BMC Medicine (Nov 2022)

Optimal target of LDL cholesterol level for statin treatment: challenges to monotonic relationship with cardiovascular events

  • Masashi Sakuma,
  • Satoshi Iimuro,
  • Tomohiro Shinozaki,
  • Takeshi Kimura,
  • Yoshihisa Nakagawa,
  • Yukio Ozaki,
  • Hiroshi Iwata,
  • Katsumi Miyauchi,
  • Hiroyuki Daida,
  • Satoru Suwa,
  • Ichiro Sakuma,
  • Yosuke Nishihata,
  • Yasushi Saito,
  • Hisao Ogawa,
  • Masunori Matsuzaki,
  • Yasuo Ohashi,
  • Isao Taguchi,
  • Shigeru Toyoda,
  • Teruo Inoue,
  • Ryozo Nagai

DOI
https://doi.org/10.1186/s12916-022-02633-5
Journal volume & issue
Vol. 20, no. 1
pp. 1 – 13

Abstract

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Abstract Background Aggressive lipid lowering by high-dose statin treatment has been established for the secondary prevention of coronary artery disease (CAD). Regarding the low-density lipoprotein cholesterol (LDL-C) level, however, the “The lower is the better” concept has been controversial to date. We hypothesized that there is an optimal LDL-C level, i.e., a “threshold” value, below which the incidence of cardiovascular events is no longer reduced. We undertook a subanalysis of the REAL-CAD study to explore whether such an optimal target LDL-C level exists by a novel analysis procedure to verify the existence of a monotonic relationship. Methods For a total of 11,105 patients with CAD enrolled in the REAL-CAD study, the LDL-C level at 6 months after randomization and 5-year cardiovascular outcomes were assessed. We set the “threshold” value of the LDL-C level under which the hazards were assumed to be constant, by including an artificial covariate max (0, LDL-C − threshold) in the Cox model. The analysis was repeated with different LDL-C thresholds (every 10 mg/dl from 40 to 100 mg/dl) and the model fit was assessed by log-likelihood. Results For primary outcomes such as the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization, the model fit assessed by log-likelihood was best when a threshold LDL-C value of 70 mg/dl was assumed. And in the model with a threshold LDL-C ≥ 70 mg/dl, the hazard ratio was 1.07 (95% confidence interval 1.01–1.13) as the LDL-C increased by 10 mg/dl. Therefore, the risk of cardiovascular events decreased monotonically until the LDL-C level was lowered to 70 mg/dl, but when the level was further reduced, the risk was independent of LDL-C. Conclusions Our analysis model suggests that a “threshold” value of LDL-C might exist for the secondary prevention of cardiovascular events in Japanese patients with CAD, and this threshold might be 70 mg/dl for primary composite outcomes. Trial registration http://www.clinicaltrials.gov . Unique identifier: NCT01042730.

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