Lipid-Modifying Agents, From Statins to PCSK9 Inhibitors
Open accessAbstract
Mendelian randomization studies and randomized trials have conclusively demonstrated that lower low-density lipoprotein (LDL) cholesterol results in fewer cardiovascular events. This review describes key stages in the evolution of LDL cholesterol-lowering treatment. Data from over 25 cardiovascular outcome trials confirm that, within a few years, statins lower the relative risk of major atherosclerotic events by about 22% per 38.7 mg/dl (1 mmol/l) reduction in LDL cholesterol, with similar benefit across patient subgroups. Meta-analyses of these trials have established the safety of statins with regard to nonvascular mortality and cancer. Other agents available for prescription include ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which both reduce major atherosclerotic events in proportion to their effects on LDL cholesterol and have good safety profiles, though PCSK9 inhibitors remain costly. Investigational LDL cholesterol-lowering agents currently being tested in cardiovascular outcome studies are bempedoic acid, an adenosine triphosphate-citrate lyase inhibitor that reduces cholesterol synthesis, and inclisiran, a double-stranded small interfering ribonucleic acid that inhibits PCSK9 synthesis.
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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 [22]
The Ezetimibe section reports LDL-C reductions of 19% with ezetimibe alone and 23% when added to a statin, within the claimed range. The bempedoic acid passage reports 18% when added to statins, also within the claimed range, but 22% as monotherapy. No passage in our copy supports the claimed ∼36–40% reduction for their combination (searched for the combination and its percentages). Page numbers were not available in the indexed passages. (LLM, conf=0.88)
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- Authors
- Preiss, D., Tobert, J. A., Hovingh, G. K., & Reith, C.
- Affiliations
- University of Oxford (GB)
- Novo Nordisk (Denmark) (DK)
- Corresponding author
- Preiss, David
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2020-04
- Volume
- 75
- Issue
- 16
- Pages
- 1945-1955
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W3016672286
- Cited by
- 75
- References
- 63
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 7 · 2023: 14 · 2022: 11 · 2021: 11 · 2020: 9
- FWCI
- 2.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- BHF Centre of Research Excellence, Oxford
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- lipid-lowering therapy, LDL cholesterol, statins, PCSK9 inhibitors, ezetimibe, bempedoic acid, inclisiran, cardiovascular outcome trials, atherosclerotic cardiovascular disease, cholesterol synthesis inhibition, siRNA, drug safety
- MeSH terms
- Anticholesteremic Agents, Cardiovascular Diseases, Humans, Cholesterol, LDL, Mendelian Randomization Analysis
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