Canagliflozin’s Renal and Cardiovascular Benefits in People with Heart Failure 

CREDENCE trial shows that canagliflozin, an SGLT2 inhibitor, lowers the risk of cardiovascular and renal events in patients with T2DM, regardless of prior history of heart failure.  

Several studies have shown that diabetic nephropathy alone, or in combination with hypertensive nephropathy, are the most common causes of end-stage renal disease (ESRD) in developed and developing countries. Thus, ESRD is a worldwide public health problem with an enormous financial burden for healthcare systems. Furthermore, it is well established that cardiovascular disease (CVD), where the heart and blood vessels are negatively impacted, is the number one cause of death in people living with diabetes, resulting in 70% of deaths in people with type 2 diabetes mellitus (T2DM). In addition, people with diabetes are two to four times as likely to have heart disease or a stroke than people without diabetes. Therefore, sodium-glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels in patients with T2DM. Later, several RCTs showed that SGLT2 inhibitors reduce the risk of cardiovascular (CV) events, including hospitalization for heart failure (HHF) in patients with T2DM and patients with heart failure (HF) with reduced ejection fraction (EF) independent of the presence or absence of diabetes. However, it remains uncertain whether CV and renal benefits and safety outcomes of canagliflozin are preserved regardless of prior history of HF. Therefore, investigators tested whether canagliflozin, an SGLT2 inhibitor, safely decreases CV and renal events in participants with T2DM and nephropathy with and without a prior history of HF before randomization, as additional analysis of CREDENCE trial data.  

Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) was a multicenter, international, double-blind, randomized, placebo-controlled trial. Eligible patients were ≥30 years of age, had T2DM (HbA1c of 6.5 to 12%), had chronic kidney disease (CKD, eGFR of 30 to <90 ml/min/1.73 m2, and albumin to creatinine ratio between 301 and 5000 mg/g), are on a stable dose of either ACE-inhibitor or ARB. Patients were randomized 1:1 to canagliflozin 100mg or placebo. The primary endpoint was ESRD composite, doubling serum creatinine (SCr), or renal or CV death. Primary, secondary outcomes were 1). a composite of cardiovascular death or hospitalization for HF (HHF), 2). Hospitalization for HF, and 3). Composite of cardiovascular death, MI, stroke, or hospitalization for HF or unstable angina. Statistical tests used for this study were the χ2 test for categorical variables, a t-test for continuous normally distributed variables, Cox proportional hazards regression, and a Wilcoxon 2-sample test for continuous variables with a skewed distribution-which was evaluated using an Anderson–Darling test. Two-tailed P value<0.05 was considered statistically significant without adjustment for multiple comparisons. 

At baseline, 652 (15%) out of total 4,401 participants had a history of HF, with 204 (31%) had NYHA Class I, 359 (55%) with NYHA Class II, 70 (11%) with NYHA Class III, and 19 (3%) with missing NYHA HF classification. Participants with HF were older, had a high prevalence of established CVD, and had a higher percentage on beta-blockers and loop diuretics than participants without HF. At the end of median follow-up of 2.62 years, canagliflozin significantly reduced the risk of the primary composite outcome, composite of CV death and HHF, and HHF alone (p≤0.01 for all outcomes). Although not statistically significant, canagliflozin consistently reduced the primary composite endpoint, CV death or HHF, HHF alone, and renal outcomes events compared with placebo in participants with and without a history of HF (all P interaction > 0.150). For participants with HF stratified by NYHA class, canagliflozin reduced the risk of the primary composite endpoint compared with placebo with no evidence of heterogeneity of treatment effect by NYHA class subgroup (P interaction=0.227). However, canagliflozin use led to a significantly decreased risk of all adverse events (AEs) compared with placebo, though with some evidence of treatment effect heterogeneity by prior history of HF (P interaction .024).  

This analysis of CREDENCE study data shows that canagliflozin’s beneficial cardiovascular and renal effects are not more significant in patients with HF history. Canagliflozin safely reduced renal and CV events in participants with T2DM and nephropathy with consistent effects in patients with or without a prior history of HF. In patients without a prior history of HF, canagliflozin use was associated with robust effect sizes to reduce CV death and HHF and HHF alone. This study used data from the CREDENCE study, which was terminated early at a planned interim analysis, and thus, it may have limited the power of some secondary outcomes. A randomized study with a larger sample size may be needed to explore this study’s findings further. 

Practice Pearls: 

• Canagliflozin Cardiovascular Assessment Study (CANVAS) Program analyzed the benefit of canagliflozin on CV death or HHF compared with placebo and found that canagliflozin has potentially more significant benefit in those with a prior history of HF compared to those without a history of HF. 
• Several studies, such as DAPA-HF, EMPEROR-REDUCED, and SOLOIST-WHF, showed that SGLT2 inhibitors have greater efficacy, specifically in patients with HF.  
• 2019 European Society of Cardiology guidelines highly recommends (Recommendation class I, LOE A) SGLT2 inhibitor (empagliflozin, canagliflozin, and dapagliflozin) initiation in patients with T2DM to lower the risk of HF hospitalization. 

Sarraju, Ashish et al. “Effects of canagliflozin on cardiovascular, renal, and safety outcomes in participants with type 2 diabetes and chronic kidney disease according to the history of heart failure: Results from the CREDENCE trial.“ American heart journal vol. 233 (2021): 141-148. doi:10.1016/j.ahj.2020.12.008 

Kandarp Mehta, MS, PharmD Candidate, University of Colorado Anschutz Medical Campus, Skaggs School of Pharmacy and Pharmaceutical Sciences