Study OBSERVEs no increased risk of below-knee amputation with canagliflozin
The sodium glucose co-transporter 2 (SGLT-2) inhibitor canagliflozin does not appear to increase the risk of below-knee lower extremity amputations over other SGLT2 inhibitors or non-SGLT2 inhibitor antihyperglycaemic agents in patients with type 2 diabetes (T2D), but may reduce the risk of hospitalization for heart failure (HHF), according to findings of the US-based OBSERVE-4D* study.
“We did not observe an increased risk in amputation with canagliflozin or any of the SGLT2 inhibitors, and we confirmed they can have an important and positive impact on reducing a patient’s risk of HHF,” said study lead investigator Professor John Buse from the University of North Carolina School of Medicine in Chapel Hill, North Carolina, US.
Researchers of this retrospective observational study used data from four US administrative claims databases to identify patients with T2D who were new users (median <6 months) of canagliflozin (n=142,800), other SGLT2 inhibitors (empagliflozin or dapagliflozin; n=110,897), or non-SGLT2 inhibitor antihyperglycaemic agents (n=460,885). Among these, 43,043, 31,011, and 141,579 new users of canagliflozin, other SGLT2 inhibitors, and non-SGLT2 inhibitors, respectively, had established cardiovascular disease.
New users of canagliflozin did not have a higher risk of below-knee lower extremity amputation compared with new users of other SGLT2 inhibitors (hazard ratio [HR], 1.14, 95 percent confidence interval [CI], 0.67–1.93; p=0.53) or non-SGLT2 inhibitors (HR, 0.75, 95 percent CI, 0.40–1.41; p=0.30). [ADA 2018, abstract 4-LB; Diabetes Obes Metab 2018;doi: 10.1111/dom.13424]
The results of the on-treatment analysis also showed a reduction in the risk of HHF with canagliflozin over non-SGLT2 inhibitors (HR, 0.39, 95 percent CI, 0.26–0.60; p<0.001) though there was no difference in HHF risk with canagliflozin vs other SGLT2-inhibitors (HR, 0.90, 95 percent CI, 0.71–1.13; p=0.28).
The findings were similar in a sub-population analysis of patients with existing cardiovascular disease where the rates of below-knee lower extremity amputation among new canagliflozin users were similar to that of new users of other SGLT2 inhibitors (HR, 1.08, 95 percent CI, 0.63–1.82; p=0.85) and non-SGLT2 inhibitors (HR, 0.72, 95 percent CI, 0.34–1.51; p=0.29), while the risk of HHF was lower with canagliflozin than with non-SGLT2 inhibitor users (HR, 0.44, 95 percent CI, 0.36–0.54; p<0.001) but similar to that of patients using other SGLT2 inhibitors (HR, 0.70, 95 percent CI, 0.30–1.63; p=0.06).
“The results of the OBSERVE-4D study suggest that canagliflozin has a similar profile compared to other SGLT2 inhibitors as they are used in routine clinical practice,” said the researchers.
“It is noteworthy that, in this study, the decreased risk of HHF was consistent among all new users, as well as within the subpopulation with established cardiovascular disease, even in light of the substantial increase in baseline risk for patients with established cardiovascular disease,” they added.
However, they also pointed out that in the CANVAS** study, the amputation risk emerged following 6–12 months of exposure to canagliflozin [N Engl J Med 2017;377:644-657] and as such, this study may not have detected the risk during this period, which highlights the need for longer-term observational studies.
“These real-world results further characterize canagliflozin’s safety and efficacy profile and will help physicians make more informed treatment decisions to support their patients’ T2D care,” said the researchers.
“Of course, when physicians evaluate the best treatment for their patients, they should consider the factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Our research indicates that the overall benefit-risk profile of SGLT2 inhibitors is positive, and physicians should feel comfortable and confident in prescribing the class to their patients,” said Buse.