Key result
Long-term metformin is linked to ~49% higher vitamin B12 deficiency odds without altering depressive symptoms.
Why the study?
Long-term metformin use may lead to vitamin B12 deficiency, which has been linked to depression.
Does long-term metformin use cause vitamin B12 deficiency and subsequent depressive symptoms in individuals with or at risk for type 2 diabetes?
RCT (n=1,666)
randomized
Does long-term metformin use cause vitamin B12 deficiency and subsequent depressive symptoms in individuals with or at risk for type 2 diabetes?
Odds Ratio: 1.49 (95% CI 1.08–1.91)
p-value: p=0.004
Long-term metformin use is associated with an increased risk of vitamin B12 deficiency, but this does not lead to increased depressive symptoms over time.
May warrant B12 monitoring in long-term metformin users; confirms risk but leaves depression link open.
Introduction and Objective: Metformin effectively improves glycemic control in individuals with type 2 diabetes (T2D) and prediabetes. However, long-term use may lead to vitamin B12 deficiency, which has been linked to depression. We examined long-term differences in B12 levels and depression by treatment assignment in the DPPOS and evaluated whether B12 levels mediated any observed differences in depressive symptoms. Methods: DPPOS participants randomized to the metformin or placebo arms were included. B12 levels were evaluated at 18, 20, and 23 years post randomization. Depressive symptoms were assessed mid-year and annually over 23 years using the Beck Depression Inventory. Between-group differences in B12 were evaluated using multivariable linear regression. Longitudinal trajectories of depressive symptoms were analyzed using linear mixed-effects models with treatment × time interactions. Mediation of depression differences by B12 levels was tested using multilevel modeling. Results: The final analytic sample included 1,666 participants (65% female, 57% White, 21% Black, 16% Hispanic). Metformin assignment was associated with lower B12 levels over follow-up compared with placebo (β= -0.026, SE= 0.011, p= .0017). In adjusted logistic regression, participants in the metformin arm had higher odds of B12 deficiency than those receiving placebo (OR= 1.49, 95% CI: 1.08-1.91, p= 0.004). Depressive symptom trajectories did not differ between treatment groups over follow-up (b= -0.013, p= 0.636). B12 levels were not associated with depressive symptom trajectories and did not mediate the association between treatment arm and depressive symptoms. Conclusion: Findings support B12 deficiency as a consequence of long-term metformin use but do not suggest that metformin is associated with change in depression symptoms over time or that B12 levels are implicated in these changes among individuals with or at risk for T2D. Further examination of other potential consequences of B12 deficiency in this population is needed. Disclosure J.S. Gonzalez: None. L. Nandoo: None. C. Hoogendoorn: None. C. Schechter: None.
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GONZALEZ et al. (2026) conducted an RCT in Type 2 diabetes and prediabetes (n=1,666). Metformin vs. Placebo was evaluated on Vitamin B12 deficiency (OR 1.49, 95% CI 1.08-1.91, p=0.004). Long-term metformin use was associated with higher odds of vitamin B12 deficiency compared to placebo (OR 1.49; 95% CI 1.08-1.91; p=0.004), but did not alter depressive symptom trajectories.
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