New analysis of pooled data has provided more reassurance that the SGLT2 inhibitor canagliflozin is not associated with a higher risk of limb amputations, Australian researchers say.
The concern about amputation risk was raised years ago in CANVAS trial findings – and reported here in the limbic – but has not been reproduced in subsequent studies such as CREDENCE and the mechanism still remains unexplained.
The latest study, led by the George Institute, NSW, compared patient data between the trials and also looked at pooled patient data.
It confirmed the almost two-fold amputation risk seen in CANVAS (HR 1.8) and was unable to identify any biologically or clinically plausible reasons for the higher risk as compared to no increased risk observed in CREDENCE (HR 1.03).
“In particular, there was no evidence that the main difference between the studies, the proportions of patients with nephropathy and the proportions of patients with established [cardiovascular disease], were reasons for the observed variation in effects on amputation risk,” the study said.
When the data from both studies were pooled, amounting to more than 14,000 patients, there was no increased risk in patients treated with canagliflozin based on the duration of follow-up.
The study found previous amputation was the strongest predictor of subsequent amputation risk.
Lead author and cardiologist Dr Clare Arnott told the limbic the potential amputation risk with the SGLT2 inhibitor was an important issue to review.
“Initially there was concern that this would represent a ‘class effect’ however robust randomised data in large patient datasets has disproved this – dapagliflozin in DECLARE-TIMI and DAPA-HF no increase amputation risk; empagliflozin in EMPA-REG no increase in amputation.”
“It was then considered a possible canagliflozin alone risk from the data of CANVAS/CANVAS-R, until the CREDENCE trial.”
Dr Arnott said there was no evidence that differences in participant characteristics between the trials explained the differences in amputation risk, nor was there any interaction between demographic, clinical, laboratory, or medication variables and treatment effect in the pooled dataset.
“Notably, there was no evidence that difference in follow-up affected amputation risk, or that the protocol amendment addressing foot care that was implemented during CREDENCE explained the null effect on amputations in that trial.”
She said she hoped that as more data became available from large randomised datasets such as DAPA-CKD, that clinicians will have more confidence in prescribing SGLT2 inhibitors given the impressive cardiovascular and renal benefits they afford.
“People with T2DM and CKD are at an elevated risk of peripheral vascular disease and amputation and thus I think limb assessment and proactive limb care should form part of routine clinical care, regardless of medications used.”