Sex-Specific Lipid, Apolipoprotein B, and Lipoprotein(a) Responses to Berberine Based on 2 Randomized Placebo-Controlled Trials

BACKGROUND: Berberine improves lipid metabolism and may influence sex hormones, raising the possibility of sex-specific treatment responses which remain poorly understood. OBJECTIVES: To evaluate the sex-specific lipid-modifying effects of berberine. METHODS: We conducted a randomized placebo-controlled trial (NCT06782646) in 100 women aged 20 to 65 years in Hong Kong receiving berberine (500 mg orally twice daily) or placebo for 12 weeks. For sex-specific comparisons, stored samples from a completed randomized trial in 84 men using the same intervention (NCT03770325) were used. The primary outcome was apolipoprotein B (apoB). Other outcomes included total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein(a) (Lp(a)), sex hormones, and nuclear magnetic resonance (NMR)-based lipid fractions. Biomarkers were measured at baseline and 8- and 12-week postintervention. Linear mixed-effects models were used for repeated measurements. Sex difference was examined using heterogeneity tests. RESULTS: At week 12, berberine reduced apoB by -1.18 SD (95% CI: -1.53 to -0.82); reductions were also seen in total cholesterol (-1.15 SD, 95% CI: -1.51 to -0.79), LDL cholesterol (-1.06 SD, 95% CI: -1.44 to -0.69), triglycerides (-0.77 SD, 95% CI: -1.14 to -0.41), and Lp(a) (-0.71 SD, 95% CI: -1.12 to -0.31), with improvements across LDL and very-low-density lipoprotein subclasses. Men showed similar trends, but the magnitude was greater in women for apoB, total cholesterol, LDL cholesterol, and Lp(a). Berberine decreased total testosterone in women (-0.42 SD, 95% CI: -0.82 to -0.03) but increased it in men (0.43 SD, 95% CI: 0.004 to 0.85). CONCLUSIONS: Berberine reduced atherogenic lipids, apoB, and Lp(a), with greater efficacy in women than in men. These findings support berberine as a complementary treatment and underscore the importance of sex-specific treatments.