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COMMENT

Lp(a) is an apolipoprotein B100 (apo B) containing LDL-like plasma lipoprotein rich in cholesterol, which differs from LDL as it contains an additional plasminogen-like protein, apolipoprotein(a), attached to the apolipoprotein B moiety of LDL via a single disulphide bond. Lp(a) levels are stable in a given individual over time, and under strict genetic control. There has been much scientific debate as to whether a raised Lp(a) level is a risk factor for cardiovascular disease (CVD). However, a growing body of evidence from meta-analyses, Mendelian randomisation studies and genetic analyses supports elevated Lp(a) as a causal risk factor for the development of atherosclerosis and CVD, independent of LDL cholesterol levels.(2-5) A position paper from the European Atherosclerosis Society Consensus Panel also affirmed the role of Lp(a) as a CV risk factor, and proposed a threshold Lp(a) level of ≥50 mg/dL indicative of high risk for CVD.(1)

It is therefore plausible that Lp(a) may contribute to lipid-related CV risk in statin-treated patients. Indeed, this report from the JUPITER study group in a low-risk group characterised by low LDL cholesterol levels suggests that this is the case. Among statin-treated patients, each 1-SD increment in Lp(a) concentration was associated with 27% increase in risk for CVD events. Moreover, in a subgroup of statin-treated patients with elevated Lp(a) levels consistent with elevated CV risk (≥ 50 mg/dL), there was a 67% increase in CVD risk compared with individuals with lower levels. It is important to note that this analysis was adjusted for conventional risk factors, including high-density lipoprotein (HDL), total cholesterol, LDL cholesterol and triglycerides. These findings from JUPITER are in line with recent results from the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/ High Triglyceride and Impact on Global Health Outcomes) study which implicated Lp(a) as a contributor to residual CV risk in individuals at high CV risk with atherogenic dyslipidaemia, the combination of elevated triglycerides and low plasma HDL cholesterol concentration.(6)

Taken together, these data suggest that Lp(a) measurement merits consideration for therapeutic intervention beyond statin therapy. The stumbling block is that there are no treatments currently available that specifically target Lp(a). Therapies that have a significant Lp(a)-lowering effect also influence other risk factors. Indeed, this is the case for niacin (nicotinic acid) which was previously recommended as a therapeutic intervention by the EAS Consensus Panel,1 but is no longer a therapeutic option beyond North and South America following withdrawal of niacin/laropiprant. Additionally, monoclonal antibodies targeting proprotein convertase subtilisin kexin type 9 (PCSK9) have been shown to reduce Lp(a). In the most recent analysis including data from more than 1300 patients,7 there was significant reduction in Lp(a) of 25-30% with evolocumab (AMG 145). Moreover, the absolute reduction in Lp(a) was larger in statin-treated patients with elevated Lp(a) levels (>125 nmol/L or ∼50 mg/dL) than that observed in patients with lower Lp(a) levels.

In conclusion, this report from the JUPITER trial adds to emerging evidence that implicates Lp(a) as a contributor to lipid-related residual CV risk. In the absence of a specific therapy for Lp(a), however, an outcomes study to test whether its contribution to residual risk is modifiable is not yet feasible.