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CREDENCE Trial Shows Renal and Cardiovascular Protection

Jun 8, 2019
 
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Marian Ayad, BPharm, PharmD candidate, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences

Strong results for the CREDENCE trial motivate the ADA to update its Standard of Care for patients with diabetes.

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.

According to the CDC, an estimate of 38% of the reported causes of End-stage Kidney Disease in the United States is caused by diabetes. The CREDENCE trial, published recently in April, 2019, was even stopped early, based on the recommendation of the steering committee, at a planned interim analysis after revealing promising results that may help improve renal outcomes for our patients. In addition to that, the ADA, on June 3rd, 2019, updated 2 subsections to the 2019 Standards of Medical Care in Diabetes, based on the findings of this trial!

This trial design is 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 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.

Practice Pearls:

  • About 38% of the reported cases of end-stage kidney disease in the United States appears to be caused by diabetes, according to the CDC.  
  • The Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE) trial suggests that Canagliflozin provides renal and cardiovascular protection in patients with type 2 diabetes with chronic kidney disease.
  • The ADA, on June 3rd, 2019, updated sections of the “Standards of Medical Care in Diabetes” based on the promising findings of the CREDENCE trial.

Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019 April 14. https://doi.org/10.1056/NEJMoa1811744.

American Diabetes Association. 10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes—2019 [http://care.diabetesjournals.org/living-standards]. Diabetes Care 2019;42(Suppl. 1):S103–S123.

American Diabetes Association. 11. Microvascular complications and foot care: Standards of Medical Care in Diabetes—2019 [http://care.diabetesjournals.org/living-standards]. Diabetes Care 2019;42(Suppl. 1):S124–S138.

Centers for Disease Control and Prevention. Chronic Kidney Disease in the United States, 2019. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2019. https://www.cdc.gov/kidneydisease/publications-resources/2019-national-facts.html.

Marian Ayad, BPharm, PharmD candidate, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences