Gender and region disparities in plasma PCSK9 levels: a systematic review and meta-analysis.

INTRODUCTION: Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) levels may differ by sex and geographic region, but evidence remains inconsistent. This systematic review and meta-analysis quantifies these differences in adults with hyperlipidaemia, atherosclerotic cardiovascular disease (ASCVD) or elevated ASCVD risk. METHODS: We searched MEDLINE, Web of Science, Cochrane Central and EMBASE through August 2024 for studies reporting plasma PCSK9 in ≥10 adults. Two reviewers extracted data and assessed bias. Random-effects models pooled standardised mean differences (SMDs) or means; heterogeneity was evaluated by I2, with subgroup and sensitivity analyses exploring its sources. RESULTS: For gender, 13 studies (5 706 participants) showed significantly higher PCSK9 in females than males (SMD -0.35, 95% CI -0.49 to -0.20; p=0.033; I2=54%). Single-sex studies corroborated this: female-only mean 350.66 ng/mL (95% CI 301.86 to 399.46) versus male-only 228.36 ng/mL (95% CI 176.33 to 280.39). For region, 63 studies (34 802 participants) from Asia, Europe and North America yielded no significant overall difference (p=0.569); after outlier exclusion, pooled means were 250.39 (95% CI 217.70 to 283.08), 269.27 (95% CI 230.24 to 308.31) and 301.76 (95% CI 194.28 to 409.23) ng/mL, with I2=0% within subgroups. Sensitivity analyses confirmed robustness; most studies were high quality. GRADE (Grading of Recommendations, Assessment, Development and Evaluation) certainty was moderate for sex and low for region. CONCLUSIONS: In these clinical populations, women have higher circulating PCSK9 levels than men, while regional differences were not statistically significant. These findings support gender-conscious interpretation of baseline PCSK9 values but do not establish PCSK9 inhibitor dosing or treatment strategies.