Registry study supports SGLT2 inhibitor amputation risk
medwireNews: A registry study in The BMJ finds a small but significant increased risk for amputations in patients with type 2 diabetes using sodium-glucose cotransporter (SGLT)2 inhibitors.
The researchers identified 17,213 new users of SGLT2 inhibitors from Swedish and Danish registries and matched them on the propensity to be prescribed these medications to an equal number of new users of glucagon-like peptide (GLP)-1 receptor agonists.
They found that, over a median 39 weeks of follow-up, lower-limb amputations occurred at a rate of 2.7 per 1000 person–years in the SGLT2 inhibitor users, compared with 1.1 per 1000 person–years in the GLP-1 receptor agonist users. This equated to a 2.32-fold increased relative risk.
The significant risk increase was consistent regardless of patients’ age and sex, and whether or not they had pre-existing cardiovascular or peripheral artery disease.
The increased amputation risk with SGLT2 inhibition was first noted in the CANVAS trial, with canagliflozin, and has since been variously refuted and supported by a number of real-world data studies, including OBSERVE-4D, which found no evidence for an increased amputation risk with canagliflozin.
John Buse (University of North Carolina at Chapel Hill, USA), who was an OBSERVE-4D investigator, told medwireNews that in the current study, the “use of GLP-1 receptor agonists as the active comparator likely eliminates many confounders.”
He said: “No ‘real world evidence’ ever provides a definitive answer, but I do think this is the best study published to date on the topic.”
The matched patients were aged an average of 61 years, 61% were men, and 50% had been taking diabetes medications for at least 7 years. Almost all were taking other diabetes medications in addition to an SGLT2 inhibitor or GLP-1 receptor agonist, with 29% using basal insulin and 16% also using a rapid-acting insulin.
The majority (61%) of patients in the SGLT2 inhibitor group were using dapagliflozin, with 38% using empagliflozin and just 1% canagliflozin.
“Interestingly, the lack of exposure in this Scandinavian population to canagliflozin suggests that the amputation signal first observed in CANVAS may be a class effect,” said Buse.
“Most importantly though, the absolute risk increase is quite small suggesting that for patients at high risk of [cardiovascular disease], [chronic heart failure] or [chronic kidney disease events], the benefits of the class far outweigh the potential harms.
“That said, these issues should be part of the shared decision-making in diabetes prescribing.”
In line with previous research and the known mechanism of SGLT2 inhibition, the rate of diabetic ketoacidosis was also significantly increased in the SGLT2 inhibitor users relative to the GLP-1 receptor agonist users, at 1.3 versus 0.6 events per 1000 person–years, for a 2.14-fold relative risk increase.
However, rates of bone fracture, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis did not significantly differ between the two groups, report Peter Ueda (Karolinska University Hospital, Stockholm, Sweden) and study co-authors.
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