Lastly, first approved in 2015 and later indicated for heart failure with reduced ejection fraction (HFrEF), ARNI combines ARBs with neprilysin inhibitors, which on one side benefit from the degradation natriuretic peptides, and on the other maintain low levels of ATII, decreasing its effects on volemia and vascular endothelial function, which would otherwise be elevated in the presence of a neprilysin inhibitor only. Here, MME is linked to heart failure.