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Randomized Controlled Trial
. 2025 Apr 1;48(4):596-604.
doi: 10.2337/dc24-2110.

Risk of Incident Diabetes Related to Lipoprotein(a), LDL Cholesterol, and Their Changes With Alirocumab: Post Hoc Analyses of the ODYSSEY OUTCOMES Randomized Trial

Gregory G Schwartz  1 , Michael Szarek  1   2   3 , J Wouter Jukema  4   5 , Christa M Cobbaert  6 , Esther Reijnders  6 , Vera A Bittner  7 , Markus Schwertfeger  8 , Deepak L Bhatt  9 , Sergio Fazio  10 , Genevieve Garon  11 , Shaun G Goodman  12   13 , Robert A Harrington  14 , Harvey D White  15 , Philippe Gabriel Steg  16
Affiliations
Randomized Controlled Trial

Risk of Incident Diabetes Related to Lipoprotein(a), LDL Cholesterol, and Their Changes With Alirocumab: Post Hoc Analyses of the ODYSSEY OUTCOMES Randomized Trial

Gregory G Schwartz et al. Diabetes Care. .

Abstract

Objective: Previous genetic and clinical analyses have associated lower lipoprotein(a) and LDL cholesterol (LDL-C) with greater risk of new-onset type 2 diabetes (NOD). However, PCSK9 inhibitors such as alirocumab lower both lipoprotein(a) and LDL-C without effect on NOD.

Research design and methods: In a post hoc analysis of the ODYSSEY OUTCOMES trial (NCT01663402), we examined the joint prediction of NOD by baseline lipoprotein(a), LDL-C, and insulin (or HOMA-insulin resistance [HOMA-IR]) and their changes with alirocumab treatment. Analyses included 8,107 patients with recent acute coronary syndrome on optimized statin therapy, without diabetes at baseline, assigned to alirocumab or placebo with median follow-up 2.4 years. Splines were estimated from logistic regression models.

Results: Lower baseline lipoprotein(a) and higher baseline insulin or HOMA-IR independently predicted 782 cases of NOD; baseline LDL-C did not predict NOD. Alirocumab reduced lipoprotein(a) and LDL-C without affecting insulin or NOD risk (odds ratio [OR] vs. placebo 0.998; 95% CI 0.860-1.158). However, in logistic regression, decreased lipoprotein(a) and LDL-C on alirocumab were independent, opposite predictors of NOD. OR for NOD for 25% and 50% lipoprotein(a) reductions on alirocumab were 1.12 (95% CI 1.01-1.23) and 1.24 (1.02-1.52). OR for NOD for 25% and 50% LDL-C reductions on alirocumab were 0.88 (95% CI 0.80-0.97) and 0.77 (0.64-0.94).

Conclusions: Baseline lipoprotein(a) was inversely associated with risk of NOD. Alirocumab-induced reductions of lipoprotein(a) and LDL-C were associated with increased and decreased risk of NOD, respectively, without net effect on NOD. Ongoing trials will determine the impact of larger and longer lipoprotein(a) reductions on NOD.

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Conflict of interest statement

Duality of Interest. G.G.S. reports research grants from the U.S. Department of Veterans Affairs Cooperative Studies Program, research support to the University of Colorado from AstraZeneca, Sanofi, and Silence Therapeutics, and support from the University of Oxford for travel to trial meetings. M.Sz. reports serving as a consultant or receiving research support, or both, from CiVi Biopharma, Resverlogix, Lexicon Pharmaceuticals, Baxter, Esperion, Amarin, NewAmsterdam Pharma, Sanofi, and Regeneron Pharmaceuticals, Inc. J.W.J. reports his department has received research grants from and/or he was a speaker (with or without lecture fees) for Continuing Medical Education accredited meetings sponsored/supported by Abbott, Amarin, Amgen, Athera Healthcare, BIOTRONIK, Boston Scientific, DalCor Pharmaceuticals, Daiichi Sankyo, Edwards Lifesciences, GE HealthCare, Johnson and Johnson, Lilly, Medtronic, Merck & Co., Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Shockwave Medical, the Netherlands Heart Foundation, CardioVascular Research the Netherlands, the Netherlands Heart Institute, and the European Community Framework KP7 Programme. C.M.C. reports research collaboration with Roche Diagnostics. V.A.B. reports grant support from Sanofi, Regeneron Pharmaceuticals, Amgen, AstraZeneca, DalCor Pharmaceuticals, Esperion, and Novartis; consulting fees from Pfizer; honoraria from Medscape; and fees for data safety monitoring boards for the National Institutes of Health and for Verve Therapeutics. M.Sc. is an employee of Roche Diagnostics International Ltd. and may hold shares in the company. D.L.B. discloses the following relationships: Advisory Board for ANGIOWave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; Board of Directors for American Heart Association New York City, ANGIOWave (stock options), Bristol-Myers Squibb (stock), DRSLINQ (stock options), and High Enroll (stock); consultant for Broadview Ventures, GlaxoSmithKline, Hims, SFJ Pharmaceuticals, and Youngene Therapeutics; data monitoring committees for 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, 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; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the NIH-funded MINT Trial); and received honoraria from 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), CSL Behring (AHA lecture), 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), WebMD (CME steering committees), Wiley (steering committee); a relationship with Clinical Cardiology (Deputy Editor); a patent for Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon Pharmaceuticals; neither I nor Brigham and Women's Hospital receive any income from this patent); research funding from Abbott, Acesion Pharma, Afimmune, Aker BioMarine, Alnylam Pharmaceuticals, Amarin, Amgen, AstraZeneca, Bayer, Beren Therapeutics, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor Pharma, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl Health, Garmin, HLS Therapeutics, Idorsia, Ironwood Pharmaceuticals, Ischemix, Janssen, Javelin Biotech, Lexicon Pharmaceuticals, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio Pharmaceuticals, PLx Pharma, Recardio, Regeneron Pharmaceuticals, Reid Hoffman Foundation, Roche, Sanofi, Stasys Medical, Synaptic Medical, The Medicines Company, Youngene, and 89Bio; royalties from Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; Trustee for American College of Cardiology; and unfunded research for FlowCo. S.F. is an employee of Regeneron Pharmaceuticals and may hold shares in the company. G.G. is an employee of Sanofi and may hold shares in the company. S.G.G. reports research grant support (e.g., steering committee or data and safety monitoring committee) or speaker/consulting honoraria (e.g., advisory boards) from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Daiichi Sankyo/American Regent, Eli Lilly, Esperion Therapeutics, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Merck, Novartis, Novo Nordisk, PendoPharm/Pharmascience, Pfizer, Regeneron Pharmaceuticals, Sanofi, Servier, and Valeo Pharma; and salary support/honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) chair, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, PERFUSE Research Institute, and the TIMI Study Group (Brigham Health). R.A.H. reports research grants from the Patient-Centered Outcomes Research Institute, National Institutes of Health, CSL, and Janssen; consulting for Atropos Health, Bitterroot Bio, Bridge Bio, Bristol-Myers Squibb, ForeSight Medical, and Element Science; and serving on the boards of directors for the American Heart Association (unpaid) and Cytokinetics. H.D.W. reports grant support paid to the institution for the ODYSSEY OUTCOMES trial from Sanofi and Regeneron Pharmaceuticals, for the STRENGTH Trial from Omthera Pharmaceuticals, for the HEART-FID Study from American Regent, for the Dal GenE study from DalCor Pharma UK Inc, for the AEGIS II Study from CSL Behring, for the Clear Outcomes Study from Esperion Therapeutics, for the SOLIST-WHF and SCORED studies from Sanofi Aventis Australia Pty Ltd, for the Librexia AF and ACS studies from Janssen, and for ISCHEMIA and the MINT studies from the National Institutes of Health. He also received personal fees as a steering committee member for DalCor Pharma UK, CSL Behring, Sanofi Australia Pty Ltd, Janssen, and Esperion Therapeutics. He was on advisory boards for CSL Behring and Genentech. P.G.S. reports grants, personal fees, and nonfinancial support from Sanofi; grants and personal fees from Amarin, Servier, and Bayer; and personal fees from Amgen, AstraZeneca, BMS Medical, Boehringer Ingelheim, Idorsia, Pfizer, and Novartis. No other potential conflicts of interest relevant to this article were reported.

Figures

None
Graphical abstract
Figure 1
Figure 1
Baseline distributions of biomarkers. Biomarkers include lipoprotein(a) (A), LDL-C (B), insulin (C), glucose (D), and HOMA-IR (E). Data include both treatment groups. Lipoprotein(a), Lp(a).
Figure 2
Figure 2
Distribution of percent change in lipoprotein(a), LDL-C, and insulin in the alirocumab (upper panel) and placebo (lower panel) groups. Black vertical lines indicate median changes. The high proportion of participants with zero percent change of lipoprotein(a) concentration is due to measurements below the lower limit of quantification both at baseline and at month 4. Lipoprotein(a), Lp(a).
Figure 3
Figure 3
Splines for risk of NOD through 4 years after randomization within the alirocumab group as a function of percent change in insulin, lipoprotein(a), and LDL-C between baseline and month 4 measurements (n = 3,877). Each spline had a statistically significant relationship with NOD, with P < 0.0001, P = 0.038, and P = 0.036 for percent change in insulin, lipoprotein(a), and LDL-C, respectively. Solid line indicates predicted probability of NOD, and shaded area indicates 95% CI. Lipoprotein(a), Lp(a).
See this image and copyright information in PMC

References

    1. Gudbjartsson DF, Thorgeirsson G, Sulem P, et al. . Lipoprotein(a) concentration and risks of cardiovascular disease and diabetes. J Am Coll Cardiol 2019;74:2982–2994 - PubMed
    1. Kaya A, Onat A, Yüksel H, et al. . Lipoprotein(a)-activated immunity, insulin resistance and new-onset diabetes. Postgrad Med 2017;129:611–618 - PubMed
    1. Kronenberg F, Mora S, Stroes ESG, et al. . Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J 2022;43:3925–3946 - PMC - PubMed
    1. Langsted A, Nordestgaard BG, Kamstrup PR.. Low lipoprotein(a) levels and risk of disease in a large, contemporary, general population study. Eur Heart J 2021;42:1147–1156 - PubMed
    1. Mora S, Kamstrup PR, Rifai N, et al. . Lipoprotein(a) and risk of type 2 diabetes. Clin Chem 2010;56:1252–1260 - PMC - PubMed

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