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Cited by 848Lipoproteins and Cardiovascular HealthCancer, Lipids, and MetabolismBlood Pressure and Hypertension Studies

Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease

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Yusuf, Salim, Bosch, Jackie, Dagenais, Gilles, Zhu, Jun, Xavier, Denis, Liu, Lisheng, Pais, Prem, López-Jaramillo, Patricio +25 more·2016·New England Journal of Medicine
DOI 10.1056/nejmoa1600176
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Abstract

BACKGROUND: Previous trials have shown that the use of statins to lower cholesterol reduces the risk of cardiovascular events among persons without cardiovascular disease. Those trials have involved persons with elevated lipid levels or inflammatory markers and involved mainly white persons. It is unclear whether the benefits of statins can be extended to an intermediate-risk, ethnically diverse population without cardiovascular disease. METHODS: In one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 participants in 21 countries who did not have cardiovascular disease and were at intermediate risk to receive rosuvastatin at a dose of 10 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second coprimary outcome additionally included revascularization, heart failure, and resuscitated cardiac arrest. The median follow-up was 5.6 years. RESULTS: The overall mean low-density lipoprotein cholesterol level was 26.5% lower in the rosuvastatin group than in the placebo group. The first coprimary outcome occurred in 235 participants (3.7%) in the rosuvastatin group and in 304 participants (4.8%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.64 to 0.91; P=0.002). The results for the second coprimary outcome were consistent with the results for the first (occurring in 277 participants [4.4%] in the rosuvastatin group and in 363 participants [5.7%] in the placebo group; hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P<0.001). The results were also consistent in subgroups defined according to cardiovascular risk at baseline, lipid level, C-reactive protein level, blood pressure, and race or ethnic group. In the rosuvastatin group, there was no excess of diabetes or cancers, but there was an excess of cataract surgery (in 3.8% of the participants, vs. 3.1% in the placebo group; P=0.02) and muscle symptoms (in 5.8% of the participants, vs. 4.7% in the placebo group; P=0.005). CONCLUSIONS: Treatment with rosuvastatin at a dose of 10 mg per day resulted in a significantly lower risk of cardiovascular events than placebo in an intermediate-risk, ethnically diverse population without cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; HOPE-3 ClinicalTrials.gov number, NCT00468923.).

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Crossref · 10.1056/nejmoa1600176

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  • Three large, randomized trials of statin versus placebo where specific cognitive tests were performed showed no differences between statin and placebo.

    “First, there are three large, randomized trials of statin versus placebo where specific cognitive tests were performed, and no differences were seen between statin and placebo (166-169).”

    From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [169]

    The Methods (p. 1) identify a large randomized comparison of rosuvastatin with placebo. The available Results (p. 1) report cardiovascular outcomes and other adverse events, but do not report specific cognitive tests or a comparison of cognitive results between groups (searched: cognitive, memory, dementia, neuropsychological tests). The paper therefore supports the trial description, not the cognitive-outcome claim. (LLM, conf=0.83)

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  • Three large randomized trials of statin versus placebo with specific cognitive tests found no differences between statin and placebo.

    “First, there are three large, randomized trials of statin versus placebo where specific cognitive tests were performed, and no differences were seen between statin and placebo (160–163).”

    From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [163]

    The Methods (p. 1) describe a large randomized trial comparing rosuvastatin with placebo. The available passages report cardiovascular outcomes, not specific cognitive tests or cognitive results, so they do not support the claimed absence of a cognitive difference. This paper also cannot by itself establish the sentence’s count of three trials. (LLM, conf=0.79)

    Experimental — accuracy not yet measured

  • The HOPE-3 trial showed that low-dose statin therapy reduced the composite cardiovascular outcome by 24% but had no significant effect on mortality.

    “The Heart Outcomes Prevention Evaluation 3 (HOPE-3), published in 2016, showed that low-dose statin therapy reduced the composite cardiovascular outcome by 24% but had no significant effect on mortality.19”

    From Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients (2023) · cites this paper as [19]

    The Methods (p. 1) identify HOPE-3’s 10-mg-per-day rosuvastatin comparison, and the Results (p. 1) report a hazard ratio of 0.76 for the first composite cardiovascular outcome—a 24% relative reduction. The passages available in our copy do not report a separate mortality result, so they do not support the claim that mortality was unaffected; searches for mortality and all-cause death found no such result. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The effectiveness of statins for preventing the first occurrence and recurrence of stroke in Japanese populations was confirmed in a sub-analysis of the MEGA study and in the JELIS study.

    “The effectiveness of statins for preventing the first occurrence and recurrence of stroke in Japanese populations was confirmed in a sub-analysis of the MEGA study620, 621) and in the JELIS study622).”

    From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [621]

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Authors
Yusuf, S., Bosch, J., Dagenais, G., Zhu, J., Xavier, D., Liu, L., Pais, P., López-Jaramillo, P., Leiter, L. A., Dans, A., Avezum, A., Piegas, L. S., Parkhomenko, A., Keltai, K., Keltai, M., Sliwa, K., Peters, R. J. G., Held, C., Chazova, I., Yusoff, K., Lewis, B. S., Jansky, P., Khunti, K., Toff, W. D., Reid, C. M., Varigos, J., Sanchez-Vallejo, G., McKelvie, R., Pogue, J., Jung, H., Gao, P., Diaz, R., & Lonn, E.
Affiliations
  • St. Michael's Hospital (CA)
  • Semmelweis University (HU)
  • Uppsala University (SE)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2016-05-26
Volume
374
Issue
21
Pages
2021-2031
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1600176
OpenAlex
W2313998826
Cited by
848
References
23
Citations by year
2026: 32 · 2025: 52 · 2024: 61 · 2023: 66 · 2022: 84 · 2021: 90 · 2020: 75 · 2019: 109 · 2018: 101 · 2017: 97 · 2016: 78
FWCI
142.16
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-nd)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • eSpace (Curtin University) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Leicester Research Archive (University of Leicester) (submittedVersion, other-oa)
Funders
  • AstraZeneca
  • Canadian Institutes of Health Research (IR2-91038))
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
Keywords
rosuvastatin, statins, cholesterol lowering, intermediate cardiovascular risk, primary prevention, cardiovascular events, LDL cholesterol, ethnic diversity, C-reactive protein, cataract surgery, statin adverse effects, muscle symptoms, diabetes risk, cardiovascular mortality, myocardial infarction, stroke, heart failure, revascularization, cardiac arrest, cardiovascular risk stratification, lipid-lowering therapy
MeSH terms
Rosuvastatin Calcium, Aged, Cardiovascular Diseases, Double-Blind Method, Female, Humans, Hypercholesterolemia, Cholesterol, LDL, Male, Middle Aged, Risk Factors, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Medication Adherence

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