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Association Between Baseline LDL-C Level and Total and Cardiovascular Mortality After LDL-C Lowering: A Systematic Review and Meta-analysis
Open accessAbstract
Importance: Effects on specific fatal and nonfatal end points appear to vary for low-density lipoprotein cholesterol (LDL-C)-lowering drug trials. Objective: To evaluate whether baseline LDL-C level is associated with total and cardiovascular mortality risk reductions. Data Sourcesand Study Selection: Electronic databases (Cochrane, MEDLINE, EMBASE, TCTMD, ClinicalTrials.gov, major congress proceedings) were searched through February 2, 2018, to identify randomized clinical trials of statins, ezetimibe, and PCSK9-inhibiting monoclonal antibodies. Data Extraction and Synthesis: Two investigators abstracted data and appraised risks of bias. Intervention groups were categorized as "more intensive" (more potent pharmacologic intervention) or "less intensive" (less potent, placebo, or control group). Main Outcomes and Measures: The coprimary end points were total mortality and cardiovascular mortality. Random-effects meta-regression and meta-analyses evaluated associations between baseline LDL-C level and reductions in mortality end points and secondary end points including major adverse cardiac events (MACE). Results: In 34 trials, 136 299 patients received more intensive and 133 989 received less intensive LDL-C lowering. All-cause mortality was lower for more vs less intensive therapy (7.08% vs 7.70%; rate ratio [RR], 0.92 [95% CI, 0.88 to 0.96]), but varied by baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with greater reductions in all-cause mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.91 [95% CI, 0.86 to 0.96]; P = .001; absolute risk difference [ARD], -1.05 incident cases per 1000 person-years [95% CI, -1.59 to -0.51]), but only when baseline LDL-C levels were 100 mg/dL or greater (P < .001 for interaction) in a meta-analysis. Cardiovascular mortality was lower for more vs less intensive therapy (3.48% vs 4.07%; RR, 0.84 [95% CI, 0.79 to 0.89]) but varied by baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with a greater reduction in cardiovascular mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.86 [95% CI, 0.80 to 0.94]; P < .001; ARD, -1.0 incident cases per 1000 person-years [95% CI, -1.51 to -0.45]), but only when baseline LDL-C levels were 100 mg/dL or greater (P < .001 for interaction) in a meta-analysis. Trials with baseline LDL-C levels of 160 mg/dL or greater had the greatest reduction in all-cause mortality (RR, 0.72 [95% CI, 0.62 to 0.84]; P < .001; 4.3 fewer deaths per 1000 person-years) in a meta-analysis. More intensive LDL-C lowering was also associated with progressively greater risk reductions with higher baseline LDL-C level for myocardial infarction, revascularization, and MACE. Conclusions and Relevance: In these meta-analyses and meta-regressions, more intensive compared with less intensive LDL-C lowering was associated with a greater reduction in risk of total and cardiovascular mortality in trials of patients with higher baseline LDL-C levels. This association was not present when baseline LDL-C level was less than 100 mg/dL, suggesting that the greatest benefit from LDL-C-lowering therapy may occur for patients with higher baseline LDL-C levels.
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“Studies have shown that dyslipidemia, particularly elevated low-density lipoprotein cholesterol (LDL-C), is an independent risk factor for CHD (3–5).”
From Remnant cholesterol, lipid ratios, and the severity of coronary artery lesions: a retrospective cohort study in patients with coronary heart disease (2025) · cites this paper as [4]
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“Similarly, a recent meta-analysis showed that intensive lowering of LDL cholesterol (primarily with the use of statins) resulted in a mortality benefit that was observed only among patients with a baseline LDL cholesterol level of 100 mg or more per deciliter. 20”
From Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome (2018) · cites this paper as [20]
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- TiceJA; Institute for Clincal and Economic Review (ICER). Evolocumab for treatment of high cholesterol: clinical effectiveness: new evidence update. Institute for Clincal and Economic Review website. https://icer-review.org/material/pcks9-inhibitors-neu/. June 13, 2017. Accessed March 16, 2018.
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Metadata
- Authors
- Navarese, E. P., Robinson, J. G., Kowalewski, M., Kolodziejczak, M., Andreotti, F., Bliden, K., Tantry, U., Kubica, J., Raggi, P., & Gurbel, P. A.
- Affiliations
- Inova Health System (US)
- University of Iowa (US)
- Antoni Jurasz University Hospital (PL)
- Systematic Investigation and Research on Interventions and Outcomes (SIRIO) MEDICINE Cardiovascular Research Network
- Università Cattolica del Sacro Cuore (IT)
- Nicolaus Copernicus University (PL)
- University of Alberta (CA)
- Corresponding author
- Robinson, Jennifer G.
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2018-04-17
- Volume
- 319
- Issue
- 15
- Pages
- 1566
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC5933331
- OpenAlex
- W2800876320
- Semantic Scholar
- e998030b0bef031f54619a07cde9f01df4ce9807
- Cited by
- 549
- References
- 58
- Citations by year
- 2026: 36 · 2025: 74 · 2024: 81 · 2023: 70 · 2022: 56 · 2021: 76 · 2020: 62 · 2019: 68 · 2018: 26
- FWCI
- 12.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
- Keywords
- LDL cholesterol, LDL cholesterol lowering, statins, ezetimibe, PCSK9 inhibitors, all-cause mortality, cardiovascular mortality, major adverse cardiac events, lipid-lowering therapy, dose-response relationship, treatment intensity, risk stratification, randomized controlled trials, meta-regression, risk of bias assessment, risk difference, relative risk, number needed to harm
- MeSH terms
- Ezetimibe, Proprotein Convertase 9, PCSK9 Inhibitors, Antibodies, Monoclonal, Anticholesteremic Agents, Cardiovascular Diseases, Humans, Cholesterol, LDL, Mortality, Regression Analysis, Risk, Confounding Factors, Epidemiologic, Hydroxymethylglutaryl-CoA Reductase Inhibitors
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