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Macrovascular Residual Risk Studies

12 July 2018
Lipoprotein(a) and residual cardiovascular risk
Genetic variants in the LPA gene, a key determinant of lipoprotein(a) levels, are associated with coronary heart disease events in statin-treated individuals. These findings implicate lipoprotein(a) as a potential contributor to residual cardiovascular risk.
Wei WQ, Li X, Feng Q et al. LPA variants are associated with residual cardiovascular risk in patients receiving statins. Circulation 2018 doi: 10.1161/CIRCULATIONAHA.117.031356. [Epub ahead of print]
Objective: To investigate the role of variation at the LPA locus, a determinant of lipoprotein(a) [Lp(a)] levels, as a contributor to residual cardiovascular risk in statin-treated cohorts.
Study design: Two-stage genome-wide association study of coronary heart disease (CHD) events during statin therapy using data from the Electronic Medical Records and Genomics (eMERGE) Network, a consortium of US cohorts with DNA samples linked to electronic health record data.  Replication analyses were made using the Partners HealthCare Biobank, which joined the eMERGE network after the initial GWAS.
Study population: Data analyses were performed on 3,099 cases with CHD events on statin therapy and 7,681 controls. The replication cohort analysed data from 160 CHD cases and 1,112 controls.
Efficacy variables:

·  Genetic variation at the LPA locus

·   CHD events during statin therapy, defined as an acute myocardial infarction or the need for coronary revascularization that occurred at least 180 days following the earliest recorded date of statin use.

Methods: Genotyping was performed using commercially available genome-wide single nucleotide polymorphism (SNP) arrays with quality control criteria for variants before imputation. The primary analysis was a meta-analysis of cases and controls identified at four eMERGE sites. Assuming an additive effect of SNP alleles on CHD, risk logistic regression was used to investigate the relationship between genetic variation and the risk of developing a CHD event after statin exposure. Adjustment was made for age, sex, type 2 diabetes mellitus, hypertension, smoking status, prior CHD history, and the top 10 components for ancestry.  The analysis was run on each cohort individually, followed by a meta-analysis of the four cohorts. Replication analyses were performed separately.

·  The meta-analysis identified 7 SNPs at a genome-wide level of significance within the LPA locus associated with CHD events on statin treatment. For the most significant association (rs10455872 variant), the odds ratio for CHD events was 1.58, 95% CI 1.35-1.86, P=2.6×10−10). A similar association for this variation was shown in the replication cohort.

·   The association of this SNP with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol [LDL-C) (odds ratio 1.62, 95% CI 1.17-2.24, p=0.004) and persisted in individuals with LDL-C ≤70mg/dL (odds ratio 2.43, 95% CI 1.18-4.75, p=0.015).

Authors’ conclusion: Genetic variations at the LPA locus is associated with CHD events during statin therapy independent of the extent of LDL-C lowering. This finding provides support for exploring strategies targeting circulating concentrations of Lp(a) to reduce CHD events in patients receiving statins.


It is well recognised that residual cardiovascular risk persists despite well managed LDL-C levels with statin therapy.1 Even the addition of novel LDL-lowering agents resulting in very low LDL-C levels fails to eliminate this risk.2 Perhaps the strongest evidence to date for contributors to lipid-related residual cardiovascular risk is for triglyceride-rich lipoproteins and their remnants, supported by genetic and observational studies, although the ‘holy grail’ of reduction in cardiovascular outcomes with therapies targeting these atherogenic lipoproteins has yet to be attained.3

Other lipoproteins may also contribute to lipid-related residual cardiovascular risk. Over the last decade there has been a resurgence of interest in Lp(a), with an accumulating body of evidence implicating Lp(a) as an independent and likely causal risk factor for cardiovascular disease.4 The LPA gene, which is highly polymorphic, is a major determinant of apolipoprotein(a) [(apo(a)] size and hence circulating Lp(a) levels.4 Novel agents targeting apo(a) are now entering phase III trials. The question therefore, is whether Lp(a) is a potential contributor to residual cardiovascular risk, given that such studies will test the efficacy of these agents in individuals who will be receiving concomitant lipid lowering therapy.

The results of this study provide support for this proposal.  Adding to evidence that genetic variants in LPA are associated with risk for ischaemic heart disease,5 this study has also shown an association between two LPA variants and CHD risk in individuals on statin therapy. This association was independent of LDL-C levels and persisted in individuals with LDL-C levels below goal (<70 mg/dl or 1.8 mmol/L). These findings suggest that targeting elevated Lp(a) in individuals on statin therapy may offer another option for reducing lipid-related residual cardiovascular risk.


1. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26. doi: 10.1186/1475-2840-13-26.

2. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.

3. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.

4. Tsimikas S, Fazio S, Ferdinand KC et al. NHLBI Working Group Recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis. J Am Coll Cardiol 2018;71:177-92.

5. Kamstrup PR. Lipoprotein(a) and ischemic heart disease--a causal association? A review. Atherosclerosis 2010;211:15-23.

Key words residual cardiovascular risk; lipoprotein(a); genetic study; statin therapy