乌鸦传媒

ORLANDO -- Treatment with canagliflozin in patients with type 2 diabetes showed no increased risk for amputation, the OBSERVE-4D study showed.

New users treated with canagliflozin (Invokana) did not see any significant elevated risk for below-knee amputations (BKA) compared to treatment with new users on other antihyperglycemic agents that weren't SGLT-2 inhibitor agents (HR 0.75, 95% CI 0.40-1.41, P=0.25), reported John Buse, MD, PhD, of the University of North Carolina School of Medicine in Chapel Hill, and colleagues.

Risk for BKA was generally similar across this class of treatments, and KA risk was not significantly different between canagliflozin use and other SGLT-2 inhibitors (HR 1.14, 95% CI 0.67-1.93, P=0.48), they said in a late-breaking abstract presentation at the American Diabetes Association (ADA) annual meeting,

These findings also held up in another analysis in an intent-to-treat population that compared canagliflozin use to other SGLT-2 inhibitors (HR 1.13, 95% CI 0.99-1.29, P=0.06), as well as treatment with other antihyperglycemic agents (HR 1.01, 95% CI 0.93-1.10, P=0.71).

As was expected, heart risk was cut with canagliflozin use in the analysis, similar to what was seen in the CANVAS program presented at the 2017 ADA meeting. Specifically, Buse's group found a reduced risk for hospitalized heart failure with new use of canagliflozin versus other antihyperglycemic agents (HR 0.39, 95% CI 0.26-0.60, P=0.01). Risk for hospitalized heart failure not different between new canagliflozin use compared to treatment with other SGLT-2 inhibitors (HR 0.90, 95% CI 0.71-1.13, P=0.22).

"The amputations in the CANVAS trial largely occurred in patients who had prior amputations -- so they'd lost a toe -- and in the trial, they lost their foot or they lost their leg," Buse explained to 乌鸦传媒. "For patients who have not had amputations, that don't have neuropathy, that aren't smokers and don't have advanced peripheral vascular disease, I would feel very reassured that there's essentially zero risk of amputation," he stated, adding that if he had a patient with heart failure or clinical cardiovascular disease, he would "definitely use an SGLT-2 inhibitor."

"In a patient who's had an amputation and has heart failure, I still might use an SGLT-2 inhibitor. It's a matter of balancing perceived risks and perceived benefits," he recommended.

In a subgroup analysis of patients with established clinical cardiovascular disease, which included patients with prior heart attacks, strokes and other heart events, there were similar outcomes seen on BKA and hospitalized heart failure risk.

The real-world analysis used pharmacoepidemiology to draw upon 142,000 canagliflozin users appearing in four different U.S. administration claims databases. They were compared with 110,000 patients on treatment with other SGLT-2 inhibitors, including dapagliflozin and empagliflozin, as well as 460,000 patients on other antihyperglycemic agents, which included DPP-4 inhibitors, GLP-1 receptor agonists, thiazolidinediones, sulfonylureas, insulins, acarbose, bromocriptine, miglitol, nateglinide, and repaglinide. Among this patient group, median exposure to canagliflozin was <6 months.

"The average exposure to a drug in the U.S. is 6 months, and we can say with pretty great certainty that there's not an amputation problem in the use of an SGLT-2 inhibitor for at least 6 months...so as the drug is being used in the U.S., it seems to be pretty safe" Buse said. He noted there is less evidence confirming the safety with long-term use.

"I think this is to some extent reassuring," commented Robert Eckel, MD, of the University of Colorado Anschutz Medical Campus. Eckel, who was not involved with the study, cautioned that a randomized clinical trial is needed to confirm these observed findings.

Buse stated that OBSERVE-4D study findings have been accepted for publication.

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