medwireNews: A study of patients from US administrative claims databases finds no evidence that use of canagliflozin increases the risk for below the knee amputation when compared with other sodium-glucose cotransporter (SGLT)2 inhibitors or with other antidiabetic medications.
The research, which was reported at the ADA’s 78th Scientific Sessions in Orlando, Florida, USA, and simultaneously published in Diabetes, Obesity and Metabolism, also confirms that the beneficial effect of SGLT2 inhibitors on heart failure is present in real-world use.
These databases yielded 142,800 new users of canagliflozin, 110,897 of other SGLT2 inhibitors, and 460,885 of other antidiabetic agents. Rates of below the knee amputation among patients taking canagliflozin ranged from 1.0 to 5.0 per 1000 person–years across the databases.
Patrick Ryan (Janssen Research & Development, LLC, Titusville, New Jersey, USA) and co-researchers matched canagliflozin users with users of other SGLT2 inhibitors or antidiabetic agents by a score for the propensity to receive canagliflozin rather than medications from other classes, which was based on factors including demographics, pre-existing conditions, medications, and Charlson comorbidity index.
The team found that canagliflozin did not increase users’ amputation risk, at nonsignificant hazard ratios of 1.14 versus other SGLT2 inhibitors and 0.75 versus all other antidiabetic medications. This was an on-treatment analysis looking only at time periods in which patients were actually taking their medication; findings were similar in an intention-to-treat analysis, involving all patients from the first time they received a medication.
In the case of heart failure hospitalization, canagliflozin use was associated with a significant 61% reduction in risk versus non-SGLT2 inhibitor medications. And the same was true for other SGLT2 inhibitors, which reduced the risk by a significant 57%.
The findings were consistent when the analyses were restricted to patients with established cardiovascular disease, with canagliflozin having a positive effect on heart failure hospitalization and a neutral effect on amputation risk.
Speaking to medwireNews, study co-author John Buse (University of North Carolina School of Medicine, Chapel Hill, USA) said that the increased amputation risk reported in the CANVAS trials last year was “an important signal,” because it was observed in both CANVAS and CANVAS-R.
“I suspect it’s related to very high-risk patients, who had a biologic effect of the drug that somehow tipped the balance in their pathway to amputation,” he said. “How that happens, I don’t know – there are people who theorize that the excess urination leads to a bit of dehydration, which leads to thickening of the blood that leads to perhaps a little bit more sludging in the extremities when people are standing on their feet. There could just be a slight tilt in that balance.”
However, the increased amputation risk was not observed in the empagliflozin trial, EMPA-REG OUTCOMES, and as Buse pointed out, “it’s hard to miss a below the knee amputation.”
This underscores the importance of conducting further large real-world studies similar to OBSERVE-4D, he said, to help determine if the increased risk in CANVAS was “a spurious observation” or if “SGLT2 inhibitors do increase the risk of amputation and that EMPA-REG and this analysis just haven’t been able to find it.”
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