Pharmacological lipid-modification therapies for prevention of ischaemic heart disease: current and future options
Open accessAbstract
Atherosclerosis and its clinical manifestation as ischaemic heart disease remains a considerable health burden. Given that many factors contribute to ischaemic heart disease, a multifactorial approach to prevention is recommended, starting with lifestyle advice, smoking cessation, and control of known cardiovascular risk factors, such as blood pressure and lipids. Within the lipid profile, the principal target is lowering LDL cholesterol, firstly with lifestyle interventions and subsequently with pharmacological therapy. Statins are the recommended first-line pharmacological treatment. Some individuals might require further lowering of LDL cholesterol or be unable to tolerate statins. Additional therapies targeting different pathways in cholesterol metabolism are now available, ranging from small molecules taken orally, to injectable therapies. Examples include ezetimibe, which targets Niemann-Pick C1-like protein, and monoclonal antibodies that target PCSK9. Phase 3 trials have also been completed for bempedoic acid (targeting ATP-citrate lyase) and inclisiran (an interference RNA-based therapeutic targeting hepatic PCSK9 synthesis). In addition to LDL cholesterol, mendelian randomisation studies support a causal role for lipoprotein(a) and triglycerides in ischaemic heart disease. In this Series paper, we appraise currently available and emerging therapies for lowering LDL cholesterol, lipoprotein(a), and triglycerides for prevention of ischaemic heart disease.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Ezetimibe lowers LDL-C by 18-25%, bempedoic acid by 17-21%, and their combination by ∼36-40%.
“This substantially exceeded other oral non-statin therapies, as ezetimibe lowers LDL-C by 18–25%, bempedoic acid by 17–21%, and their combination by ∼36–40% [[21], [22], [23], [24]]”
From Oral PCSK9 inhibitors for elevated LDL-C: A systematic review and meta-analysis of randomized trials (2026) · cites this paper as [21]
Cites
Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease
Sabatine, M. S., Giugliano, R. P., Keech, A. C., Honarpour, N., Wiviott, S. D., Murphy, S. A., Kuder, J. F., Wang, H., Liu, T., Wasserman, S. M., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1615664 · Cited by 6,138 · see citing works
Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes
Cannon, C. P., Blazing, M. A., Giugliano, R. P., McCagg, A., White, J. A., Theroux, P., Darius, H., Lewis, B. S., Ophuis, T. O., Jukema, J. W., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1410489 · Cited by 4,487 · 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
Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome
Schwartz, G. G., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1801174 · Cited by 3,634 · 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
2016 ESC/EAS Guidelines for the Management of Dyslipidaemias
Catapano, A. L., Graham, I., De Backer, G., Wiklund, O., Chapman, M. J., Drexel, H., Hoes, A. W., Jennings, C. S., Landmesser, U., Pedersen, T. R., et al. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehw272 · Cited by 3,162 · see citing works
High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.
Gordon, D. J., Probstfield, J. L., Garrison, R. J., Neaton, J. D., Castelli, W. P., Knoke, J. D., Jacobs, D. R., Bangdiwala, S., & Tyroler, H. A. (1989) · Circulation · doi:10.1161/01.cir.79.1.8 · Cited by 3,162 · see citing works
Effects of torcetrapib in patients at high risk for coronary events
Barter, P. J., Caulfield, M., Eriksson, M., Grundy, S. M., Kastelein, J. J. P., Komajda, M., Lopez-Sendon, J., Mosca, L., Tardif, J.-C., Waters, D. D., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa0706628 · Cited by 3,139 · see citing works
Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy
The AIM-HIGH Investigators (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1107579 · Cited by 2,911 · see citing works
Effects of dalcetrapib in patients with a recent acute coronary syndrome
Schwartz, G. G., Olsson, A. G., Abt, M., Ballantyne, C. M., Barter, P. J., Brumm, J., Chaitman, B. R., Holme, I. M., Kallend, D., Leiter, L. A., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1206797 · Cited by 2,022 · see citing works
Self-citationFifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin
Canner, P. L., Berge, K. G., Wenger, N. K., Stamler, J., Friedman, L., Prineas, R. J., & Friedewald, W. (1986) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(86)80293-5 · Cited by 1,824 · see citing works
Effects of extended-release niacin with laropiprant in high-risk patients
The HPS2-THRIVE Collaborative Group (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1300955 · Cited by 1,668 · see citing works
Genetically Elevated Lipoprotein(a) and Increased Risk of Myocardial Infarction
Kamstrup, P. R. (2009) · JAMA · doi:10.1001/jama.2009.801 · Cited by 1,357 · see citing works
A Test in Context: Lipoprotein(a)
Tsimikas, S. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2016.11.042 · Cited by 1,137 · see citing works
Loss-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
Effects of anacetrapib in patients with atherosclerotic vascular disease
The HPS3/TIMI55–REVEAL Collaborative Group (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1706444 · Cited by 1,047 · see citing works
Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk: Insights From the FOURIER Trial
O’Donoghue, M. L., Fazio, S., Giugliano, R. P., Stroes, E. S. G., Kanevsky, E., Gouni-Berthold, I., Im, K., Lira Pineda, A., Wasserman, S. M., Češka, R., et al. (2019) · Circulation · doi:10.1161/circulationaha.118.037184 · Cited by 984 · see citing works
Marine n−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer
Manson, J. E., Cook, N. R., Lee, I.-M., Christen, W., Bassuk, S. S., Mora, S., Gibson, H., Albert, C. M., Gordon, D., Copeland, T., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1811403 · Cited by 979 · see citing works
Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis
Jun, M., Foote, C., Lv, J., Neal, B., Patel, A., Nicholls, S. J., Grobbee, D. E., Cass, A., Chalmers, J., & Perkovic, V. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60656-3 · Cited by 933 · see citing works
Self-citationSafety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol
Ray, K. K., Bays, H. E., Catapano, A. L., Lalwani, N. D., Bloedon, L. T., Sterling, L. R., Robinson, P. L., & Ballantyne, C. M. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1803917 · Cited by 807 · see citing works
Self-citationViney, N. J., van Capelleveen, J. C., Geary, R. S., Xia, S., Tami, J. A., Yu, R. Z., Marcovina, S. M., Hughes, S. G., Graham, M. J., Crooke, R. M., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)31009-1 · Cited by 754 · see citing works
Ference, 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-citationTriglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies
(2010) · The Lancet · doi:10.1016/s0140-6736(10)60545-4 · Cited by 716 · see citing works
Coding Variation in <i>ANGPTL4,</i> <i>LPL,</i> and <i>SVEP1</i> and the Risk of Coronary Disease
Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1507652 · Cited by 493 · see citing works
Tsimikas, S., Viney, N. J., Hughes, S. G., Singleton, W., Graham, M. J., Baker, B. F., Burkey, J. L., Yang, Q., Marcovina, S. M., Geary, R. S., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(15)61252-1 · Cited by 460 · see citing works
Ballantyne, C. M., Banach, M., Mancini, G. B. J., Lepor, N. E., Hanselman, J. C., Zhao, X., & Leiter, L. A. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.06.002 · Cited by 422 · see citing works
Pradhan, 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
Ray, K. K., Colhoun, H. M., Szarek, M., Baccara-Dinet, M., Bhatt, D. L., Bittner, V. A., Budaj, A. J., Diaz, R., Goodman, S. G., Hanotin, C., et al. (2019) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(19)30158-5 · Cited by 315 · see citing works
Self-citationMabuchi, H., Haba, T., Tatami, R., Miyamoto, S., Sakai, Y., Wakasugi, T., Watanabe, A., Koizumi, J., & Takeda, R. (1981) · New England Journal of Medicine · doi:10.1056/nejm198108273050902 · Cited by 262 · see citing works
Sabatine, M. S., De Ferrari, G. M., Giugliano, R. P., Huber, K., Lewis, B. S., Ferreira, J., Kuder, J. F., Murphy, S. A., Wiviott, S. D., Kurtz, C. E., et al. (2018) · Circulation · doi:10.1161/circulationaha.118.034309 · Cited by 255 · see citing works
Nicholls, 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-citationPuri, R., Nissen, S. E., Shao, M., Elshazly, M. B., Kataoka, Y., Kapadia, S. R., Tuzcu, E. M., & Nicholls, S. J. (2016) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.116.307601 · Cited by 143 · see citing works
Self-citationKosoglou, T., Meyer, I., Veltri, E. P., Statkevich, P., Yang, B., Zhu, Y., Mellars, L., Maxwell, S. E., Patrick, J. E., Cutler, D. L., et al. (2002) · British Journal of Clinical Pharmacology · doi:10.1046/j.1365-2125.2002.01633.x · Cited by 117 · see citing works
Ida, S., Kaneko, R., & Murata, K. (2019) · Cardiovascular Diabetology · doi:10.1186/s12933-019-0845-x · Cited by 61 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol
Ray, K. K., Wright, R. S., Kallend, D., Koenig, W., Leiter, L. A., Raal, F. J., Bisch, J. A., Richardson, T., Jaros, M., Wijngaard, P. L. J., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1912387 · Cited by 1,665 · see citing works
Self-citationSchooling, C., Zhao, J., Au Yeung, S., & Leung, G. (2020) · eLife · doi:10.7554/elife.58567 · Cited by 39 · see citing works
Oral PCSK9 inhibitors for elevated LDL-C: A systematic review and meta-analysis of randomized trials
Karthikeyan, A., Karp, A., Maliha, M., Kharawala, A., Mangalesh, S., Shah, P., Modak, V., Alper, A., Doshi, A., Murli, H., et al. (2026) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2026.101659 · Cited by 2 · see citing works
“…trials [20] This substantially exceeded other oral non-statin therapies, as ezetimibe lowers LDL-C by 18 – 25%, bempedoic acid by 17 – 21%, and their combination by ~36 – 40% [21 – 24] We then examined whether differences in LDL-C response could be explained by variations in calculation methods.”
- Authors
- Ray, K. K., Corral, P., Morales, E., & Nicholls, S. J.
- Affiliations
- Imperial College London (GB)
- Universidad Fraternidad de Agrupaciones Santo Tomás de Aquino (AR)
- Monash University (AU)
- Corresponding author
- Ray, Kausik K
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 394
- Issue
- 10199
- Pages
- 697-708
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2969859411
- Cited by
- 94
- References
- 36
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 11 · 2023: 14 · 2022: 13 · 2021: 21 · 2020: 19
- FWCI
- 2.73
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by-nc-nd)
- Funders
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- National Institutes of Health
- NIHR Imperial Biomedical Research Centre
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- atherosclerosis, LDL cholesterol lowering, statins, ezetimibe, PCSK9 inhibitors, bempedoic acid, inclisiran, lipoprotein(a), triglycerides, cholesterol metabolism, lipid-lowering therapy, Mendelian randomization
- MeSH terms
- Proprotein Convertase 9, Antibodies, Monoclonal, Anticholesteremic Agents, Humans, Lipoproteins, Cholesterol, LDL, Risk Factors, Triglycerides, Myocardial Ischemia, Hydroxymethylglutaryl-CoA Reductase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
