HOMAGE: Spironolactone has pleiotropic mechanism of action
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Spironolactone reduces levels of biomarkers linked to fibrosis, inflammation, congestion and vascular function, according to findings from the HOMAGE study presented at the virtual Heart Failure Society of America Scientific Meeting.
Spironolactone, a mineralocorticoid receptor antagonist sometimes used to treat patients with HF, could potentially be used to prevent HF in addition to improving the condition of patients with established HF, Joao Pedro Ferreira, MD, PhD, research doctor at Clinical Investigation Centre Pierre Drouin (CIC-P), Nancy, France, said during a presentation.
“Identifying the mechanisms underlying the effect of spironolactone in patients at risk for developing HF is relevant for better understanding of the disease processes and drug mechanisms of action,” he said. “We have assessed the impact of spironolactone on multiple plasma protein biomarkers and respective underlying biological pathways.”
The researchers measured 276 biomarker levels in plasma samples from 527 participants using CVD II, CVD III and inflammation panels (Olink Proseek) at baseline, 1 month and 9 months and assessed the effect of spironolactone on the biomarkers by analysis of covariance.
“We found that spironolactone reduced the levels of collagen type 1, reflecting a decrease in the synthesis of collagen; decreased the level of matrix metalloproteinase-2, which might reflect a favorable effect on the extracellular matrix; and also decreased the levels of N-terminal pro-B-type natriuretic peptide, reflecting a positive impact on cardiac remodeling,” Ferreira said during the presentation.
In addition, he said, spironolactone “decreased the levels of pappalysin A, a protein that has been linked to metabolic processes and new-onset diabetes.”
Spironolactone increased the levels of renin, factors related to hemostasis and proteins related to anti-inflammatory properties, he noted.
“There are six main networks or clusters of the effect of spironolactone,” Ferreira said. “These are the renin-angiotensin-aldosterone pathway, the hemostasis and proteolysis, the effect on adipokines, the effect on the extracellular matrix, the effect on adhesion molecules and the anti-inflammatory effect.”
The study “confirms, for the first time in a clinical setting, many results that have only been described in experimental models,” he said. “This study highlights the usefulness of proteomics for pathophysiological and pharmacological clinical investigations.”
The findings “should be of extreme value in developing a more personalized approach to the selection of patients who might best respond to spironolactone and to prevent rather than to treat heart failure,” Bertram Pitt, MD, emeritus professor of medicine at the University of Michigan School of Medicine, said in a discussant presentation.
He concluded that the findings “are of extreme importance, especially in light of new findings relating to the incidence of primary aldosteronism. It’s likely some patients in the HOMAGE study had primary aldosteronism but were not detected. There’s increased need for therapy using mineralocorticoid receptor antagonists like spironolactone that is far greater than many of us would ever have thought. The information provided in HOMAGE will be very useful in helping to detect these patients and determine the effectiveness of spironolactone.”
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Ferreira JP, et al. Late-breaking clinical trials I. Presented at: Heart Failure Society of America Scientific Meeting; Sept. 30-Oct. 6, 2020 (virtual meeting).
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