SGLT2 inhibitors and doubled risk for amputations in the US: How and Why?

This from colleagues publishing in Lancet Diabetes and Endocrinology evaluating data from the recent CANVAS trial.

In that programme, the sodium-glucose co-transporter-2 (SGLT2) inhibitor canagliflozin significantly reduced the risk of cardiovascular events by 14% but doubled the risk of amputation in patients with type 2 diabetes.¹ This unexpected adverse event has not emerged in studies on dapagliflozin or empagliflozin.

Full text for the study can be found here.

Further summary here from our colleagues in Padova:

In [further] summary, this pharmacovigilance analysis confirms that use of canagliflozin, but not dapagliflozin or empagliflozin, might be associated with an increased risk of amputations.¹ However, FAERS data analysis has important limitations because there is no definite causal link between drug exposure and adverse event, PRRs do not inform on the true risk in clinical practice, records are often incomplete, and US FDA warnings might result in stimulated reporting. Additionally, we cannot exclude the possibility that some data from patients in the CANVAS trials might not also have appeared in the FAERS dataset (appendix). Further details are provided in the appendix, along with caveats on concluding in favour of a non-class-effect, and notes about potential mechanisms.