Risk of Anemia With Metformin Use in Type 2 Diabetes: A MASTERMIND Study

Abstract

Objective: To evaluate the association between metformin use and anemia risk in type 2 diabetes, and the time-course for this, in a randomized controlled trial (RCT) and real-world population data.

Research design and methods: Anemia was defined as a hemoglobin measure of <11 g/dL. In the RCTs A Diabetes Outcome Progression Trial (ADOPT; n = 3,967) and UK Prospective Diabetes Study (UKPDS; n = 1,473), logistic regression was used to model anemia risk and nonlinear mixed models for change in hematological parameters. In the observational Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) population (n = 3,485), discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk.

Results: In ADOPT, compared with sulfonylureas, the odds ratio (OR) (95% CI) for anemia was 1.93 (1.10, 3.38) for metformin and 4.18 (2.50, 7.00) for thiazolidinediones. In UKPDS, compared with diet, the OR (95% CI) was 3.40 (1.98, 5.83) for metformin, 0.96 (0.57, 1.62) for sulfonylureas, and 1.08 (0.62, 1.87) for insulin. In ADOPT, hemoglobin and hematocrit dropped after metformin initiation by 6 months, with no further decrease after 3 years. In UKPDS, hemoglobin fell by 3 years in the metformin group compared with other treatments. At years 6 and 9, hemoglobin was reduced in all treatment groups, with no greater difference seen in the metformin group. In GoDARTS, each 1 g/day of metformin use was associated with a 2% higher annual risk of anemia.

Conclusions: Metformin use is associated with early risk of anemia in individuals with type 2 diabetes, a finding consistent across two RCTs and replicated in one real-world study. The mechanism for this early fall in hemoglobin is uncertain, but given the time course, is unlikely to be due to vitamin B₁₂ deficiency alone.

Figure 1

Plots of hematological changes over time using nonlinear mixed models. Data are presented as plots of predictions of the fixed effects for each treatment at each study visit. ADOPT trial: Hb (A), Hct (B), and Hb adjusted for Hct (C). UKPDS trial: Hb (D), PCV (E), and Hb adjusted for PCV (F).

Figure 2

Plot of unadjusted rates of anemia by cumulative exposure to metformin standardized (within 10-year age bands) to the age distribution (overall person-years) of the whole study population. The terms for ever-exposure and cumulative exposure were given a visual representation by plotting a regression line through the unadjusted rates of anemia grouped by cumulative metformin exposure, representing the linear effect of cumulative exposure.