Lp(a) and LDL-c are independent and additive predictors of ASCVD risk

A large meta-analysis of 6 statin trials also showed that ASCVD risk was increased in statin-treated patients with elevated Lp(a), even when they achieved the lowest LDL-c, and those with the highest levels of both Lp(a) and LDL-c were at the highest risk.

This summary is based on the publication of Bhatia HS, Wandel S, Willeit P, et al. - Independence of Lipoprotein(a) and Low-Density Lipoprotein Cholesterol-Mediated Cardiovascular Risk: A Participant-Level Meta-Analysis. Circulation. 2025 Jan 28;151(4):312-321. doi: 10.1161/CIRCULATIONAHA.124.069556

Introduction and methods

Background

LDL-c and Lp(a) levels are independently associated with increased risk of ASCVD [1-3]. With the emergence of Lp(a) targeted therapies [11], it is important to understand the relationship between Lp(a), LDL-c, and ASCVD risk and the corresponding therapeutic implications.

Aim of the study

The authors examined the associations of baseline LDL-c and Lp(a) levels with ASCVD risk in patients treated with statins or placebo and the association of baseline Lp(a) levels with ASCVD risk across statin-achieved LDL-c levels.

Methods

In a participant-level meta-analysis, data were collected from patients enrolled in 6 placebo-controlled RCTs of statin treatment: 4D Study (Die Deutsche Diabetes Dialyse), 4S (Scandinavian Simvastatin Survival Study), CARDS (Collaborative Atorvastatin Diabetes Study), JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin), LIPID (Long-Term Intervention With Pravastatin in Ischaemic Disease), and MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering) [12-17]. All trials, except for the 4D Study, showed a beneficial effect of statin treatment on CV outcomes. LDL-c and Lp(a) measurements were available for 27,658 participants. Median follow-up time was 2.8 years (range: 2.0–5.5).

Outcome

The primary endpoint was the incidence of ASCVD, defined as fatal or nonfatal CHD, fatal or nonfatal stroke, or any coronary or carotid revascularization.

Main results

Associations of baseline LDL-c and Lp(a) with ASCVD risk

• Baseline Lp(a) and LDL-c levels were independently associated with ASCVD risk (HR for Lp(a) per SD: 1.07; 95%CI: 1.04–1.10; P<0.001; HR for LDL-c per SD: 1.06; 95%CI: 1.02–1.10; P=0.001; P for multiplicative interaction between Lp(a) and LDL-c=0.170).

• Among patients treated with placebo, both Lp(a) and LDL-c levels were associated with ASCVD risk (HR for Lp(a) per SD: 1.05; 95%CI: 1.01–1.10; P=0.013; HR for LDL-c per SD: 1.08; 95%CI: 1.03–1.14; P=0.002).

• Among statin-treated patients, Lp(a) levels were also associated with ASCVD risk (HR per SD: 1.08; 95%CI: 1.04–1.11; P<0.001), whereas there was no significant association for LDL-c levels (HR per SD: 1.04; 95%CI: 0.98–1.10; P=0.170).

• Above the reference Lp(a) level of 5 mg/dL, the risk of ASCVD log-linearly increased with increasing Lp(a) levels in statin- and placebo-treated patients (P for multiplicative interaction between Lp(a) and LDL-c=0.125).

Association of baseline Lp(a) with ASCVD risk stratified by statin-achieved LDL-c

• Next, statin-treated patients were categorized by baseline Lp(a) level (dichotomized at 50 mg/dL (≈125 nmol/L)– a threshold that is recommended in some guidelines [1]) and quartiles of achieved LDL-c level on statin therapy. The observed rate of ASCVD events increased with increasing baseline Lp(a) and achieved LDL-c levels, with patients with Lp(a) >50 mg/dL and LDL-c level in the highest quartile (>140.8 mg/dL) having the highest ASCVD risk compared with the reference group of patients with Lp(a) ≤50 mg/dL and achieved LDL-c level in the lowest quartile (<77.3 mg/dL mg/dL) (10.30 vs. 3.15 events per 100 patient-years; HR: 1.90; 95%CI: 1.46–2.48).

• Even among participants in the lowest achieved LDL-c quartile, patients with Lp(a) >50 mg/dL had a greater ASCVD risk than those with Lp(a) ≤50 mg/dL (HR: 1.38; 95%CI: 1.06–1.79). 

• When the absolute change in LDL-c levels was analyzed, there was a similar trend of increasing ASCVD risk with increasing baseline Lp(a) levels and smaller absolute LDL-c change. Even patients with the largest absolute LDL-c change (−192.6 to −52.09 mg/dL) had an increased ASCVD risk when their baseline Lp(a) level was >50 mg/dL compared with ≤50 mg/dL (HR: 1.28; 95%CI: 1.09–1.50).

Conclusion

In this large participant-level meta-analysis of 6 statin trials, baseline LDL-c and Lp(a) levels were independently and additively associated with increased ASCVD risk. Among statin-treated patients, elevated Lp(a) levels were associated with increased ASCVD risk across quartiles of achieved LDL-c level and absolute LDL-c change. Patients with the highest levels of both Lp(a) and LDL-c were at the highest risk. According to the authors, their results show that “potent LDL-c level reduction did not offset Lp(a)-mediated risk [and] emphasize the need for testing and incorporation of Lp(a) into cardiovascular risk assessment.”

Find this article online at Circulation.

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