High-dose, diazoxide-mediated insulin suppression boosts weight loss induced by lifestyle intervention

Abstract

Context: Obesity-related hyperinsulinism may impede lifestyle-initiated weight loss. Objective: Proof-of-concept study to investigate the amplifying effects of diazoxide (DZX)mediated insulin suppression on lifestyle-induced weight loss in nondiabetic, hyperinsulinemic, obese men. Design: Twelve-month study comprising an initial 6-month, double-blind trial, followed by a partially de-blinded 6-month extension in men with obesity with a body mass index of 30 to 37.5 kg/m 2 and a fasting serum C-peptide level .1.00 nM. Patients were randomized into three treatment groups: DZX + placebo (DZX + PL), DZX + metformin (DZX + MTF), and double PL (PL + PL). Results: At 6 months, DZX treatment was associated with a 6.1-kg PL-subtracted decline in fat mass (FM), and at 12 months, FM had decreased by a total of 15.7 6 2.5 kg. Twelve months of DZX treatment was also associated with a significant decline in systolic (26.6%) and diastolic (28.6%) blood pressure and low-density lipoprotein-cholesterol (218%) and triglycerides (243%) and a 39% rise in high-density lipoprotein-cholesterol. These effects were achieved at the cost of a small rise in fasting glucose (95% CI: 0.2 to 1.0 mM) and hemoglobin A1 c (95% CI: 20.08% to 0.44%). There were no differences between DZX monotherapy and the combination of DZX + MTF. Conclusion: High-dose DZX treatment of 1 year resulted in a substantial decrease in FM, blood pressure, and lipid levels at the cost of a small rise in blood glucose levels.