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Cited by 61Lipoproteins and Cardiovascular HealthCholesterol and Lipid MetabolismAcute Myocardial Infarction Research

Effects of high-density lipoprotein targeting treatments on cardiovascular outcomes: A systematic review and meta-analysis

Open access
Riaz, Haris, Khan, Safi U, Rahman, Hammad, Shah, Nishant P, Kaluski, Edo, Lincoff, A Michael, Nissen, Steven E·2019·European Journal of Preventive Cardiology
DOI 10.1177/2047487318816495PMC PMC7879587
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Abstract

Background: The effects of increasing high-density lipoprotein cholesterol on cardiovascular outcomes remain uncertain. Design: We conducted a meta-analysis to investigate the effects of high-density lipoprotein cholesterol modifiers (niacin, fibrates and cholesteryl ester transfer protein inhibitors) on cardiovascular outcomes. Methods: Thirty-one randomized controlled trials (154,601 patients) with a follow-up of 6 months or more and a sample size of 100 or more patients were selected using MEDLINE, EMBASE and CENTRAL database (inception January 2018). Results: High-density lipoprotein cholesterol modifiers had no statistically significant effect on cardiovascular mortality in terms of relative risk (RR) (RR 0.94, 95% confidence interval (CI) 0.89–1.00, P = 0.05, I 2 = 13%) or absolute risk (risk difference −0.0001, 95% CI −0.0014, 0.0011, P = 0.84, I 2 = 28%). High-density lipoprotein cholesterol modifiers reduced the RR of myocardial infarction (RR 0.87, 95% CI 0.82–0.93, P < 0.001, I 2 = 37%). This significant effect was derived by the use of fibrates (RR 0.80, 95% CI 0.73–0.87, P < 0.001, I 2 = 22%) and meta-regression analysis showed that this benefit was consistent with an absolute reduction in low-density lipoprotein cholesterol. High-density lipoprotein cholesterol modifiers had no effect on stroke (RR 1.00, 95% CI 0.93–1.09, P = 0.94, I 2 = 25%) or all-cause mortality (RR 1.02, 95% CI 0.97–1.08, P = 0.48, I 2 = 49%). Meta-regression analyses failed to demonstrate a significant association of pharmacologically increased high-density lipoprotein cholesterol with key endpoints. In studies with background statin therapy, high-density lipoprotein cholesterol modifiers had no statistically significant impact on cardiovascular mortality, myocardial infarction, stroke or all-cause mortality ( P > 0.05). Conclusion: The use of high-density lipoprotein cholesterol modifying treatments had no significant effect on cardiovascular mortality, stroke or all-cause mortality. The beneficial effect on myocardial infarction was lost when drugs were used with statin therapy.

AI snapshot

Written from the paper’s full text.

TL;DR

In a meta-analysis of 31 randomized controlled trials and 154,601 patients, HDL cholesterol-modifying drugs did not significantly reduce cardiovascular mortality, stroke, or all-cause mortality. A modest reduction in myocardial infarction was seen with fibrates, but this benefit was linked to LDL cholesterol lowering and disappeared in trials with background statin therapy.

Key findings

  • HDL cholesterol modifiers had no statistically significant effect on cardiovascular mortality (RR 0.94, 95% CI 0.89–1.00, P = 0.05, I² = 13%) or all-cause mortality (RR 1.02, 95% CI 0.97–1.08, P = 0.48, I² = 49%).
  • They reduced myocardial infarction overall (RR 0.87, 95% CI 0.82–0.93, P < 0.001, I² = 37%), with the effect derived from fibrates (RR 0.80, 95% CI 0.73–0.87, P < 0.001, I² = 22%); absolute risk reduction was four MIs per 1000 patients (RD −0.004, 95% CI −0.006, −0.001, P = 0.02, I² = 52%).
  • Stroke was unaffected (RR 1.00, 95% CI 0.93–1.09, P = 0.94, I² = 25%). Meta-regression found no significant association between pharmacologically increased HDL cholesterol and key endpoints; the MI benefit with fibrates was consistent with LDL cholesterol reduction.
  • In trials without background statin therapy, HDL cholesterol modifiers reduced cardiovascular mortality (RR 0.88, 95% CI 0.79–0.98, P = 0.02, I² = 31%) and MI (RR 0.78, 95% CI 0.71–0.85, P < 0.001, I² = 9%); in trials with background statin therapy, effects on cardiovascular mortality, MI, stroke, and all-cause mortality were not statistically significant (P > 0.05).

Methods

  • Systematic review and meta-analysis of randomized controlled trials comparing HDL cholesterol-targeting treatments (niacin, fibrates, CETP inhibitors) with control; inclusion required follow-up ≥6 months, sample size ≥100, and reporting of at least one clinical event.
  • Searched MEDLINE, EMBASE, and CENTRAL from inception to 15 January 2018; 31 RCTs (154,601 patients) were included, with mean age 58.4 ± 6.7 years, 78% men, mean baseline HDL cholesterol 42.7 ± 4.9 mg/dL, and mean follow-up 3.2 ± 1.6 years.
  • Outcomes were pooled using DerSimonian and Laird random-effects models; dichotomous outcomes reported as risk ratio and risk difference, continuous variables as mean difference, with heterogeneity assessed by Cochrane Q and I², publication bias by funnel plot and Egger’s test, and subgroup/meta-regression analyses for background statin therapy and lipid changes.

Limitations

  • The paper states that this was a pooled analysis of individual trials without access to individual patient data, that endpoint definitions and adjudication may have varied across trials, and that background therapies varied over time, especially with newer CETP inhibitor trials almost uniformly using background statin therapy.
  • Evident from the text: lipid-parameter analyses showed very high heterogeneity (e.g., I² = 98% for HDL cholesterol and LDL cholesterol changes), and the meta-regression analyses are trial-level and cannot establish causality.
  • The paper also notes that observational data on surrogate endpoints should be considered hypothesis-generating only, and that treatment benefit requires large, adequately powered outcome trials.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1177/2047487318816495

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 5 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    There was a significant interaction between drug class and the effect of LDL cholesterol reduction on MI (Pinteraction=0.01).

    “In the case of niacin (RR 0.58, 95% CI 0.32–1.1, P = 0.06, R2 = 97%) and CETP inhibitors (RR 0.49, 95% CI 0.10–2.63, P = 0.34, R2 = 5%) no significant benefit per unit decrease in LDL cholesterol was observed (Pinteraction = 0.01) (Figure 3).”
    Quote in the paperSubstantial claim
  • Findingown data

    CETP inhibitors had no significant effect on myocardial infarction.

    “neither CTEP inhibitors nor niacin had significant effects on MI.”
    Quote in the paperSubstantial claim
  • Findingown data

    CETP inhibitors reduced triglycerides (MD −8.72, 95% CI −11.12, −6.32, P<0.001, I2=44%).

    “HDL cholesterol modifiers were associated with a significant reduction in triglycerides (mg/dL) (MD −10.94, 95% CI −13.25, −8.62, P < 0.001, I2 = 79%), with maximum reduction provided by fibrates (MD −44.50, 95% CI −54.73, −34.26, P < 0.001, I2 = 40%), followed by niacin (MD −31.41, 95% CI, −49.38, −13.44, P < 0.001, I2 = 80%) and CETP inhibitors (MD −8.72, 95% CI, −11.12, −6.32, P < 0.001, I2 = 4”
    Quote in the paperNot a substantial claim
  • Findingown data

    Fibrates provided the maximum reduction in triglycerides (MD −44.50, 95% CI −54.73, −34.26, P<0.001, I2=40%).

    “HDL cholesterol modifiers were associated with a significant reduction in triglycerides (mg/dL) (MD −10.94, 95% CI −13.25, −8.62, P < 0.001, I2 = 79%), with maximum reduction provided by fibrates (MD −44.50, 95% CI −54.73, −34.26, P < 0.001, I2 = 40%), followed by niacin (MD −31.41, 95% CI, −49.38, −13.44, P < 0.001, I2 = 80%) and CETP inhibitors (MD −8.72, 95% CI, −11.12, −6.32, P < 0.001, I2 = 4”
    Quote in the paperNot a substantial claim
  • Findingown data

    Meta-regression did not show a significant association between the risk of stroke and absolute change in HDL cholesterol (slope 0.002, P=0.97; R2=0).

    “Meta regression analysis did not show a significant association between the risk of stroke and absolute change in HDL cholesterol (slop: 0.002, P = 0.97; R2 = 0, Supplementary Figure 4).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 4
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Findingnone given

    In the included trials, the new studies on CETP inhibition almost uniformly had background statin therapy, whereas background statin therapy was inconsistent in older studies of fibrates and niacin.

    “The new studies on CETP inhibition almost uniformly have background statin therapy, whereas such therapy was inconsistent with the older studies of fibrates and niacin.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Data abstraction was done by two authors independently on a prespecified data collection form.

    “The data abstraction was done by two authors (SUK and HR) independently on a prespecified data collection form.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Two authors independently screened studies based on prespecified inclusion criteria.

    “Two authors (SUK and HR) independently screened studies based on prespecified inclusion criteria.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Meta-regression analyses confirmed that the observed MI benefit by fibrates was due to LDL cholesterol reduction and there is a lack of association between HDL cholesterol and a reduction in the outcomes of interest.

    “Meta-regression analyses confirmed that the observed MI benefit by fibrates was due to LDL cholesterol reduction and there is a lack of association between HDL cholesterol and a reduction in the outcomes of interest.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The meta-analysis was performed and reported in accordance with Cochrane collaboration guidelines and PRISMA guidelines.

    “This meta-analysis was performed and reported in accordance with Cochrane collaboration guidelines8 and preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.9”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Higgins JPT and Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [ updated March 2011]. The Cochrane Collaboration, 2011 Available at http://handbook.cochrane.org.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [9] Moher D, Liberati A, Tetzlaff J, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ (Clinical Research ed) 2009; 339: b2535. PMC2714657 19622551 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The apparent clinical benefits of these therapies are driven by the studies of the pre-statin era, and the use of effective statins as background therapy had nullified the influence of HDL-raising therapies.

    “The apparent clinical benefits of these therapies are driven by the studies of the pre-statin era, and the use of effective statins as background therapy had nullified the influence of HDL-raising therapies.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The quality of the trials was assessed using the Cochrane bias risk assessment tool.

    “The quality of the trials was assessed using the Cochrane bias risk assessment tool14 (Supplementary Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Higgins JPT, Altman DG, Gøtzsche PC, The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ (Clinical Research ed) 2011; 343: d5928. PMC3196245 22008217 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Publication bias was assessed using funnel plot and Egger's regression test.

    “Publication bias was assessed using funnel plot and Egger’s regression test.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Egger M, Davey Smith G, Schneider M, Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical Research ed) 1997; 315: 629– 634. PMC2127453 9310563 source

      Not checked in the free run.

8 of 8

  • The paper relies on this without support.

    The endpoint definitions used in the individual trials are sufficiently comparable to be pooled in the meta-analysis.

    “The definitions of the endpoints were taken as reported in the individual trial.”
    “We relied on the endpoint definitions of the individual studies and the possibility of heterogeneity in the outcome definitions cannot be excluded.”

  • The paper relies on this without support.

    Trial-level aggregate data are sufficient to estimate the effects of HDL cholesterol modifiers on cardiovascular outcomes.

    “The major limitations of this analysis are that this is a pooled analysis of individual trials as we did not have access to the individual patient data.”
2 of 2

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?

  • Mendelian randomization studies have provided accumulating evidence against the observational results that high levels of HDL-C are protective against CHD risk.

    “MR studies have provided accumulating evidence against the observational results above.136–140”

    From Mendelian randomization (2022) · cites this paper as [140]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Overall LDL cholesterol estimate is not centered in its confidence interval

    Minor

    For a mean difference, the reported 95% confidence interval has a midpoint of −10.805 mg/dL, not the stated estimate of −10.58 mg/dL. The gap is larger than rounding to two decimal places can explain.

    Reported -10.58 · recomputed -10.805

1 of 1

The citation lists haven’t been fetched yet

References 47 · Cited by 61

Authors
Riaz, H., Khan, S. U., Rahman, H., Shah, N. P., Kaluski, E., Lincoff, A. M., & Nissen, S. E.
Affiliations
  • Cleveland Clinic (US)
  • West Virginia University (US)
  • Guthrie Robert Packer Hospital (US)
Corresponding author
Riaz, Haris
ORCID
Venue
European Journal of Preventive Cardiology
Publisher
Oxford University Press (OUP)
Published
2018-12-06
Volume
26
Issue
5
Pages
533-543
ISSN
  • 2047-4873 (ISSN-L)
  • 2047-4881
DOI
10.1177/2047487318816495
PMC
PMC7879587
OpenAlex
W2905047802
Semantic Scholar
0ecc7f169160115b0a056e3dccf0e0517e660930
Cited by
61
References
47
Citations by year
2026: 4 · 2025: 4 · 2024: 8 · 2023: 12 · 2022: 10 · 2021: 10 · 2020: 10 · 2019: 3
FWCI
1.28
Type
journal article
Language
en
Open access
Licence
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations
  • European Journal of Preventive Cardiology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
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 › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
Keywords
HDL cholesterol, nicotinic acid, fibrates, cholesteryl ester transfer protein inhibitors, cardiovascular outcomes, cardiovascular mortality, myocardial infarction, stroke, all-cause mortality, statin therapy
MeSH terms
Adult, Aged, Hypolipidemic Agents, Cardiovascular Diseases, Female, Humans, Cholesterol, HDL, Male, Middle Aged, Niacin, Risk Factors, Biomarkers, Up-Regulation, Randomized Controlled Trials as Topic, Treatment Outcome, Risk Assessment, Dyslipidemias, Cholesterol Ester Transfer Proteins

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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.

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Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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