No Increased Amputation Risk Noted with Canagliflozin in Patients with T2D in Study

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In addition to showing no significant imbalance of BKLE amputation, the study also identified a HHF reduction in the general T2D population.

When compared to other sodium glucose cotransporter 2 inhibitors (SGLT2i) or non-SGLT2i anti-hyperglycemic medicines, patients with type 2 diabetes (T2D) who were assigned canagliflozin (Invokana, Janssen) did not have an increased risk of below-knee extermity amputation, according to study results presented at the American Diabetes Association (ADA) 78th Scientific Sessions held this week. In addition to the general T2D population, similar results were also seen in a subset of patients with T2D and established cardiovascular disease.

The study, OBSERVE-4D is a real-world observational study of more than 700,000 patients with type 2 diabtes, which is evaluating the risk of below-knee amputation and hospitalization for heart failure (HHF) across anti-hyperglycemic therapies. Janssen supported the research.

Data from the integrated analysis of the CANVAS and CANVAS-R trials, reported at the ADA meeting in 2017, suggested an increased risk of amputation with canagliflozin. In that analysis, there was an increased risk of amputation (6.3 vs. 3.4/1000 patient-years) corresponding to a hazard ratio (HR) of 1.97. The highest absolute risk of amputation occurred in patients with a prior history of amputation or peripheral vascular disease, but the relative risk for amputation with canagliflozin was comparable across these subgroups. These findings were then reflected in the US Prescribing Information for canagliflozin.

In the OBSERVE-4D analysis, researchers observed no increased risks across the therapy comparisons for BKLE amputations in the general T2D population:

  • Canagliflozin vs. all non-SGLT2i medicines: HR = 0.75, 95% CI (0.40, 1.41), P=0.30.
  • Canagliflozin vs. other SGLT2i medicines: HR = 1.14 95% CI (0.67, 1.93),P=0.53.
  • Other SGLT2i medicines vs. all non-SGLT2i medicines: HR = 0.84 95% CI (0.27, 2.55), P=0.68.

These amputation rates were also consistent in a sub-population with established cardiovascular disease.

In addition to showing no significant imbalance of BKLE amputation, the study also identified a HHF reduction in the general T2D population that was consistent with rates seen in randomized clinical trials and other real-world evidence studies including the SGLT2i class. The HHF result is a positive confirmatory finding and supports the internal validity of the study results:

"OBSERVE-4D depicts how Invokana and other SGLT2is are being used by people with type 2 diabetes, including in those with established CV disease, in the real world," John Buse, MD, PhD, Chief of the Division of Endocrinology and Director of the Diabetes Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina said in a press release about the findings. "The overall benefit-risk profile of SGLT2is is positive, and physicians should feel comfortable and confident in prescribing the class to their appropriate patients."

For more on this topic, watch our interview with Paul Burton, MD, Vice President, Janssen Scientific Affairs, LLC, below.