Our study on the long term effects of metformin treatment on serum concentrations of vitamin B-12, folate, and homocysteine in patients with type 2 diabetes treated with insulin had three main findings. Firstly, metformin significantly reduced concentrations of vitamin B-12, in accordance with findings from previous studies.13 18 19
Importantly, our study shows that this decrease is not a transitory phenomenon, but persists and grows over time. Secondly, a small, significant decrease in folate concentrations was found in the metformin group compared with the placebo group; however, this reduction was not statistically significant after adjustments for body mass index and smoking. Thirdly, the decrease in vitamin B-12 concentrations was associated with an increase in homocysteine levels, which was not statistically significant. Further analyses, however, showed that homocysteine concentrations did increase in individuals in whom vitamin B-12 levels decreased below the concentration generally considered to indicate clinical deficiency—that is, 150 pmol/l.
The finding of decreases in vitamin B-12 concentration during metformin treatment is not novel and has been reported before. A novel finding here, however, is that the decrease in vitamin B-12 levels is progressive. Furthermore, concentrations in some patients drop to the level at which most authorities agree vitamin substitution is required. This is also a novel finding, because although earlier trials in well fed, middle aged patients showed that metformin decreases vitamin B-12 concentrations, levels recorded remained within the normal range.5 6 14
Metformin is thought to induce malabsorption of vitamin B-12 and intrinsic factor in the ileum, an effect that can be reversed by increasing calcium intake.6 18
The consequences of clinically important decreases in vitamin B-12 concentrations—such as macrocytic anaemia, neuropathy, and mental changes—can be profound. We note that there is no consensus on the issue of whether “asymptomatic” vitamin B-12 deficiency should be treated.20
However, studies show that some symptoms of vitamin B-12 deficiency are difficult to diagnose and can be irreversible, and treatment of vitamin B-12 deficiency is relatively easy, cheap, safe, and effective,21 22 23 24
in effect arguing in favour of treatment. In addition, although the necessity of treating “spontaneous” vitamin B-12 deficiency may be debated, one should be more easily inclined to treat drug induced vitamin B-12 deficiency, as a key principle of drug prescription is to do no harm. On the other hand, our study shows that it is reasonable to assume harm will eventually occur in some patients with metformin induced low concentrations of vitamin B-12.
Folate concentration increased in both the metformin group and the placebo group, possibly as a result of dietary counselling received by all patients throughout the trial. Our short term interim analysis showed a significantly larger increase in folate concentration in the placebo group,12
a finding that was initially replicated in the current analysis but that disappeared after adjustment for body mass index and smoking.
Previous studies have shown either no or small effects of metformin treatment on concentrations of homocysteine.13 14 25 26
We clearly show that homocysteine concentrations do increase with decreasing levels of vitamin B-12 (fig 4). The finding that metformin treatment significantly lowered concentrations of vitamin B-12 but did not significantly alter levels of homocysteine probably reflects the relatively low incidence of vitamin B-12 deficiency in the entire study population. As treatment with metformin continues, however, we expect that vitamin B-12 levels will continue to decrease, making increases in homocysteine concentrations inevitable in time.
Strengths and limitations of study
Strengths of our study include the randomised, placebo controlled, double blind design and its relatively long follow-up of 4.3 years, as well as frequent serum collection. Furthermore, the study was conducted in a non-academic setting and, therefore, the findings have high value in a community setting.
Another strength is that we used last observation carried forward in this analysis because this method is considered more conservative than general mixed model analysis, “freezing” any observed divergence between two groups by retaining the last observation made. In a mixed model analysis with missing data, estimations of future observations are made on the basis of observations made earlier in the trial, thereby reflecting a divergence more accurately but less conservatively.
Limitations of our study include the fact that we measured only total vitamin B-12 levels and not levels of holotranscobalamin II or methylmalonic acid, which may have been more precise indicators of vitamin B-12 status. Finally, it is likely that, if anything, we underestimated the impact of metformin treatment on the risk of clinically important vitamin B-12 deficiency. We showed that metformin treatment was associated not only with a raised risk of developing vitamin B-12 concentrations below 150 pmol/l but also with an elevated risk of developing vitamin B-12 levels between 150 and 220 pmol/l, which is likely to represent clinically important vitamin B-12 deficiency in at least some individuals.27
A further reason that we may have somewhat underestimated the adverse effects of metformin is that all participants in our trial received frequent dietary counselling, which may have attenuated the impact of metformin treatment on vitamin status and may not be available in routine clinical practice.
Conclusions and policy implications
In conclusion, we showed that in patients with type 2 diabetes being treated with insulin, those additionally treated with metformin had a seven percentage point greater absolute risk of vitamin B-12 deficiency than those treated with placebo during 4.3 years of follow-up. In addition, the reduction in vitamin B-12 concentration associated with metformin increased with time.
Current guidelines indicate that metformin is a cornerstone in the treatment of type 2 diabetes, but make no recommendations on the detection and prevention of vitamin B-12 deficiency during treatment. Our data provide a strong case for routine assessment of vitamin B-12 levels during long term treatment with metformin.
What is already known on this topic
- Metformin is considered a cornerstone in the treatment of type 2 diabetes and is frequently prescribed
- Metformin is known to induce malabsorption of vitamin B-12 and may be associated with decreased folate concentrations, which might, in turn, result in an increase in homocysteine concentrations
- Few and only short term data exist on the effect of metformin treatment on vitamin B-12, folate, and homocysteine
What this study adds
- Long term treatment with metformin in patients with type 2 diabetes receiving insulin increases the risk of vitamin B-12 deficiency, which results in higher levels of homocysteine
- The negative effect of metformin on vitamin B-12 concentrations increases over time
- Our data provide a strong case for routine assessment of vitamin B-12 levels during long term treatment with metformin