Association of lowering apolipoprotein B with cardiovascular outcomes across various lipid-lowering therapies: systematic review and meta-analysis of trials
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Aims: The effect of therapeutic lowering of apolipoprotein B (apoB) on mortality and major adverse cardiovascular events is uncertain. It is also unclear whether these potential effects vary by different lipid-lowering strategies. Methods: A total of 29 randomized controlled trials were selected using PubMed, Cochrane Library and EMBASE through 2018. We selected trials of therapies which ultimately clear apolipoprotein B particles by upregulating low-density lipoprotein receptor (LDL-R) expression (statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, bile acid sequestrants) or therapies which reduce apolipoprotein B independent of LDL-R (cholesteryl ester transfer protein inhibitor, fibrates, niacin, omega-3 fatty acids) with sample size of ≥1000 patients and follow-up of ≥1 year. The meta-regression and meta-analyses were constructed using a random effects model. Results: In 332,912 patients, meta-regression analyses showed relative risks of 0.95 for all-cause mortality (95% confidence interval 0.92–0.99) and 0.93 (0.88–0.98) for cardiovascular mortality for every 10 mg/dL decrease in apolipoprotein B by all interventions combined. Reduction in all-cause mortality was limited to statins (0.92 (0.86–0.98)). For MACE, the relative risk per 10 mg/dL reduction in apolipoprotein B was 0.93 (0.90–0.97) for all therapies combined, with both statin (0.88 (0.83–0.93)) and non-statin therapies (0.96 (0.94–0.99)). which clear apolipoprotein B by upregulating LDL-R showing significant reductions; whereas interventions which lower apolipoprotein B independent of LDL-R did not demonstrate this effect (1.02 (0.81–1.30)). Conclusion: While both statin and established non-statin therapies (PCSK9 inhibitor and ezetimibe) reduced cardiovascular risk per decrease in apolipoprotein B, interventions which reduce apolipoprotein B independently of LDL-R were not associated with cardiovascular benefit.
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Type 2 diabetes dyslipidemia is marked by elevated triglyceride-rich lipoproteins (VLDL), intermediate-density lipoprotein, and remnant particles, which metabolically lead to low HDL-C and increased small dense LDL-C.
“T2D dyslipidemia is characterized by increased levels of triglyceriderich lipoproteins (VLDL), intermediate-density lipoprotein, and remnant particlesdall apo Becontaining particlesd which metabolically lead to low levels of HDL-C and increased levels of small, dense LDL-C.”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [311]
The Introduction (page unavailable) identifies VLDL and intermediate-density lipoproteins as apoB-containing particles. The Discussion (page unavailable) mentions patients with type 2 diabetes who have high triglycerides and low HDL-C, but it does not establish that this profile characterizes type 2 diabetes generally or that the particles metabolically cause low HDL-C and increased small, dense LDL-C. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMeta-analyses of lipid-lowering trials showed that statins and other therapies which clear apoB-containing lipoproteins by upregulating LDL receptor expression, such as PCSK9 inhibitors, reduce cardiovascular risk proportional to the decrease in apoB concentration observed in these trials.
“Meta-analyses of lipid-lowering trials showed that statins and other therapies which clear apoB-containing lipoproteins by upregulating LDL receptor expression, such as PCSK9 inhibitors, reduce cardiovascular risk proportional to the decrease in apoB concentration observed in these trials [77,78].”
From Quantifying atherogenic lipoproteins for lipid-lowering strategies: Consensus-based recommendations from EAS and EFLM (2020) · cites this paper as [78]
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- Authors
- Khan, S. U., Khan, M. U., Valavoor, S., Khan, M. S., Okunrintemi, V., Mamas, M. A., Leucker, T. M., Blaha, M. J., & Michos, E. D.
- Affiliations
- West Virginia University (US)
- East Carolina University (US)
- Royal Stoke University Hospital (GB)
- Johns Hopkins University (US)
- Corresponding author
- Khan, Safi U
- ORCID
- Venue
- European Journal of Preventive Cardiology
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-09-02
- Volume
- 27
- Issue
- 12
- Pages
- 1255-1268
- ISSN
- 2047-4873 (ISSN-L)
- 2047-4881
- PMC
- PMC7489462
- OpenAlex
- W2972061003
- Cited by
- 67
- References
- 67
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 11 · 2023: 18 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 1
- FWCI
- 0.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Preventive Cardiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Johns Hopkins University
- National Institute of General Medical Sciences (U54GM104942)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- apolipoprotein B, LDL receptor, statins, ezetimibe, PCSK9 inhibitors, bile acid sequestrants, CETP inhibitors, fibrates, nicotinic acid, omega-3 fatty acids, lipid-lowering therapy, major adverse cardiovascular events, all-cause mortality, cardiovascular mortality
- MeSH terms
- Hypolipidemic Agents, Apolipoproteins B, Cardiovascular Diseases, Humans, Prognosis, Risk Factors, Biomarkers
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