Source/Disclosures
Disclosures: One of the authors reports he receives research support from AstraZeneca, Bayer and Merck Sharp & Dohme, and personal fees from Bayer, Intarcia, Merck Sharp & Dohme, Novartis and Novo Nordisk. The other authors report no relevant financial disclosures.
September 10, 2020
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Metformin increases risk for moderate anemia in type 2 diabetes

Source/Disclosures
Disclosures: One of the authors reports he receives research support from AstraZeneca, Bayer and Merck Sharp & Dohme, and personal fees from Bayer, Intarcia, Merck Sharp & Dohme, Novartis and Novo Nordisk. The other authors report no relevant financial disclosures.
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Analyses of data from two clinical trials and a real-world study revealed an increased risk for anemia among adults with type 2 diabetes prescribed metformin.

“In this study, including data from two randomized controlled trials, ... we have shown that metformin consistently causes an early reduction in hemoglobin and increases rates of moderate anemia,” Ewan R. Pearson, FRCP, PHD, professor of diabetic medicine and head of the division of population health and genomics at the School of Medicine at the University of Dundee, U.K., and colleagues wrote. “The absolute hemoglobin reductions are not large, although this does translate to a large increase in moderate anemia rates, with an overall effect in the real-world population study of a 2% increase risk of anemia per year per 1 g per day of metformin.”

Doctor holding test tube labeled Anemia
Source: Adobe Stock

Researchers analyzed data from the randomized controlled trials — A Diabetes Outcome Progression Trial (ADOPT) and the U.K. Prospective Diabetes Study (UKPDS) — to detect the effects of metformin at specific follow-up points. In ADOPT, adults recently diagnosed with type 2 diabetes (n = 3,967, 58% men) were randomly assigned to thiazolidinedione, metformin or sulfonylurea monotherapy. Blood samples were collected at baseline, 6 months and 1 year and then annually up to 5 years. In UKPDS, adults with newly diagnosed type 2 diabetes (n = 1,473, 47.1% men) were randomly assigned to a conventional diet with no medication or to insulin, sulfonylurea or metformin. Blood samples were collected at baseline, 3, 6 and 9 years.

Researchers also analyzed routine clinical data from the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study. The data included information on prescriptions and routine laboratory tests. Adults with type 2 diabetes (n = 3,485) diagnosed in 1996 or later were included if they had a baseline hemoglobin measurement with no anemia. Researchers used these data to evaluate the effects of metformin exposure over time.

In ADOPT, the use of metformin (adjusted OR = 1.93; 95% CI, 1.1-3.38) and TZDs (aOR = 4.18; 95% CI, 2.5-7) increased the odds of developing moderate anemia when compared with sulfonylureas. Older participants, those with lower baseline hemoglobin and men were at greater risk for moderate anemia. The ADOPT group saw a similar drop in hemoglobin at 6 months after treatment started with both metformin and TZDs. No further decreases were reported after 3 years.

In the UKPDS group, metformin also increased the odds for moderate anemia when compared with diet (aOR = 4.42; 95% CI, 2.28-8.57). The ORs were lower for insulin (aOR = 1.79; 95% CI, 0.73-4.42) and sulfonylureas (aOR = 0.53; 95% CI, 0.19-1.48). Lower baseline hemoglobin was a predictor for moderate anemia.

In UKPDS, the metformin group had a greater reduction in hemoglobin in the first measurement 3 years after treatment started compared with all other groups. Hemoglobin decreased from baseline for all groups at years 6 and 9, but the metformin group had the largest drop when compared with the diet group.

In GoDARTS, 2,487 of 3,485 individuals had been exposed to metformin by the end of follow-up. Increased cumulative metformin exposure of 1 g per day for 1 year slightly increased the odds of moderate anemia (OR = 1.02; 95% CI, 1.01-1.04).

“In this study, we show for the first time that metformin use is associated with the risk of moderate anemia in individuals with type 2 diabetes and that this finding is consistent across two randomized controlled trials and replicated in one real-world study of routinely collected data,” researchers wrote. “Furthermore, in the large, observational, population-based study with a maximum follow-up period of almost 20 years, we show that each gram per day of metformin use was associated with a 2% higher risk of moderate anemia per year.”

Researchers noted that because the mechanisms for metformin-related anemia are still unknown and the effects modest, they would not advocate discontinuation of metformin, even for users with anemia, due to its benefits. However, people with type 2 diabetes using metformin should anticipate a reduction in hemoglobin.