American Diabetes Association
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Risk of anaemia with metformin use in type 2 diabetes: A MASTERMIND study

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posted on 2020-08-18, 18:50 authored by Louise A Donnelly, John M Dennis, Ruth L Coleman, Naveed Sattar, Andrew T Hattersley, Rury R Holman, Ewan R Pearson
Objective: To evaluate the association between metformin use and anaemia risk in type 2 diabetes, and the time-course for this, in randomised controlled trial (RCT) and real-world population data.

Research design and methods: Anaemia was defined as a haemoglobin measure less than 11g/dL. In RCTs (ADOPT (n=3,967), UKPDS (n=1,473)), logistic regression was used to model anaemia risk and non-linear mixed models for change in haematological parameters.In the observational GoDARTS population (n=3,485), discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anaemia risk.

Results: In ADOPT, compared with sulfonylureas, the odds ratio(OR)(95%CI) for anaemia 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, haemoglobin and haematocrit dropped following metformin initiation by six months, with no further decrease after three years. In UKPDS, haemoglobin fell by three years in the metformin group compared to other treatments. At years six and nine, haemoglobin was reduced in all treatment groups, with no greater difference seen in the metformin group. In GoDARTS, each 1g/day of metformin use was associated with a 2% higher annual risk of anaemia.

Conclusions: Metformin use is associated with early risk of anaemia 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 haemoglobin is uncertain, but given the time course is unlikely to be due to vitamin B12 deficiency alone.


This work was supported by the Medical Research Council (UK) (MR/N00633X/1). JMD is the recipient of an Exeter Diabetes Centre of Excellence Independent Fellowship funded by Research England’s Expanding Excellence in England (E3) fund. ERP holds a Wellcome Trust New Investigator award (102820/Z/13/Z). ATH is a NIHR Senior Investigator and a Wellcome Trust Senior Investigator (098395/Z/12/Z). JMD and ATH are supported by the NIHR Exeter Clinical Research Facility. RRH is an Emeritus NIHR Senior Investigator. The views expressed are those of the authors and not necessarily those of the MRC, the NIHR or the Wellcome Trust.


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