Time course of LDL-C lowering after initiation of PCSK9 inhibition or bempedoic acid in atherosclerotic cardiovascular disease

Background Current guidelines recommend aggressive lipid-lowering therapy (LLT) in high-risk cardiovascular patients. Recent evidence suggests that not only the extent of atherogenic lipoprotein reduction, but also the speed of lipid profile optimisation may be clinically relevant. Novel agents such as evolocumab, inclisiran, and bempedoic acid (BA) have recently emerged; however, comparative data on their time course of low-density lipoprotein cholesterol (LDL-C) lowering remain limited. Aim To compare the time course and speed of LDL-C reduction with evolocumab, inclisiran, and BA in patients with atherosclerotic cardiovascular disease (ASCVD). Methods This prospective, observational study included 60 patients with ASCVD, who initiated therapy with evolocumab (n = 23), inclisiran (n = 19), or BA (n = 18). Lipid profiles, including LDL-C, apolipoprotein B (ApoB), apolipoprotein A1, HDL-cholesterol, triglycerides, and lipoprotein(a) [Lp(a)], were assessed at baseline and at 1, 2, and 6 weeks after initiation. Results All three therapies significantly reduced LDL-C levels; evolocumab showed the fastest and greatest LDL-C reduction at 1 week (median LDL-C 27.0 mg/dL), corresponding to an absolute decrease of –44.2 mg/dL (–62.1%) from baseline. BA reduced LDL-C by –16.6 mg/dL (–26.6%, p=0.009) and inclisiran by –32.4 mg/dL (–42.0%, p=0.033), respectively. Evolocumab uniquely demonstrated significant reductions in ApoB (–0.40 g/L, –46.0%, p<0.001) and Lp(a) ((–0.09 g/L, –32.1%, p<0.001), whereas inclisiran moderately reduced ApoB, and BA showed minimal effects on these parameters. HDL-cholesterol and triglyceride levels remained unchanged across groups. Conclusion Evolocumab provided rapid and pronounced improvements in LDL-C, ApoB, and Lp(a) compared to inclisiran and BA, even on a background of optimised LLT. These findings support incorporating novel LLTs, particularly evolocumab, to further reduce cardiovascular risk in patients inadequately controlled with standard therapies.