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

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.

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.

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.

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.