Aldosterone antagonists play ‘central role’ in heart, kidney disease
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Mineralocorticoid receptor antagonists, particularly the most recently approved agent finerenone, should play a “central role” in the treatment of diabetic kidney disease and its related cardiovascular consequences, according to a speaker.
Aldosterone, the mineralocorticoid receptor and the intracellular protein Rac1 are part of a “triangle” of multidirectional potentiating factors in inflammation and fibrosis, Christian W. Mende, MD, FACP, FACN, FASN, FAHA, clinical professor of medicine and specialist in clinical hypertension at the University of California San Diego, said during a presentation at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. Overactivation of all three is present in multiple states, including diabetes, chronic kidney disease and heart failure, leading to chronic inflammation that is difficult to treat.
“Mineralocorticoid receptor antagonists are important therapeutic options for diabetic kidney disease and heart failure, in addition to the SGLT2 inhibitors,” Mende said. “Particularly for those who cannot tolerate the SGLT2 inhibitor, an MRA, like finerenone, is a logical choice.”
Recent MRA data
Metabolic, hemodynamic and inflammatory and fibrotic factors work together to drive diabetic kidney disease, currently the leading cause of end-stage renal disease in the U.S. and a cause of increased CV risk. Traditional MRA therapy for DKD has been spironolactone; however, renin-angiotensin-aldosterone system blockade therapy has been limited due to rising potassium levels often seen with such therapy, Mende said.
In August 2021, the FDA approved the novel nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia, Bayer) for reducing risks for kidney and heart complications for adults with CKD associated with type 2 diabetes. The agent comes with several advantages over its MRA predecessors, Mende said.
“Finerenone has a much shorter half-life and has equal potency to spironolactone,” Mende said. “It has a 1:1 ratio from heart to kidney. Finerenone does not cross the blood/brain barrier; does not have any interference with testosterone, estrogens or progesterone; and there is less hyperkalemia, though that is still a side effect for all MRAs.”
Mende highlighted two studies examining the use of finerenone in patients with DKD:
FIDELIO-DKD — Data from FIDELIO-DKD demonstrated that, compared with placebo, finerenone reduced risks for the composite primary endpoint of time to kidney failure and a sustained decrease of estimated eGFR greater than or equal to 40% from baseline during a period of at least 4 weeks. Investigators also found an 18% reduced risk for renal death during a median duration of follow-up of 2.6 years when added to maximum tolerated dose of guideline-directed therapy. In additional FIDELIO-DKD analyses, finerenone reduced the incidence of CV events regardless of CVD status.
FIGARO-DKD — In an analysis of the FIGARO-DKD trial, which included a cohort of patients with less-severe renal disease than those in the companion FIDELIO-DKD trial, finerenone reduced CV event risk by 13% for adults with DKD compared with placebo, primarily driven by a 29% reduction in HF hospitalizations. 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 arm.
“We are approaching double and potentially triple therapy now for CKD and DKD, with ACE inhibitors, SGLT2 inhibitors for patients with and without diabetes, and at this point, MRAs have come into play with the approval of finerenone,” Mende said.
Combination therapy questions
In FIDELIO-DKD, researchers observed a 37% reduction in urinary albumin-to-creatinine ratio among participants assigned finerenone and prescribed an SGLT2 inhibitor at baseline, compared with a 31% reduction among those who received finerenone and were not taking an SGLT2 inhibitor at baseline. However, the subgroup of participants prescribed SGLT2 inhibitors was small, making up just 4.6% of the cohort.
“The real key question we have with adding finerenone to SGLT inhibitor therapy is how much more reduction of eGFR or loss of function does one get on top of ACE inhibitors and SGLT2 inhibitors?” Mende said. “How much does a third drug, finerenone, have to offer?”
Mende said there is a need for data on reducing risk for reduction in renal function with combination therapy in DKD.
“I would love to see a study where finerenone is added to an SGLT2 inhibitor plus an ACE inhibitor and see what the total outcome for albuminuria is as well as protection of renal function,” Mende said.
References:
Bakris GL, et a. N Engl J Med. 2021; doi:10.1056/NEJMoa2025845.
Filippatos G, et al. Circulation. 2020; doi:10.1161/CIRCULATIONAHA.120.051898.
Pitt B, et al. N Engl J Med. 2021; doi:10.1056/NEJMoa2110956.
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Mende CW. The contemporary approach to MRA, aldosterone in the kidney and the heart. Presented at: World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease; Dec. 2-4, 2021; Los Angeles (hybrid meeting).
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