Physicians' Academy for Cardiovascular Education

LDL-c reductions below 1.6 mmol/L provide additional vascular risk benefit

Efficacy and Safety of Further Lowering of Low-Density Lipoprotein Cholesterol in Patients Starting With Very Low Levels: A Meta-analysis

Literature - Sabatine MS, Wiviott SD, Im KA et al. - JAMA Cardiol 2018; published online ahead of print

Introduction and methods

The Cholesterol Treatment Trialists Collaboration (CTTC), a meta-analysis of 26 statin trials, demonstrated a 22% relative risk reduction in major vascular events (MVE) per 1 mmol/L (38.7 mg/dL) reduction in LDL-c, including patients with baseline LDL-c levels as low as ≤2 mmol/L (77.3 mg/dL) [1]. However, it is not clear whether this clinical benefit applies also to patients with baseline LDL-c levels below that.

This meta-analysis evaluated the efficacy and safety of lowering LDL-c levels in patients with median LDL-c levels ≤1.8 mmol/L (70 mg/dL). The CTTC was used to evaluate this objective in patients receiving statins. Trials with other lipid-lowering medications (OLLM), given on top of statins, were assessed through a literature search and meta-analysis, which was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [2]. Eligible for the OLLM meta-analysis were randomized, double-blind, controlled outcome studies including patients with mean or median LDL-c levels ≤1.8 mmol/L.

For each trial, the risk ratio (RR) per 1 mmol/L difference in LDL-c between treatment arms was calculated. A fixed-effects inverse-weighting model was used to assess the results. The association between achieved LDL-c and estimated 5-year rate of MVE (including coronary heart death, myocardial infarction, ischemic stroke, or coronary revascularization) was evaluated.

Main results

The literature search identified three eligible OLLM secondary prevention trials: IMPROVE-IT [3], FOURIER [4] and REVEAL [5].

In a subgroup of patients with a mean LDL-c level of 1.7 mmol/L (median: 1.6-1.8 mmol/L) in the control arm (baseline LDL-c for the experimental group was not reported), the RR for MVE per 1 mmol/L LDL-c reduction was:

In the OLLM studies, the significant association between LDL-c levels and MVE persisted until LDL-c levels reached 0.5 mmol/L (21 mg/dL) (β: 0.35; 95%CI: 0.25-0.45; P <0.001).

There was no increased risk of serious adverse events, myalgias and/or myositis, elevation in the level of aminotransferases, new onset diabetes, hemorrhagic stroke, or cancer in any of the trials individually or when meta-analyzed.


LDL-c reductions reaching a median of 0.5 mmol/L (21 mg/dL) in patients with median LDL-c levels of 1.6-1.8 mmol/L (63 mg/dL) in the control arm are associated with a risk reduction in MVE, without an accompanying increased risk of adverse events. The risk of MVE was reduced by 21% per 1 mmol/L LDL-c reduction, which was of the same magnitude as that observed in the CTCC with starting LDL-c levels almost twice as high.

Editorial comment

In his editorial article, Gotto [6] discusses the study published by Sabatine et al., which he characterizes as being ‘extremely well done’. He notes that these data provide a solid reason to update the current American Heart Association/American College of Cardiology 2013 guidelines, which may not recommend the optimal risk reduction achievable, and he concludes: ‘Whether one calls it a target or a threshold, practicing physicians need some guidance as they venture into achieved levels of LDL-C levels that are as foreign as travel to outer space. I have confidence that the new guidelines will be closer to a global positioning system map rather than just a compass and the stars. Treating physicians should apply informed clinical judgment to each individual patient.’


Show references

Download the slide Find this article online at JAMA Cardiology