title: Improved Insulin Sensitivity With Angiotensin Receptor Neprilysin Inhibition in Individuals With Obesity and Hypertension.
abstract: Natriuretic peptide (NP) deficiency and sustained renin-angiotensin system activation are associated with impaired oxidative metabolism and predispose to type-2 diabetes. We hypothesized that sacubitril/valsartan (LCZ696), which augments NP through neprilysin inhibition while blocking angiotensin II type-1 (AT1)-receptors, improves insulin sensitivity, lipid mobilization, and oxidation. After 8 weeks of treatment of obese patients with hypertension, sacubitril/valsartan 400 mg q.d., but not amlodipine 10 mg q.d., was associated with a significant increase from baseline in the insulin sensitivity index (hyperinsulinemic-euglycemic clamp), and tended to be higher in patients treated with sacubitril/valsartan compared to amlodipine. Abdominal adipose tissue interstitial glycerol concentrations increased with sacubitril/valsartan, but decreased with amlodipine. Whole-body lipolysis and substrate oxidation did not change with either treatment. Results confirm that sacubitril/valsartan treatment leads to a metabolic benefit in the study population and supports the relevance of neprilysin inhibition along with AT1-receptor blockade in the regulation of human glucose and lipid metabolism.
authors.affiliation: Institute for Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Jordan
authors.affiliation: Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Stinkens
authors.affiliation: Profil, Neuss, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Jax
authors.affiliation: Institute for Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Engeli
authors.affiliation: Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: E E
authors.initials: EE
authors.lastname: Blaak
authors.affiliation: Institute for Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: May
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Havekes
authors.affiliation: Institute for Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schindler
authors.affiliation: Translational Medicine, Novartis Pharma AG, Basel, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Albrecht
authors.affiliation: Biostatistical Sciences, Integrated Development Functions and Regions, Novartis Healthcare Pvt. Ltd, Hyderabad, India.
authors.forename: P
authors.initials: P
authors.lastname: Pal
authors.affiliation: Profil, Neuss, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Heise
authors.affiliation: Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: G H
authors.initials: GH
authors.lastname: Goossens
authors.affiliation: Translational Medicine, Novartis Pharma AG, Basel, Switzerland.
authors.forename: T H
authors.initials: TH
authors.lastname: Langenickel
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000328:Adult; D000613:Aminobutyrates / Q000494:pharmacology* / Q000627:therapeutic use; D017311:Amlodipine / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds; D004338:Drug Combinations; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D005990:Glycerol / Q000032:analysis; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D045265:Natriuretic Peptides / Q000235:genetics / Q000378:metabolism; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009765:Obesity / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D004338:Drug Combinations; D045265:Natriuretic Peptides; D013777:Tetrazoles; D017311:Amlodipine; D000068756:Valsartan; D015260:Neprilysin; D005990:Glycerol; C549068:sacubitril and valsartan sodium hydrate drug combination