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Original Investigation
March 14, 2022

Evaluating the Association Between Low-Density Lipoprotein Cholesterol Reduction and Relative and Absolute Effects of Statin Treatment: A Systematic Review and Meta-analysis

Author Affiliations
  • 1HRB Centre for Primary Care Research, RCSI University of Medicine and Health Sciences, Mercer St Lower, Dublin, Ireland
  • 2Institute for Scientific Freedom, Copenhagen, Denmark
  • 3Institute for Evidence-Based Healthcare, Faculty of Health Sciences & Medicine, Bond University, Robina, Queensland, Australia
  • 4Department of Public Health and Primary Care, Trinity College Dublin, Dublin, Ireland
  • 5Independent researcher, Dublin, Ireland
  • 6Division of Cardiology, Department of Medicine, University of New Mexico, Albuquerque
JAMA Intern Med. 2022;182(5):474-481. doi:10.1001/jamainternmed.2022.0134
Key Points

Question  What is the association between statin-induced reductions in low-density lipoprotein cholesterol (LDL-C) levels and the absolute and relative reductions in individual clinical outcomes, such as all-cause mortality, myocardial infarction, or stroke?

Findings  In this meta-analysis of 21 randomized clinical trials in primary and secondary prevention that examined the efficacy of statins in reducing total mortality and cardiovascular outcomes, there was significant heterogeneity but also reductions in the absolute risk of 0.8% for all-cause mortality, 1.3% for myocardial infarction, and 0.4% for stroke in those randomized to treatment with statins compared with control, with relative risk reductions of 9%, 29%, and 14%, respectively. A meta-regression was inconclusive regarding the association between the magnitude of statin-induced LDL-C reduction and all-cause mortality, myocardial infarction, or stroke.

Meaning  The study results suggest that the absolute benefits of statins are modest, may not be strongly mediated through the degree of LDL-C reduction, and should be communicated to patients as part of informed clinical decision-making as well as to inform clinical guidelines and policy.

Abstract

Importance  The association between statin-induced reduction in low-density lipoprotein cholesterol (LDL-C) levels and the absolute risk reduction of individual, rather than composite, outcomes, such as all-cause mortality, myocardial infarction, or stroke, is unclear.

Objective  To assess the association between absolute reductions in LDL-C levels with treatment with statin therapy and all-cause mortality, myocardial infarction, and stroke to facilitate shared decision-making between clinicians and patients and inform clinical guidelines and policy.

Data Sources  PubMed and Embase were searched to identify eligible trials from January 1987 to June 2021.

Study Selection  Large randomized clinical trials that examined the effectiveness of statins in reducing total mortality and cardiovascular outcomes with a planned duration of 2 or more years and that reported absolute changes in LDL-C levels. Interventions were treatment with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) vs placebo or usual care. Participants were men and women older than 18 years.

Data Extraction and Synthesis  Three independent reviewers extracted data and/or assessed the methodological quality and certainty of the evidence using the risk of bias 2 tool and Grading of Recommendations, Assessment, Development and Evaluation. Any differences in opinion were resolved by consensus. Meta-analyses and a meta-regression were undertaken.

Main Outcomes and Measures  Primary outcome: all-cause mortality. Secondary outcomes: myocardial infarction, stroke.

Findings  Twenty-one trials were included in the analysis. Meta-analyses showed reductions in the absolute risk of 0.8% (95% CI, 0.4%-1.2%) for all-cause mortality, 1.3% (95% CI, 0.9%-1.7%) for myocardial infarction, and 0.4% (95% CI, 0.2%-0.6%) for stroke in those randomized to treatment with statins, with associated relative risk reductions of 9% (95% CI, 5%-14%), 29% (95% CI, 22%-34%), and 14% (95% CI, 5%-22%) respectively. A meta-regression exploring the potential mediating association of the magnitude of statin-induced LDL-C reduction with outcomes was inconclusive.

Conclusions and Relevance  The results of this meta-analysis suggest that the absolute risk reductions of treatment with statins in terms of all-cause mortality, myocardial infarction, and stroke are modest compared with the relative risk reductions, and the presence of significant heterogeneity reduces the certainty of the evidence. A conclusive association between absolute reductions in LDL-C levels and individual clinical outcomes was not established, and these findings underscore the importance of discussing absolute risk reductions when making informed clinical decisions with individual patients.

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