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Independence of Lipoprotein(a) and Low-Density Lipoprotein Cholesterol-Mediated Cardiovascular Risk: A
Harpreet S Bhatia1, Simon Wandel2, Peter Willeit3
1Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla (H.S.B., S.T.).
Insights
High lipoprotein(a) [Lp(a)] levels significantly increase atherosclerotic cardiovascular disease (ASCVD) risk, independent of low-density lipoprotein cholesterol (LDL-C). Lowering LDL-C does not eliminate the elevated ASCVD risk associated with high Lp(a) levels.
Area of Science:
- Cardiology
- Genetics
- Preventive Medicine
Background:
- Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] are independently linked to atherosclerotic cardiovascular disease (ASCVD).
- The combined impact of Lp(a) and LDL-C levels on ASCVD risk requires further elucidation.
Purpose of the Study:
- To investigate the association between Lp(a) and LDL-C levels and ASCVD risk.
- To determine if LDL-C lowering mitigates Lp(a)-associated ASCVD risk.
Main Methods:
- A meta-analysis of 27,658 participants from 6 placebo-controlled statin trials.
- Assessed the association of baseline Lp(a) and LDL-C levels with ASCVD events using multivariable models.
- Evaluated the joint association of Lp(a) and achieved LDL-C levels with ASCVD risk.
Main Results:
- Elevated Lp(a) levels showed a log-linear association with increased ASCVD risk.
- Individuals with Lp(a) >50 mg/dL had higher ASCVD risk across all LDL-C levels.
- The highest ASCVD risk was observed with Lp(a) >50 mg/dL and high LDL-C levels.
Conclusions:
- Lp(a) and LDL-C levels independently and additively contribute to ASCVD risk.
- LDL-C reduction alone may not fully counteract the risk posed by elevated Lp(a).
Background:
Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) levels are independently associated with atherosclerotic cardiovascular disease (ASCVD). However, the relationship between Lp(a) level, LDL-C level, and ASCVD risk at different thresholds is not well defined.
Methods:
A participant-level meta-analysis of 27 658 participants enrolled in 6 placebo-controlled statin trials was performed to assess the association of LDL-C and Lp(a) levels with risk of fatal or nonfatal coronary heart disease events, stroke, or any coronary or carotid revascularization (ASCVD). The multivariable-adjusted association between baseline Lp(a) level and ASCVD risk was modeled continuously using generalized additive models, and the association between baseline LDL-C level and ASCVD risk by baseline Lp(a) level by Cox proportional hazards models with random effects. The joint association between Lp(a) level and statin-achieved LDL-C level with ASCVD risk was evaluated using Cox proportional hazards models.
Results:
Compared with an Lp(a) level of 5 mg/dL, increasing levels of Lp(a) were log-linearly associated with ASCVD risk in statin- and placebo-treated patients. Among statin-treated individuals, those with Lp(a) level >50 mg/dL (≈125 nmol/L) had increased risk across all quartiles of achieved LDL-C level and absolute change in LDL-C level. Even among those with the lowest quartile of achieved LDL-C level (3.1-77.0 mg/dL), those with Lp(a) level >50 mg/dL had greater ASCVD risk (hazard ratio, 1.38 [95% CI, 1.06-1.79]) than those with Lp(a) level ≤50 mg/dL. The greatest risk was observed with both Lp(a) level >50 mg/dL and LDL-C level in the fourth quartile (hazard ratio, 1.90 [95% CI, 1.46-2.48]).
Conclusions:
These findings demonstrate the independent and additive nature of Lp(a) and LDL-C levels for ASCVD risk, and that LDL-C lowering does not fully offset Lp(a)-mediated risk.
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