Very Low Levels of Atherogenic Lipoproteins and the Risk for Cardiovascular Events: A Meta-analysis of Statin Trials

S. Matthijs Boekholdt, MD, PHD; G. Kees Hovingh, MD, PHD; Samia Mora, MD, MHS; Benoit J. Arsenault, PHD; Pierre Amarenco, MD; Terje R. Pedersen, MD, PHD; John C. LaRosa, MD; David D. Waters, MD; David A. DeMicco, DPHARM; R. John Simes, MD; Antony C. Keech, MBBS, MSC; David Colquhoun, MD; Graham A. Hitman, MD; D. John Betteridge, MD; Michael B. Clearfield, DO; John R. Downs, MD; Helen M. Colhoun, MD; Antonio M. Gotto, Jr, MD, DPHIL; Paul M. Ridker, MD, MPH; Scott M. Grundy, MD, PHD; John J.P. Kastelein, MD, PHD


J Am Coll Cardiol. 2014;64(5):485-494. 

In This Article

Abstract and Introduction


Background Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not well-documented.

Objectives The aim of this meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk.

Methods This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up.

Results Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval [CI]: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB.

Conclusions The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels.


There is a wealth of evidence that high-dose statin therapy reduces both levels of atherogenic lipoproteins and cardiovascular disease (CVD) risk beyond that achieved with usual-dose statin therapy.[1] However, the evidence on the efficacy of statin therapy is interpreted on the basis of mean reductions of low-density lipoprotein cholesterol (LDL-C) and mean reductions of CVD risk within randomized trials. There is large interindividual variation in the extent of reduction of atherogenic lipoprotein levels achieved with statin therapy. Post-hoc analyses of randomized trials suggest that the benefits of statin therapy depend on the extent of achieved LDL-C reduction.[2,3] In addition, patients achieving very low LDL-C levels have been shown to be at very low CVD risk, although the number of patients achieving such very low levels in any given single trial is usually small.[4–5]

The guideline-recommended marker of atherogenic lipoproteins is LDL-C, but we have recently shown that among patients treated with statin therapy, non–high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (apoB) are at least as strongly associated with CVD risk.[7] Current guidelines consider the target LDL-C level to be in the range of 70 to 130 mg/dl, but observational evidence suggests that this range might be too conservative. Interestingly, novel lipid-lowering therapies, including mipomersen and inhibitors of proprotein convertase subtilisin/kexin 9 (PCSK9), may allow the majority of patients to reach LDL-C levels <70 mg/dl.[8–9] However, it is unclear whether pharmacological interventions resulting in atherogenic lipoprotein levels in this anticipated treatment range are beneficial in terms of CVD risk.

It was therefore our objective with this study to assess: 1) the variability of LDL-C, non-HDL-C, and apoB reduction achieved with established statin therapy; 2) the proportion of patients not reaching guideline-recommended LDL-C, non-HDL-C, or apoB levels despite being treated with high-dose statin therapy; and 3) the association between achieved very low LDL-C, non-HDL-C, or apoB levels and the risk for major cardiovascular events.