Background: Chronic kidney disease (CKD) risk is elevated in patients with type 2 diabetes mellitus (T2DM). Disease management in these patients has been generally focused on glycemic control and controlling other renal and cardiac risk factors as, historically, few protective therapies have been available. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial of canagliflozin was the first study to demonstrate renal protection with a sodium glucose co-transporter 2 inhibitor in patients with T2DM and CKD, and these results could have important implications for clinical practice. Summary: In CREDENCE, participants with T2DM and estimated glomerular filtration rate 30–<90 mL/min/1.73 m<sup>2</sup> and urinary albumin-creatinine ratio >300–5,000 mg/g who were treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for ≥4 weeks prior to randomization at either the maximum labeled or tolerated dose were randomized to receive either canagliflozin 100 mg or placebo. Canagliflozin significantly reduced the risk of the primary composite outcome of doubling of serum creatinine, end-stage kidney disease, or renal or cardiovascular (CV) death compared with placebo (hazard ratio 0.70, 95% CI 0.59–0.82; p = 0.00001). Canagliflozin also reduced the risk of secondary renal and CV outcomes. The safety profile of canagliflozin in CREDENCE was generally similar to previous studies of canagliflozin. No imbalances were observed between canagliflozin and placebo in the risk of amputation or fracture in the CREDENCE population. Key Messages: The positive renal and CV effects of canagliflozin observed in the CREDENCE trial could have a substantial impact on improving outcomes for patients with T2DM and CKD.