Abstract
LCZ696 simultaneously inhibits neprilysin, thereby augmenting natriuretic peptide (NP) availability, and blocks AT 1 -receptors. NPs released during exercise promote lipid mobilization and oxidation. Therefore, we investigated whether LCZ696 treatment augments lipid mobilization and oxidation at rest and during exercise. In this double-blind study, 98 patients with mild-to-moderate hypertension and abdominal adiposity were randomized to LCZ696 400 mg or amlodipine (AML) 10 mg once daily for 8 weeks. At baseline and week 8, abdominal subcutaneous adipose tissue lipolysis (microdialysis), whole-body lipolysis (glycerol tracer kinetics), and substrate oxidation and energy expenditure (indirect calorimetry) were assessed at rest and during exercise (60 min cycling at approximately 50% of peakVO 2 ). LCZ696 and AML groups had comparable baseline characteristics with regards to age, blood pressure and body mass index (LCZ696 32.6±4.6 kg/m 2 , AML 33.3±4.4 kg/m 2 ). Abdominal subcutaneous adipose tissue lipolysis at rest was increased with LCZ696 compared to AML (interstitial glycerol concentrations at week 8; 80.5 μmol/L vs. 64.0 μmol/L; p=0.020). The apparent exercise-induced increase in adipose tissue lipolysis was more pronounced with LCZ696 compared to AML at 15 and 30 min of exercise (interstitial glycerol concentrations at week 8; 15 min exercise: 153.1 μmol/L vs. 128.8 μmol/L, p=0.014; 30 min exercise: 187.63 μmol/L vs. 149.19 μmol/L, p=0.010). However, whole-body lipolysis at rest and during exercise was not significantly different between groups. While respiratory quotient increased with exercise in both treatment groups, energy expenditure and substrate oxidation at rest and during exercise did not differ between treatments. In conclusion, 8 weeks of treatment with LCZ696 vs. AML increased lipid mobilization from abdominal subcutaneous adipose tissue at rest and during physical exercise in obese, hypertensive patients, while whole-body lipolysis and lipid oxidation remained unchanged. This study therefore suggests an improvement in lipid mobilization with LCZ696 and supports a central role of NPs in the crosstalk between human cardiovascular and metabolic regulation.
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