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13 March 2014
Lipoprotein(a): overlooked component of residual cardiovascular risk?

This analysis from the JUPITER study implicates lipoprotein(a) as a contributor to lipid-related residual cardiovascular risk.

Khera AV, Everett BM, Caulfield MP, Hantash FM, Wohlgemuth J, Ridker PM, Mora S. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin).Circulation 2014;129:635-42
Comments & References
Objective To investigate the association of baseline and on-treatment lipoprotein(a) [Lp(a)] concentrations with incident cardiovascular disease (CVD) events in statin-treated patients with low LDL (low-density lipoprotein) cholesterol concentrations in the JUPITER trial.
Study design JUPITER was a primary prevention, randomized, double-blind, placebo-controlled multicentre trial. Patients were randomly allocated to rosuvastatin 20 mg/day or placebo. This was a pre-specified analysis designed before measurement of Lp(a) levels.
Study population

The JUPITER study included 17,802 asymptomatic treatment-naïve subjects with LDL cholesterol <130 mg/dL (3.4 mmol/L) and a high-sensitivity C-reactive protein (hsCRP) level ≥2.0 mg/L. Patients with diabetes mellitus, or triglycerides >500 mg/dL (5.6 mmol/L) were excluded. Due to ethnic variation in Lp(a) levels, this analysis was limited to eligible white subjects (n=7746).

Primary variable • Primary JUPITER outcome, i.e. a composite of incident myocardial infarction, stroke, hospitalisation for unstable angina, arterial revascularisation, or cardiovascular death
• Lp(a) concentrations, measured with an assay that is not affected by kringle IV type 2 repeats.
Methods Cox proportional hazard regression analysis was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the primary outcome. These were reported per 1-standard deviation (SD) increment in logarithmic (ln) Lp(a) concentration, and according to Lp(a) quartiles. The effect of Lp(a) levels at baseline and after 1 year of treatment (on-treatment) was analysed.
Main results

Of white patients with Lp(a) analyses (n=7,746), median age was 66 years and 33% were female; 3,882 were treated with rosuvastatin. At baseline, median (interquartile range) LDL cholesterol was 110 (96–120) mg/dL [2.8 (2.5-3.1) mmol/L] and Lp(a) was 23 (10–50) nmol/L.

Over a median 2 year follow-up, the primary end point occurred in 210 subjects. Both baseline Lp(a) and on-statin Lp(a) concentration were associated with an increased risk of CVD (Table 1).  
For both baseline and on-treatment Lp(a) concentration, patients with elevated Lp(a) levels according to recent consensus (i.e. Lp(a) concentration ³50 mg/dL or ~108 nmol/L),1 had a larger increase in CV risk than those with lower Lp(a) levels. For statin-treated patients, there was almost a doubling in risk (Table 1).

Table 1. Association between Lp(a) and residual risk for CVD in white subjects in JUPITER


Adjusted HR (95% confidence intervals)

Baseline Lp(a)


Per 1 SD increase in Lp(a)

1.18 (1.03–1.35), p=0.02

³Threshold for high risk vs. <threshold*

1.57 (1.08–2.27), p=0.02



On-statin Lp(a)


Per 1-SD increment in Lp(a)

1.27 (1.01-1.59), p=0.04

³Threshold for high risk vs. <threshold*

1.67; (0.93–3.02), p=0.09

*50 mg/dL or ~108 nmol/L according to recent consensus1

Author's conclusion Among white JUPITER participants treated with potent statin therapy, elevated Lp(a) was a significant determinant of residual risk.


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.

References 1.Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53.
2. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of
prospective studies. Circulation 2000;102:1082-5.
3. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009;301:2331-9.
4. Erqou S, Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of coronary heart
disease, stroke, and nonvascular mortality. JAMA 2009;302:412-23.
5. Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level
and coronary disease. N Engl J Med 2009;361:2518-28.
6. Albers JJ, Slee A, O’Brien KD, Robinson JG, Kashyap ML, Kwiterovich PO Jr, Xu P, Marcovina SM. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/ High Triglyceride and Impact on Global Health Outcomes). J Am Coll Cardiol 2013;62:1575–9.
7. Raal FJ, Giugliano RP, Sabatine MS et al. Reduction in lipoprotein (a) with the PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of over 1300 patients in 4 phase 2 trials. J Am Coll Cardiol. 2014 Jan 27. pii: S0735-1097(14)00281-2.