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-analysisLiterature - 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) . 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 . 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.
The literature search identified three eligible OLLM secondary prevention trials: IMPROVE-IT , FOURIER  and REVEAL .
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 three OLLM studies: 0.79 (95%CI: 0.70-0.88; P <0.001)
- in the CTTC: 0.78 (95%CI: 0.65-0.94)
- in all studies combined: 0.79 (95%CI: 0.71-0.87; P <0.001)
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.
In his editorial article, Gotto  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.’