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

JAMA Intern Med. 2022 May 1;182(5):474-481. doi: 10.1001/jamainternmed.2022.0134.


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.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Cardiovascular Diseases*
  • Cholesterol, LDL
  • Female
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
  • Male
  • Myocardial Infarction* / drug therapy
  • Myocardial Infarction* / epidemiology
  • Myocardial Infarction* / prevention & control
  • Randomized Controlled Trials as Topic
  • Stroke* / prevention & control


  • Cholesterol, LDL
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors