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/m2 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 ± 2.5 kg. Twelve months of DZX treatment was also associated with a significant decline in systolic (-6.6%) and diastolic (-8.6%) blood pressure and low-density lipoprotein-cholesterol (-18%) and triglycerides (-43%) 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 A1c (95% CI: -0.08% 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.
Subject(s)
Diazoxide/administration & dosage , Healthy Lifestyle/physiology , Hyperinsulinism/therapy , Insulin Antagonists/administration & dosage , Obesity/therapy , Weight Loss/drug effects , Adult , Blood Glucose/analysis , Blood Glucose/drug effects , Body Mass Index , Body Weight/drug effects , Body Weight/physiology , Diazoxide/adverse effects , Dose-Response Relationship, Drug , Double-Blind Method , Humans , Hyperglycemia/chemically induced , Hyperglycemia/epidemiology , Hyperglycemia/prevention & control , Hyperinsulinism/blood , Hyperinsulinism/etiology , Hyperinsulinism/metabolism , Hypoglycemic Agents/administration & dosage , Insulin/blood , Insulin/metabolism , Insulin Antagonists/adverse effects , Male , Metformin/administration & dosage , Middle Aged , Obesity/blood , Obesity/complications , Obesity/metabolism , Potassium Channels/agonists , Potassium Channels/metabolism , Treatment Outcome , Weight Loss/physiologyABSTRACT
Context: It has been suggested that stimulation of lipolysis by diazoxide (DZX)-mediated insulin suppression may be useful in treating obesity. However, the optimal dose to promote lipolysis without causing hyperglycemia is unknown. Objective: To assess the effects of DZX in nondiabetic obese men on lipid and glucose metabolism. Design: Double-blind, placebo (PL)-controlled, 6-month trial in men with a body mass index of 30 to 37.5 kg/m2 treated with a combination of caloric restriction, a standardized exercise program, and DZX or PL dose escalation. Results: The mean maximal tolerated dose of DZX was 422 ± 44 mg/d (range, 200 to 700 mg/d). Dose-limiting events were edema (n = 11), hyperglycemia (n = 6), and nausea (n = 2). After dose reduction to a level free of clinical side effects, DZX treatment was associated with a markedly greater decrease in fasting insulin levels than PL (-72.3 ± 3.5% vs -23.0 ± 12.6%; P < 0.001) and a significant improvement of blood pressure and plasma lipid levels. The decline in insulin levels occurred at the cost of a small increase in plasma glucose (0.6 ± 0.2 mmol/L vs -0.1 ± 0.1 mmol/L; P = 0.04) and hemoglobin A1C (0.2 ± 0.1% vs 0.0 ± 0.1%; P = 0.17). Conclusion: In nondiabetic obese men, insulin levels can be reduced up to 70% without major metabolic side effects. The marked intersubject variation in maximal tolerated dose indicates that DZX dose titration needs to be individualized.
Subject(s)
Blood Glucose/metabolism , Caloric Restriction , Diazoxide/pharmacology , Exercise Therapy , Insulin/blood , Lipid Metabolism/drug effects , Lipolysis/drug effects , Obesity/therapy , Adult , Body Mass Index , Diazoxide/therapeutic use , Double-Blind Method , Humans , Lipids/blood , Male , Middle Aged , Obesity/drug therapy , Obesity/metabolism , Young AdultABSTRACT
OBJECTIVE: Hormone therapy (HT) is the most effective treatment of postmenopausal (PMP) flushing; however, its use is often contraindicated. As an alternative option, we explored the efficacy of the luteinizing hormone-releasing hormone (LHRH) receptor antagonist cetrorelix in women with severe PMP flushing. METHODS: We conducted an open-label treatment with cetrorelix 250 µg twice a day on 10 women with a baseline daily flush score of 15 or higher for a period of 4 to 6 weeks. The response to treatment was evaluated through monitoring serum gonadotropin levels, flush scores, and quality of life. RESULTS: At baseline, the mean (SEM) daily flush score was 36.1 ± 1.8 (mean ± SEM range, 29-44). All women demonstrated a decrease in serum luteinizing hormone and follicle-stimulating hormone during treatment, but the premenopausal levels of both gonadotropins were reached in only two women. The mean daily flush score decreased by 42.0% ± 7.7% (P < 0.001). This was caused by a decrease in flush frequency of 26.2% ± 6.0% (P < 0.01) and by a decrease in flush severity of 21.2% ± 7.7% (P < 0.05). CONCLUSIONS: In an open-label setting, luteinizing hormone-releasing hormone receptor blockade reduced PMP flushing by at least 25% in 8 of 10 women with severe flushing. A placebo-controlled study will be needed to demonstrate the true benefit of this approach. The present data suggest that the treatment period must be longer than 6 weeks to capture the maximal effect.