Can Metformin Cause Megaloblastic Anemia?
Yes, metformin can cause megaloblastic anemia through vitamin B12 deficiency, particularly in patients over 60 years old with prolonged exposure to the medication. This occurs because metformin interferes with vitamin B12 absorption in the gastrointestinal tract, leading to deficiency that manifests as megaloblastic anemia in susceptible individuals 1, 2.
Mechanism and Clinical Evidence
Metformin reduces serum vitamin B12 levels by 19-29% compared to controls, with deficiency developing in a dose-dependent manner 1. The prevalence of frank vitamin B12 deficiency (<300 pg/mL) ranges from 9.5% to 22.2% in metformin-treated patients compared to only 2.4% in non-users, with an adjusted odds ratio of 2.92 (95% CI: 1.26-6.78) 1.
Vitamin B12 deficiency from metformin directly causes megaloblastic anemia by impairing DNA synthesis in rapidly dividing cells, including bone marrow precursors 2, 3. This results in the characteristic large, immature red blood cells (megaloblasts) and hypersegmented neutrophils seen in megaloblastic anemia 3.
High-Risk Populations Requiring Vigilant Monitoring
Patients over 60 years old warrant particularly close surveillance because elderly patients have greater likelihood of hepatic, renal, or cardiac impairment that compounds metformin's effects on vitamin B12 absorption 1. Additional high-risk groups include:
- Patients on metformin >4 years 1
- Patients with anemia or peripheral neuropathy 4, 1
- Vegetarians/vegans 1
- Patients with history of gastric/small bowel surgery 1, 2
- Patients on high-dose metformin (≥2000 mg/day) 5
Monitoring Recommendations
The American Diabetes Association recommends periodic measurement of vitamin B12 levels in all metformin-treated patients, with annual monitoring specifically for those on metformin >4 years 1, 6. When assessing for deficiency, measure multiple biomarkers when possible, not just serum B12 alone 1:
- Serum vitamin B12
- Methylmalonic acid (MMA)
- Homocysteine
Elevated MMA and homocysteine indicate tissue-level functional deficiency even when serum B12 appears borderline 1.
Clinical Presentation
A documented case illustrates the clinical reality: a 62-year-old patient on metformin for 4 years presented with altered general condition, nausea, vomiting, abdominal pain, palpitations, and dyspnea, ultimately diagnosed with megaloblastic anemia from vitamin B12 deficiency 2. The symptoms resolved after vitamin B12 injection 2.
Megaloblastic anemia from metformin may also present with peripheral neuropathy, as vitamin B12 deficiency causes both hematologic and neurologic manifestations 4, 3. Irreparable neuropathic damage may occur with undiagnosed deficiency 1.
Management
Vitamin B12 supplementation (oral or intramuscular) can rapidly reverse deficiency, and patients should not discontinue metformin solely for B12 deficiency 1, 2. Multivitamin supplementation may protect against deficiency (OR 0.23; p<0.001), though this should not replace monitoring 1.
Critical Caveat
Despite the risk of vitamin B12 deficiency and megaloblastic anemia, metformin remains first-line therapy for type 2 diabetes due to its proven efficacy in reducing mortality and cardiovascular complications 4. The key is proactive monitoring and supplementation, not avoidance of metformin 1, 6.