Combined metformin and exenatide versus only metformin treatments in polycystic ovary syndrome with abdominal obesity and network pharmacology of gene expression: evidence from a randomized clinical trial.

OBJECTIVE: To evaluate (1) the metabolic and endocrine effects of metformin combined with exenatide versus only metformin treatments in patients with polycystic ovary syndrome (PCOS) and abdominal obesity (AO) and (2) to determine the molecular mechanisms by which the combined treatment acts on PCOS patients. DESIGN: Randomized controlled trial of PCOS patients with AO to receive combined treatment with metformin-exenatide or metformin alone, and network pharmacology of gene expression in PCOS patients under the combined exposure. SETTING: Tertiary teaching hospital. PATIENTS: Women with PCOS and AO who fulfilled the Rotterdam Criteria under combined treatment with daily cyclical ethinylestradiol (35 μg/day) and cyproterone acetate (2 mg/day). INTERVENTION: Patients were randomized to either combined oral metformin (1500 mg/day) and exenatide (2 mg weekly subcutaneous injection,  = 35 women) treatment or metformin alone ( = 31 women) for 12 weeks. Network pharmacological prediction of gene expression under the combined exposure was studied. MAIN OUTCOME MEASURES: (1) Basal and after both treatments anthropometric, endocrine, and metabolic changes were compared. (2) Network pharmacological prediction and gene expression were studied in patients under metformin-exenatide treatment. Venn diagram and Markov Cluster Algorithm diagram of core targets for AO were applied to identify key targets. RESULTS: Both treatments displayed (1) reductions of total testosterone, insulin, and lipoprotein levels and (2) increases of high-density lipoprotein cholesterol and apolipoprotein A1. We identified PCOS, AO, and comorbid genes further intersected with 269 combination therapy genes. Network pharmacology identified 154 key PCOS genes for drug regulation, including 29 closely related to AO and metabolism. CONCLUSION: Both treatments improved glucose and lipid metabolism, weakening insulin resistance and improving some biochemical indexes. Network pharmacology identified genes related to AO and metabolism in patients with PCOS under the metformin-exenatide treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT04029272.