Relationship of Lipoproteins to Cardiovascular Events
Open accessAbstract
Objectives This study sought to examine the relationship between niacin treatment, lipoproteins, and cardiovascular (CV) outcomes in this secondary analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial. Background During a 3-year follow-up in 3,414 patients with established CV disease and low high-density lipoprotein cholesterol (HDL-C) levels, combined niacin + low-density lipoprotein cholesterol (LDL-C)-lowering therapy did not reduce CV events compared with LDL-C-lowering therapy alone. Methods Subjects taking simvastatin and/or ezetimibe were randomized to receive extended-release (ER) niacin 1,500 to 2,000 mg or minimal immediate-release niacin (≤ 150 mg) as placebo at bedtime. LDL-C levels in both groups were maintained from 40 to 80 mg/dl. Hazard ratios were estimated by using Cox proportional hazards models for relationships between lipoproteins and the composite endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom-driven revascularization. Results CV outcomes were not associated with ER niacin in any baseline lipoprotein tertile. In a subset of patients in both the highest triglyceride (≥ 198 mg/dl) and lowest HDL-C (<33 mg/dl) tertiles, ER niacin showed a trend toward benefit (hazard ratio: 0.74, p = 0.073). In-trial LDL-C levels, non-HDL-C levels, and the total cholesterol/HDL-C ratio were positively associated with CV events in the control group, but these relationships were absent in the ER niacin group. Conclusions Baseline lipoprotein tertiles did not predict differential benefit or harm with ER niacin added to LDL-C-lowering therapy, but a small dyslipidemic subgroup may benefit. ER niacin attenuated expected relationships of lipoprotein risk factors with CV events, raising the possibility that nonlipoprotein actions of niacin could affect risk. (Niacin Plus Statin to Prevent Vascular Events [AIM-HIGH]; NCT00120289).
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Subgroup analyses suggested possible benefits to TG lowering in patients with dyslipidemia.
“subgroup analyses suggested possible benefits to TG lowering in patients with dyslipidemia.5, 6”
From Rationale and design of <scp>REDUCE‐IT</scp> : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [5]
The Results section reports a trend toward fewer cardiovascular events with ER niacin in a subgroup with high triglycerides and low HDL-C; the Discussion describes this as possible benefit. The analysis does not establish that triglyceride lowering itself produced the benefit: niacin also raises HDL-C, and the Discussion raises the possibility of nonlipoprotein effects. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRandomized data from large outcome studies across broad populations regarding pharmacological TG lowering and effect on CV outcomes have been mixed.
“However, randomized data from large outcome studies across broad populations regarding pharmacological TG lowering and effect on CV outcomes have been mixed (Table 4).1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24”
From Rationale and design of <scp>REDUCE‐IT</scp> : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [5]
The Introduction (page not provided) reports mixed cardiovascular outcomes across niacin trials: AIM-HIGH and HPS2-THRIVE found no benefit, while earlier trials reported fewer events. The Discussion (page not provided) also notes a possible benefit in a high-triglyceride subgroup and similar findings in fibrate trials. These passages support mixed results for drugs that lower triglycerides, but not the narrower characterization of the evidence as large outcome studies across broad populations specifically testing triglyceride lowering. (LLM, conf=0.83)
Experimental — accuracy not yet measuredAny benefits to TG-lowering therapies may be most pronounced among statin-treated patients in the higher range of TG elevation (≥200 mg/dL), for whom randomized prospectively designed outcome studies have not been previously conducted prior to REDUCE-IT.
“Finally, any benefits to TG‐lowering therapies may be most pronounced among statin‐treated patients in the higher range of TG elevation (ie, ≥200 mg/dL),4, 5, 6 for whom randomized prospectively designed outcome studies have not been previously conducted prior to the REDUCE‐IT study.”
From Rationale and design of <scp>REDUCE‐IT</scp> : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [5]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredSubgroup and post hoc analyses of outcome studies suggest possible reductions in major CV events with TG-lowering therapy.
“Furthermore, TG reduction lowers several inflammatory markers associated with CV risk, and subgroup and post hoc analyses of outcome studies suggest possible reductions in major CV events with TG‐lowering therapy.3, 4, 5, 6, 7, 8, 9, 10, 11”
From Rationale and design of <scp>REDUCE‐IT</scp> : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [5]
The subgroup data from ACCORD Lipid, AIM-HIGH, and JELIS trials further support a prospective study of EPA in a broader patient population with hypertriglyceridemia, as a potential add-on to statin therapy to reduce residual CV risk.
“The subgroup data (Table 5) from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid,6 Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM‐HIGH),5 and JELIS4 trials further support a prospective study of EPA in a broader patient population with hypertriglyceridemia, as exemplified in REDUCE‐IT, as a potent”
From Rationale and design of <scp>REDUCE‐IT</scp> : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [5]
Triglyceride elevation is an independent risk factor for cardiovascular events.
“Clinical and epidemiological studies have demonstrated that triglyceride (TG) elevation is an independent risk factor for increased cardiovascular (CV) events”
From Rationale and design of <scp>REDUCE‐IT</scp> : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [5]
The Results section on lipoprotein variables reports significant prediction of cardiovascular events for LDL-C, non-HDL-C, and TC/HDL-C in the control group, but gives no separate finding that elevated triglycerides independently predict events. The Methods include triglycerides in a multivariable model, and the Results discuss a high-triglyceride/low-HDL subgroup in relation to niacin treatment benefit; neither establishes the claimed independent risk factor. Searched for triglyceride-specific associations and independent risk. (LLM, conf=0.73)
Experimental — accuracy not yet measuredTG reduction lowers several inflammatory markers associated with CV risk.
“Furthermore, TG reduction lowers several inflammatory markers associated with CV risk, and subgroup and post hoc analyses of outcome studies suggest possible reductions in major CV events with TG‐lowering therapy.3, 4, 5, 6, 7, 8, 9, 10, 11”
From Rationale and design of <scp>REDUCE‐IT</scp> : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [5]
The Discussion describes niacin suppressing inflammatory responses in endothelial cells and macrophages, but does not say that triglyceride reduction lowers inflammatory markers associated with cardiovascular risk. Searches for triglyceride reduction and inflammatory markers found no passage establishing that link. The paper separately reports a possible cardiovascular-event benefit in a small dyslipidemic subgroup, which addresses the citing sentence’s other clause, not the quoted claim. (LLM, conf=0.74)
Experimental — accuracy not yet measuredEpidemiological, biological, and genetic studies have provided robust evidence of a strong association between elevated TG levels and higher rates of CV events.
“Epidemiological, biological, and genetic studies have provided robust evidence of a strong association between elevated TG levels and higher rates of CV events.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11”
From Rationale and design of <scp>REDUCE‐IT</scp> : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [5]
The Results (pages unavailable) examine triglycerides alongside other lipoproteins, but report positive associations with cardiovascular events for LDL-C and non-HDL-C, not triglycerides specifically. The reported trend toward benefit from niacin in a high-triglyceride, low-HDL-C subgroup does not establish the claimed association. Searches for triglyceride-related cardiovascular risk and epidemiological or genetic evidence found no passage in our copy stating the claim. (LLM, conf=0.72)
Experimental — accuracy not yet measured
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- Authors
- Guyton, J. R., Slee, A. E., Anderson, T., Fleg, J. L., Goldberg, R. B., Kashyap, M. L., Marcovina, S. M., Nash, S. D., O'Brien, K. D., Weintraub, W. S., Xu, P., Zhao, X.-Q., & Boden, W. E.
- Affiliations
- Duke University (US)
- University of Calgary (CA)
- National Heart, Lung, and Blood Institute (US)
- University of Miami (US)
- University of California, Irvine (US)
- University of Washington (US)
- SUNY Upstate Medical University (US)
- Albany Stratton VA Medical Center Albany (US)
- Corresponding author
- Guyton, John R.
- ORCID
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 62
- Issue
- 17
- Pages
- 1580-1584
- ISSN
- 0735-1097 (ISSN-L)
- PMC
- PMC3862446
- OpenAlex
- W2189339462
- Cited by
- 182
- References
- 23
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 10 · 2023: 6 · 2022: 6 · 2021: 5 · 2020: 15 · 2019: 16 · 2018: 12 · 2017: 15 · 2016: 28 · 2015: 33 · 2014: 22 · 2013: 3
- FWCI
- 26.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (U01-HL-081616, U01-HL-081649)
- Abbott Laboratories
- Merck & Co.
- Regeneron
- Sanofi US
- Genzyme Corporation, Isis Pharmaceuticals
- Amgen
- Amarin
- GlaxoSmithKline
- Merck
- Roche
- Abbott
- AstraZeneca
- Eli Lilly
- Sanofi
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- nicotinic acid, lipoproteins, cardiovascular events, AIM-HIGH trial, extended-release niacin, low HDL cholesterol, triglycerides, LDL-C lowering therapy, simvastatin, ezetimibe, non-HDL cholesterol, TC/HDL-C ratio, cardiovascular risk prediction
- MeSH terms
- Aged, Anticholesteremic Agents, Cardiovascular Diseases, Double-Blind Method, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Lipoproteins, Cholesterol, HDL, Male, Middle Aged, Niacin, Prospective Studies, Triglycerides, Global Health, Biomarkers, Treatment Outcome, Metabolic Syndrome
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