Can long-term use of metformin (biguanide oral hypoglycemic agent) cause suboptimal ferritin levels in adults with type 2 diabetes?

Can Long-Term Metformin Use Cause Suboptimal Ferritin Levels?

Yes, long-term metformin use is associated with reduced ferritin levels, though the evidence is emerging and less established than the well-documented vitamin B12 deficiency. While current guidelines focus primarily on vitamin B12 monitoring, recent research demonstrates that metformin affects iron metabolism and ferritin levels in patients with type 2 diabetes.

Evidence for Metformin's Effect on Ferritin

Direct Evidence of Ferritin Reduction

• A 2023 study demonstrated that both metformin monotherapy and metformin/gliptin combination therapy resulted in significant decreases in serum ferritin levels after 1 year of treatment 1
• The ferritin reduction occurred regardless of whether metformin was used alone or in combination with DPP-4 inhibitors, suggesting metformin itself drives this effect 1
• A 2025 cross-sectional study found that metformin users had significantly lower serum iron levels (16.3 vs 17.3 µmol/L, p=0.02) compared to non-users, with iron-related parameters consistent with latent iron deficiency 2
• Multiple regression analysis identified metformin use as an independent predictor of reduced serum iron levels (B = -2.49 µmol/L, p=0.004), even after controlling for other variables that influence metal dynamics 2

Mechanism: Metal-Chelating Activity

• Metformin's metal-chelating activity affects multiple minerals simultaneously, reducing copper and iron while increasing zinc levels 2
• This metal-chelating property has been implicated in metformin's pleiotropic effects, including antitumorigenic and anti-inflammatory actions 2

Current Guideline Recommendations

Focus on Vitamin B12, Not Ferritin

• The American Diabetes Association strongly recommends periodic measurement of vitamin B12 levels in metformin-treated patients, especially those with anemia or peripheral neuropathy 3
• This recommendation has been consistent across multiple guideline iterations (2019,2021,2023) and carries a Grade B evidence level 3
• Current guidelines do not specifically address ferritin monitoring, focusing instead on vitamin B12 deficiency as the primary nutritional concern 3, 4, 5

Established Vitamin B12 Deficiency Risk

• The risk of vitamin B12 deficiency increases substantially after 4-5 years of metformin use, with deficiency rates reaching 22-54% depending on dose and duration 5
• Long-term metformin use (>4 years) is definitively associated with biochemical vitamin B12 deficiency 4, 5
• The Diabetes Prevention Program Outcomes Study found that low B12 occurred more often in metformin users at 5 years (4.3% vs 2.3%, p=0.02), with each year of metformin use increasing the odds of B12 deficiency by 13% 6

Clinical Implications and Monitoring Strategy

When to Suspect Iron/Ferritin Issues

• Consider ferritin assessment in metformin-treated patients who develop unexplained anemia that is not explained by vitamin B12 deficiency alone 7, 1
• Monitor patients on metformin for more than 1 year, as significant ferritin reductions have been documented at this timeframe 1
• Be particularly vigilant in patients with additional risk factors for iron deficiency (menstruating women, vegetarians, chronic kidney disease, gastrointestinal bleeding) 1

Practical Monitoring Algorithm

• Baseline assessment: Check vitamin B12 and ferritin levels before starting metformin 5
• Annual monitoring for patients on metformin >4 years: vitamin B12 levels are mandatory per guidelines 3, 5
• Consider adding ferritin to annual monitoring panels, especially if:
  • Patient develops anemia 4, 7, 1
  • Peripheral neuropathy symptoms emerge 3, 6
  • Metformin dose ≥1500 mg daily 5
  • Duration of therapy >1 year 1

Important Caveats

• Vitamin B12 deficiency remains the primary and best-established nutritional complication of long-term metformin use, with robust guideline support 3, 4, 5
• The ferritin data is newer and less extensively studied, but the 2025 evidence identifying metformin as an independent predictor of reduced iron levels is compelling 2
• One contradictory study from China found metformin associated with decreased risk of iron deficiency anemia admission, though this may reflect population-specific factors or confounding variables 8
• Ferritin can be used as an indicator of glycemic control achievement, with lower levels potentially correlating with better glucose management 1

Management When Deficiencies Occur

• For vitamin B12 deficiency: Supplementation with therapeutic B-complex vitamins is safe and recommended, particularly for prophylaxis in long-term users 5
• For iron/ferritin deficiency: Standard iron supplementation protocols apply, though specific guidance for metformin-induced iron deficiency is not yet established in guidelines 1, 2
• Do not discontinue metformin solely for nutritional deficiencies unless contraindications develop; metformin remains first-line therapy with proven mortality and complication reduction benefits 3, 4