Abstract
Canagliflozin slows the progression of chronic kidney disease in patients with type 2 diabetes and induces a reversible acute drop in estimated glomerular filtration rate (eGFR), believed to be a hemodynamic effect. Predictors of the initial drop and its association with long-term eGFR trajectories and safety outcomes are unknown. To assess this, we performed a post-hoc analysis of 4289 participants in the CREDENCE trial with type 2 diabetes and chronic kidney disease equally split into treatment and placebo groups who had eGFR measured at both baseline and week three. The eGFR was categorized at week three as greater than a 10% decline; between 0 and 10% decline; and no decline. Long-term eGFR trajectories and safety outcomes were estimated in each category of acute eGFR change by linear mixed effects models and Cox regression after adjustment for baseline characteristics and medications use. Significantly more participants in the canagliflozin (45%) compared to the placebo (21%) group experienced an acute drop in eGFR over 10%. An over 30% drop occurred infrequently (4% of participants with canagliflozin and 2% with placebo). The odds ratio for a drop in eGFR over 10% with canagliflozin compared to placebo was significant at 3.03 (95% confidence interval 2.65, 3.47). Following the initial drop in eGFR, multivariable adjusted long-term eGFR trajectories, as well as overall and kidney safety profiles, in those treated with canagliflozin were similar across eGFR decline categories. Thus, although acute drops in eGFR over 10% occurred in nearly half of all participants following initiation of canagliflozin, the clinical benefit of canagliflozin was observed regardless. Additionally, safety outcomes were similar among subgroups of acute eGFR drop.
Highlights
Sodium glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the risk of kidney and cardiovascular outcomes in people with type 2 diabetes
In an additional analysis using the predicted likelihood of an acute estimated glomerular filtration rate (eGFR) drop >10%, the effects of canagliflozin relative to placebo on adverse events were consistent regardless of a likelihood of an eGFR drop >10% above or below the median (P for interaction >0.51; Supplementary Table S6). In this post hoc analysis of the CREDENCE trial, we demonstrated that an initial drop in eGFR in response to canagliflozin is common, but a larger drop of 30% in eGFR
We demonstrated that the long-term eGFR trajectories as well as overall and renal safety profiles during canagliflozin treatment were similar regardless of the initial eGFR drop, except when it unusually exceeded 30%, when adverse events and renal-related adverse events were reported more frequently
Summary
Sodium glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the risk of kidney and cardiovascular outcomes in people with type 2 diabetes. SGLT2 inhibitors cause an acute reduction in intraglomerular pressure and glomerular filtration rate.[1] Large cardiovascular outcome trials have. A better characterization of the acute drop in eGFR and its association with long-term eGFR trajectories and safety outcomes is required to support appropriate use of SGLT2 inhibitors in clinical practice. We performed a post hoc analysis of the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial to determine the predictors of an acute eGFR decline following initiation of the SGLT2 inhibitor canagliflozin and its associations with long-term eGFR trajectories and safety outcomes
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