Advancing ASCVD Management with PCSK9 Inhibitors

In this episode, ‘Advancing ASCVD Management with PCSK9 Inhibitors,' the panelists explore the clinical evidence base for PCSK9 inhibitors, beginning with a review of outcomes trial data from FOURIER and ODYSSEY Outcomes showing 50 to 60% LDL reductions with evolocumab and alirocumab, and relative risk reductions of approximately 15% in secondary prevention, rising to 25% in the more recent VICTORION primary prevention trial. Both FOURIER and ODYSSEY Outcomes demonstrated reductions in total mortality, and safety data have consistently shown no concerning signals at very low LDL levels, including no adverse cognitive effects even at dramatically reduced LDL concentrations. The panel also highlights that PCSK9 inhibitors provide an additional 25% reduction in lipoprotein(a), with patients carrying higher baseline levels deriving greater absolute benefit, a finding now reflected in the 2026 guidelines recommending PCSK9 inhibitor consideration in high-risk secondary prevention patients with elevated lipoprotein(a).

The panelists also reference the VICTORION-INITIATE trial, which demonstrated that facilitating early initiation of inclisiran through a dedicated support team improved both adherence and overall cardiovascular risk factor management, reinforcing the value of structured implementation approaches over sequential therapy escalation.

The conversation then turns to enlicitide, an investigational oral PCSK9 inhibitor described as a macrocyclic peptide that binds to PCSK9 in serum and prevents LDL receptor degradation through the same biological mechanism as monoclonal antibodies. Data from the Coral Reef lipids trial show nearly identical LDL lowering with enlicitide compared to injectable monoclonal antibodies, with outcomes trial results from Coral Reef anticipated through 2029.

The next episode in this series, 'Safety, Tolerability, and Patient-Centered Decision-Making in ASCVD Lipid Therapy,' features the panelists advancing their conversation on ASCVD and focusing on the safety and tolerability profiles of statins, PCSK9 inhibitors, and emerging oral therapies, while examining how patient preferences, dosing frequency, and shared decision-making shape individualized treatment choices.