Expanding the triglyceride range in clinical trials: therapeutic opportunities
Open accessAbstract
Background and Aims: Guidelines focus on individuals with triglycerides between 2.3 and 5.6 mmol/L (200 and 499 mg/dL). The hypotheses that triglycerides across the full biological range and within this constrained range associated with cardiovascular risk were re-assessed. Methods: Multivariable-adjusted hazard ratios for major cardiovascular events and death according to baseline triglycerides among 119 573 individuals with triglycerides across the full biological range from the Copenhagen General Population Study, among 27 757 individuals with baseline triglycerides between 2.3 and 5.6 mmol/L from the Copenhagen General Population Study and the Women’s Health Study cohorts, and among 31 272 individuals with mild-to-moderate hypertriglyceridaemia from the PROMINENT, REDUCE-IT, and STRENGTH trials were calculated. Results: Increasing triglycerides across the full range (0.3 to 11.2 mmol/L) were associated with an increasing risk of major cardiovascular events (N = 12 241). In the cohorts, combined hazard ratios [95% confidence interval (triglyceride range in mmol/L)] for major cardiovascular events (N = 3928) from lowest to highest triglyceride quartile were 1.0 [referent (range: < 2.5)], 0.95 [0.87–1.04 (range: 2.5 to <3.0)], 1.04 [0.95–1.13 (range: 3.0 to <3.6)], and 1.13 [1.04–1.23 (range: ≥ 3.6)]. In the three contemporary trials, the corresponding hazard ratios (N = 4265 cardiovascular events) from lowest to highest quartile were 1.0 [referent (ranges for PROMINENT/REDUCE-IT/STRENGTH: < 2.6/2.0/2.2)], 1.01 [0.93–1.10 (ranges: 2.6 to <3.1/2.0 to <2.5/2.2 to <2.7)], 1.05 [0.96–1.14 (ranges: 3.1 to <3.9/2.5 to <3.1/2.7 to < 3.5)] and 1.09 [1.00–1.19 (ranges: ≥ 3.9/3.1/3.5)]. In neither cohorts nor trials were triglycerides across this range strongly associated with risk of cardiovascular or all-cause death. Conclusions: Individuals with mild-to-moderate hypertriglyceridaemia may not express the same magnitude of cardiovascular risk as that observed across the full range of plasma triglycerides. Future triglyceride-lowering therapy trials may want to consider enrolment across a wider range of triglyceride levels if there is no prior history of pancreatitis nor excessive alcohol intake.
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Hypertriglyceridemia is common and is associated with an increased risk of atherosclerosis.
“H ypertriglyceridemia is common and is associated with an increased risk of atherosclerosis, 1-4”
From Targeting <i>APOC3</i> with Olezarsen in Moderate Hypertriglyceridemia (2025) · cites this paper as [4]
Cites
Regression Modeling Strategies
Harrell, F. E. (2001) · Springer series in statistics · doi:10.1007/978-1-4757-3462-1 · Cited by 9,270 · see citing works
Helsinki Heart Study: Primary-Prevention Trial with Gemfibrozil in Middle-Aged Men with Dyslipidemia
Frick, M. H., Elo, O., Haapa, K., Heinonen, O. P., Heinsalmi, P., Helo, P., Huttunen, J. K., Kaitaniemi, P., Koskinen, P., Manninen, V., et al. (1987) · New England Journal of Medicine · doi:10.1056/nejm198711123172001 · Cited by 3,881 · see citing works
Rubins, H. B., Robins, S. J., Collins, D., Fye, C. L., Anderson, J. W., Elam, M. B., Faas, F. H., Linares, E., Schaefer, E. J., Schectman, G., et al. (1999) · New England Journal of Medicine · doi:10.1056/nejm199908053410604 · Cited by 3,439 · see citing works
Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia
Bhatt, D. L., Steg, P. G., Miller, M., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Doyle, R. T., Juliano, R. A., Jiao, L., Granowitz, C., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1812792 · Cited by 3,317 · see citing works
Self-citationEffects of Combination Lipid Therapy in Type 2 Diabetes Mellitus
(2010) · New England Journal of Medicine · doi:10.1056/nejmoa1001282 · Cited by 2,837 · see citing works
Grundy, S. M., Stone, N. J., Bailey, A. L., Beam, C., Birtcher, K. K., Blumenthal, R. S., Braun, L. T., de Ferranti, S., Faiella-Tommasino, J., Forman, D. E., et al. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.11.003 · Cited by 2,691 · see citing works
Nordestgaard, B. G., Benn, M., Schnohr, P., & Tybjærg-Hansen, A. (2007) · JAMA · doi:10.1001/jama.298.3.299 · Cited by 2,058 · see citing works
Self-citationA Randomized Trial of Low-Dose Aspirin in the Primary Prevention of Cardiovascular Disease in Women
Ridker, P. M., Cook, N. R., Lee, I.-M., Gordon, D., Gaziano, J. M., Manson, J. E., Hennekens, C. H., & Buring, J. E. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa050613 · Cited by 1,945 · see citing works
Self-citationAtherogenesis: a postprandial phenomenon.
Zilversmit, D. B. (1979) · Circulation · doi:10.1161/01.cir.60.3.473 · Cited by 1,701 · see citing works
Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women
Bansal, S., Buring, J. E., Rifai, N., Mora, S., Sacks, F. M., & Ridker, P. M. (2007) · JAMA · doi:10.1001/jama.298.3.309 · Cited by 1,619 · see citing works
Self-citationTriglycerides and cardiovascular disease
Nordestgaard, B. G., & Varbo, A. (2014) · The Lancet · doi:10.1016/s0140-6736(14)61177-6 · Cited by 1,419 · see citing works
Self-citationManninen, V, Tenkanen, L., Koskinen, P., Huttunen, J. K., Mänttäri, M., Heinonen, O. P., & Frick, M. H. (1992) · Circulation · doi:10.1161/01.cir.85.1.37 · Cited by 1,329 · see citing works
Nordestgaard, B. G. (2016) · Circulation Research · doi:10.1161/circresaha.115.306249 · Cited by 1,116 · see citing works
Self-citationRemnant Cholesterol as a Causal Risk Factor for Ischemic Heart Disease
Varbo, A., Benn, M., Tybjærg-Hansen, A., Jørgensen, A. B., Frikke-Schmidt, R., & Nordestgaard, B. G. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.08.1026 · Cited by 1,115 · see citing works
Self-citationLoss-of-Function Mutations in <i>APOC3,</i> Triglycerides, and Coronary Disease
The TG and HDL Working Group of the Exome Sequencing Project, N. H. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1307095 · Cited by 1,071 · see citing works
Nicholls, S. J., Lincoff, A. M., Garcia, M., Bash, D., Ballantyne, C. M., Barter, P. J., Davidson, M. H., Kastelein, J. J. P., Koenig, W., McGuire, D. K., et al. (2020) · JAMA · doi:10.1001/jama.2020.22258 · Cited by 1,028 · see citing works
Self-citationGinsberg, H. N., Packard, C. J., Chapman, M. J., Borén, J., Aguilar-Salinas, C. A., Averna, M., Ference, B. A., Gaudet, D., Hegele, R. A., Kersten, S., et al. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab551 · Cited by 979 · see citing works
Self-citationLoss-of-Function Mutations in <i>APOC3</i> and Risk of Ischemic Vascular Disease
Jørgensen, A. B., Frikke-Schmidt, R., Nordestgaard, B. G., & Tybjærg-Hansen, A. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1308027 · Cited by 919 · see citing works
Self-citationRelation of Gemfibrozil Treatment and Lipid Levels With Major Coronary Events
Robins, S. J., Collins, D. E., Wittes, J. T., Papademetriou, V., DEEDWANIA, P. C., Schaefer, E. J., McNamara, J. R., Kashyap, M. L., Hershman, J. M., WEXLER, L. F., et al. (2001) · JAMA · doi:10.1001/jama.285.12.1585 · Cited by 916 · see citing works
Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk
Das Pradhan, A., Glynn, R. J., Fruchart, J.-C., MacFadyen, J. G., Zaharris, E. S., Everett, B. M., Campbell, S. E., Oshima, R., Amarenco, P., Blom, D. J., et al. (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2210645 · Cited by 749 · see citing works
Self-citationFerence, B. A., Kastelein, J. J. P., Ray, K. K., Ginsberg, H. N., Chapman, M. J., Packard, C. J., Laufs, U., Oliver-Williams, C., Wood, A. M., Butterworth, A. S., et al. (2019) · JAMA · doi:10.1001/jama.2018.20045 · Cited by 724 · see citing works
Self-citationEffects of n−3 Fatty Acid Supplements in Diabetes Mellitus
The ASCEND Study Collaborative Group (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1804989 · Cited by 698 · see citing works
Effect of Diabetes on Progression of Coronary Atherosclerosis and Arterial Remodeling
Nicholls, S. J., Tuzcu, E. M., Kalidindi, S., Wolski, K., Moon, K.-W., Sipahi, I., Schoenhagen, P., & Nissen, S. E. (2008) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2008.03.051 · Cited by 349 · see citing works
Self-citationPradhan, A. D., Paynter, N. P., Everett, B. M., Glynn, R. J., Amarenco, P., Elam, M., Ginsberg, H., Hiatt, W. R., Ishibashi, S., Koenig, W., et al. (2018) · American Heart Journal · doi:10.1016/j.ahj.2018.09.011 · Cited by 319 · see citing works
Self-citationBaseline Characteristics of Participants in the Women's Health Study
Rexrode, K. M., Lee, I.-M. M., Cook, N. R., Hennekens, C. H., & Buring, J. E. (2000) · Journal of Women s Health & Gender-Based Medicine · doi:10.1089/152460900318911 · Cited by 307 · see citing works
Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease
Abdelhamid, A. S., Brown, T. J., Brainard, J. S., Biswas, P., Thorpe, G. C., Moore, H. J., Deane, K. H., Summerbell, C. D., Worthington, H. V., Song, F., et al. (2020) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd003177.pub5 · Cited by 295 · see citing works
Nonfasting mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis
Pedersen, S. B., Langsted, A., & Nordestgaard, B. G. (2016) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2016.6875 · Cited by 270 · see citing works
Self-citationNiacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk
Chapman, M. J., Redfern, J. S., McGovern, M. E., & Giral, P. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.01.008 · Cited by 227 · see citing works
Shaikh, M., Wootton, R., Nordestgaard, B. G., Baskerville, P., Lumley, J. S., La Ville, A. E., Quiney, J., & Lewis, B. (1991) · Arteriosclerosis and Thrombosis: A Journal of Vascular Biology · doi:10.1161/01.atv.11.3.569 · Cited by 206 · see citing works
Self-citationBhatt, D. L., Steg, P. G., Brinton, E. A., Jacobson, T. A., Miller, M., Tardif, J., Ketchum, S. B., Doyle, R. T., Murphy, S. A., Soni, P. N., et al. (2017) · Clinical Cardiology · doi:10.1002/clc.22692 · Cited by 183 · see citing works
Self-citationBjörnson, E., Adiels, M., Taskinen, M.-R., Burgess, S., Rawshani, A., Borén, J., & Packard, C. J. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehad337 · Cited by 183 · see citing works
Ridker, P. M., Chasman, D. I., Zee, R. Y. L., Parker, A. N., Rose, L. M., Cook, N. R., Buring, J. E., & for the Women’s Genome Health Study Working Group (2007) · Clinical Chemistry · doi:10.1373/clinchem.2007.099366 · Cited by 169 · see citing works
Self-citationNicholls, S. J., Lincoff, A. M., Bash, D., Ballantyne, C. M., Barter, P. J., Davidson, M. H., Kastelein, J. J. P., Koenig, W., McGuire, D. K., Mozaffarian, D., et al. (2018) · Clinical Cardiology · doi:10.1002/clc.23055 · Cited by 167 · see citing works
Self-citationChange in Body Mass Index Associated With Lowest Mortality in Denmark, 1976-2013
Afzal, S., Tybjærg‐Hansen, A., Jensen, G. B., & Nordestgaard, B. G. (2016) · JAMA · doi:10.1001/jama.2016.4666 · Cited by 153 · see citing works
Self-citationRidker, P. M., Rifai, N., MacFadyen, J., Glynn, R. J., Jiao, L., Steg, P. G., Miller, M., Brinton, E. A., Jacobson, T. A., Tardif, J.-C., et al. (2022) · Circulation · doi:10.1161/circulationaha.122.059410 · Cited by 131 · see citing works
Self-citationBhatt, D. L., Steg, P. G., Miller, M., Brinton, E. A., Jacobson, T. A., Jiao, L., Tardif, J.-C., Gregson, J., Pocock, S. J., & Ballantyne, C. M. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.06.043 · Cited by 97 · see citing works
Self-citationDoi, T., Langsted, A., & Nordestgaard, B. G. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab555 · Cited by 87 · see citing works
Self-citationClinical Trial Design for Triglyceride-Rich Lipoprotein-Lowering Therapies
Malick, W. A., Waksman, O., Do, R., Köenig, W., Pradhan, A. D., Stroes, E. S. G., & Rosenson, R. S. (2023) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2023.02.034 · Cited by 36 · see citing works
Self-citationTang, F., Wang, J., Nicholas, S., Qian, D., & Liu, R. (2021) · Lipids in Health and Disease · doi:10.1186/s12944-021-01449-1 · Cited by 6 · see citing works
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Targeting <i>APOC3</i> with Olezarsen in Moderate Hypertriglyceridemia
Bergmark, B. A., Marston, N. A., Prohaska, T. A., Alexander, V. J., Zimerman, A., Moura, F. A., Kang, Y. M., Weinland, J., Murphy, S. A., Goodrich, E. L., et al. (2025) · New England Journal of Medicine · doi:10.1056/nejmoa2507227 · Cited by 78 · see citing works
Chapman, M. J., Packard, C. J., Björnson, E., Ginsberg, H. N., & Borén, J. (2025) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2025.120529 · Cited by 32 · see citing works
Effect of ANGPTL3 Inhibition With Solbinsiran in Preclinical and Early Human Studies
Ray, K. K., Linnebjerg, H., Michael, L. F., Shen, X. P., Ma, X., Lim, S., Zhen, Y., Dudek, H., Abrams, M., Saxena, U. H., et al. (2025) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2025.03.005 · Cited by 26 · see citing works
Hvid, K., Balling, M., Afzal, S., & Nordestgaard, B. G. (2025) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwaf203 · Cited by 15 · see citing works
Self-citationTargeting Triglycerides: The Rise of Apolipoprotein C3 and Angiopoietin-Like Protein 3 Inhibitors
Mansoor, T., Nambi, V., Parikh, S. S., Misra, A., Ismayl, M., Sullivan, C., Sperling, L. S., Virani, S. S., Rifai, M. A., Koshy, S. K. G., et al. (2025) · American Journal of Cardiovascular Drugs · doi:10.1007/s40256-025-00748-7 · Cited by 4 · see citing works
“Furthermore, it may be beneficial for future TG-lowering trials to include a broader variety of TG levels as mild-to-moderate hypertriglyceridemia may not pose the same level of cardiovascular risk as that seen with TG levels across the full range [81].”
Therapy for mixed dyslipidaemia through ANGPTL3 inhibition
Santos, R. D. (2025) · The Lancet · doi:10.1016/s0140-6736(25)00613-0 · Cited by 4 · see citing works
Self-citationLi, G., He, L., Bai, X., Chen, S., Dai, H., He, G., Yang, Y., Zhang, X., Cui, J., Li, X., et al. (2025) · The Lancet Regional Health - Western Pacific · doi:10.1016/j.lanwpc.2025.101689 · Cited by 3 · see citing works
Watts, G. F., & Chan, D. C. (2025) · European Heart Journal · doi:10.1093/eurheartj/ehae931 · Cited by 4 · see citing works
Santos, R. D., Ray, K. K., Bacquer, D. D., Jennings, C. S., Kotseva, K., Rydén, L., Lip, G. Y. H., Erlund, I., Ganly, S., Vihervaara, T., et al. (2025) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2025.119215 · Cited by 4 · see citing works
Self-citationCrea, F. (2025) · European Heart Journal · doi:10.1093/eurheartj/ehaf271 · Cited by 2 · see citing works
Huai, B., Yao, D., Wang, Y., Zang, J., Huang, Z., Yang, H., Li, W., & Wang, D. (2026) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-025-10724-w · Cited by 2 · see citing works
“Secondary outcomes included cardiovascular death and all-cause death [16].”
Triglyceride reduction after MI and major adverse outcomes in SWEDEHEART—insights for future trials
Schubert, J. R., Hagström, E., Westerbergh, J., Leósdóttir, M., & Ray, K. K. (2026) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwag076 · Cited by 4 · see citing works
Watts, G. F., Scott, R., Sullivan, D., BAKER, J., Clifton, P. M., Hamilton, J., Given, B. D., Melquist, S., Zhou, R., Gaudet, D., et al. (2026) · Nature Medicine · doi:10.1038/s41591-026-04307-8 · Cited by 3 · see citing works
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- Authors
- Nordestgaard, A. T., Pradhan, A. D., Everett, B. M., MacFadyen, J. G., Bhatt, D. L., Visseren, F. L. J., Libby, P., Santos, R. D., Nissen, S. E., Nordestgaard, B. G., & Ridker, P. M.
- Affiliations
- Brigham and Women's Hospital (US)
- Icahn School of Medicine at Mount Sinai (US)
- University Medical Center Utrecht (NL)
- Universidade de São Paulo (BR)
- Cleveland Clinic (US)
- University of Copenhagen (DK)
- Corresponding author
- Ridker, Paul M
- ORCID
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2025-02-14
- Volume
- 46
- Issue
- 19
- Pages
- 1835-1848
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- OpenAlex
- W4407592781
- Cited by
- 20
- References
- 42
- Citations by year
- 2026: 8 · 2025: 12
- FWCI
- 18.70
- Type
- journal article
- Language
- en
- Open access
- green
- dspace.library.uu.nl
- Locations
- European Heart Journal (publishedVersion)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Kowa Research Institute
- AstraZeneca
- Independent Research Fund Denmark (3165-00227B)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- triglycerides, hypertriglyceridemia, cardiovascular risk, major adverse cardiovascular events, cardiovascular mortality, triglyceride-lowering therapy, omega-3 fatty acids, statins, triglyceride-lowering drugs, Copenhagen General Population Study, Women's Health Study, REDUCE-IT trial
- MeSH terms
- Adult, Aged, Cardiovascular Diseases, Clinical Trials as Topic, Female, Humans, Male, Middle Aged, Triglycerides, Hypertriglyceridemia
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