Study on Amputation Risk with Canagliflozin

USA: The increased amputation risk associated with the use of the diabetes drug canagliflozin is small and most obvious in older adults having cardiovascular disease, according to a recent study in the journal BMJ. The results help to contextualize amputation risk associated with routine care use of canagliflozin.

Canagliflozin (Invokana), an SGLT2 inhibitor, is an oral antidiabetic drug used for the management of type 2 diabetes. The drug reduces the risk of cardiovascular mortality, stroke, and myocardial infarction. Additional benefits include reductions in systolic blood pressure, weight, and proteinuria, and a reduction in the rate of hospital admission for heart failure and renal failure. The use of SGLT2 inhibitors, however, is also associated with an increased risk of important adverse events.

The CANVAS (CANagliflozin cardioVascular Assessment Study) Program had found an increased amputation risk with canagliflozin in comparison with placebo. Michael Fralick, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA, and colleagues estimated the rate of lower limb amputation among adults newly prescribed canagliflozin according to age and cardiovascular disease.

The authors propensity score-matched 1:1 patients newly prescribed canagliflozin with patients newly prescribed a glucagon-like peptide-1 (GLP-1) receptor agonist. Hazard ratios and rate differences per 1000 person-years were computed for the rate of lower limb amputation in the following four groups:

• Group 1: Patients aged less than 65 years without baseline cardiovascular disease
• Group 2: Patients aged less than 65 with baseline cardiovascular disease
• Group 3: Patients aged 65 or older without baseline cardiovascular disease
• Group 4: Patients aged 65 or older with baseline cardiovascular disease

The primary outcome measure was lower limb amputation requiring surgery.

Key Findings of the Study

• Across the three databases, 310,840 propensity score-matched adults who started canagliflozin or a GLP-1 agonist were identified.
• The hazard ratio and rate difference per 1000 person-years for amputation in adults receiving canagliflozin compared with a GLP-1 agonist for each group was:
  • Group 1: Hazard ratio 1.09, rate difference 0.12
  • Group 2: Hazard ratio 1.18, rate difference 1.06
  • Group 3: Hazard ratio 1.30, rate difference 0.47
  • Group 4: Hazard ratio 1.73, rate difference 3.66

"Our results suggest that the increased amputation risk with canagliflozin is small and most obvious on an absolute scale among adults aged 65 or older having the cardiovascular disease at baseline, resulting in nearly four more amputations in 1000 person-years with canagliflozin than with a GLP-1 agonist, corresponding to a number needed to treat for an additional harmful outcome of 556 patients at six months," wrote the authors. "These findings help to contextualize the risk of amputation in routine care and can help patient-physician decision making before prescribing canagliflozin."

The study, "Risk of amputation with canagliflozin across categories of age and cardiovascular risk in three US nationwide databases: cohort study," is published in the journal BMJ.

DOI: https://doi.org/10.1136/bmj.m2812