TY - JOUR

T1 - Effect of Sacubitril/Valsartan on Exercise-Induced Lipid Metabolism in Patients with Obesity and Hypertension

AU - Engeli, Stefan

AU - Stinkens, Rudi

AU - Heise, Tim

AU - May, Marcus

AU - Goossens, Gijs H.

AU - Blaak, Ellen E.

AU - Havekes, Bas

AU - Jax, Thomas

AU - Albrecht, Diego

AU - Pal, Parasar

AU - Tegtbur, Uwe

AU - Haufe, Sven

AU - Langenickel, Thomas H.

AU - Jordan, Jens

N1 - Funding Information: This study was funded by Novartis Pharma AG, Basel, Switzerland. Funding Information: S. Engeli has received significant financial support to conduct clinical studies from Novartis and Boehringer-Ingelheim, and modest lecture fees from Pfizer. T. Heise reports speaker honoraria and travel grants from Eli Lilly, Mylan and Novo Nordisk, honoraria for advisory panels from Novo Nordisk; and through Profil received research funds from Adocia, Astra Zeneca, Becton Dickinson, Biocon, Boehringer-Ingelheim, Dance Pharmaceuticals, Eli Lilly, Grünenthal, Gulf Pharmaceuticals, Johnson & Johnson, Marvel, Medimmune, Medtronic, Novartis, Novo Nordisk, Roche Diagnostics, Sanofi, Senseonics, and Zealand Pharma. J. Jordan served as consultant for Novartis, Boehringer-Ingelheim, Sanofi, Orexigen, Riemser, and Vivus; and is cofounder of Eternygen GmbH. D. Albrecht, P. Pal, and T.H. Langenickel are employees of Novartis. The other authors report no conflicts.

PY - 2018/1

Y1 - 2018/1

N2 - Sacubitril/valsartan (LCZ696), a novel angiotensin receptor-neprilysin inhibitor, was recently approved for the treatment of heart failure with reduced ejection fraction. Neprilysin degrades several peptides that modulate lipid metabolism, including natriuretic peptides. In this study, we investigated the effects of 8 weeks' treatment with sacubitril/valsartan on whole-body and adipose tissue lipolysis and lipid oxidation during defined physical exercise compared with the metabolically neutral comparator amlodipine. This was a multicenter, randomized, double-blind, active-controlled, parallel-group study enrolling subjects with abdominal obesity and moderate hypertension (mean sitting systolic blood pressure =130-180 mm Hg). Lipolysis during rest and exercise was assessed by microdialysis and [1,1,2,3,3-2H]-glycerol tracer kinetics. Energy expenditure and substrate oxidation were measured simultaneously using indirect calorimetry. Plasma nonesterified fatty acids, glycerol, insulin, glucose, adrenaline and noradrenaline concentrations, blood pressure, and heart rate were also determined. Exercise elevated plasma glycerol, free fatty acids, and interstitial glycerol concentrations and increased the rate of glycerol appearance. However, exercise-induced stimulation of lipolysis was not augmented on sacubitril/valsartan treatment compared with amlodipine treatment. Furthermore, sacubitril/valsartan did not alter energy expenditure and substrate oxidation during exercise compared with amlodipine treatment. In conclusion, sacubitril/valsartan treatment for 8 weeks did not elicit clinically relevant changes in exercise-induced lipolysis or substrate oxidation in obese patients with hypertension, implying that its beneficial cardiovascular effects cannot be explained by changes in lipid metabolism during exercise.

AB - Sacubitril/valsartan (LCZ696), a novel angiotensin receptor-neprilysin inhibitor, was recently approved for the treatment of heart failure with reduced ejection fraction. Neprilysin degrades several peptides that modulate lipid metabolism, including natriuretic peptides. In this study, we investigated the effects of 8 weeks' treatment with sacubitril/valsartan on whole-body and adipose tissue lipolysis and lipid oxidation during defined physical exercise compared with the metabolically neutral comparator amlodipine. This was a multicenter, randomized, double-blind, active-controlled, parallel-group study enrolling subjects with abdominal obesity and moderate hypertension (mean sitting systolic blood pressure =130-180 mm Hg). Lipolysis during rest and exercise was assessed by microdialysis and [1,1,2,3,3-2H]-glycerol tracer kinetics. Energy expenditure and substrate oxidation were measured simultaneously using indirect calorimetry. Plasma nonesterified fatty acids, glycerol, insulin, glucose, adrenaline and noradrenaline concentrations, blood pressure, and heart rate were also determined. Exercise elevated plasma glycerol, free fatty acids, and interstitial glycerol concentrations and increased the rate of glycerol appearance. However, exercise-induced stimulation of lipolysis was not augmented on sacubitril/valsartan treatment compared with amlodipine treatment. Furthermore, sacubitril/valsartan did not alter energy expenditure and substrate oxidation during exercise compared with amlodipine treatment. In conclusion, sacubitril/valsartan treatment for 8 weeks did not elicit clinically relevant changes in exercise-induced lipolysis or substrate oxidation in obese patients with hypertension, implying that its beneficial cardiovascular effects cannot be explained by changes in lipid metabolism during exercise.

KW - exercise-induced lipolysis

KW - hypertension

KW - lipid metabolism

KW - natriuretic peptide, neprilysin

KW - obesity

KW - sacubitril/valsartan

UR - http://www.scopus.com/inward/record.url?scp=85038373677&partnerID=8YFLogxK

U2 - 10.1161/HYPERTENSIONAHA.117.10224

DO - 10.1161/HYPERTENSIONAHA.117.10224

M3 - Article

C2 - 29180454

AN - SCOPUS:85038373677

VL - 71

SP - 70

EP - 77

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 1

ER -