CREDENCE Trial Shows Renal & Cardiovascular Protection

Jun 8, 2019 | Diabetes Type 2, Renal, The George Institute for Global Health


As a consequence of the results of CREDENCE, the ADA updates its Standard of Care for patients with diabetes.

According to the CDC, an estimated 38% of the reported causes of End-stage Kidney Disease in the United States is caused by diabetes reports Diabetes In Control.  Due to the positive results of the CREDENCE study the American Diabetes Association (ADA) updated its Standards of Medical Care in Diabetes.

The Study

The CREDENCE study was stopped early due to the obvious promising results potentially improving renal outcomes for patients. Herein we utilize the summary from Diabetes in Control.

The goal of this study is to assess whether canagliflozin has a renal and vascular protective effect in reducing the progression of renal impairment relative to placebo in participants with type 2 diabetes mellitus (T2DM), Stage 2 or 3 chronic kidney disease (CKD) and macroalbuminuria, who are receiving standard of care including a maximum tolerated labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).

A double-blind randomized trial where patients with type 2 diabetes and chronic kidney disease were randomly assigned to either receive 100mg daily of Canagliflozin (N=2202) or placebo (N=2199). All patients had a GFR of 30 to <90ml/min/1.73m2, albuminuria >300 to 5000, and were receiving a stable dose of an angiotensin receptor blocker or an angiotensin converting enzyme inhibitor. There was no significant difference in baseline characteristics between groups. The primary and secondary outcomes of the trial were both analyzed using a stratified Cox proportional-hazards model

The Results

The results led to the ADA updating its Standard of Care.  The CREDENCE trial (Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy) showed promising renal outcomes improvement in patients with type 2 diabetes and kidney disease. The primary outcome of the trial was defined as a composite of end-stage kidney disease, a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Secondary outcomes hierarchically were as follows:

1st: A composite of cardiovascular death or hospitalization for heart failure.

2nd: A composite of cardiovascular death, MI, or stroke.

3rd: Hospitalization for HF.

4th: A composite of end-stage kidney disease, doubling of the serum creatinine level, or renal death.

5th: Cardiovascular death.

6th: Death from any cause.

7th: A composite of cardiovascular death, MI, stroke, or hospitalization for HF or unstable angina.

Canagliflozin showed superiority compared to placebo, with a 30% lower relative risk (hazard ratio, 0.70; 95% [CI], 0.59-0.82; P=0.00001) of the primary composite outcome, end-stage kidney disease (hazard ratio, 0.68; 95% [CI], 0.54-0.86; P=0.002), doubling of serum creatinine level (hazard ratio, 0.60; 95% [CI], 0.48-0.76; P<0.001), exploratory outcome of dialysis, kidney transplantation, or renal death (hazard ratio, 0.72; 95% [CI], 0.54-0.97), renal specific composite outcome with a 34% relative risk reduction in the Canagliflozin group (hazard ratio, 0.66; 95% [CI], 0.53-0.81; P<0.001), death from cardiovascular cause (hazard ratio, 0.78; 95% [CI], 0.61-1.00; P=0.05), death from any cause (hazard ratio, 0.83; 95% [CI], 0.68-1.02).

There were no significant differences between both groups in adverse events, risk of lower limb amputation, and rates of fractures. The risk of diabetic ketoacidosis was low in the Canagliflozin group (2.2 per 1000 patient-years), but still higher compared to the placebo group (0.2 per 1000 patient-years).

In a nutshell, patients in the Canagliflozin group had a lower risk of kidney failure and cardiovascular events at a median follow-up of 2.62 years. The results of this trial suggest that Canagliflozin (SGLT2 inhibitor) may be a great option for renal and cardiovascular protection in patients with type 2 diabetes with chronic kidney disease without an increased risk of serious adverse events.

Based on the results of the CREDENCE trial, the American Diabetes Association recently incorporated updates in annotations (highlighted in yellow) to two subsections, section 10 and section 11, of the “Standards of Medical Care in Diabetes: Living Standards of Medical Care in Diabetes” to include the findings and discuss this critical trial. The ADA also updated recommendations and removed section 11.8 of section 11, as the trial findings revealed that it is no longer recommended to continue the monitoring of urinary-albumin-to creatinine ratio in patients with albuminuria treated with an ACE inhibitor or an angiotensin receptor blocker.

What is Canagliflozin?

It was developed by Mitsubishi Tanabe Pharma and is marketed under license by Janssen, division of Johnson & Johnson. It was first approved by the FDA on March 29, 203, and became the first SGLT inhibitor in the United States.

The Sponsor & Collaborator

The study was sponsored by Janssen and supported by The George Institute for Global Health.

Lead Research/Investigator

Meg J. Jardine, The George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, Australia


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