Potential for residual cardiovascular risk reduction: Eligibility for icosapent ethyl in the <scp>VERTIS CV</scp> population with type 2 diabetes and atherosclerotic cardiovascular disease

Cardiovascular (CV) disease is the leading cause of morbidity and mortality for people with type 2 diabetes (T2D).1, 2 Accordingly, CV risk reduction is a key component of the standard of care for T2D, with professional society treatment recommendations endorsing a multifactorial approach that simultaneously targets individual atherosclerotic CV disease (ASCVD) risk factors.1, 3 These risk factors include obesity, physical inactivity, smoking, hypertension, hyperglycaemia, insulin resistance/hyperinsulinaemia and dyslipidaemia.1, 3, 4 With regards to lipids, statins are the mainstay for ASCVD risk reduction for people with T2D, but even when low-density lipoprotein cholesterol (LDL-C) levels are controlled, residual ASCVD risk remains.5, 6 Results from the REDUCE-IT trial demonstrated that icosapent ethyl (IPE) decreased the risk of ischaemic events, including CV death, in a population with established ASCVD or with diabetes plus other ASCVD risk factors, whose LDL-C levels on statin treatment were 41-100 mg/dl with elevated fasting triglyceride (TG) levels (135-499 mg/dl).7 The prevalence of these criteria in populations with T2D and ASCVD is not well documented. We conducted post hoc analyses to explore eligibility for IPE therapy, according to the REDUCE-IT criteria, in a clinical trial population with T2D and ASCVD. The present post hoc analyses were based on data from the VERTIS CV trial (NCT01986881). During VERTIS CV, participants with T2D and established ASCVD were enrolled across 34 countries.8 Full eligibility criteria for VERTIS CV were reported previously, including a requirement for the dose of any lipid-modifying medication to be stable for at least 4 weeks, and the exclusion of participants with fasting TG >600 mg/dl at screening.8 Eligibility for IPE therapy in the VERTIS CV population at baseline was assessed according to the REDUCE-IT trial inclusion criteria (receiving statin therapy, fasting TG 135-499 mg/dl and LDL-C 41-100 mg/dl).7 The characteristics of four subgroups were evaluated based on fasting lipid levels at baseline: (a) TG <135 mg/dl and LDL-C <70 mg/dl; (b) TG <135 mg/dl and LDL-C ≥70 mg/dl; (c) TG ≥135 mg/dl and LDL-C <70 mg/dl; and (d) TG ≥135 mg/dl and LDL-C ≥70 mg/dl, the LDL-C threshold being in widespread clinical use.1 These analyses were irrespective of treatment allocation (ertugliflozin or placebo) in VERTIS CV. The VERTIS CV trial population (n = 8246) had a mean age of 64.4 years, duration of T2D 13.0 years, and glycated haemoglobin 8.2%.8 Among 8208 participants (99.5%) with a fasting baseline TG measurement, median TG was 153.0 mg/dl (Q1-Q3: 111-216 mg/dl) and 4960 (60.4%) had TG ≥135 mg/dl. Among 8105 participants (98.3%) with a fasting baseline LDL-C measurement, median LDL-C was 82.0 mg/dl (Q1-Q3: 61-110 mg/dl) and 5294 (65.3%) had LDL-C ≥70 mg/dl (see Table S1 for further data). Across the four subgroups based on baseline TG and LDL-C thresholds there were few notable differences in demographic and clinical characteristics (Table 1). Most participants were receiving antihypertensive medication and/or antiplatelet or anticoagulant therapies (Table S1). Lipid-modifying medication was used by 84.5% of participants, which was a statin in most cases (81.8%), with small numbers of participants taking ezetimibe (3.6%), fibrate (8.1%), niacin (1.0%), or omega 3 fish oil (4.7%); eight participants (0.1%) were receiving IPE (Table S1). The REDUCE-IT trial inclusion criteria were met by 29.6% of the overall VERTIS CV population at baseline, with a further 30.3% not meeting the full REDUCE-IT criteria but having baseline TG >135 mg/dl (Figure 1). Results from these post hoc analyses of baseline data from the VERTIS CV trial found considerable potential for residual CV risk reduction in this clinical trial population with T2D and ASCVD who were already receiving standard of care. These data show that 29.6% of participants in VERTIS CV would be eligible for IPE therapy based on the REDUCE-IT trial inclusion criteria. At the time of randomization, which spanned December 2013 to April 2017,8 0.1% of participants in the VERTIS CV population were receiving IPE at baseline. The REDUCE-IT trial,7 with primary results published in 2019, found a reduction in CV events when IPE was added to statins in those with or without diabetes at baseline. The prespecified REDUCE-IT DIABETES analyses found a large absolute risk reduction in the first CV events and a large reduction in total CV events with IPE in the subgroup with diabetes.9 Consequently, treatment guidelines were updated to include the addition of IPE where indicated.1, 3 In the present analyses, an additional 30.3% of participants in VERTIS CV had TG >135 mg/dl without meeting the REDUCE-IT trial's criteria with respect to statin use and/or LDL-C level, suggesting further potential for lipid management in this population. In addition, we found that 18.2% of participants in VERTIS CV were not receiving statin therapy at baseline. Suboptimal use of statins has been reported elsewhere.10 Furthermore, 65.3% of participants had LDL-C ≥70 mg/dl when measured at baseline in VERTIS CV, suggesting that in the majority of the population, LDL-C management could be improved. While the addition of non-statin agents (such as ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitor) to statins may be considered to further reduce LDL-C,1, 3 the baseline data from VERTIS CV suggest that only a minority of participants were prescribed combination lipid-modifying therapy. While the REDUCE-IT trial eligibility criteria included elevated TG,7 informing the cut off for the current post hoc analyses, it should be noted that this is a means to identify risk and the benefit of IPE may not directly relate to the amount of TG lowering. With regards to other TG-lowering agents, the effect of fibrates on CV events is unclear1, 3 and research is ongoing for other promising agents (such as angiopoietin-like protein 3 inhibitors). In conclusion, based on baseline lipid profiles and treatment observed in the contemporary VERTIS CV trial, and in the context of guideline recommendations based on the REDUCE-IT trial results, these data highlight the need to scrutinize, and potentially intensify, lipid therapies in more than half of people with T2D and ASCVD. All authors contributed to the acquisition, analysis, or interpretation of data, and had full access to all of the data. All authors contributed to drafting the manuscript and revising it critically for important intellectual content. All authors approved the final version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Editorial support was provided by Kim Russell, PhD, of Engage Scientific Solutions (Horsham, UK) and was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Pfizer Inc., New York, NY, USA. Some of these data were presented at the American Diabetes Association (ADA), 82nd Scientific Sessions, June 3-7 March 2022, New Orleans, LA, USA. This analysis was sponsored by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Pfizer Inc., New York, NY, USA. JMK reports non-financial compensation: Pfizer. DLB discloses the following relationships - Advisory Board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences and Stasys; Board of Directors: AngioWave (stock options), Boston VA Research Institute, Bristol-Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care and TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis and 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 (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; 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), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees) and Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), and VA CART Research and Publications Committee (Chair); 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, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene and 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte and Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda. SD-J has led clinical trials for AstraZeneca, Boehringer Ingelheim and Novo Nordisk, Inc.; has received consulting fees from AstraZeneca, Boehringer Ingelheim, Janssen, Merck & Co. Inc. and Sanofi; and has equity interests in Jana Care, Inc. and Aerami Therapeutics. DZIC has received consulting fees and/or speaking honorarium from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, AbbVie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL Behring, Otsuka, Novartis, Youngene, Lexicon, and Novo Nordisk and has received operational funding for clinical trials from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL Behring and Novo Nordisk. FC has received research grants from Swedish Research Council, Swedish Heart & Lung Foundation, and King Gustav V and Queen Victoria Foundation; as well as fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, Novo Nordisk, Boehringer Ingelheim, and Pfizer. DKM has received consulting fees from Afimmune, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, CSL Behring, Esperion, Lexicon, Lilly USA, Merck Sharp & Dohme, Metavant, Novo Nordisk, Pfizer Inc., GlaxoSmithKline and Sanofi US; and has received payment for expert testimony from Kirkland & Ellis on behalf of Boehringer Ingelheim. REP has received fees (directed to his institution) from AstraZeneca, Glytec, LLC, Hanmi Pharmaceutical Co., Ltd, Janssen, Lexicon Pharmaceuticals, Inc., Merck & Co. Inc., Mundipharma, Novo Nordisk, Pfizer, Poxel SA, Sanofi, Sanofi US Services, Inc., Scohia Pharma Inc. and Sun Pharmaceutical Industries. C-CL is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. NBC, RF, and JPM are employees and shareholders of Pfizer Inc. CPC has received research grants from Amgen, Better Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Merck, Novo Nordisk and Pfizer; fees from Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Lexicon, Merck, Pfizer, Rhoshan and Sanofi; as well as serving on Data and Safety Monitoring Boards for the Veteran's Administration, Applied Therapeutics and Novo Nordisk. Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information. TABLE S1. CV medication use and fasting lipids at baseline. 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