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Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials
Open accessAbstract
Background Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy.Methods A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48,421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis.Findings When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1·34 (95% CI 1·22-1·47, p<0·0001) and that for the high genetic risk category was 1·72 (1·55-1·92, p<0·0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0·0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0·0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT.Interpretation A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy.Funding National Institutes of Health.
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“Our finding that a polygenic risk score has robust associations with incident coronary events is well aligned with previous studies of both primary and secondary prevention populations.16–24”
From Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease (2016) · cites this paper as [22]
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“For example, we previously showed that a high polygenic risk for CAD may be offset by either of two interventions: adherence to a healthy lifestyle or cholesterol-lowering therapy with statin medications.19–21”
From Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations (2018) · cites this paper as [20]
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“These risk alleles, when aggregated into a polygenic risk score, are predictive of incident coronary events and provide a continuous and quantitative measure of genetic susceptibility.16–24”
From Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease (2016) · cites this paper as [22]
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1 retracted
Reduced dietary salt for the prevention of cardiovascular disease
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Self-citationRosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein
Ridker, P. M., Danielson, E., Fonseca, F. A. H., Genest, J., Gotto, A. M., Kastelein, J. J. P., Koenig, W., Libby, P., Lorenzatti, A. J., MacFadyen, J. G., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0807646 · Cited by 6,674
Self-citationCholesterol Treatment Trialists' (CTT) Collaboration (2010) · The Lancet · doi:10.1016/s0140-6736(10)61350-5 · Cited by 6,550
Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes
Cannon, C. P., Braunwald, E., McCabe, C. H., Rader, D. J., Rouleau, J. L., Belder, R., Joyal, S. V., Hill, K. A., Pfeffer, M. A., & Skene, A. M. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040583 · Cited by 4,938
Self-citationSever, P., Dahlöf, B., Poulter, N. R., Wedel, H., Beevers, G., Caulfield, M. J., Collins, R., Kjeldsen, S. E., Kristinsson, A., McInnes, G. T., et al. (2003) · The Lancet · doi:10.1016/s0140-6736(03)12948-0 · Cited by 3,790
Self-citationRosuvastatin to Prevent Vascular Events in Men and Women With Elevated C-Reactive Protein
Ridker, P. M., Danielson, E., Fonseca, F. A. H., Genest, J. J., Gotto, A. M., Kastelein, J. J. P., Köenig, W., Libby, P., Lorenzatti, A. J., MacFadyen, J. G., et al. (2009) · Obstetrical & Gynecological Survey · doi:10.1097/01.ogx.0000344393.60303.0a · Cited by 3,641
Self-citationCollaborators, C. T. T. (. (2012) · The Lancet · doi:10.1016/s0140-6736(12)60367-5 · Cited by 2,833
Statins for the primary prevention of cardiovascular disease
Taylor, F., Huffman, M. D., Macedo, A. F., Moore, T. H., Burke, M., Davey Smith, G., Ward, K., Ebrahim, S., & Gay, H. C. (2013) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd004816.pub5 · Cited by 1,934
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Benjamin, E. J., Muntner, P., Alonso, A., Bittencourt, M. S., Callaway, C. W., Carson, A. P., Chamberlain, A. M., Chang, A. R., Cheng, S., Das, S. R., et al. (2019) · Circulation · doi:10.1161/cir.0000000000000659 · Cited by 9,036
2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes
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2016 European Guidelines on cardiovascular disease prevention in clinical practice
Piepoli, M. F., Hoes, A. W., Agewall, S., Albus, C., Brotons, C., Catapano, A. L., Cooney, M.-T., Corrà, U., Cosyns, B., Deaton, C., et al. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehw106 · Cited by 6,457
Metadata
- Authors
- Mega, J. L., Stitziel, N. O., Smith, J. G., Chasman, D. I., Caulfield, M. J., Devlin, J. J., Nordio, F., Hyde, C. L., Cannon, C. P., Sacks, F. M., Poulter, N. R., Sever, P. S., Ridker, P. M., Braunwald, E., Melander, O., Kathiresan, S., & Sabatine, M. S.
- Affiliations
- Brigham and Women's Hospital (US)
- Washington University in St. Louis (US)
- Broad Institute (US)
- Queen Mary University of London (GB)
- Quest Diagnostics (United States) (US)
- Pfizer (United States) (US)
- Imperial College London (GB)
- Lund University (SE)
- Corresponding author
- Mega, Jessica L
- Stitziel, Nathan O
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2015-06
- Volume
- 385
- Issue
- 9984
- Pages
- 2264-2271
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC4608367
- OpenAlex
- W2171705978
- Cited by
- 704
- References
- 46
- Citations by year
- 2026: 40 · 2025: 48 · 2024: 51 · 2023: 69 · 2022: 78 · 2021: 83 · 2020: 78 · 2019: 59 · 2018: 62 · 2017: 53 · 2016: 57 · 2015: 25
- FWCI
- 12.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by-nc-nd)
- Funders
- National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) (RC1 HL099634)
- NIH and the NHLBI (grant K08 HL114642)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Keywords
- coronary artery disease, polygenic risk score, genetic variants, statin therapy, primary prevention, secondary prevention, number needed to treat, risk stratification, JUPITER trial, ASCOT trial, CARE trial, PROVE IT-TIMI 22, recurrent cardiovascular events, Malmö Diet and Cancer Study, cardiovascular risk prediction, treatment benefit stratification, LDL cholesterol lowering
- MeSH terms
- Coronary Disease, Humans, Primary Prevention, Recurrence, Treatment Outcome, Risk Assessment, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Secondary Prevention, Numbers Needed To Treat
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