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Risk of Anemia with Metformin Use in Patients with Type 2 Diabetes

Jan 12, 2021
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Aleksandra Kusic, PharmD Candidate, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences

Metformin use can reduce protein hemoglobin levels that carry oxygen in the blood, thus increasing anemia risk for type 2 diabetes patients.

Metformin is a common medication prescribed for patients with type 2 diabetes. It is one of the initially prescribed medications to reduce glucose levels and increase insulin sensitivity. It can be used alone or with other agents to treat patients with type 2 diabetes. Diabetes progression can cause kidney damage, which can lead to anemia. Metformin use in two studies showed that it could reduce protein hemoglobin levels that carry oxygen in the blood. Other medications that can decrease hemoglobin include Angiotensin-converting enzyme (ACE) inhibitors, fibrates, and thiazolidinediones. The mechanism of how metformin causes moderate anemia is unknown. The mastermind study analysis of two randomized control studies, A Diabetes Outcome Progression Trial (ADOPT) and U.K. Prospective Diabetes Study (UKPDS), with a replicated real-world study, collectively indicate an anemia risk within the first few years after beginning metformin. The Mastermind study’s purpose was to combine trial results to detect the association between metformin use and an increased, moderate anemia rate in patients with type 2 diabetes.  


There were 3,967 patients evaluated in the ADOPT trial and 1,473 in the UKPDS trial using the logistic regression model to indicate anemia’s risk. Also, nonlinear mixed models were used to detect the change in hematological parameters. The cumulative effects were assessed using the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) with 3,485 patients utilizing the discrete-time failure analysis method to model the cumulative risk of anemia with metformin use. The GoDARTS patient population was specific to patients diagnosed before two years, and the follow-up was tracked using the electronic health record data.  The MASTERMIND study defined anemia as a hemoglobin measure of <11g/dL when evaluating the results. It is essential to determine how much of a decrease in the hemoglobin there was with metformin and how long the levels continue to be lower than normal.  

The ADOPT trial had compared patients taking metformin, sulfonylureas, and thiazolidinediones with the risk of anemia over a 5-year follow-up period. The results indicated that the odds of anemia for patients taking metformin are more significant with the odds ratio of 1.93 (95% CI, 1.10-3.38) when compared to sulfonylureas, and quadrupled for those taking thiazolidinediones with the odds ratio of 4.8 (95% CI, 2.50-7.00). Also, hemoglobin and hematocrit decreased at the beginning of six months of therapy with metformin, but there was no decrease after three years. The UKPDS trial showed similar results with the odds ratio of developing anemia being greatest with metformin at 3.40 (95% CI, 1.98-5.83), with 0.96 (95% CI, 0.57-1.62) for sulfonylureas, and 1.08 (95% CI, 0.62-1.87) for insulin therapy. The hemoglobin levels fell by three years for patients that were using metformin; although, at six and nine years, hemoglobin had reduced in all participants regardless of the therapy. Therefore, in both of these trials, anemia was observed at the beginning of therapy.  The GoDARTS population for each 1g/day of metformin corresponded with a 2% higher annual risk of anemia. Therefore, this study determined that the dose of metformin impacts the risk of developing anemia. Hemoglobin reductions were not considered large for all analyzed studies but enough to be categorized as moderate anemia risk. 

This data indicates that metformin is associated with an increased risk of developing anemia in type 2 diabetes patients. Researchers do not advise the discontinuation of this medication in all patients regardless of whether they have anemia; however, they want patients to understand that taking it puts them at risk for developing anemia early in their therapy. Clinicians who prescribe metformin should counsel their patients on the symptoms of anemia, which include fatigue, weakness, dizziness, cold hands and feet, etc. Patients should be advised to contact their physician if they experience any symptoms associated with anemia. Although the mechanism for the decrease in hemoglobin with metformin use is unsure, it is essential to know that it can occur. 

Practice Pearls:  

  • Metformin treatment is associated with an early risk of anemia for patients with type 2 diabetes. 
  • The odds of developing anemia are more significant with the use of metformin than with other diabetes medications.  
  • Clinicians should counsel patients on the early symptoms of anemia when they prescribe metformin, equipping them to self-detect its early signs.  


Donnelly, Louise A., et al.Risk of Anemia With Metformin Use in Type 2 Diabetes: A MASTERMIND Study 


Aleksandra Kusic, PharmD Candidate, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences  



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