Finerenone shows HF benefit in mild to moderate diabetic kidney disease: FIGARO-DKD
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The nonsteroidal mineralocorticoid receptor antagonist finerenone reduced CV event risk by 13% for adults with diabetic kidney disease compared with placebo, primarily driven by a 29% reduction in HF hospitalizations.
In an analysis of the FIGARO-DKD trial — a cohort of patients with less-severe renal disease than those in the companion FIDELIO-DKD trial — researchers also observed a nonsignificant but favorable trend for reduction in severe renal outcomes, including a reduction in the need for renal replacement therapy among participants in the finerenone (Kerendia, Bayer) arm.
“Importantly, this was a very well-tolerated drug,” Bertram Pitt, MD, emeritus professor of medicine at the University of Michigan School of Medicine, said during a press conference at the European Society of Cardiology Congress. “As you would expect, there was hyperkalemia, but the people who had to stop because of hyperkalemia compared with placebo was less than 1%. You will never see that in this type of population with the steroidal mineralocorticoid receptor antagonists.”
Benefit in stable renal disease
As Healio previously reported, FIDELIO-DKD demonstrated finerenone delayed progression of CKD by reducing the combined risk for time to first occurrence of renal failure, defined as a sustained decrease of estimated glomerular filtration rate (eGFR) of at least 40% from baseline for at least 4 weeks, or renal death. Finerenone also reduced the risk for the key secondary endpoint, a composite of time to first occurrence of CV death, nonfatal MI, nonfatal stroke or HF hospitalization. Participants in FIGARO had less-severe renal disease compared with those in FIDELIO, Pitt said.
FIGARO-DKD was a double-blind trial that involved 7,437 adults with type 2 diabetes and stage 1-4 CKD who were randomly assigned oral finerenone 10 to 20 mg or placebo. Participants were treated with renin–angiotensin system blockade adjusted before randomization to the maximum tolerated dose.
The findings were simultaneously published in The New England Journal of Medicine.
During a median follow-up of 3.4 years, the primary outcome — a composite of CV death, nonfatal MI, nonfatal stroke or HF hospitalization — occurred in 12.4% of the finerenone group compared with 14.2% of the placebo group (HR = 0.87; 95% CI, 0.76-0.98; P = .03). The benefit was driven primarily by a lower incidence of hospitalization for HF (HR = 0.71; 95% CI, 0.56-0.9), according to the results.
Kidney failure, a sustained decrease of at least 40% from baseline in eGFR or renal death, a secondary outcome of the trial, occurred in 9.5% of the finerenone group compared with 10.8% of the placebo group (HR = 0.87; 95% CI, 0.76-1.01; P = .069).
There were no between-group differences in adverse events; however, the incidence of hyperkalemia-related discontinuation was higher with finerenone (1.2%) than with placebo (0.4%), Pitt said.
Albuminuria assessment ‘essential’
Pitt noted that 62% of participants in FIGARO-DKD had a normal eGFR that was over 60 mL/min/1.73 m2 despite evidence of an increase in urinary albumin-to-creatinine ratio — a group that may typically be ignored by cardiologists who only review the eGFR measurement and a group that has not been vigorously studied, he said.
“What we know from this study and other studies is that it is essential that you get a urine sample and if you have albuminuria, that patient has an increased risk, and now we know we can do something about it,” Pitt said. “There is tremendous opportunity to intervene early with a mineralocorticoid receptor antagonist — finerenone — and treat these patients.”
Prespecified meta-analysis, overall CV benefit
In a separate prespecified meta-analysis of individual patient data from FIDELIO and FIGARO (n = 13,171), in which 40% of participants had albuminuric CKD with preserved kidney function (mean eGFR, 57.6 mL/min/1.73 m2), researchers found that finerenone reduced risk for a composite CV outcome of time to CV death, nonfatal MI, nonfatal stroke or HF hospitalization by 14% compared with placebo (HR = 0.86; 95% CI, 0.78-0.95; P = .0018).
Finerenone also reduced risk for a composite renal outcome of a 57% or greater decline in eGFR, time to kidney failure or renal death by 23% compared with placebo (HR = 0.77; 95% CI, 0.67-0.88; P = .0002).
“Finerenone is an effective treatment option for CV and kidney protection for patients with mild to severe CKD and type 2 diabetes,” Gerasimos Filippatos, MD, FESC, FHFA, FACC, professor of cardiology at the National and Kapodistrian University of Athens in Greece, said during a press conference. “What is also extremely important is the results show that [urinary albumin-to-creatinine ratio] monitoring in patients with type 2 diabetes is important for the identification of patients who can benefit from treatment with finerenone independent of eGFR, as we see from the results in FIDELITY.”
References:
- Filippatos G, et al. Hot Line: FIGARO-DKD/FIDELITY Analysis. Presented at: European Society of Cardiology Congress; Aug. 27-30, 2021 (virtual meeting).
- Pitt B, et al. N Engl J Med. 2021; doi:10.1056/NEJMoa2110956.
Perspective
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Ian de Boer, MD, MS
Patients with diabetic kidney disease are at high risk for kidney disease progression and CV. It is exciting that we now have multiple options to improve health outcomes for these patients. It is more important than ever to screen and diagnose patients with diabetes who have CKD, and to define and implement approaches to select and prescribe evidence-based therapies safely and effectively.
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Katherine R. Tuttle, MD, FASN, FACP, FNKF
The FIGARO trial results, along with the companion FIDELITY meta-analysis adding FIDELIO, now extend and reaffirm the clear kidney and heart protective effects of finerenone for people with type 2 diabetes and CKD. Risks of the composite kidney disease outcome (substantial eGFR decline by 57%, kidney failure and death due to kidney disease) was meaningfully reduced in the meta-analysis that included individuals across a broad range of eGFR and albuminuria. Importantly, the composite CV outcome (CV death, nonfatal MI, nonfatal stroke or hospitalization for HF) was also reduced in a clinically impactful manner. We now have another agent that is poised to deliver substantially better outcomes in this high-risk population. Our challenge now is to quickly move forward with dissemination and implementation for the many people who stand to benefit from this important advance in therapy.
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Robert C. Stanton, MD
Many studies have shown that increasing levels of albumin in the urine (routinely measured as the urine albumin/creatinine ratio) are associated with increasing risk for CVD (eg, Ninomiya T, et al J Am Soc Nephrol. 2009; doi:10.1681/ASN.2008121270). Moreover, decreasing GFR leads to increased CV risk, as shown in the Ninomiya study. It is important to know that these are independent risk factors for CVD. So both urine albumin/creatinine ratio and eGFR need to be routinely monitored to assess CV risk in addition to renal risk. And the combination of increased urine albumin/creatinine ratio and decreased GFR has an additive effect on CV risk, as also shown in the Ninomiya study. This increased CV risk is observed in all people with signs of kidney disease but is more severe in people with diabetes. Thus, the need for cardioprotective drugs in this population is of paramount importance.
In recent years, results from GLP-1 receptor agonist studies (eg, Marso SP, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1603827) and SGLT2 inhibitor studies in people with diabetes (and in people with nondiabetic kidney disease for the SGLT2 inhibitors; eg, Heerspink HJL, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2024816) have shown that these drugs have significant cardioprotective benefits.
The results from the FIGARO-DKD trial are a welcome addition to the armamentarium for both treatment of diabetic kidney disease and prevention of worse CV outcomes even in patients with well-preserved GFR. Of note though, the primary CV benefit for finerenone was primarily for fewer hospitalizations for HF (which is certainly important), whereas there were no major effects for other CV outcomes. But to interpret these results properly, it is important to remember that finerenone was added to maximal RAAS inhibition along with excellent control of blood sugar (mean hemoglobin A1c at baseline, 7.7%) and BP (mean systolic BP at baseline, 136 mm Hg). Thus, it is impressive that any additional benefit was observed.
Lastly, although the risk for hyperkalemia was not excessively high in this study, potassium levels need to be monitored, especially if this drug is added to an ACE inhibitor or angiotensin receptor blocker. It is very encouraging that there are now three new classes of medications that have cardioprotective effects in people with type 2 diabetes. Whether combinations of these classes offer further benefits remains to be studied.
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Pitt B, et al. Hot Line: FIGARO-DKD/FIDELITY Analysis. Presented at: European Society of Cardiology Congress; Aug. 27-30, 2021 (virtual meeting).
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