Although the widely used drug metformin has proven to be a safe and effective treatment for diabetes, even the best medications can sometimes have unwanted side effects. According to a study just published in the journal Diabetes Care, metformin appears to carry a small risk of moderate anemia.
The researchers, who were from the School of Medicine at the University of Dundee in Dundee, Scotland, based their findings on two randomized controlled trials (RCTs) and one real-world study.
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The first trial is known as A Diabetes Outcome Progression Trial, or ADOPT. It’s a randomized, double-blind, parallel-group study that was started in 2002. From this trial, the researchers identified nearly 4,000 patients recently diagnosed with type 2 diabetes. About one-third were taking sulfonylureas, which are common diabetes medications, one-third were using thiazolidinediones (medications that treat insulin resistance), and one-third were taking metformin. After five years of follow-up, the researchers reported that the odds of the participants in the metformin group developing anemia were almost twice as high as in the sulfonylurea group. The participants in the thiazolidinedione group, however, were even more likely to develop anemia than those in the metformin group.
The second trial the researchers examined was UKPDS, or The UK Prospective Diabetes Study, which was a randomized, multi-center trial of diabetes therapies on over 5,000 patients with newly diagnosed diabetes that ran from 1977 to 1997. It was the largest and longest diabetes study ever conducted. Many papers utilizing its database have been published and more are still appearing. The authors of the new Diabetes Care paper identified nearly 1,500 UKPDS patients with type 2 diabetes. About one out of five were using metformin and approximately one out of three were taking sulfonylureas. The rest were being treated either with insulin or with diet alone. The researchers determined that after nine years of follow-up, anemia rates were 6.3% in the metformin group, 1.1% in the sulfonylureas group, 2.5% in the insulin group, and 1.7% in the diet group.
The researchers noted that the onset of anemia occurred fairly quickly in the affected people. In the ADOPT trial, a decline in hemoglobin (the red blood cells that contain most of the body’s iron) was noted at the first six-month measurement. In UKPDS, a similar decline was found at the first three-year measurement. In the ADOPT group, however, no further decline was noted after three years. In UKPDS, all of the four treatment groups showed lower hemoglobin by years six and nine. By that point there was no difference between the metformin users and the other participants.
Finally, the researchers looked at a real-world study called GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland), which recruited more than 20,000 type 2 diabetes patients from 1998 to 2015 and is now in its fifth phase. According to data taken from this study, each gram per day of metformin was associated with a 2% higher risk of anemia.
The researchers were unable to explain why metformin users were more likely to develop anemia. Because it’s previously been shown that people who take metformin tend to have a deficiency of vitamin B12, the researchers at first wondered if the anemia might be related to the vitamin B12 deficiency, but then they ruled it out. As they explained, “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.” Instead, they wrote, “It is more likely that this initial greater risk of anemia with metformin can be attributed to an immediate effect of metformin on hemoglobin, particularly in light of the ADOPT data, where we see a significant change at six months.”
The researchers pointed out that although the relationship between metformin and anemia now seems to be established, the effect is not great and in no way implies that anyone should discontinue metformin. According to lead study author Ewan R. Pearson, MD, professor of diabetic medicine at the University of Dundee, “Because the mechanisms for metformin-related moderate anemia are unknown, the effects are modest, and the benefits of metformin are proven, we would not in any way advocate avoidance or discontinuation of metformin, even in patients with anemia, but a reduction in hemoglobin in the first few years after initiation of metformin might be anticipated.”