Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

Literature - Perkovic V, Jardine MG, Neal B et al., - New Engl J Med. 2019. April 14, DOI: 10.1056/NEJMoa1811744

Presented during ISN-WCN 2019 in Melbourne, Australia on April 15, 2019.

Introduction and methods

The increasing prevalence of type 2 diabetes (T2DM) is accompanied by a substantial increase in end-stage kidney disease (ESKD). Renin-angiotensin system blockade is currently the only approved treatment for renoprotection in patients with T2DM.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels in patients with T2DM. In trials set up to demonstrate safety of SGLT2 inhibitors, the treatment was also found to reduce CV events [1-3]. Secondary and exploratory analyses of these trials suggested that SGLT2 inhibition might improve renal outcomes. However, the precise effects of SGLT2 inhibition on kidney function remained to be elucidated, since few patients reached ESKD and most trial patients were at low risk for kidney failure [3-5].

The CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial [6] was therefore set up to assess the effects of the SGLT2 inhibitor canagliflozin on renal outcomes in patients with T2DM (HbA1c 6.5% to 12.0%) and albuminuric kidney disease (eGFR 30 to 90 ml/min/1.73² and urinary albumin-to-creatinine ratio 300-5000, measured in milligram and gram, respectively). All patients were on a stable dose of ACE inhibitor or ARB for at least 4 weeks before randomization. 4401 Patients were randomized to canagliflozin (100 mg orally once daily) or matching placebo, with stratification according to eGFR categories at screening. The primary endpoint was a composite of ESKD (dialysis ≥30 days, kidney transplantation, or eGFR <15 ml/min/1.73² ≥30 days), doubling of serum creatinine level from baseline ≥30 days, or death from renal or CV disease.

Screening and randomization started in March 2014. In July 2018, the requisite number of primary outcome events to trigger an interim analysis was reached. The data monitoring committee advised that the prespecified efficacy criteria for early cessation of the trial had been achieved, after which the recommendation to stop the trial was accepted. This was after a median follow-up of 2.62 years (range 0.02 to 4.53).

Main results

• The primary composite outcome was seen significantly less often in the canagliflozin group than in the placebo group (43.2 vs 61.2 per 1000 patient-years (PY), HR: 0.70, 95%CI: 0.59-0.82, P=0.00001).
• The effect of canaglifozin was consistent for the component of ESKD (HR: 0.68, 95%CI: 0.54-0.86, P=0.002) and across renal components, including the doubling of serum creatinine (HR: 0.60, 95%CI: 0.48-0.76, P<0.001).
• The exploratory outcome of dialysis, kidney transplantation or renal death was also reduced (HR: 0.72, 95%CI: 0.54-0.97).
• Patients randomized to canagliflozin also showed a lower risk of several secondary outcomes, tested in a hierarchical fashion. This included: CV death or hospitalization for HF (HR: 0.69, 95%CI: 0.57-0.83), CV death, MI or stroke (HR: 0.80, 95%CI: 0.67-0.95) and hospitalization for HF (HR: 0.61, 95%CI: 0.47-0.80).
• The composite of ESDK, doubling of serum creatinine level or renal death was reduced in the canagliflozin-treated group (HR: 0.66, 95%CI: 0.53-0.81, P<0.001).
• The risk of CV death was not significantly different between groups (HR: 0.78, 95%CI: 0.61-1.00, P=0.05). Thus, all subsequent outcomes in the hierarchical testing sequence were not formally tested.
• Rates of adverse events and serious adverse events were similar between groups. No significant difference was seen in the risk of lower-limb amputation (12.3 vs. 11.2 per 1000 PY with canagliflozin vs. placebo, HR: 1.1, 95%CI: 0.79-1.56) and fractures (HR: 0.98, 95%CI: 0.70-1.37). Diabetic ketoacidosis was seen more often with canagliflozin (2.2 vs. 0.2 per 1000 PY).

Conclusion

References

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