Risk of cardiovascular events and mortality associated with LDL and non-HDL cholesterol levels after statin initiation for primary prevention: A multiregional cohort study
10 affiliations
- 1Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
- 2Precision Healthcare and Drug Safety (PRISM) Research Group, Centre for Academic Primary Care, School of Medicine, University of Nottingham, Nottingham, United Kingdom
- 3Medicines Intelligence Research Group, School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
- 4GSK R&D Global Headquarters, London, United Kingdom
- 5Research Department of Practice and Policy, School of Pharmacy, University College London, London, United Kingdom
- 6Centre for Medicines Optimisation Research and Education, University College London Hospitals NHS Foundation Trust, London, United Kingdom
- 7Accident and Emergency Department, Queen Mary Hospital, Pok Fu Lam, Hong Kong SAR, China
- 8The University of Hong Kong Shenzhen Institute of Research and Innovation, Shenzhen, China
- 9Macau University of Science and Technology, Macau SAR, China
- 10Aston Centre of Excellence in Pharmacotherapy Optimisation and Pharmacoepidemiology Research, Aston Pharmacy School, Aston University, Birmingham, United Kingdom
Abstract
Background: The cardiovascular and mortality benefits of achieving guideline-recommended concentrations of low-density lipoprotein (LDL) and non-high-density lipoprotein (non-HDL) cholesterol with statins in primary prevention remain uncertain. Methods and findings: In this new-user cohort study, we used electronic healthcare databases from Hong Kong (HK), New Zealand (NZ) and the United Kingdom (UK) to identify 185,237 patients initiating statins between 1 January 2007 and 31 December 2012 (with follow-up to 31 December 2017) without atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease. Associations between LDL and non-HDL cholesterol measured within 2 years post-initiation with the outcomes of major adverse cardiovascular events (MACE) or all-cause mortality were assessed in landmark analyses using multivariable Cox regression adjusted for age, sex, hypertension, atrial fibrillation, diabetes mellitus, dyslipidaemia, obesity, smoking, alcohol misuse, rheumatoid arthritis, systemic lupus erythematosus and connective tissue disorders, severe mental illness, antihypertensive drugs, antidiabetic drugs, antiplatelet drugs, and anticoagulant drugs. Estimates were pooled using random-effects meta-analysis. At 2 years, LDL cholesterol was <1.4 mmol/L in 7,084 (3.8%), 1.4–1.7 mmol/L in 21,893 (11.8%), 1.8–2.5 mmol/L in 81,941 (44.2%) and ≥2.6 mmol/L in 74,294 (40.1%) patients. Mean duration of follow-up for the primary outcome of MACE was 6.5 years in HK, 5.6 years in NZ and 5.4 years in UK. versus an LDL cholesterol ≥2.6 mmol/L, adjusted hazard ratios (HR) for MACE were 0.80 (95% CI [0.77,0.83]) for 1.8–2.5 mmol/L, 0.79 (0.66,0.94) for 1.4–1.7 mmol/L and 0.82 (0.60,1.12) for <1.4 mmol/L. Non-HDL cholesterol showed similar estimates for MACE (e.g., HR 0.75, [0.72,0.79] for 2.6–3.3 mmol/L versus ≥3.4 mmol/L). In continuous analysis, the association with MACE was approximately log-linear across achieved LDL and non-HDL cholesterol in HK and the UK, whereas in NZ estimates were less consistent and imprecise at the lowest concentrations. After adjustment for confounding factors, very low LDL (HR 1.06, [0.96,1.16]) and non-HDL cholesterol (HR 0.98, [0.84,1.14]) were not associated with all-cause mortality. Limitations include heterogeneity across cohorts, which may reflect confounding by indication where treatment intensity was guided by cardiovascular risk, and residual confounding from comorbidities, lifestyle interventions and disease severity. Estimates are also conditional on patients having initiated statins, survived to the landmark, and undergone follow-up lipid testing. Conclusions: Lower achieved LDL and non-HDL cholesterol after statin initiation was associated with a reduction in MACE, with limited evidence of an increase in all-cause mortality at very low concentrations after adjustment for confounding. Additional reductions in cardiovascular events could be obtained by achieving guideline-recommended non-HDL cholesterol levels of at least <3.4 mmol/L after statin initiation for primary prevention. Why was this study done?: What did the researchers do and find?: What do these findings mean?: Joseph Edgar Blais and colleagues analysed data from more than 185,000 statin users across Hong Kong, New Zealand, and the UK, finding that lower achieved LDL and non-HDL cholesterol levels after statin initiation were associated with lower rates of major cardiovascular events in primary prevention.
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BibTeX
@article{blais2026risk,
title = {{Risk of cardiovascular events and mortality associated with LDL and non-HDL cholesterol levels after statin initiation for primary prevention: A multiregional cohort study}},
author = {Joseph Edgar Blais and Ralph Kwame Akyea and William Harrison and Amy Hai Yan Chan and Wenfang Zhong and Stephen Franklin Weng and Kebede Abera Beyene and Wallis C. Y. Lau and Kenneth K. C. Man and Nadeem Qureshi and Esther Wai Yin Chan and Ian Chi Kei Wong and Jeff Harrison},
journal = {PLOS Medicine},
year = {2026},
month = nov,
doi = {10.1371/journal.pmed.1005012},
url = {https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005012},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Risk of cardiovascular events and mortality associated with LDL and non-HDL cholesterol levels after statin initiation for primary prevention: A multiregional cohort study
AU - Joseph Edgar Blais
AU - Ralph Kwame Akyea
AU - William Harrison
AU - Amy Hai Yan Chan
AU - Wenfang Zhong
AU - Stephen Franklin Weng
AU - Kebede Abera Beyene
AU - Wallis C. Y. Lau
AU - Kenneth K. C. Man
AU - Nadeem Qureshi
AU - Esther Wai Yin Chan
AU - Ian Chi Kei Wong
AU - Jeff Harrison
PY - 2026
DA - 2026/11/03
JO - PLOS Medicine
DO - 10.1371/journal.pmed.1005012
UR - https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005012
AB - Background: The cardiovascular and mortality benefits of achieving guideline-recommended concentrations of low-density lipoprotein (LDL) and non-high-density lipoprotein (non-HDL) cholesterol with statins in primary prevention remain uncertain. Methods and findings: In this new-user cohort study, we used electronic healthcare databases from Hong Kong (HK), New Zealand (NZ) and the United Kingdom (UK) to identify 185,237 patients initiating statins between 1 January 2007 and 31 December 2012 (with follow-up to 31 December 2017) without atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease. Associations between LDL and non-HDL cholesterol measured within 2 years post-initiation with the outcomes of major adverse cardiovascular events (MACE) or all-cause mortality were assessed in landmark analyses using multivariable Cox regression adjusted for age, sex, hypertension, atrial fibrillation, diabetes mellitus, dyslipidaemia, obesity, smoking, alcohol misuse, rheumatoid arthritis, systemic lupus erythematosus and connective tissue disorders, severe mental illness, antihypertensive drugs, antidiabetic drugs, antiplatelet drugs, and anticoagulant drugs. Estimates were pooled using random-effects meta-analysis. At 2 years, LDL cholesterol was <1.4 mmol/L in 7,084 (3.8%), 1.4–1.7 mmol/L in 21,893 (11.8%), 1.8–2.5 mmol/L in 81,941 (44.2%) and ≥2.6 mmol/L in 74,294 (40.1%) patients. Mean duration of follow-up for the primary outcome of MACE was 6.5 years in HK, 5.6 years in NZ and 5.4 years in UK. versus an LDL cholesterol ≥2.6 mmol/L, adjusted hazard ratios (HR) for MACE were 0.80 (95% CI [0.77,0.83]) for 1.8–2.5 mmol/L, 0.79 (0.66,0.94) for 1.4–1.7 mmol/L and 0.82 (0.60,1.12) for <1.4 mmol/L. Non-HDL cholesterol showed similar estimates for MACE (e.g., HR 0.75, [0.72,0.79] for 2.6–3.3 mmol/L versus ≥3.4 mmol/L). In continuous analysis, the association with MACE was approximately log-linear across achieved LDL and non-HDL cholesterol in HK and the UK, whereas in NZ estimates were less consistent and imprecise at the lowest concentrations. After adjustment for confounding factors, very low LDL (HR 1.06, [0.96,1.16]) and non-HDL cholesterol (HR 0.98, [0.84,1.14]) were not associated with all-cause mortality. Limitations include heterogeneity across cohorts, which may reflect confounding by indication where treatment intensity was guided by cardiovascular risk, and residual confounding from comorbidities, lifestyle interventions and disease severity. Estimates are also conditional on patients having initiated statins, survived to the landmark, and undergone follow-up lipid testing. Conclusions: Lower achieved LDL and non-HDL cholesterol after statin initiation was associated with a reduction in MACE, with limited evidence of an increase in all-cause mortality at very low concentrations after adjustment for confounding. Additional reductions in cardiovascular events could be obtained by achieving guideline-recommended non-HDL cholesterol levels of at least <3.4 mmol/L after statin initiation for primary prevention. Why was this study done?: What did the researchers do and find?: What do these findings mean?: Joseph Edgar Blais and colleagues analysed data from more than 185,000 statin users across Hong Kong, New Zealand, and the UK, finding that lower achieved LDL and non-HDL cholesterol levels after statin initiation were associated with lower rates of major cardiovascular events in primary prevention.
SN - 1549-1676
ER -