Continued efficacy of LDL-c lowering, even below 40 mg/dL, in high risk patients

Cardiovascular Benefit of Lowering LDL Cholesterol Below 40 mg/dl

Literature - Marston NA, Giugliano RP, Park J-G et al., - Circulation 2021, 10.1161/CIRCULATIONAHA.121.056536

Introduction and methods

In the FOURIER trial, LDL-c levels were lowered by the PCSK9 inhibitor evolocumab from a median of 93 mg/dL to 30 mg/dL [1]. It is unknown however whether there is still additional benefit of lowering LDL-c below thresholds in the guidelines, for example below 40 mg/dL.

Therefore, an exploratory analysis of FOURIER was conducted utilizing comparisons of randomized groups and analyzing in the context of the magnitude of LDL-c lowering below targets.

FOURIER was a CV outcomes trial in which evolocumab was compared to placebo in 27,564 patients with stable ASCVD on optimal statin therapy [1]. Endpoint was major adverse cardiovascular events (MACE), defined as CV death, MI or stroke. Median follow-up was 2.2 years. Ultracentrifugation was done when LDL- c was<40 mg/dL. 65% of Patients on evolocumab achieved an LDL <40 mg/dL.

Main results

  • The further baseline LDL-c levels were<93 mg/dL, the greater the proportion of LDL-c lowering was <40 mg/dL.
  • A consistent benefit on MACE of LDL-c lowering was seen regardless of how low the baseline LDL-c was (and lower LDL-c baseline was associated with greater proportion of patients reaching LDL-c <40 mg/dL) (Pinteraction=0.78).
  • A similar pattern was seen for apoB and non-HDL-c lowering.
  • There was no difference in absolute risk reduction at lower baseline LDL-c.


This exploratory analysis of FOURIER showed that lowering LDL-c below 40 mg/dL results in continued benefit with regard to MACE reduction in patients with ASCVD.


1. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376:1713-1722.

Find this article online at Circulation

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