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To the Editor:Dual angiotensin II receptor and neprilysin inhibition with LCZ696 provides additive blood pressure lowering in hypertensive patients, likely because of the well-characterized cardiovascular and renal natriuretic peptide actions.1 However, increased natriuretic peptide availability through neprilysin inhibition could also affect human lipid metabolism. The response could be exploited therapeutically. Yet, adverse effects on metabolic and cardiovascular risk cannot be excluded. Natriuretic peptides stimulate lipolysis in human adipocytes through natriuretic peptide receptor-A activation.2 The response is not attenuated by β-adrenergic receptor blockade in vitro and in vivo. Atrial and brain natriuretic peptides are more potent lipolytic agents than the prototypical β-adrenoreceptor agonist isoproterenol. Systemic atrial natriuretic peptide infusion dose-dependently increases circulating free fatty acid and glycerol concentrations3 and improves postprandial lipid oxidation in human subjects.4 Therefore, medications raising systemic natriuretic peptide levels, such as LCZ696, could augment lipid mobilization and lipid oxidation. Improved lipid mobilization may be beneficial in overweight and obese patients in terms of weight loss. On the other hand, excessive lipid mobilization could promote muscular and hepatic ectopic fat storage and, thus, insulin resistance. …

Metabolic Actions Could Confound Advantageous Effects of Combined Angiotensin II Receptor and Neprilysin Inhibition