Risk of Cardiovascular Events in Patients With CKD and Type 2 Diabetes

A 2004 landmark study demonstrated an association between chronic kidney disease (CKD) and an increased risk of cardiovascular events. There were associations between lower levels of estimated glomerular filtration rate (eGFR) and higher risk of mortality from any cause, cardiovascular events, and hospitalizations. It is well established that the risk of kidney outcomes is modifiable in patients with type 2 diabetes.

According to Rajv Agarwal, MD, MBBS, MS, and colleagues, the modifiability of cardiovascular risk associated with CKD in patients with type 2 diabetes in a broad population, even in those with an eGFR of ≥60 mL/min/1.73 m² and defined by albuminuria, is unclear. The FIDELITY (Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD) trial analysis is a prespecified pooled analysis of two phase 3 trials examining the efficacy and safety of finerenone, a selective, nonsteroidal mineralocorticoid receptor antagonist.

Using data from the pooled analysis, Dr. Agarwal et al tested whether the risk of cardiovascular disease associated with CKD, as defined jointly by eGFR and albuminuria, was modifiable with finerenone in patients with type 2 diabetes. The researchers also estimated the population-wide benefit in the United States if all eligible patients were treated with finerenone. Results were reported in JAMA Cardiology.

To simulate the number of composite cardiovascular events that may be prevented per year with finerenone at a population level, the analysis combined the data from the pooled analysis and data from the National Health and Nutrition Examination Survey (NHANES). Data were analyzed over 4 years of consecutive NHANES data cycles (2015-2016 and 2017-2018).

The key outcome in the current analysis was a composite cardiovascular outcome of time to cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Cox proportional hazards models, stratified by study, region, eGFR, and albuminuria categories at screening, and history of cardiovascular disease were used to analyze the outcome. Analyses were performed in the full analysis set that comprised all randomly assigned patients with the exception of those with critical Good Clinical Practice violations.

The current subanalysis utilized the FIDELITY study sample as a model. The model included 13,026 patients with CKD and type 2 diabetes. Mean age was 64.8 years, 69.8% (n=9088) were male, and 30.2% (n=3938) were female. There was a broad range of eGFR and urine albumin to creatinine ratio (UACR) values. Self-reported race and ethnicity categories were Asian (22.2%; n=2894), Black or African American (4.0%; n=522), Hispanic (16.1%; n=2099), White (68.1%; n=8869), and other or not reported (5.7%; n=741). Mean eGFR was 57.6 mL/min/1.73 m² and median UACR was 515 mg/g.

Based on Kidney Disease: Improving Global Outcomes risk scores, 10.2% of the cohort (n=1323/13,026) was categorized as at moderate risk, 41.0% (n=5345/13,026) as at high risk, and 48.3% (n=6288/13,026) as at very high risk. The scores were based on a combination of UACR and eGFR categories according to individual baseline values. The cohort was largely balanced in characteristics at baseline between eGFR and UACR categories. However, the prevalence of a history of atherosclerotic cardiovascular disease increased with lower eGFR and was higher in patients with UACR less than 300 mg/g compared with those with UACR 300 mg/g or greater (52.6%; n=2279/4329 and 42.1%; n=3655/8692, respectively).

Median follow-up in the FIDELITY trial was 3 years. During the follow-up period, the incidence rate of cardiovascular events was higher among patients in lower eGFR and higher UACR categories. Among patients in the placebo arm with an eGFR of 90 mL/min/1.73 m² or greater, the incidence rates per 100 patient-years were 2.38 (95% CI, 1.03-4.29) in patients with UACR less than 300 mg/g and 3.78 (95% CI, 2.91-4.75) in those with UACR of 300 mg/g or greater. In those with eGFR less than 30 mL/min/1.73 m², the incidence rates increased to 6.54 (95% CI, 4.19-9.40) versus 8.74 (95% CI, 6.78-10.93), respectively.

Overall, there was an association between finerenone and a reduction in the risk of cardiovascular events versus placebo (hazard ratio, 0.86; 95% CI, 0.78-0.95; P=.002). The association between finerenone and reduction in the risk of cardiovascular events remained across ranges of eGFR and UACR. There was no significant interaction between the outcome of finerenone versus placebo across eGFR and UACR groups (P for interaction=.66).

Results of modeling the predictive probability of a cardiovascular event at 4 years demonstrated a higher risk for patients with higher levels of albuminuria in patients with eGFR less than 60 mL/min/1.73 m² as well as those with eGFR 60 mL/min/1.73 m² or greater. There was an association between finerenone and a reduction in risk of cardiovascular events across the range of UACR in both eGFR groups.

There was a higher risk of cardiovascular events at 4 years seen in patients with UACR of 300 mg/g or greater with lower levels of eGFR. There was an association between finerenone and a reduction in the risk of cardiovascular events across all ranges of eGFR in both UACR groups.

In the simulation of prevention of cardiovascular events in the United States, in the overall FIDELITY study population, based on differences in incidence rates per 100 patient-years between the finerenone and placebo arms, the total excess number of cardiovascular events that would be prevented per 10,000 patient-years was 67 (95% CI, 24-111). Based on the 6.4 million estimated individuals with albuminuric CKD and type 2 diabetes eligible for finerenone and the differences in incidence rates per 100 patient-years between the finerenone and placebo arms, the simulated total number of preventable cardiovascular events per year was estimated at 38,359 events (95% CI, 31.741-44.852), including the prevention of approximately 14,000 hospitalizations for heart failure.

Limitations to the study findings included exclusion of patients receiving dialysis or those with stage 5 CKD and those with UACR less than 30 mg/g at screening from the FIDELITY trial, as well as the lack of inclusion of significant numbers of Black and Hispanic patients.

In summary, the authors said, “Results of the present subanalysis of the FIDELITY trial suggest that CKD-associated composite cardiovascular risk, driven in part by reduction in hospitalization for heart failure, was modifiable with finerenone treatment. Identifying patients with moderately to severely increased albuminuria and eGFR of 60 or greater and treating them to reduce cardiovascular risk will have public health implications.”

Takeaway Points

1. Researchers performed a subanalysis of data from the FIDELITY trial to examine whether cardiovascular risk is modifiable in patients with chronic kidney disease (CKD) and type 2 diabetes.
2. There was an association between finerenone treatment and a reduction in cardiovascular risk in patients with CKD, type 2 diabetes, estimated glomerular filtration rate >25 mL/min/1.73 m², and moderately to severely increased albuminuria.
3. A simulation model suggested that over 1 year, finerenone may prevent 38,359 cardiovascular events.

Source: JAMA Cardiology