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Multicenter Study

Global Variation in Lipoprotein(a) Levels Among Patients With Coronary Heart Disease: Insights From the INTERASPIRE Study and Implications for Emerging Lp(a)-Lowering Therapies

Fotios Barkas et al. J Am Coll Cardiol. .

Abstract

Background: Lipoprotein(a) [Lp(a)] is a common risk factor for atherosclerotic cardiovascular disease, potentially more atherogenic per particle than low-density lipoprotein. An estimated 1.5 billion individuals globally have elevated levels ≥125 nmol/L, considered as a risk-enhancing threshold. Although Lp(a) levels vary by ethnicity, ongoing trials of novel therapies in predominantly secondary prevention patients use fixed Lp(a) enrollment thresholds.

Objectives: The purpose of this study was to assess Lp(a) levels in coronary heart disease (CHD) patients across geographical regions, providing inference on the proportions potentially eligible for future Lp(a)-lowering therapies and whether these vary by region and country.

Methods: INTERASPIRE (International Action on Secondary Prevention through Intervention to Reduce Events)enrolled adults hospitalized with CHD in the previous 6 to 24 months. Lp(a) levels were available in 13 countries across 6 World Health Organization (WHO) regions: Africa (Kenya, Nigeria, Tanzania), Americas (Argentina, Colombia), Eastern Mediterranean (UAE), Europe (Poland, Portugal), South-East Asia (Indonesia), and Western Pacific (China, Malaysia, Philippines, Singapore). Lp(a) measurements were performed once and centrally in Helsinki using an isoform-independent assay for 11 countries, and locally in Indonesia and China with standardization to the core laboratory. Lp(a) levels are reported as median (Q1-Q3) and proportions above different thresholds.

Results: Lp(a) results were available for 3,928 patients from 13 countries (mean age: 60.2 ± 10.2 years; 21.1% women). Median Lp(a) was 32 nmol/L (Q1-Q3: 11-89 nmol/L) overall, with 17.6% having levels ≥125 nmol/L. Median levels varied by region-highest in Africa (62 nmol/L) and lowest in Western Pacific (22 nmol/L)-and also between countries within regions: Europe (Portugal: 59 nmol/L vs Poland: 19.5 nmol/L), South America (Colombia: 46 nmol/L vs Argentina: 32 nmol/L) and Western Pacific (Malaysia: 39.5 nmol/L vs Philippines: 14 nmol/L). Overall, the proportions of patients with Lp(a) ≥150, 175, and 200 nmol/L (hence eligibility for future Lp(a)-lowering therapies) were 13.0%, 9.3%, and 6.2%, respectively, with eligibility also varying among countries: highest in Portugal (25.5%, 18.3%, and 11.6%) and lowest in Philippines (4.3%, 2.5%, and 1.3%).

Conclusions: The vast majority of patients with CHD have Lp(a) levels far below what is considered a typical risk-enhancing threshold, suggesting that the attributable risk from Lp(a) is more complex than previously perceived. Furthermore, wide geographical variations in Lp(a) levels above entry criteria for ongoing trials could impact equitable access to therapies, if these trials are positive.

Keywords: apolipoprotein B; atherosclerotic cardiovascular disease; cardiovascular risk; cholesterol; coronary heart disease; lipoprotein (a).

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Conflict of interest statement

Funding Support and Author Disclosures The INTERASPIRE survey was supported through investigator-initiated research grants to the European Society of Cardiology from Pfizer; to the National Institute for Prevention and Cardiovascular Health from Abbott, Novartis, Pfizer, Sanofi, and Viatris; and also from the International Atherosclerosis Society (through a grant from Amarin) and the European Atherosclerosis Society. The sponsors of the INTERASPIRE surveys had no role in the design, data collection, data analysis, data interpretation, decision to publish, or writing of the manuscript. Dr Barkas has received research grants from Amgen, Boehringer Ingelheim, Eli Lilly, Novartis, and Novo Nordisk; and has received honoraria from Menarini Hellas, Novartis, Novo Nordisk, Sanofi, and Viatris. Dr Brandts has received research grants from Amgen, AstraZeneca, and Sanofi; and has received speaker honoraria from Amgen, Daiichi-Sankyo, Novartis, Novo Nordisk, and Sanofi. Dr Ryden has received research grants from Boehringer Ingelheim, Swedish Heart and Lung Foundation, Erling Persson Foundation, and Novo Nordisk; and has received honoraria from Bayer, Boehringer Ingelheim, and Novo Nordisk. Dr Lip is a consultant/speaker for Bristol Myers Squibb/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Anthos, without personal remuneration. Dr Santos has received honoraria related to consulting, research, and/or speaker activities from Amryt, Amgen, Daiichi-Sankyo, Esperion, Eli Lilly, Kowa, Libbs, Novo Nordisk, Novartis, Torrent, PTC Therapeutics, and Sanofi/Regeneron. Dr Libby is an unpaid consultant to or involved in clinical trials for Amgen, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Novo Nordisk, Novartis, and Sanofi-Regeneron; is a member of the scientific advisory board for Amgen, Caristo Diagnostics, CSL Behring, Elucid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Novartis, PlaqueTec, Polygon Therapeutics, TenSixteen Bio, Soley Thereapeutics, and XBiotech; his laboratory has received research funding in the last 2 years from Novartis, Novo Nordisk, and Genentech; is on the Board of Directors of XBiotech; and has a financial interest in Xbiotech, a company developing therapeutic human antibodies, in TenSixteen Bio, a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential (CHIP) to discover and develop novel therapeutics to treat age-related diseases, and in Soley Therapeutics, a biotechnology company that is combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics; his interests were reviewed and are managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. Dr Abreu has received a grant from SPC for laboratory testing for this study in Portugal; and has received honoraria from Ferrer and Daiichi-Sankyo. Dr Tan has received research and educational grants from Medtronic, Amgen, AstraZeneca, Roche Edwards, Abbott Vascular and Menarini; has received consulting fees from J and J and Medtronic; has received honoraria from AstraZeneca, Amgen, Medtronic, Abbott Vascular, Biosensors, Boehringer Ingelheim, and Novartis; has participated on a Data Safety Monitoring Board or Advisory Board of Novartis and Medtronic; and is a Board Member of Singapore Heart Foundation, Asian Pacific Society of Singapore, Singapore Cardiac Society, and World Heart Federation. Dr Wood has received research grants from the European Atherosclerosis Society, European Society of Cardiology, International Atherosclerosis Society, Novartis, Pfizer, Sanofi, and Viatris to the National Institute for Prevention and Cardiovascular Health. Dr Ray has received unrestricted research grants (last 3 years) to Imperial College London, Amgen, Sanofi, Regeneron, Daiichi-Sankyo, and Ultragenix; has received consulting fees from Novartis, Daiichi-Sankyo, Kowa, Esperion, Novo Nordisk, Merck Sharp & Dohme, Lilly, Silence Therapeutics, AZ, New Amsterdam Pharma, Bayer, Beren Therapeutics, CLEERLY, EMENDOBIO, SCRIBE, CRISPR, VAXXINITY, Amarin, Regeneron, Ultragenix, Cargene, and Resverlogix for serving as a member of the SC or EC of clinical trials and roles as PI, NLI, attending advisory boards, providing advice on data its interpretation, and future lines of research; has received lecture fees from Novartis, Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Viatris, Amarin, Biologix Pharma, Sanofi, Amgen, Esperion, Daiichi-Sankyo, and Macleod Pharma for CME and non-CME symposia at international meetings; has stock options from New Amsterdam Pharma and PEMI31; serves as President of the European Atherosclerosis Society (unpaid); and has received support from the Imperial NIHR Biomedical Research Centre. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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