Abstract

AIMS: The SGLT2 inhibitor canagliflozin was associated with increased amputation risk in the CANVAS Program but not in CREDENCE. We explored possible explanations for these differences in amputation risk.METHODS: We performed a pooled analysis of patient-level data from the CANVAS Program and CREDENCE trial. Patient characteristics associated with amputation risk were assessed in univariable and multivariable regression models and compared between studies. Effects of canagliflozin on amputation risk were determined from Cox proportional hazards models and compared between studies, subgroups, and for a range of amputation outcomes. Effects over time were explored by cumulative event curves.RESULTS: In the CANVAS Program (n=10,142; median follow-up 2·4y) and CREDENCE trial (n=4401; median follow-up 2·5y), 2·3% and 5·3% of participants, respectively, reported baseline amputation history. Key differences at baseline were the proportions with nephropathy (CREDENCE higher, 100% vs 17·5%) and cardiovascular disease (CANVAS Program higher, 66% vs 50%). There were 133 amputations in CREDENCE (3·0% annual event rate) and 187 amputations in CANVAS (1·8% annual event rate), with prior amputation being the strongest predictor of future amputation in both groups. Effects of canagliflozin on amputation risk were significantly different between trials (pheterogeneity 0·02, I2 =82%), but this was not explained by participant or trial differences. There was no evidence that foot disease management protocols instituted during CREDENCE ameliorated amputation risk.CONCLUSIONS: We identified no explanation for the difference in amputation risk between CREDENCE and the CANVAS Program. In the context of null effects of SGLT2 inhibition on amputation in CREDENCE and all other large trials, there is a possibility that the finding in CANVAS was the result of chance. This article is protected by copyright. All rights reserved.

View details for DOI 10.1111/dom.14091

View details for PubMedID 32436638