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

• Published in: Obesity (Silver Spring, Md.) Vol. 27; no. 1; p. 59
• Main Authors: Zemel, Michael B, Kolterman, Orville, Rinella, Mary, Vuppalanchi, Raj, Flores, Omar, Barritt, 4th, A Sidney, Siddiqui, Mohammad, Chalasani, Naga
• Format: Journal Article
• Language: English
• Published: United States 01.01.2019
• Subjects: 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
• ISSN: 1930-739X
• DOI: 10.1002/oby.22346

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