Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have shown significant benefits as a lipid-lowering therapy and have reduced cardiovascular risks in patients with hypercholesterolemia. Recent advancements included oral PCSK9 inhibitors (PCSK9i), which may provide advantages over injectable options. Purpose We aimed to assess the efficacy and safety of oral PCSK9i in reducing LDL-C levels, triglycerides, and apolipoprotein B compared with placebo in hypercholesterolemic populations. Methods This systematic review and meta-analysis included randomized placebo-controlled trials of oral PCSK9i vs. Placebo in patients with hypercholesterolemia at varying levels of ASCVD risk, and on stable lipid-lowering therapies. PubMed, Embase, and Cochrane were searched. Mean difference (MD) and odds ratio (OR) with 95% CI were pooled across trials for continuous and binary endpoints, respectively. Results Out of 266 database results, three randomized trials and 638 patients were included; 494 (77.4%) received oral PCSK9i. The average patient age was 64.3 years and 58.3% were male. Mean LDL-C levels (MD=-47.36%, 95% CI: -56.97, -37.75; p0.00001), triglycerides (MD=-15.47%; 95% CI: -20.51, -10.42; p=0.0003), and ApoB (MD=-42.08%; 95% CI: -52.04, -32.12; p0.0001) were significantly reduced in patients treated with oral PCSK9i compared with placebo. Serious adverse events were not increased with oral PCSK9i (OR=0.60; 95% CI: 0.24, 1.53; p=0.29) versus placebo. Conclusion Oral PCSK9i represents a promising frontier in lipid management. Their mechanism of action is well-established, and early-phase studies suggest comparable lipid-lowering efficacy to injectable therapies. By addressing the limitations of current therapies, oral PCSK9i could redefine hypercholesterolemia treatment paradigms, improving accessibility, adherence, and outcomes. However, their long-term efficacy, safety, and cardiovascular benefits must be validated in larger, longer-duration trials. Oral PCSK9i may bridge critical gaps in the global fight against ASCVD as the field advances.Forest plots of oral PCSK9i vs Placebo Graphical abstract
Ho et al. (2025) studied this question.