Abstract
BACKGROUND AND AIMS: Randomized trials showed efficacious lipid-lowering with PCSK9 inhibitors (PCSK9i), but real-world treatment is often limited by statin-associated side effects (SASE). We quantified the effectiveness, safety and cardiovascular outcomes of alirocumab, evolocumab and inclisiran in a national prospective registry. METHODS: This was a prospective registry-based study of patients initiating a PCSK9i. Lipid trajectories were assessed at 0, 3, 9, 21, and 33 months. The average treatment effect of PCSK9i on lipid trajectories and cardiovascular outcomes was estimated by inverse probability of treatment weighting (IPTW) using covariate balancing propensity scores. RESULTS: One thousand three hundred eighty five patients (median age 64 years; 52% women; median baseline low-density lipoprotein cholesterol [LDL-C] 4 mmol/L, 57% SASE) were included and followed for 2459 patient-years. In patients on alirocumab (N = 598), evolocumab (N = 693), or inclisiran (N = 94), mean unadjusted LDL-C reductions were − 58.2% (–1.98 mmol/L), − 58.9% (–2.09 mmol/L), and − 33.2% (–1.17 mmol/L), respectively (p < 0.001). IPTW-adjusted LDL-C reductions remained numerically greater for monoclonal antibodies but were no longer significantly different long-term. Predictors of greater LDL-C reduction were longer treatment duration, male sex, higher age, statin co-therapy and first-line use (p < 0.001). Adverse events occurred in 31% of patients. Major adverse cardiovascular events were infrequent (2.6 per 100 person-years) with no significant between-drug differences after IPTW. CONCLUSIONS: PCSK9i are safe in real-world practice. Alirocumab and evolocumab achieve trial-like LDL-C reductions, while inclisiran shows attenuated effectiveness without statins. Meaningful residual risk persists despite therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12944-026-02897-3.