Evaluation of evolocumab on saphenous vein graft patency following coronary artery bypass graft surgery in people living with and without diabetes in the NEWTON ‐ CABG CardioLink ‐5 trial

Compared to people without diabetes, those living with diabetes have smaller coronary vessels and experience more aggressive atherosclerosis, more diffuse coronary lesions, and more extensive disease.1 Almost half of the individuals undergoing coronary artery bypass graft (CABG) surgery live with diabetes2 and this proportion is likely to continue rising. Of note, CABG surgery remains the recommended cornerstone treatment of individuals living with diabetes and multivessel coronary artery disease.3, 4 Low-density lipoprotein cholesterol (LDL-C) is a reliable predictor of long-term major adverse cardiac or cerebrovascular events (MACCEs) among those who have undergone CABG.5 In a pooled analysis of three randomised clinical trials (RCTs) that followed a total of 4050 individuals living with established coronary heart disease and type 2 diabetes, lower LDL-C levels 1 year following revascularisation procedures was associated with significantly less MACCE.6 The same study further reported that when compared to optimal medical therapy, CABG was associated with MACCE reductions as long as LDL-C had declined unlike percutaneous coronary intervention where MACCE benefits were only evident among those who achieved a 1 year post-revascularisation LDL-C of less than 70 mg/dL.6 Saphenous veins remain widely used conduits for CABG surgery despite their persistently high failure rates. A 2023 pooled analysis of seven RCTs revealed that approximately 20% of saphenous vein grafts (SVGs) failed within a median time to CABG imaging of 1.02 years.7 This is concerning since graft failure is associated with adverse cardiac events and mortality. Furthermore, there is currently no therapy that can prevent SVG failure. The impetus for this pre-specified sub-analysis of the NEWTON-CABG CardioLink-5 (Effect of Evolocumab on Saphenous Vein Graft Patency Following Coronary Artery Bypass Surgery; ClinicalTrials.gov NCT03900026)8 trial was the persistent paucity of information on the longevity of bypass graft patency in the setting of diabetes. This sub-analysis therefore sought to evaluate SVG disease rates, SVG patency and SVG plaque volumes in addition to the efficacy of evolocumab versus placebo by baseline diabetes status. NEWTON-CABG CardioLink-5 was a multicentre, double-blind, randomised trial that involved early initiation of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab (140 mg every 2 weeks) versus placebo in statin-treated (moderate to high intensity) adults who had undergone CABG surgery with at least two SVGs.8 There was no pre-specified LDL-C entry criterion. Country- and site-specific ethics boards approved the protocol. Participants provided written informed consent prior to study entry. The primary efficacy endpoint (vein graft disease rate, VGDR) was the proportion of SVGs with 50% or greater stenosis or total occlusion 24 months after the index CABG procedure. The secondary efficacy endpoints were: the proportion of SVGs that were totally (100%) occluded at 24 months; the proportion of participants with at least one totally (100%) occluded SVG at 24 months; and the hierarchical composite of cardiovascular death, myocardial infarction, coronary revascularisation, number of SVGs with 100% stenosis at the end-of-study visit, number of SVGs with 50%–99% stenosis at end of study, number of totally (100%) occluded arterial grafts at end of study, and total plaque volume at end of study (each assessed by total wins for each treatment group and WIN ratio). The median baseline LDL-C for the entire NEWTON-CABG CardioLink-5 cohort was 71.5 mg/dL and, as previously reported, evolocumab did not improve 24-month SVG patency, reduce total occlusion rates, or lower the proportion of participants with at least one occluded SVG.8 Efficacy analyses for this sub-analysis were performed on the modified intention-to-treat population, that is, the 554 randomised participants from Canada, Australia, Hungary, and the United States who received at least one dose of the investigational product (evolocumab or placebo) and had at least one evaluable SVG 24 months post-surgery (Figure 1A). The median age was 66 years, approximately 15% were women, and the median time from CABG surgery to randomisation was 13 days. Participants with a diabetes diagnosis in their charts or an HbA1C 6.5% or higher were included in the “Diabetes” group (n = 271; median HbA1c 7.0%); others were classified as having “No Diabetes” (n = 283; median HbA1c 5.7%). The “Diabetes” group compared with the “No Diabetes” group had fewer white participants (62.2% vs. 76.3%) and significantly higher body mass index (median 28.6 vs. 27.8 kg/m2), systolic blood pressure (median 126 vs. 120 mmHg), and circulating levels of triglycerides (median 142 vs. 129 mg/dL), as well as lower LDL-C (median 59 vs. 83 mg/dL) and non-high-density lipoprotein cholesterol (median 88 vs. 109 mg/dL) levels (all p < 0.05). Proportionally less of the “No Diabetes” than “Diabetes” group had previously undergone a percutaneous coronary intervention (13.1% vs. 20.7%; p < 0.002). Over 96% of both groups were on ASA and one-third on a P2Y12 inhibitor (no diabetes 34.4%; diabetes 27.8%). Among those with “No Diabetes,” 0.4% were treated with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) whereas 29.9%, 27.3%, 5.2%, and 2.2% of the “Diabetes” group were treated with insulin, an SGLT2i, a glucagon-like peptide-1 receptor agonist (GLP-1RA), and both an SGLT2i and GLP-1RA, respectively. The temporal percentage changes in and achieved LDL-C levels are summarised in Figure 1B. The efficacy of evolocumab versus placebo on the primary endpoint (proportion of SVGs with at least 50% stenosis/evaluated grafts) was comparable between the groups (Figure 2A). As shown in Figure 2B, the “Diabetes” group had similar VGDRs (odds ratio [OR] 95% confidence interval [CI] = 0.95 [0.70, 1.29]) at 24 months to the “No Diabetes” group. The percentages of completely occluded SVGs (OR [95% CI] = 0.86 [0.61, 1.20]), proportions of participants with at least one completely (100%) occluded SVG, and composite clinical wins (WIN ratio [95% CI] = 1.04 [0.86, 1.26]) for the “Diabetes” and “No Diabetes” groups were comparable (Figure 2C). People living with diabetes experience a higher mortality rate and greater need for repeat revascularisation procedures post-coronary revascularisation.9 In the current work, SVG failure rates were similar in the “No Diabetes” and “Diabetes” groups. This is noteworthy and in stark contrast to the risk for stent-related thrombosis where the gap between individuals living with diabetes and without diabetes, while persistent, has narrowed.10 The overall neutral results of NEWTON-CABG CardioLink-5 may reflect the low baseline LDL-C values and relatively short follow-up duration. SVG failures appeared to be unaffected by evolocumab despite the expected steep LDL-C decrease and slow recovery after month 3, suggesting that SVG quality and technical factors, rather than LDL-C levels, may have been more critical to early SVG failure. Regardless, that SVG disease burden remained high despite the median baseline LDL-C of 77.3 mg/dL underscores the need for robust study of cardiac revascularisation options for people living with versus without diabetes and for investigations seeking alternate biological targets and mechanistic interventions to improve clinical care and narrow knowledge gaps. Individuals living with diabetes are a growing high-risk population with elevated rates of surgical mortality and post-cardiac surgery readmissions. The NEWTON-CABG CardioLink-5 trial demonstrated in a post-CABG statin-treated population that the LDL-C-lowering efficacy of evolocumab was independent of diabetes status and that there was no diabetes status-treatment interaction for the primary endpoint. The data herein should not and do not detract from the established cardiovascular benefits of intensive LDL-C lowering in individuals who undergo CABG, regardless of whether they have diabetes or not. Hwee Teoh, Subodh Verma, C. David Mazer, and Lawrence A. Leiter developed the concept of the analysis. Michael Szarek performed the analysis. Hwee Teoh wrote the first draft of the manuscript. All authors reviewed the results and interpreted the findings; reviewed/edited the manuscript and approved the final version of the manuscript. Subodh Verma, C. David Mazer, and Lawrence A. Leiter are the guarantors of the work and, as such, had full access to all data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. Dr. Subodh Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery. Dr. Aishwarya Krishnaraj was supported by the Canada Graduate Research Scholarships-Doctoral (CGRS D) program from the Canadian Institutes of Health Research. Dr. C. David Mazer is supported by a Merit Award from the University of Toronto Department of Anesthesiology and Pain Medicine and holds the Cara Phelan Chair in Critical Care at St. Michael's Hospital-Unity Health Toronto. Amgen Canada funded this investigator-initiated study. This study was funded by Amgen Canada. Dr. Hwee Teoh: Personal fees from the Canadian Medical and Surgical Knowledge Translation Research Group and LMC Healthcare. Dr. Subodh Verma: Grants and/or research support and/or speaking honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Heart Research Centre, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Humber River Health, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management Inc., Sanofi, and Sun Pharma. Dr. G. B. John Mancini: Research support from speaking honoraria and/or acting as an advisor to Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, GSK, HLS Therapeutics, Merck, Novartis, Novo Nordisk, Esperion, and Ultragenyx. Dr. Michael Szarek: Salary support from CPC, a non-profit academic research organisation affiliated with the University of Colorado, that receives or has received research grant/consulting funding between July 2021 and July 2025 from the following organisations: 35Pharma, Inc., Abbott Labratories, Agios Pharmaceuticals, Inc., Alexion Pharma Godo Kaisha, American Heart Association, American Journal Managed Care, Amgen Inc., Amgen USA, Inc., Anthos Therapeutics, Inc., Arrowhead Pharmaceuticals, AstraZeneca Pharma India, AstraZeneca Pharmaceuticals LP, AstraZeneca UK Ltd., Autonomy Bio, Inc., Bayer, Bayer Aktiengesellschaft, Beth Israel Deaconess Medical Center, Better Therapeutics, Boston Clinical Research Institute, LLC, Bristol-Myers Squibb, Cleerly, Inc., Clergy United for the Transformation of Sandtown, Colorado Dept of Public Health and Environment, Congress Inc., Cook Regentec LLC, Eidos Therapeutics, Inc., EluraBio, Inc., Esperion Therapeutics, Inc., Faraday Pharmaceuticals, Inc., Gasherbrum Bio Inc., Insmed, IsomAb Limited, JanOne Biotech Holdings, Inc., Janssen Global Services, Janssen Pharmaceuticals, Inc., Janssen Scientific Affairs LLC, Las Animas and Huerfano Counties, District Health Dept, Lexicon Pharmaceuticals, Inc., Lilly USA, LLC, Medison Pharma, Medpace, Inc., Merck Sharp & Dohme Corp., Nectero Medical, Inc., NewAmsterdam Pharma, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer, Piper Sandler & Co, PPD Development, L.P., Prothena Biosciences Limited, Regeneron, Regents of the University of Colorado (aka UCD), Sanifit Therapeutics S.A., Sanofi, Silence Therapeutics PLC, Stanford University, Stealth BioTherapeutics Inc., The Brigham and Women's Hospital, Thrombosis Research Institute, Tourmaline Bio, Inc., University of Colorado, University of Pittsburgh, VarmX, Verve Therapeutics, WraSer, LLC. Consultant or research support (or both) from Amarin, Lexicon, NewAmsterdam, Novartis, Regeneron, Sanofi, Silence, and Tourmaline. Dr. Michael J. Koren: Employee of a clinical research company supported by grants from multiple manufacturers of lipid and other therapeutics. Dr. Stephen J. Nicholls: Grant/research support from Amgen, Anthera, AstraZeneca, Cerenis, Cyclarity, Eli Lilly, Esperion, InfraReDx, NewAmsterdam Pharma, Novartis, Resverlogix, Roche, Sanofi-Regeneron, The Medicines Company, and LipoScience; and was a consultant for Abcentra, Akcea, Amarin, Anthera, AstraZeneca, Boehringer Ingelheim, CSL Behring, CSL Seqirus, Daiichi Sankyo, Eli Lilly, Esperion, Merck, Omthera, Resverlogix, Sanofi-Regeneron, Scribe, Silence Therapeutics, Takeda, and Vaxxinity. Dr. Deepak L. Bhatt: Advisory Board: Angiowave, Antlia Bioscience, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, E-Star Biotech, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, NirvaMed, Novo Nordisk, Repair Biotechnologies, Stasys, Tourmaline Bio; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); Consultant: Alnylam, Altimmune, Broadview Ventures, Corcept Therapeutics, Corsera, GlaxoSmithKline, Hims, SERB, SFJ, Summa Therapeutics, Worldwide Clinical Trials; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research, Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Duke Clinical Research Institute, Engage Health Media, HMP Global (Editor in Chief, Journal of Invasive Cardiology), Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Philips (Becker's Webinar on AI), Population Health Research Institute, WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor); Progress in Cardiovascular Diseases (Deputy Editor); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Alnylam, Amarin, Amgen, AstraZeneca, Atricure, Bayer, Boehringer Ingelheim, Boston Scientific, CellProthera, Cereno Scientific, Chiesi, Cleerly, CSL Behring, Faraday Pharmaceuticals, Fractyl, Idorsia, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, MiRUS, Moderna, Novartis, Novo Nordisk, Pfizer, PhaseBio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); Site Co-Investigator: Cleerly. Dr. C. David Mazer: Received advisory board honoraria/consulting fees from Amgen, Alexion, AstraZeneca, BioAge, Biotest, Boehringer Ingelheim, Cardior, Cytosorbents, Delex, ONA, PhaseBio, Sandoz, Trimedic Therapeutics, VarmX, and Werfen as well as data safety monitoring board stipends from Beth Israel Deaconess Medical Center, Cerus, and Takeda. Dr. Lawrence A. Leiter: Research support from speaking honoraria and/or acting as an advisor to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, GSK, HLS Therapeutics, Merck, Novartis, Novo Nordisk, and Regeneron as well as a member of a DSMB for CRISPR Therapeutics and vTv Therapeutics. Mr. Adrian Quan, Ms. Randi Elituv, Ms. Meena Verma, Ms. Elizabeth Misner, Dr. Aishwarya Krishnaraj, Dr. Peter Jüni: No conflicts of interest. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.70590. Trial data may be available for academic non-commercial purposes upon execution of a data sharing agreement.