麻豆果冻传媒影音

An investigational anti-mineralocorticoid agent slowed chronic kidney disease (CKD) progression in people with type 2 diabetes, the showed.

Study co-author , of Indiana University, presented the findings in a virtual presentation at the recent Kidney Week 2020 Meeting. In this MedPage Today video, Agarwal discusses the key study results and takeaways.

Following is a transcript of his remarks:

In FIDELIO-DKD, we hypothesized that the MR antagonism with finerenone would slow kidney disease progression and reduce cardiovascular morbidity and mortality in patients with advanced CKD and type 2 diabetes. We included patients with diabetes with an EGFR between 25 and 75 and moderately to severely elevated albuminuria. We included patients who had serum potassium of 4.8 millimoles per liter or less. We excluded patients with symptomatic heart failure with a reduced ejection fraction.

FIDELIO-DKD, together with its ongoing sister study, FIGARO-DKD, form the largest clinical trial program in patients with CKD and type 2 diabetes. The trial included a run-in period of 4 to 16 weeks during which time RAS therapy was optimized to a maximally-tolerated labeled dose. 5,734 patients were randomized 1:1 to finerenone or placebo.

The endpoints included a primary kidney composite and a key secondary cardiovascular composite. Further hierarchical endpoints are listed here. Studies like this require a global effort. 48 countries, more than 1,000 sites, and 99.7% completed the study. The mean age was around 66, blood pressure 138 over 76, 99.8% of patients who are on RAS blocker at baseline.

Glycemic control as assessed by A1C was good. Two-thirds on insulin, 5% on SGLT2 inhibitor. Mean EGFR was around 44, and over half had EGFR below 45, and almost 90% of the patients had severely elevated albuminuria.

First, we look at the effects on USER. Finerenone provoked an additional 31% reduction in albuminuria at month 4 and this was sustained over the trial. The improvement in albuminuria was despite only modest effects on blood pressure and there was no difference in A1C.

Now, the primary endpoint, the kidney failure outcome. In the placebo group, 600 patients experienced the kidney failure endpoint compared to 504 in the finerenone group. This is an 18% relative risk reduction with a highly statistically significant P value of 0.0014. The individual components of the primary endpoint show that all kidney failure outcomes were reduced and the point estimate of the components trended to favor finerenone.

The key secondary endpoint was cardiovascular. The number of patients with this event in the placebo group was 420 compared with 367 in the finerenone group, relative risk reduction 14%, and a P value less than 0.05 indicating a cardiovascular benefit of finerenone.

The third pre-specified hierarchical endpoint was all-cause mortality. Although the hazard ratio was less than 1, this was not statistically significant, therefore all other endpoints that were below this were not formally tested. But of great interest, a secondary kidney composite endpoint included the decline in EGFR of 57% or more, equivalent to a doubling of serum creatinine. Protection from kidney failure is even greater when using the secondary endpoint. These data clearly support the primary endpoint results.

Translating these results to practice requires consideration of the numbers needed to treat. For the primary kidney-specific endpoint over 3 years, 29 patients needed to be treated to prevent one event and for the CV endpoint, 42 patients. Finerenone will have consistent effects on the primary endpoint components and across key subgroups.

Safety in the trial was established by investigator-reported adverse events. Overall, these were similar between groups, as were serious adverse events. Adverse events leading to study drug discontinuation were slightly higher with finerenone and the most common reasons in the finerenone group were hyperkalemia and serum potassium increases.

Mean serum potassium levels were higher with finerenone over the course of the trial. The maximum difference between groups was 0.23 millimoles per liter at month 4. Examination of the number of episodes of hyperkalemia during the trial just gives us even a better picture. If a patient had even one episode of an increase in serum potassium, such a patient would be counted as one who experienced an adverse event due to hyperkalemia.

However, the clinical impact of hyperkalemia can be better assessed by examining how many patients died or were hospitalized, or permanently discontinued the study drug. First, there were no deaths due to hyperkalemia and only a small proportion of patients were hospitalized or permanently discontinued study treatment.

As you are aware, acute kidney injury is of concern with MRAs, but AKI-adverse events were balanced between groups. Our patients had advanced CKD and were treated with maximally tolerated dose of an ACE or ARB, and except for temporary withdrawal of the study drug, potassium management was at the investigators' discretion.

In this high-risk population, finerenone was well tolerated. Overall, treatment-emergent adverse effects were similar between groups. Finerenone led to a mean increase in serum potassium of 0.2 millimoles per liter across subpopulations versus placebo.

While there was hyperkalemia, this was easily managed by temporarily holding finerenone, and this worked. Only 2.3% of the patients in the finerenone group had to stop treatment because of hyperkalemia, compared to 0.9% in the placebo group.

To conclude, in patients with CKD and type 2 diabetes treated with an optimized RAS therapy, finerenone was well tolerated and significantly reduced the risk of kidney disease progression by an additional 18%, as well as reducing CV events by an additional 14%.

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