High Lp(a) levels associated with increased CV risk despite statin treatment
Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials
Introduction and methods
Existing data show that elevated lipoprotein(a) (Lp[a]) levels are associated with increased risk of CHD, stroke, peripheral arterial disease, and calcific aortic valve stenosis [1-3]. However, the contribution of high Lp(a) levels to CV events in patients with established CVD with or without statin therapy is unclear.
This meta-analysis of the Lipoprotein(a) Studies Collaboration used 7 randomized, placebo-controlled trials [4-10] of statins with individual patient-level data for CVD outcomes and Lp(a) measurements at baseline and follow-up (under statin treatment), and evaluated the associations of baseline and on-treatment Lp(a) levels with CV risk.
In each study, CV outcomes, including fatal or non-fatal CHD, stroke, or revascularization procedures, were stratified by predefined Lp(a) groups (15 to <30 mg/dL, 30 to <50 mg/dL, and ≥50 mg/dL, vs <15 mg/dL).
- Out of a total of 45,044 patients, 35% were excluded because of missing Lp(a) measurements, leaving a sample of 29,069 patients for analysis, out of whom 14,536 patients were randomly allocated to statin treatment.
- The effect of statin treatment on Lp(a) concentration was heterogeneous across trials. The pooled percentage change was –0.4% (95%CI: –7 to 7), with 3 trials showing a mean increase (between 2% and 15%) and 4 trials showing a mean decrease (between –1% and –13%) in Lp(a) levels.
- The age- and gender-adjusted correlations between baseline and follow-up Lp(a) were comparable in patients receiving statin treatment and in those of the placebo group (r=0.948 vs r=0.952).
- The incidence of CV events per 1,000 person-years was 55.3 (95%CI: 53.4-57.3) in those with baseline Lp(a) <15 mg/dL, 56.3 (95%CI: 52.6–60.2) in those with Lp(a) levels between 15-<30 mg/dL, 66.7 (95%CI: 62.0–71.8) in those with Lp(a) levels between 30-<50 mg/dL, and 80.0 (95%CI: 75.3–84.9) in those with Lp(a) ≥50 mg/dL.
- Among patients receiving statin therapy, the incidence of CV events per 1,000 person-years was 49.0 (95%CI: 46.5–51.6) for Lp(a) <15 mg/dL, 46.4 (95%CI: 41.6–51.7) for Lp(a) 15-<30 mg/dL, 56.2 (95%CI: 50.3–62.8) for Lp(a) 30-<50 mg/dL, and 77.2 (95%CI: 71.1–83.8) for Lp(a) ≥50 mg/dL.
- These results remained similar after additional adjustment for previous CVD, diabetes, smoking, systolic blood pressure, and lipid levels.
- After multivariable adjustment, the HRs for CV events were 1.47 (95%CI: 1.25-1.73) for patients with Lp(a) ≥50 mg/dL treated with statins, and 1.26 (95%CI: 1.06-1.50) for patients receiving placebo (P-interaction =0.031), compared with patients showing Lp(a) levels lower than 50 mg/dL during a median follow-up of one year.
Elevated Lp(a) levels of 50 mg/dL or higher, at baseline or on-treatment, were associated with an increased risk of CV events, independent of other CV risk factors. The effect was evident on treatment with either statin or placebo. These data suggest existence of a residual risk in patients with elevated Lp(a) that is not addressed by statins and support the rationale for outcomes trials to test specific therapies to lower Lp(a).