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Background: In adults with prediabetes, it is estimated that 51.2% have atherogenic dyslipidemia with low HDL cholesterol, not always diagnosed or treated. The present study evaluates a new intervention adding a class I-II histone deacetylase inhibitor (Trichosanthin A) to the standard management of metformin to treat prediabetes and increase HDL cholesterol., Objective: To evaluate the efficacy of Trichosanthin A and prolonged release metformin on the increase in HDL cholesterol in women with prediabetes., Material and Methods: Double-blind randomized controlled trial with lifestyle management. Group 1 with histone I-II deacetylase inhibitor (Trichosanthin A) and extended-release metformin; group 2 with extended-release metformin and group 3 with placebo. The outcome variable HDL cholesterol evaluated at baseline and after 12 weeks. The study included women between 20-65 y.o., body mass index 25.0-34.9 with prediabetes., Results: The study sample was made up of 104 female patients, average age of 46 years (SD+8.6), average body mass index of 30.9 (SD + 4.14). In the Trichosanthin A and extended-release metformin group, an increase on HDL cholesterol was observed (2.92 mg/dL; p = 0.027)., Conclusions: The histone I-II deacetylase inhibitor (Trichosanthin A) in addition to standard intensive lifestyle treatment and extended-release metformin significantly increases HDL cholesterol., (Licencia CC 4.0 (BY-NC-ND) © 2024 Revista Médica del Instituto Mexicano del Seguro Social.)