Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation - CREDENCE

Contribution To Literature:

Canagliflozin is superior to placebo in improving glycemic control and reducing adverse renal events among patients with DM2 and established CKD.

Description:

The goal of the trial was to assess the effect of canagliflozin on renal outcomes among patients with type 2 diabetes mellitus (DM2) and chronic kidney disease (CKD). 

Study Design

Patients were randomized in a 1:1 fashion to either canagliflozin 100 mg daily (n = 2,202) or matching placebo (n = 2,199).

  • Total number of enrollees: 4,401
  • Duration of follow-up: 2.62 years
  • Mean patient age: 63.0 years
  • Percentage female: 33.9%

Inclusion criteria:

  • Age ≥30 years
  • DM2
  • Glycosylated hemoglobin (HbA1c) of ≥6.5% and ≤12%
  • CKD with estimated glomerular filtration rate (eGFR) 30 to <90
  • Albuminuria (urinary albumin-to-creatinine ratio >300 to 5000 mg/g)
  • Stable dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) for ≥4 weeks before randomization

Exclusion criteria:

  • Nondiabetic kidney disease or type 1 diabetes
  • Treated with immunosuppression for kidney disease
  • History of dialysis or kidney transplantation
  • Dual-agent treatment with an ACEi and an ARB, a direct renin inhibitor, or a mineralocorticoid-receptor antagonist

Other salient features/characteristics:

  • White 66.6%, Asian 19.9%
  • Diagnosis of DM2: 15.8 years
  • HbA1c: 8.3%
  • eGFR 56.2 ml/min/1.73 m2

Principal Findings:

The trial stopped early due to overwhelming benefit. The primary outcome, end-stage renal disease (ESRD), doubling of serum creatinine, renal or cardiovascular (CV) death, for canagliflozin vs. placebo, was 43.2 vs. 61.2 per 1,000 patient-years (P-Y) (p = 0.00001).

  • Doubling of serum creatinine: 20.7 vs. 33.8/1,000 P-Y (p < 0.001) for canagliflozin vs. placebo
  • ESRD: 20.4 vs. 29.4/1,000 P-Y (p = 0.002) for canagliflozin vs. placebo

Secondary outcomes for canagliflozin vs. placebo:

  • All-cause mortality: 29.0 vs. 35.0/1,000 P-Y (p > 0.05)
  • CV death, myocardial infarction, stroke, hospitalization for heart failure/unstable angina: 27.0 vs. 40.4/1,000 P-Y (p < 0.001)
  • Amputation: 12.3 vs. 11.2/1,000 P-Y (p > 0.05)
  • Reduction in HbA1c at 13 weeks: 0.31%

Interpretation:

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. 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). 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.  


References:

Perkovic V, Jardine MJ, Neal B, et al., on behalf of the CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019;380:2295-306.

Editorial: Ingelfinger JR, Rosen CJ. Clinical Credence — SGLT2 Inhibitors, Diabetes, and Chronic Kidney Disease. N Engl J Med 2019;380:2371-3.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Acute Heart Failure

Keywords: Albuminuria, Angina, Unstable, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Creatinine, Diabetes Mellitus, Type 2, Glomerular Filtration Rate, Hemoglobin A, Glycosylated, Heart Failure, Kidney Failure, Chronic, Metabolic Syndrome X, Myocardial Infarction, Renal Insufficiency, Chronic, Renin-Angiotensin System, Secondary Prevention, Sodium-Glucose Transporter 2, Stroke


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