National production conditions
- Not applicable (same active substances; generics widely used in Egypt).
- Legal rules
- Drug labels and warnings are set by FDA/EMA and national regulators; Egyptian labelling not reviewed.
- Actual monitoring data
- Studies from Arab countries report the same association (I-ODD-115); no Egypt-specific study found.
A regional difference that changes the conclusion is not supported by robust data.
Statistical re-check
- NNH recomputation – 1/0.072 = 13.9 vs reported 13.8 (rounding). recalculated
- CI symmetry – RR CI symmetric on log scale; MD CI symmetric. recalculated
Certainty of the overall evidence (GRADE, simplified)
- Main outcome
- B12 deficiency with long-term metformin
- Starting level
- high (randomised trials)
- Reasons for upgrading
- dose-response
- Result
- high
Simplified assessment by a single reviewer, following the GRADE approach; not a formal GRADE panel. GRADE rates the body of evidence for one outcome, not individual studies.
Clinical guidelines and official statements checked
- ADA: 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2026 (Diabetes Care 2026;49 Suppl 1) (2026) · Original publication
Metformin use is associated with increased risk of B12 deficiency and worsening of neuropathy symptoms, suggesting periodic testing of B12 levels.
Search strategy
Documented literature searches for this review (search strings in the original database syntax).
| Database | Date | Search | Looking for | Hits | Included |
|---|---|---|---|---|---|
| PubMed | 26 October 2026 | metformin[ti] AND ("vitamin B12"[ti] OR "vitamin B-12"[ti] OR cobalamin[ti]) AND (meta-analysis[pt] OR systematic review[pt]) | both directions | 6 | |
| Europe PMC | 26 October 2026 | (metformin) AND ("vitamin B12" OR cobalamin) AND (Egypt OR Egyptian OR Saudi OR Arab) | both directions | 564 | |
| PubMed | 26 October 2026 | metformin[tiab] AND ("vitamin B12"[tiab] OR "B12"[tiab]) AND (Egypt*[tiab] OR Arab*[tiab] OR Saudi[tiab]) | both directions | 12 | |
| ADA Standards of Care 2026, Section 9 (PubMed Central) | 26 October 2026 | Fetched https://pmc.ncbi.nlm.nih.gov/articles/PMC12690185/; B12 statements. The diabetesjournals.org DOI landing pages returned HTTP 403; the identical article was read in PubMed Central. | guidelines | 1 |
Open questions
Egypt-specific prevalence data.
How deeply was this checked?
7 linked studies: 3 checked in full text (2 of them with a structured risk-of-bias assessment), 4 on the basis of the abstract, 0 bibliographically only. No formal assessment with two independent reviewers and no independent human expert review has taken place yet.
Last scientific review: 26 October 2026
In plain language
It is true that metformin, taken for years, lowers vitamin B12 in the blood, and a randomised trial showed about one extra person with deficiency for every 14 people treated for four years. This can be found with a simple blood test and treated with B12. Doctors recommend regular testing.
Studies on this claim
Studies supporting the claim (6)
-
Metformin and vitamin B12
de Jager J et al.. BMJ 2010 · PMID 20488910 · DOI 10.1136/bmj.c2181Randomised controlled trialcited by the Tayebat archivefull text, structured risk-of-bias assessment★ key studyOver 4 years metformin lowered B12 by 19%, causing deficiency in about 1 of every 14 users.
Does the study support the specific claim? Yes · Methodological quality: high · Certainty of evidence: see overall assessment of the claim
Original publication · Scientific details
Study explained simply
- What did the researchers want to find out?
Metformin and vitamin B12 deficiency
- How was the study done?
Multicentre double-blind placebo-controlled RCT (HOME trial follow-up)
- How many people, animals or samples were studied?
390; Type 2 diabetes treated with insulin
- What was actually found?
B12 -19%; NNH 13.8.
- How large was the observed effect?
-19% B12; +7.2 pp deficiency
- What do the results mean in everyday life?
Check B12 regularly on metformin.
- What are the study's limitations?
Secondary analysis; groups differed in age and smoking at baseline; one third without final blood sample; only blood levels, no clinical symptoms measured; insulin-treated patients.
- What does it say about Elawady's specific claim?
Supports C-ODD-07.
- Do the results apply to Germany and Europe?
Dutch data.
- What can explicitly not be concluded from this study?
That metformin is net harmful.
-
Metformin and B12 in US survey
Reinstatler L et al.. Diabetes Care 2012 · PMID 22179958 · DOI 10.2337/dc11-1582Cross-sectional studycited by the Tayebat archivefull text, structured risk-of-bias assessment5.8% of metformin users had B12 deficiency vs 2.4% of other diabetics.
Does the study support the specific claim? Yes · Methodological quality: moderate · Certainty of evidence: see overall assessment of the claim
Original publication · Scientific details
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.
-
Metformin and B12 over 13 years
Aroda VR et al.. J Clin Endocrinol Metab 2016 · PMID 26900641 · DOI 10.1210/jc.2015-3754Randomised controlled trialcited by the Tayebat archiveabstract checkedEach year of metformin raised the odds of B12 deficiency by about 13%.
Does the study support the specific claim? Yes · Methodological quality: moderate · Certainty of evidence: see overall assessment of the claim
Original publication · Scientific details
Study explained simply
- What did the researchers want to find out?
Long-term metformin and B12 deficiency
- How was the study done?
Secondary analysis of RCT and open-label extension (DPP/DPPOS)
- How many people, animals or samples were studied?
2,155 randomised (1,082 + 1,073); B12 measured in 1,715 at 5 years and 1,520 at 13 years; People with prediabetes and overweight
- What was actually found?
OR 1.13 per year.
- How large was the observed effect?
OR 1.13 (1.06-1.20)
- What do the results mean in everyday life?
Monitor B12.
- What are the study's limitations?
Placebo group partly unblinded after DPP; Secondary analysis
- 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?
Clinical harm magnitude.
-
ADA guideline 2026: diabetes medicines
American Diabetes Association Professional Practice Committee for Diabetes*. Diabetes Care 2026 · PMID 41358900 · DOI 10.2337/dc26-S009Guideline / position statementindependent cross-checkfull text checked★ key studyInsulin is essential in type 1 diabetes; SGLT2/GLP-1 drugs are recommended for heart and kidney protection; side effects listed.
Does the study support the specific claim? Partly · Methodological quality: high · Certainty of evidence: see overall assessment of the claim
Original publication · Scientific details
Study explained simply
- What did the researchers want to find out?
Pharmacologic glycaemic treatment
- How was the study done?
Clinical practice guideline (ADA Standards of Care 2026, Section 9)
- How many people, animals or samples were studied?
not applicable; People with type 1 and type 2 diabetes
- What was actually found?
See results.
- How large was the observed effect?
not applicable
- What do the results mean in everyday life?
Medicines chosen by benefit-risk.
- What are the study's limitations?
Partially read
- What does it say about Elawady's specific claim?
Contradicts C-INS-07, C-INS-10, C-ODD-06; supports C-ODD-07, C-INS-11.
- Do the results apply to Germany and Europe?
Consistent with ADA/EASD consensus.
- What can explicitly not be concluded from this study?
Not applicable.
-
Metformin users have about twice the risk of low vitamin B12
Yang W et al.. J Diabetes 2019 · PMID 30615306 · DOI 10.1111/1753-0407.12900Meta-analysisindependent cross-checkabstract checkedRR 2.09; B12 about 64 pmol/L lower.
RR 2.09 for deficiency; no consistent link to anaemia or neuropathy.
Does the study support the specific claim? Yes · Methodological quality: moderate · Certainty of evidence: see overall assessment of the claim
Original publication · Scientific details
Study explained simply
- What did the researchers want to find out?
Summarise metformin and B12 studies.
- How was the study done?
Meta-analysis of 31 studies.
- How many people, animals or samples were studied?
31 studies.
- What was actually found?
Lower B12 and more deficiency; no clear effect on anaemia or neuropathy.
- How large was the observed effect?
RR 2.09 (1.49-2.93).
- What do the results mean in everyday life?
Check B12 regularly when taking metformin.
- What are the study's limitations?
Mostly observational, heterogeneous.
- What does it say about Elawady's specific claim?
Supports the claim.
- Do the results apply to Germany and Europe?
High.
- What can explicitly not be concluded from this study?
That metformin should be stopped.
-
Metformin and low B12 also seen in Arab countries
Alhaji JH. Nutrients 2022 · PMID 35631186 · DOI 10.3390/nu14102046Narrative reviewindependent cross-checkabstract checked11 regional studies point to more B12 deficiency with longer and higher-dose metformin use.
Association also reported in Arab-country studies.
Does the study support the specific claim? Yes · Methodological quality: low · Certainty of evidence: see overall assessment of the claim
Original publication · Scientific details
Study explained simply
- What did the researchers want to find out?
Review Arab-region studies.
- How was the study done?
Literature review.
- How many people, animals or samples were studied?
11 studies.
- What was actually found?
Association with dose and duration.
- How large was the observed effect?
Not pooled.
- What do the results mean in everyday life?
The same monitoring advice applies in the region.
- What are the study's limitations?
Narrative, single author.
- What does it say about Elawady's specific claim?
Supports it regionally.
- Do the results apply to Germany and Europe?
Not applicable.
- What can explicitly not be concluded from this study?
Size of the effect in Egypt.
No study in this group is marked as key.
Studies contradicting or limiting the claim (0)
No studies in this group.
Studies with mixed or unclear results (1)
-
Metformin in overweight type 2 diabetes (UKPDS 34)
UKPDS Group. Lancet 1998 · PMID 9742977Randomised controlled trialindependent cross-checkabstract checked★ key studyMetformin reduced deaths from any cause by about a third over 10 years.
Does the study support the specific claim? No · Methodological quality: moderate · Certainty of evidence: see overall assessment of the claim
Original publication · Scientific details
Study explained simply
- What did the researchers want to find out?
Intensive control with metformin in overweight type 2 diabetes
- How was the study done?
RCT within UKPDS (UKPDS 34)
- How many people, animals or samples were studied?
753 (main comparison); Overweight newly diagnosed type 2 diabetes, mean age 53
- What was actually found?
Mortality -36%.
- How large was the observed effect?
RR reduction 36% (9-55)
- What do the results mean in everyday life?
Metformin is protective.
- What are the study's limitations?
Small arms; Open-label; Conflicting supplementary result
- What does it say about Elawady's specific claim?
- Do the results apply to Germany and Europe?
UK.
- What can explicitly not be concluded from this study?
Effects in non-overweight patients.
No study in this group is marked as key.
Regional context
Germany / EU
Same recommendation for monitoring in EU product information.
Egypt
Egypt has one of the highest diabetes prevalences in the region; the same drug classes and insulins are used. Access barriers and cost may make advice to stop medication attractive, which increases the practical risk of this claim. No Egypt-specific evidence changes the assessment.
What applies in my country?
General scientific assessment
True True: metformin lowers B12; the answer is monitoring and supplementation.
This statement concerns biological or medical relationships. The scientific assessment above applies regardless of the country; country-specific food data do not change it.
References
- Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial.. de Jager J et al.. BMJ 2010 · PMID 20488910 · DOI 10.1136/bmj.c2181
- Association of biochemical B₁₂ deficiency with metformin therapy and vitamin B₁₂ supplements: the National Health and Nutrition Examination Survey, 1999-2006.. Reinstatler L et al.. Diabetes Care 2012 · PMID 22179958 · DOI 10.2337/dc11-1582
- Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study.. Aroda VR et al.. J Clin Endocrinol Metab 2016 · PMID 26900641 · DOI 10.1210/jc.2015-3754
- 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2026.. American Diabetes Association Professional Practice Committee for Diabetes*. Diabetes Care 2026 · PMID 41358900 · DOI 10.2337/dc26-S009
- Associations between metformin use and vitamin B12 levels, anemia, and neuropathy in patients with diabetes: a meta-analysis.. Yang W et al.. J Diabetes 2019 · PMID 30615306 · DOI 10.1111/1753-0407.12900
- Vitamin B12 Deficiency in Patients with Diabetes on Metformin: Arab Countries.. Alhaji JH. Nutrients 2022 · PMID 35631186 · DOI 10.3390/nu14102046
- Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.. UKPDS Group. Lancet 1998 · PMID 9742977