Improved Insulin Sensitivity With Angiotensin Receptor Neprilysin Inhibition in Individuals With Obesity and Hypertension

Clin Pharmacol Ther. 2017 Feb;101(2):254-263. doi: 10.1002/cpt.455. Epub 2016 Nov 17.

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.

MeSH terms

  • Adipose Tissue / drug effects
  • Adult
  • Aminobutyrates / pharmacology*
  • Aminobutyrates / therapeutic use
  • Amlodipine / pharmacology
  • Angiotensin II Type 1 Receptor Blockers / metabolism
  • Antihypertensive Agents / pharmacology*
  • Energy Metabolism / drug effects
  • Female
  • Glycerol / analysis
  • Humans
  • Hypertension / drug therapy
  • Insulin Resistance / physiology*
  • Lipid Metabolism / drug effects
  • Male
  • Middle Aged
  • Natriuretic Peptides / genetics
  • Natriuretic Peptides / metabolism
  • Neprilysin / antagonists & inhibitors*
  • Obesity / metabolism*
  • Renin-Angiotensin System / drug effects
  • Renin-Angiotensin System / physiology
  • Tetrazoles / pharmacology*
  • Tetrazoles / therapeutic use

Substances

  • Aminobutyrates
  • Angiotensin II Type 1 Receptor Blockers
  • Antihypertensive Agents
  • Natriuretic Peptides
  • Tetrazoles
  • Amlodipine
  • Neprilysin
  • Glycerol
  • sacubitril-valsartan