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

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4 Citations (Scopus)


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.

Original languageEnglish
Article number441
JournalBMC Medicine
Issue number1
Publication statusPublished - 12-2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Medicine


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