1. Among patients with type 2 diabetes mellitus and chronic kidney disease being treated with canagliflozin, earlier reductions in albuminuria were associated with a decreased risk of adverse renal and cardiovascular outcomes.
Evidence Level Rating: 2 (Good)
In the past, post hoc analyses from clinical trials of RAAS inhibitors have shown that the magnitude of reduction of albuminuria – a strong, independent risk marker of cardiovascular and kidney disease – is associated with the degree of risk reduction. The 2019 Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that the SGLT2 inhibitor canagliflozin, originally developed a glucose-lowering agent, results in a sustained reduction in albuminuria and confers a reduced risk of kidney failure and poor cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). This post hoc analysis of the CREDENCE trial sought to answer whether early reductions in albuminuria are associated with the magnitude of risk reduction, similar to what has been observed in RAAS-modulated drugs. Briefly, CREDENCE was a double-blind, placebo-controlled randomized trial involving 4,401 patients randomized to receive 100 mg of canagliflozin daily, or matching placebo. The cohort in this analysis included 3,836 participants from CREDENCE. The primary kidney outcome was a composite of ESRD (defined as dialysis for at least 30 days, kidney transplantation, or an eGFR of < 15 mL/min/1.73 m2 sustained for at least 30 days), doubling of the serum creatinine level from baseline sustained for at least 30 days, or kidney death. The primary cardiovascular outcomes were major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, as well as a composite of hospitalization for heart failure or cardiovascular death. Overall, it was found that an early reduction in urine albumin-to-creatinine ratio (UACR) was associated favorably with kidney and cardiovascular outcomes. Indeed, each 30% decrease in UACR over the first 26 weeks of treatment was associated with significant hazard reductions for the kidney (HR 0.71, 95% CI 0.67 to 0.76, p < 0.001), MACE (HR 0.92, 95% CI 0.88 to 0.96, p < 0.001), and hospitalizations for heart failure or cardiovascular death (HR 0.86, 95% CI 0.81 to 0.90, p < 0.001) outcomes. Furthermore, the association between early reduction in UACR and the kidney outcome was stronger among patient with a lower eGFR and higher UACR; in contrast, the associations were consistent for the cardiovascular outcomes. In all, this post hoc analysis suggests that an early reduction in UACR during treatment with canagliflozin is associated with a reduced risk of adverse kidney and cardiovascular outcomes among patients with T2DM and CKD, highlighting the importance of tracking albuminuria to both guide treatment and assess prognosis.
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