Dapagliflozin-metformin combination enhances oocyte quality and reproductive outcomes in PCOS patients undergoing IVF/ICSI: a randomized controlled trial

To determine whether eight weeks of dapagliflozin plus metformin pretreatment improves oocyte quality, increases BMP15 and GDF9 expression, and enhances pregnancy outcomes in polycystic ovary syndrome (PCOS) patients undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). In this randomized, double-blind, placebo-controlled trial, 103 women with PCOS were screened and 92 randomized to four groups: placebo, metformin (500 mg BID), dapagliflozin (5 mg BID, total 10 mg/day), or combination. After eight weeks of treatment, 80 patients (20 per group) completed the study. Primary outcomes were mature oocyte count and good-quality embryo count. Secondary outcomes included clinical pregnancy rate and metabolic parameters. For primary endpoints, significance was set at P < 0.025; for key secondary endpoints, nominal P < 0.05 was considered significant; exploratory correlation analyses are reported with nominal P-values without correction. The combination group showed significantly lower HOMA-IR (3.66 ± 0.55 vs. 4.64 ± 0.40, P < 0.001) and total testosterone (0.71 ± 0.26 vs. 1.34 ± 0.43 nmol/L, P < 0.001) versus placebo. Combination therapy also significantly increased BMP15 and GDF9 expression ( P < 0.001), mature oocytes (12.85 ± 4.05 vs. 6.35 ± 4.05, P < 0.001), good-quality embryos (5.35 ± 2.40 vs. 1.65 ± 1.25, P < 0.001), and clinical pregnancy rate (75.0% vs. 15.0%, P < 0.001). Intention-to-treat analysis confirmed these findings (62.5% vs. 13.6%, P < 0.001). Nominally significant improvements were observed for BMI ( P = 0.003), waist circumference ( P = 0.012), leptin ( P = 0.004), and AMH ( P = 0.011); these should be interpreted as exploratory findings requiring confirmation. Eight-week dapagliflozin-metformin pretreatment was associated with improved metabolic profile (HOMA-IR), reduced hyperandrogenism (total testosterone), enhanced oocyte and embryo quality, higher clinical pregnancy rates, and upregulation of BMP15 and GDF9 expression in PCOS patients undergoing IVF/ICSI. These preliminary findings require confirmation in larger trials with live birth data.