Research has again linked the drug class sodium-glucose co-transporter-2 (SGLT2) inhibitors to an increased risk of amputation in people with type 2 diabetes.
SGLT2 inhibitors help to lower the blood sugar of people with type 2 diabetes by assisting the kidneys in excreting urine. But links to a higher risk of amputation have been recognised in recent years.
The European Medicines Agency and US Food and Drug Administration (FDA) both determined in 2017 that SGLT2 drug boxes should carry a warning stating an increased risk of lower-limb amputation.
Research continues to investigate the link, and this new study by Johns Hopkins Bloomberg School of Public Health researchers, in the US, again revealed higher amputation risks with the drug class.
When compared with adults with type 2 diabetes who took either sulphonylureas, metformin and glitazones, new users of SGLT2 drugs had twice the risk of undergoing lower extremity amputation. This was deemed to be statistically significant after accounting for a number of factors such as severity of diabetes and other health conditions present.
The data from 953,906 participants also revealed that new users of SGLT2 inhibitors had a higher risk of amputation than new users of DDP-4 inhibitors and GLP-1 agonists, although these findings were not statistically significant.

“Given the uncertainty regarding the true nature of the association between SLGT-2 inhibitors and amputation, clinicians and patients will have to navigate treatment choices while balancing the potential risks of these products against their benefits and alternatives,” said the study authors.
Benedict Jephcote, Editor of, commented on the findings, “The reason for the higher risk of amputations has not been fully investigated by research. However, the way in which SGLT2 inhibitors work may offer some clues.
“We know that the drugs help the body to pass glucose out through the urine when sugar levels are too high. Whilst this helps to keep sugar levels under a high level, this level may still be high enough to increase the spread of infection at the site of a wound and thus increase the risk of amputation being needed.
“This provides a possible reason but, at the moment, we cannot confirm if this is factor in the increase in amputation or not.”
Last month a tool was introduced that could help healthcare professionals determine which people with type 2 diabetes would benefit most from SGLT2 treatment.
The findings have been published in JAMA Internal Medicine.

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