Metformin can affect this through 2 different nutrient pathways: Vitamin B12, Folic Acid. This medication is commonly used for Diabetes.
Each nutrient below contributes to this impact through a different mechanism.
Low or deficient vitamin B12 status is a leading cause of megaloblastic anemia, where impaired DNA synthesis disrupts red blood cell division and produces large, fragile megaloblasts instead of healthy cells. Clinically, vitamin B12–deficiency anemia is relatively common, with some population studies suggesting that up to 10–15% of older adults have biochemical B12 deficiency and a subset of these develop overt megaloblastic changes and anemia. In addition to fatigue and pallor from reduced oxygen‑carrying capacity, patients may show macrocytosis on CBC, elevated methylmalonic acid and homocysteine, and, if unrecognized, can progress to severe anemia that coexists with potentially irreversible neurologic complications
Habeb B, Khair S, Reid A (July 14, 2025) Unmasking Pernicious Anemia: A Reversible Cause of Pancytopenia Due to Severe Vitamin B12 Deficiency. Cureus 17(7): e87911. Lee YP, Loh CH, Hwang MJ, Lin CP. Vitamin B12 deficiency and anemia in 140 Taiwanese female lacto-vegetarians. J Formos Med Assoc. 2021 Nov;120(11):2003-2009. Ankar A, Kumar A. Vitamin B12 Deficiency. 2024 Sep 10. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan–. PMID: 28722952. Wong CW. Vitamin B12 deficiency in the elderly: is it worth screening? Hong Kong Med J. 2015 Apr;21(2):155-64.
Folate (folic acid) deficiency impairs DNA synthesis in rapidly dividing cells, which leads to megaloblastic anemia characterized by enlarged red blood cells, fatigue, pallor, and sometimes shortness of breath. Population studies have shown that folate deficiency and macrocytosis can be present for months before overt symptoms appear, and in some cohorts, up to roughly one quarter of anemic adults had an underlying folate or B12 deficiency rather than iron deficiency alone. The encouraging clinical point is that, once identified, folate‑responsive megaloblastic anemia often improves within weeks of adequate folic acid repletion, with reticulocyte counts rising in about 5–7 days and hemoglobin recovering more gradually over several weeks.
Koury MJ, Price JO, Hicks GG. Apoptosis in megaloblastic anemia occurs during DNA synthesis by a p53-independent, nucleoside-reversible mechanism. Blood. 2000 Nov 1;96(9):3249-55. Daniel S. Socha, MD, Sherwin I. DeSouza, MD, Aron Flagg, MD, Mikkael Sekeres, MD, MS and Heesun J. Rogers, MD, PhD. Severe megaloblastic anemia: Vitamin deficiency and other causes. Cleveland Clinic Journal of Medicine March 2020, 87 (3) 153-164. H.B. Castellanos-Sinco, et al. Megaloblastic anaemia: Folic acid and vitamin B12 metabolism. Revista Médica del Hospital General de México. Vol. 78. Issue 3. Pages 105-150 (July - September 2015). Anis Hariz, et al. Megaloblastic Anemia. StatPearls April 3, 2023.
Some side effects may be linked to nutrient depletion caused by this medication.
Long term treatment with Biguanides, such as Metformin or Metformin combinations with other drugs, are found in research to reduce vitamin B12 absorption due to it hindering the activity of a calcium-dependent mechanism. Insufficient levels of vitamin B12 can lead to higher circulating homocysteine levels and the elevated risk of neurological problems and cardiovascular diseases.
Biguanide (anti-diabetic) drugs have been found in scientific evidence to decrease serum levels of coenzyme Q10. Type 2 diabetes can increase oxidative stress in the body, weakening its defenses and potentially harming cells. CoQ10, a powerful antioxidant, plays a crucial role in protecting cells from this damage. CoQ10 supplementation may help restore these levels, potentially improving mitochondrial function and protecting the kidneys from damage.
Research has shown that anti-diabetic Biguanide drugs may reduce folic acid absorption. Folic acid is a powerful antioxidant and low levels make the body more susceptible to oxidative stress, which can damage enzymes involved in homocysteine metabolism, and subsequently increase its accumulation. Elevated levels of homocysteine (hyperhomocysteinemia) are a risk factor for various health problems including cardiovascular diseases, neurological problems, osteoporosis, and vision problems.
Biguanides, such as Metformin or Metformin combinations with other drugs, may contribute to reduced levels of thiamine (vitamin B1) in end-stage renal failure patients. Research has found metformin encephalopathy present in patients on hemodialysis for end-stage diabetic renal failure (ESRD). Patients with ESRD should consider having thiamine (vitamin B1) status monitored and supplementing with thiamine when levels are insufficient or deficient.