Relationship between plasma apolipoproteinc3 and plasma lipoprotein(a) levels in a diverse, healthy population

Objective: Anacetrapib, a CETP inhibitor, was previously shown to decrease plasma lipoprotein (a) [Lp(a)] levels by 35-40% in subjects also taking a statin. Thus, anacetrapib is an efficacious Lp(a)-lowering agent. The goal of this study was to define the mechanism by which anacetrapib lowers plasma Lp(a) levels. Methods: 39 moderately hyperlipidemic volunteers were enrolled in a fixed-sequence study, in which 75% were on atorvastatin 20mg/day, plus placebo for four weeks (period 1), and then atorvastatin plus anacetrapib (100 mg/day) for 8 weeks (period 2). The other 25% of the subjects received double placebo for four weeks, and then placebo plus anacetrapib for 8 weeks. Turnover studies using D3-leucine were performed at the end of each period. The present analysis utilized samples from a subset of subjects (n=12) who had plasma Lp(a) levels greater than 10 nM at the end of period 1 and had a greater than 10% reduction in Lp(a) by the end of period 2. The fractional synthetic rate (FSR:equal to fractional catabolic rate at steady state) of mature Lp(a), isolated from a D:1.019-1.21 g/ml density interval, was determined from the enrichment of a leucine-containing peptide specific to apo(a). The production rate (PR) of mature Lp(a) was calculated from the FSR and the Lp(a) pool size. To date, we have calculated the FSR and PR in 4 participants. Results: Baseline Lp(a) mean levels were 45.7 ± 6.3nM in the entire group and 56.5 ± 33.6nM in the 12 qualifying subjects. Anacetrapib lowered Lp(a) by 43 ± 22% in the 12 subjects and 21 ±12% in the 4 subjects with turnover data. In these 4 subjects, the reduction in mature Lp(a) was associated with a 24% reduction in FSR and a 41% reduction in PR. Lp(a) kinetics analyses of the remaining 8 subjects are in progress. Conclusion: These preliminary results suggest that anacetrapib decreases Lp(a) levels by significantly decreasing the production of mature Lp(a). Additional analyses are planned to determine if the reduced production of Lp(a) results from decreased entry of Lp(a) into plasma or reduced conversion of a precursor form to the mature Lp(a).

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Abstract P431: ASSOCIATION OF LIPOPROTEIN(A) WITH CARDIOVASCULAR EVENTS IN YOUNG NON-FAMILIAL HYPERCHOLESTEROLEMIA

Circulation ◽

10.1161/circ.141.suppl_1.p431 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Pao-Hsien Chu

Keyword(s):

Cardiovascular Disease ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Fatty Liver ◽

Familial Hypercholesterolemia ◽

Cardiovascular Events ◽

Healthy Population ◽

Lipoprotein A ◽

A Value ◽

Artery Disease

Background and aims: Elevated lipoprotein(a) is an independent risk factor for atherosclerotic cardiovascular disease especially in familial hypercholesterolemia. The association of elevated lipoprotein(a) within non-familial hypercholesterolemia or healthy population however, is not known. Therefore, we investigated the associations between elevated lipoprotein(a) and the risk of cardiovascular disease in a non-familial hypercholesterolemia clinically healthy young age cohort. Methods: In this retrospective cohort study, we reviewed medical records of 3,427 participants with lipoprotein(a) levels from a tertiary healthcare center in Taiwan. We further classified lipoprotein(a) level into four groups and analyzed cardiovascular events. Results: Our study population had a mean age 46 years old that were 78% male. Mean total cholesterol and low-density lipoprotein level were 195 mg/dL and 118 mg/dL respectively. Overall, 12.9% of the participants had an elevated lipoprotein(a) level (>30 mg/dL), and 2.7% had a very high level (>70 mg/dL). Thirty-three events including 6 participants with stroke and 27 with coronary artery disease were identified. A lipoprotein(a) level >70 mg/dL was associated with a higher risk of coronary artery disease events in Kaplan-Meier analysis. Aging was associated with a higher lipoprotein(a) value in the male participants but not in the female participants. However, the severity of fatty liver was not positively associated with lipoprotein(a) value. Conclusions: Elevated lipoprotein(a) was associated with coronary events but not the severity of fatty liver disease in non-familial hypercholesterolemia clinically healthy population. Aging may be associated with a higher lipoprotein(a) level in males but not females.

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