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Canagliflozin Effects on Heart Failure and Cardiovascular Death

Mar 30, 2021
 
Editor: Steve Freed, R.PH., CDE

Author: Alexandria Bartley, PharmD. Candidate, Florida Agricultural & Mechanical University, College of Pharmacy and Pharmaceutical Sciences

Canagliflozin reduced risk of cardiovascular death and hospitalizations due to heart failure by 31%. 

It is known that patients with both type 2 diabetes and chronic kidney disease are at a higher risk of developing heart failure. This study is a secondary evaluation of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial. In the CREDENCE trial, canagliflozin, a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, was proven to be superior to placebo in glucose control and the number of adverse events in patients with type 2 diabetes and known cardiovascular disease. A previous relevant trial was the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME). However, the EMPA-REG OUTCOME trial evaluated patients with type 2 diabetes who were high-risk patients for cardiovascular disease, unlike the CREDENCE trial, which evaluated patients with type 2 diabetes and established cardiovascular disease.  

 

The purpose of this trial was to determine if the effects of canagliflozin on the composite of cardiovascular death and hospitalizations due to heart failure vary in the subgroups based on patients’ characteristics. According to the researchers, this trial was a randomized, double-blinded, placebo-controlled, multicenter international trial. In this trial, randomizations were done in a 1:1 ratio. The canagliflozin arm had 2,202 patients, and the placebo arm had 2,199 patients. Patients had follow-ups at weeks 3,13, and 26, and after that, they followed up every 13 weeks. The patient population had to be older than 30 years old, have type 2 diabetes, and glycosylated hemoglobin more than 6.5% but less than 12%. Also, patients had to have chronic kidney disease with an estimated glomerular filtration rate of 30 to less than 90, albuminuria, and a stable dose of either an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) for longer than four weeks before randomization. The patients could not have been treated with immunosuppression therapy for their kidney disease, have a history of dialysis or a kidney transplant, and could not be a patient with type 1 diabetes. The primary outcome was an end-stage renal disease (ESRD), doubling serum creatinine, renal or cardiovascular (CV) death. The secondary results were all-cause mortality, cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure/unstable angina, amputation, and glycosylated hemoglobin reduction. The statistical design used was Cox regression models for the hazard ratios and 95% confidence intervals and Kaplan Meier curves for subgroups of interest.            

The results of canagliflozin in this study, based on hazard ratio and confidence intervals, were significantly consistent in patients with different ages, genders, and histories of cardiovascular disease. Overall, canagliflozin reduced the risk of cardiovascular death or hospitalization of heart failure with a hazard ratio of 0.69 and a confidence interval of 0.57-0.83. The risk of cardiovascular death and hospitalizations due to heart failure was reduced by 31%. The outcome of canagliflozin on hospitalization due to heart failure alone was similar among the different subgroups with a hazard ratio of 0.61 and a confidence interval of 0.47-0.80. The effects of canagliflozin based on the history of heart failure estimated glomerular filtration rate, albuminuria, and loop diuretic use were not significant separately based on p interaction value. The risk of cardiovascular death and hospitalization due to heart failure was reduced by canagliflozin irrespective based on a loop diuretic. Also, regardless of age, sex, and estimated glomerular filtration rate, canagliflozin benefits did not differ significantly.  

The CREDENCE trial ended early due to the overwhelming benefit. Baseline characteristics were well balanced between the two treatment arms. In the subgroups of the composite outcome, the P interaction values were not significant. Significant results in the subgroups were challenging to accomplish due to the smaller sample sizes.  

Practice Pearls: 

  • Canagliflozin was able to steadily reduce the risk of cardiovascular death and hospitalizations due to heart failure in patients with both type 2 diabetes and chronic kidney disease.  
  • The patients at a higher risk of cardiovascular death and hospitalizations due to heart failure were patients with a history of cardiovascular disease or heart failure. 
  • Studies analyzing key patient characteristics help prescribers to make better-informed decisions for an individualized care plan. 

  

Zeeuw D, Arnott C, Li J-W, et al. The effects of canagliflozin on heart failure and cardiovascular death by baseline participant characteristics: analysis of the CREDENCE trial. EASD Virtual Congress. Published 2020. Accessed October 12, 2020. 

 

Alexandria Bartley, PharmD. Candidate, Florida Agricultural & Mechanical University, College of Pharmacy and Pharmaceutical Sciences