Efficacy and safety of canagliflozin are consistent across polypharmacy burden in CKD: the CREDENCE trial

BACKGROUND: Polypharmacy in chronic kidney disease (CKD) is substantial. Clinicians and patients are often reluctant to add medications to already complex regimens, partly due to concerns about diminishing efficacy and increased adverse effects. We assessed whether efficacy and safety of canagliflozin is modified by polypharmacy status in patients with type 2 diabetes and CKD. METHODS: We conducted a post-hoc analysis of the CREDENCE trial, which evaluated the effects of canagliflozin on outcomes in patients with type 2 diabetes and CKD. Participants were categorized as no polypharmacy (0-4 medicines), polypharmacy (5-9 medicines), or hyperpolypharmacy (≥10 medicines). We assessed the relative effects of canagliflozin on clinical and safety outcomes by polypharmacy status using Cox proportional hazards models. We assessed absolute benefits using Poisson regression. The primary outcome was a composite of doubling of serum creatinine, kidney failure or death due to cardiovascular or kidney disease. RESULTS: Among 4401 participants, 612 (14%), 2404 (55%), and 1385 (31%) were categorized as no polypharmacy, polypharmacy and hyperpolypharmacy, respectively. Mean number of medications was 8.3 (SD 3.77). The effect of canagliflozin on kidney and cardiovascular outcomes was consistent irrespective of polypharmacy status, with no interaction observed for safety outcomes (all P-interaction > 0.06). Rates of treatment discontinuation increased with medication burden, but were lower with canagliflozin versus placebo, regardless of polypharmacy status (P-interaction = 0.16). Incidence of all-cause hospitalization, and heart failure hospitalization or cardiovascular death increased with higher medication burden, thus absolute risk reductions were estimated to be substantially greater in patients with polypharmacy and hyperpolypharmacy. CONCLUSION: Among patients with type 2 diabetes and CKD, the efficacy and safety of canagliflozin appears consistent regardless of polypharmacy status, with larger estimated absolute reductions in hospitalizations and cardiovascular events in those experiencing polypharmacy or hyperpolypharmacy. These findings suggest that polypharmacy alone should not preclude consideration of SGLT2 inhibitor therapy in patients with CKD and type 2 diabetes for whom treatment is otherwise indicated.