Randomized Controlled Trial of a Leucine-Metformin-Sildenafil Combination (NS-0200) on Weight and Metabolic Parameters

Obesity (Silver Spring). 2019 Jan;27(1):59-67. doi: 10.1002/oby.22346.

Abstract

Objective: Leucine was previously demonstrated to allosterically activate mammalian sirtuin 1 and synergize with other sirtuin 1/AMP-activated protein kinase/nitric oxide pathway activators to modulate energy metabolism. The objective of this study was to evaluate the effects of a triple combination of leucine, metformin, and sildenafil (NS-0200) on body weight and obesity comorbidities in a phase 2 randomized trial.

Methods: A total of 91 subjects with obesity were randomized to placebo, low dose (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil), or high dose (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) twice daily for 16 weeks. Seventy subjects completed the trial and met all a priori compliance criteria. Hypertensive (n = 35) and hypertriglyceridemic (n = 22) subcohorts were also analyzed.

Results: NS-0200 dose-responsively reduced weight; high dose reduced weight by 2.4 and 5.0 kg in the full and high-triglyceride cohorts, respectively (P < 0.0001). High-dose NS-0200 treatment also decreased blood pressure (-5.5 mm Hg diastolic pressure; P = 0.011), with greater effects among hypertensive subjects. NS-0200 also significantly reduced triglycerides and hemoglobin A1c. Significant improvement in ≥ 2 comorbidities was exhibited by 54% of subjects in the high-dose arm versus 5% of placebo subjects (P = 0.0009). Treatment-emergent adverse events did not significantly differ among groups.

Conclusions: These data support further study of NS-0200 as a therapy for obesity and associated comorbidities.

Trial registration: ClinicalTrials.gov NCT02546609.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Body Weight / drug effects*
  • Double-Blind Method
  • Female
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Leucine / pharmacology
  • Leucine / therapeutic use*
  • Male
  • Metformin / pharmacology
  • Metformin / therapeutic use*
  • Middle Aged
  • Obesity / drug therapy*
  • Phosphodiesterase 5 Inhibitors / pharmacology
  • Phosphodiesterase 5 Inhibitors / therapeutic use*
  • Sildenafil Citrate / pharmacology
  • Sildenafil Citrate / therapeutic use*

Substances

  • Hypoglycemic Agents
  • Phosphodiesterase 5 Inhibitors
  • Metformin
  • Sildenafil Citrate
  • Leucine

Associated data

  • ClinicalTrials.gov/NCT02546609