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

Contribution To Literature:

The CREDENCE trial showed that 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%

Beneficial effects were noted irrespective of baseline HbA1c, including among patients with baseline HbA1c between 6.5 and 7%.

Effect on blood pressure (BP): Approximately 76% had baseline systolic BP (SBP) >130 mm Hg, and 31% had resistant hypertension. At week 3, canagliflozin-treated participants experienced a greater reduction in SBP than placebo-treated participants (-3.39 mm Hg vs. 0.11 mm Hg; difference -3.50 mm Hg, 95% confidence interval [CI] -4.27 to -2.72). This early reduction in SBP was similar across categories of baseline SBP and number of BP-lowering drug classes. These reductions appeared to be sustained over the duration of the trial. Patients in the canagliflozin arm had a lower likelihood of needing a new hypertension medication initiation (39.8% vs. 61.3%, hazard ratio [HR] 0.68, 95% CI 0.61-0.75). The effect of canagliflozin on CV outcomes was consistent across baseline BP.

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. 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).

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%).

References:

Ye N, Jardine MJ, Oshima M, et al. Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease: Insights From the CREDENCE Trial. Circulation 2021;Feb 8:[Epub ahead of print].

Cannon CP, Perkovic V, Agarwal R, et al. Evaluating the Effects of Canagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Chronic Kidney Disease According to Baseline HbA1c, Including Those With HbA1c <7%: Results From the CREDENCE Trial. Circulation 2020;141:407-10.

Presented by Dr. Christopher P. Cannon at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 17, 2019.

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: AHA Annual Scientific Sessions, AHA19, Albuminuria, Angina, Unstable, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Blood Pressure, 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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