Renal and Cardiovascular Effects of Sodium Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes and Chronic Kidney Disease: Perspectives on the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial Results

Abstract

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 m2 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.

Linear Projection of Estimated Glomerular Filtration Rate Decline with Canagliflozin and Implications for Dialysis Utilization and Cost in Diabetic Nephropathy

“…This initial drop in eGFR was followed by stabilization in eGFR decline compared to placebo from week 3 to the end of the study (-1.85 ± 0.13 vs. -4.59 ± 0.14 ml/ min/1.73 m 2 /year), which is consistent with known renal hemodynamic effects of SGLT2 inhibition [26]. Importantly, as a result of these findings, the FDA issued a new indication for canagliflozin to reduce the risk of ESKD, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with T2DM and diabetic nephropathy with albuminuria [ 300 mg/day [27]; this represented the first new indication for the reduction of ESKD risk in 20 years [28,29].…”

Systematic review and meta-analysis of head-to-head trials comparing sulfonylureas and low hypoglycaemic risk antidiabetic drugs

“…SUs were associated with higher mortality only in comparison with DPP-4 inhibitors but not with other drug classes. This finding is surprising as the collective trial evidence so far has demonstrated that DPP-4 inhibitors have neutral effect on mortality and SGLT-2 inhibitors and GLP-1 RAs may have mortality benefit [ 24 ].…”

Predictive Factors of Renal Function Decline in Patients with Type 2 Diabetes Treated with Canagliflozin in the Real-Wecan Study

“…As we pointed out in the introduction, several mechanisms may contribute to the nephroprotective effects seen with canagliflozin [ 3 , 20 ]. Well-known metabolic effects include reduction in glucotoxicity and perivisceral fat.…”

“…Restoration of tubuleglomerular balance, providing more sodium to the macula densa, normalizes the tone of the afferent arteriole and is followed by long-term eGFR stabilization and reduction in albuminuria. Finally, reduction in glucotoxicity and proteinuria and the activation of anti-inflammatory and antifibrotic pathways by canagliflozin may play a joint role in reducing tubulointerstitial damage in the diabetic kidney [ 20 ].…”