Lowering low-density lipoprotein cholesterol (LDL-C) remains a cornerstone of both the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD), supported by decades of genetic and clinical evidence confirming its causal role. (1) However, a considerable proportion of high-risk patients fail to achieve the recommended targets despite treatment with maximally tolerated statin doses.

Subcutaneous PCSK9 inhibitors (monoclonal antibodies) have represented a substantial advance in this setting, with sustained reductions in LDL-C and demonstrated clinical benefit in terms of cardiovascular events. (2) Nevertheless, their parenteral route of administration and high cost continue to limit their wider adoption.

The systematic review and meta-analysis by Masson et al. (3) updates the available evidence on five oral PCSK9 inhibitors. The authors report LDL-C reductions of nearly 58% compared with placebo, comparable in magnitude to those achieved with injectable drugs, and with no significant difference in adverse events. This meta-analysis incorporates phase 3 data on enlicitide, representing a significant advance over the largely descriptive evidence available until recently. Notably, one of the included studies demonstrated the superiority of an oral inhibitor over ezetimibe and bempedoic acid, two widely used oral alternatives. (4)

That said, several considerations temper this enthusiasm. The number of studies remains small, follow-up does not exceed 12 weeks in most studies, and the results for lipoprotein(a) showed marked statistical heterogeneity (I² = 99.2%), which calls for a more cautious interpretation of that point estimate. Furthermore, development of one of the five drugs has already been discontinued for strategic reasons, a reminder that this therapeutic class is still at an early stage. Nor should it be assumed that oral administration alone will resolve the problem of access. Indeed, while this editorial was prepared, the FDA approved enlicitide (Lipfendra) as the first commercially available oral PCSK9 inhibitor, based on the LDL-C reduction demonstrated in the CORALreef program, at a monthly list price of USD 315 —approximately half that of injectable drugs, but far from a trivial expense. The drug has not yet been approved in Argentina or elsewhere in Latin America, although it is worth noting that several centers in Argentine actively participated in the CORALreef program.

Importantly, no oral PCSK9 inhibitor has yet generated data on hard cardiovascular outcomes. The ongoing CORALreef Outcomes study will be decisive in determining whether these lipid reductions translate into concrete clinical benefits (5).

In conclusion, the study by Masson et al. provides a timely and methodologically sound synthesis of a rapidly evolving therapeutic class. Oral PCSK9 inhibitors represent one of the most promising strategies for optimizing intensive lipid-lowering therapy, but their definitive inclusion in treatment algorithms will have to await larger studies, longer follow-up, and, most importantly, results on hard cardiovascular events.