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Independence of Lp(a) and LDL-C–Mediated CV Risk
Quick Takes
- Lipoprotein(a) (Lp[a]) level is associated with increasing CV risk from 50 mg/dL to >240 mg/dL and independently of LDL-C level. There may be some risk in levels from 30-50 mg/dL.
- Elevated CV risk persists when Lp(a) level is elevated across the strata of achieved LDL-C level and change in LDL-C level, even with the lowest levels of achieved LDL-C.
- Lp(a) and LDL-C levels are independent and additive for CV risk. Reduction in LDL-C level cannot fully offset Lp(a)-mediated risk.
Study Questions:
What is the relationship between lipoprotein(a) [Lp(a)] levels, low-density lipoprotein cholesterol (LDL-C) levels, and atherosclerotic cardiovascular disease (ASCVD) risk at different thresholds?
Methods:
A participant-level meta-analysis of 27,658 participants enrolled in six 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 (log transformed) 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. Participants were categorized by baseline Lp(a) dichotomized at 50 mg/dL (~125 nmol/L) and by achieved LDL-C quartiles; by an achieved LDL-C threshold of 100 or 55 mg/dL; or by statin-achieved Lp(a) and LDL-C levels.
Results:
In the six trials, incident ASCVD was 22.2% on placebo and 18.5% on statins. Mean age was 62 ± 9 years, 28% were female, and 55% had previous CVD. Median follow-up was 2.78 (1.52, 5.26) years. Mean baseline LDL-C was 134 ± 39 mg/dL. At follow-up, mean LDL-C on statin was 87 ± 39 mg/dL and on placebo 136 ± 42 mg/dL. 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 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 [HR], 1.38; 95% confidence interval [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 (HR, 1.90; 95% CI, 1.46–2.48). There was no significant interaction among women or men, or interaction between Lp(a) and sex for ASCVD risk, or between Lp(a) and LDL-C among those ≤65 years of age (median).
Conclusions:
The authors conclude that the 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.
Perspective:
Guideline recommendations for persons with an elevated Lp(a) are to optimize other risk factors: quit smoking, blood pressure <130/80 mm Hg, exercise, ideal body weight, low saturated fat diet, statin targeting LDL-C, targeting non–high-density lipoprotein cholesterol, pre-diabetes, diabetes, and consideration of aspirin for persons without bleeding risk (Ference BA, JAMA 2022;327:1653-5). Drugs targeting Lp(a) to reduce recurrent events should be available within a few years but will be very expensive and not available for primary prevention for many years.
Clinical Topics: Dyslipidemia, Advanced Lipid Testing, Lipid Metabolism, Nonstatins, Prevention
Keywords: Cholesterol, LDL, Dyslipidemia, Heart Disease Risk Factors, Lipoprotein(a)
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