The highlights of one generic label for metformin ER tablets state that metformin may lower vitamin B12 levels. A secondary analysis of a randomized trial reported low B12 more often in the metformin group at 5 years but not at 13 years, and a review reported lower B12 in ten out of 17 observational studies, which cannot show cause and effect. A licensed provider decides about B12 testing.
What the label highlights say
The highlights section of the prescribing information for metformin ER tablets states that metformin may lower vitamin B12 levels. It says to monitor hematologic parameters annually and vitamin B12 at 2 to 3 year intervals and manage any abnormalities.
This guide cites the highlights of one generic label. A label is a regulatory document, not a study result.
What the Diabetes Prevention Program Outcomes Study reported
The original Diabetes Prevention Program was a randomized trial. It assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle-modification program.
The B12 report is a secondary analysis of that program and its Outcomes Study. It compared metformin 850 mg twice daily with placebo, then open-label metformin. That is the dose the study used, not dosing advice.
The figures below are metformin group versus placebo group.
| Question | What the source says |
|---|---|
| Low B12 (≤ 203 pg/mL) at 5 years | 4.3 vs 2.3%; P = .02 |
| Low B12 (≤ 203 pg/mL) at 13 years | 7.4 vs 5.4%; P = .12 |
| Combined low and borderline-low B12 (≤ 298 pg/mL) at 5 years | 19.1 vs 9.5%; P < .01 |
| Combined low and borderline-low B12 (≤ 298 pg/mL) at 13 years | 20.3 vs 15.6%; P = .02 |
The abstract states that low B12 occurred more often in the metformin group than placebo at 5 years but not at 13 years. Combined low and borderline-low B12 was more common in the metformin group at both time points.
It also reports that years of metformin use were associated with increased risk of B12 deficiency (odds ratio, B12 deficiency/year metformin use, 1.13; 95% confidence interval, 1.06 to 1.20).
The authors concluded that long-term use of metformin in DPPOS was associated with biochemical B12 deficiency and anemia, and that routine testing of vitamin B12 levels in metformin-treated patients should be considered.
What a review of observational studies reported
A systematic review and meta-analysis reported that ten out of 17 observational studies showed statistically significantly lower levels of vitamin B12 in patients on metformin than not on metformin. It covered any metformin dose or duration, and the abstract states no single dose. Its title refers to patients with type 2 diabetes.
Observational studies cannot show cause and effect.
Testing and who decides
The label highlights address monitoring, and the trial authors address routine testing, in the words given above. A licensed provider decides about B12 testing. Nothing here is advice to start, stop or change any medicine or supplement.
What this does not tell you
This guide covers one generic label's highlights, one secondary analysis and one review. It does not report group sizes, symptoms, or what any B12 level means for health. The trial reports an association, in its own word, and low B12 was not reported as more common in the metformin group at 13 years.
The review's studies were observational, so they cannot show cause and effect, and the abstract gives no dose. Other labels are not covered here. These sources do not decide whether anyone needs a B12 test. A licensed provider does.