Evolocumab to Reduce First Major Cardiovascular Events in Patients Without Known Significant Atherosclerosis and With Diabetes
Nicholas A. Marston, Erin A. Bohula, Ajay Bhatia, Gaetano M. De Ferrari, LA Leiter, Jose C. Nicolau, Jeong-Gun Park, S. A. Murphy, Emileigh Walsh, L. Liu, Subodh Verma, Naveed Sattar, Stephen J. Nicholls, J. Lopez-Sendon, Ioanna Gouni-Berthold, Lale Tokgozoglu, Ron Blankstein, Marcoli Cyrille, Gabriel Paiva da Silva Lima, Robert P. Giugliano, Marc S. Sabatine, VESALIUS-CV Investigators, Alberto Lorenzatti, Marcos R. Litvak Bruno, Ignacio Mackinnon, Emilio Alaguibe, Gustavo Giunta, Oscar Romano Montana, Daniel Vogel, JORGELINA SALA, Diego Besada, Angela Romero Zarante, Marisa L. Vico, Tomas E. Smith Casabella, Patricia del C. Gonzalez Colaso, Eleonora Montenegro, Cesar Javier Zaidman, Maria C. de Salvo, Eduardo R. Perna, Claudio Majul, Ruben O Garcia Duran, Miguel Hominal, Sonia Hermida, Carolina Chacon, Andrea P. Serrano, Juan P. Albisu Di Gennaro, Walter R. Stoermann, María Mansilla, Martín Koretzky, Leonardo Novaretto, Lilia Schiavi, Andres D. Orlandini, Fernando Botto, Elizabeth Gelersztein, Eduardo Blumberg, Stephen J. Nicholls, John Amerena, Walter P. Abhayaratna, Philip Roberts-Thomson, Matthew Worthley, C. Judkins, Fiona Bisshop, Alistair Begg, David Colquhoun, Karam Kostner, Ktut Arya, David Cross, A. Conradie, Jamie Morton, Peter Purnell, Andrew Hamilton, William Van Gaal, Ali Safaa, D. Eccleston, Christoph Ebenbichler, Peter Fasching, Ursula Hanusch, Bernhard Ludvik, Lukas Holzinger, Christoph H. Saely, Konstantin A. Krychtiuk, A. Kautzky-Willer, Thomas M. Stulnig, Peter Sinnaeve, Stéphane Carlier, Marc De Meulemeester, Bart Wollaert, Andre Peeters, Benjamin Scott, Philippe Vanduynhoven, Jan Verwerft, Tom Sarens, Luis A. Tavares Russo, Celia R. Echeverria Sampaio, Roberto R. Giraldez, Pedro Pimentel Filho, Joao L. Cunha Borges, Miguel Nasser Hissa, Jose A. Ribas Fortes, Rodrigo Cerci
Abstract
Importance: Intensive lowering of low-density lipoprotein cholesterol (LDL-C) levels with PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors for cardiovascular event reduction has largely been reserved for patients with significant atherosclerosis. Objective: To investigate whether evolocumab could prevent a first major cardiovascular event (MACE) in patients without known significant atherosclerosis. Design, Setting, and Participants: VESALIUS-CV was a randomized, double-blind, placebo-controlled trial of evolocumab conducted across 774 sites in 33 countries and enrolling 12 257 patients with no prior myocardial infarction or stroke, LDL-C level 90 mg/dL or greater, and qualifying atherosclerosis or high-risk diabetes. This prespecified subgroup analysis examined outcomes in patients without known significant atherosclerosis (none of the following: prior arterial revascularization, arterial stenosis ≥50%, or coronary artery calcium score ≥100 Agatston units), all of whom had diabetes. Enrollment started in June 2019 and the last patient visit was July 2025, with a median follow-up of 4.8 years. Intervention: Patients were randomized in a 1:1 ratio to subcutaneous administration of either evolocumab (140 mg every 2 weeks) or matching placebo added to optimally tolerated statin therapy. Main Outcomes and Measures: The dual primary end points were composites of coronary heart disease death, myocardial infarction, or ischemic stroke (3-P MACE) and 3-P MACE plus ischemia-driven arterial revascularization (4-P MACE). Secondary end points included all-cause mortality. Results: This predefined subgroup included 3655 patients (1849 in the evolocumab group and 1806 in the placebo group) with a median age of 65 years (57% female). Among those in the lipid substudy, the median LDL-C level at 48 weeks was 52 mg/dL in the evolocumab group vs 111 mg/dL in the placebo group (P < .001). A 3-P MACE event occurred in 83 patients (5-year Kaplan-Meier estimate, 5.0%) in the evolocumab group compared with 117 patients (5-year Kaplan-Meier estimate, 7.1%) in the placebo group (hazard ratio [HR], 0.69 [95% CI, 0.52-0.91]; P = .009; between-group difference, 2.1% [95% CI, 0.4%-3.8%]). A 4-P MACE event occurred in 127 patients (5-year Kaplan-Meier estimate, 7.6%) in the evolocumab group compared with 178 patients (5-year Kaplan-Meier estimate, 10.5%) in the placebo group (HR, 0.69 [95% CI, 0.55-0.86]; P = .001; between-group difference, 2.9% [95% CI, 0.9%-4.9%]). There were 136 deaths (5-year Kaplan-Meier estimate, 7.8%) in the evolocumab group compared with 172 deaths (5-year Kaplan-Meier estimate, 10.1%) in the placebo group (HR, 0.76 [95% CI, 0.61-0.95]). Conclusions and Relevance: In high-risk patients without known significant atherosclerosis and with diabetes, evolocumab reduced the risk of a first major cardiovascular event. Trial Registration: ClinicalTrials.gov Identifier: NCT03872401.