CREDENCE

Question

Does canagliflozin improve renal outcomes in patients with albuminuric CKD and a diagnosis of T2DM compared to placebo?

Population

• Age > 30 yrs
• T2DM (A1C 6.5 to 12.0) -- but up to 10.5% in Germany alone
• CKD, defined as:
  • eGFR 30 to 90. Target 60% of patients to have eGFR 30 to 60
  • Albuminuria with UACR 300-5000 mg/g
• Medications - stable on ACE/ARB for at least 4 weeks prior to randomization
  • Not allowed to be on dual RAS pathway inhibition (ACE, ARB, DRI, MRA)

Intervention & Control

Double-blind randomization, 1:1, to 1. Canagliflozin 100 mg daily 2. Matching placebo

Treatment continued until trial completion, dialysis, kidney transplantation, DKA, pregnancy, or receipt of disallowed therapy. Background treatment of glycemic control and CV risk modification per local guidelines.

Outcome

Outcome	Intervention	Control	HR
Primary: MAKE	43.2	61.2	0.70 (0.59 to 0.82)

Summary

1. The results of this trial indicate that canagliflozin is superior to placebo in improving glycemic control and reducing adverse renal events among patients with DM2 and established CKD. Canagliflozin also reduced CV events in this patient population. These benefits were independent of baseline HbA1c. Risk of complications, including amputation, was similar between the two groups. All patients were on baseline ACEi/ARB. A similar protective effect on renal outcomes was noted with empagliflozin in the EMPA-REG OUTCOME trial, but CREDENCE was specifically designed to enroll CKD patients, not high CV risk patients (as in EMPA-REG OUTCOME).
2. These are really important findings and suggest that canagliflozin (and perhaps the sodium–glucose cotransporter 2 class of agents) may need to be considered routinely among similar patients with DM2 and CKD who are already on a renin-angiotensin system inhibitor going forward. This may also be true for patients with so-called “well controlled diabetes” (i.e., those with HbA1c between 6.5 and 7%).
3. Between 22 to 25 patients would need to be treated for approximately 2.5 years in order to prevent one occurrence of the primary composite outcome.
4. Applies to patients with:
   1. Moderate CKD
   2. Diabetes
   3. Already on ACE/ARB

DAPA-CKD

This trial is a complement to CREDENCE, which showed cardiovascular and renal benefits of canagliflozin in patients with T2DM with mild CKD. This trial then looks at the efficacy and safety of dapagliflozin in patients with CKD, regardless of T2DM status.