Lower lipoprotein(a) reduces CVD risk irrespective of levels of LDL-C, finds study

Lower lipoprotein(a) reduces CVD risk irrespective of levels of low-density lipoprotein cholesterol, LDL-C, finds a new study presented at European Atherosclerosis Society Congress 2019. It has been suggested that elevated Lp(a) causes CVD mainly in individuals with high levels of low-density lipoprotein cholesterol (LDL-C) levels and the opposite should also be true.

Exposure to lower levels of lipoprotein(a) during one's lifetime lowers cardiovascular risk, suggests results from a Mendelian randomization analysis. The effects were not modified by gender, the presence of genetic variants that mimic the effects of antiplatelet therapy, and lower levels of low-density lipoprotein (LDL) cholesterol.

The effect of lipoprotein(a)-lowering therapies is therefore unlikely to be attenuated by treatment with low-density lipoprotein (LDL) cholesterol lowering drugs or by treatment with antiplatelet agents.

The results, presented at the European Atherosclerosis Society (EAS) 2019 Congress, showed that to achieve a reduction in disease risk compared to a 1 mmol/L reduction in LDL cholesterol, lipoprotein(a) levels would have to be lowered by around 170 mol/L.Lipoprotein(a) "does not appear to have a clinically meaningful prothrombotic effect, and therefore antiplatelet therapy or anticoagulation is unlikely to reduce the increased risk of cardiovascular disease associated with elevated lipoprotein(a)," Katzmann said at the EAS Congress.

"This means that enrolling patients on antiplatelet therapy should not increase the amount of lipoprotein(a) that must be reduced to achieve a clinically meaningful benefit in a short-term trial," he said.

"Novel therapies that potentially and specifically reduce plasma concentrations of Lp(a) by up to 70% to 80% are currently in development," the authors note.

However, it is not clear how much lipoprotein(a) has to be lowered to reduced cardiovascular risk to the same degree as a 1 mmol/L reduction in LDL cholesterol, and whether their effects on cardiovascular risk are independent.

To investigate further, and determine any gender differences in the effect of lipoprotein(a) levels and whether the protein has any significant prothrombotic effects, the researchers looked at data in the UK Biobank, which contains data on approximately 480,000 individuals of European descent. Of these, 363,186 had lipoprotein(a) measured using a single isoform sensitive assay.

This showed that the 50th percentile of lipoprotein(a) was 20.1 nmol/L, the 80th percentile was 80.9 nmol/L, the 90th percentile was 131.2 nmol/L, and the 95th percentile was 158.3 nmol/L.

A genetic score based on two LPA variants that affect lipoprotein(a) levels was then calculated to examine the effect of naturally random allocation to lower lipoprotein(a) on cardiovascular disease risk.

Key findings of the study include:

• The composite endpoint of myocardial infarction, cardiovascular death, and coronary revascularization occurred in 23,463 individuals.


• lifelong exposure to 100 nmol/L lower lipoprotein(a) levels resulted in an odds ratio of the composite endpoint of 0.67, or a relative risk reduction of 33%.


• The greatest effect was seen for coronary revascularization, at an odds ratio of 0.59 per 100 nmol/L reduction, followed by myocardial infarction, at an odds ratio of 0.69, and cardiovascular death, at 0.71.


• A 1 mmol/L reduction in LDL-cholesterol levels was associated with an odds ratio of the composite endpoint of 0.50, or a relative risk reduction of 50%.


• To achieve the same effect on the cardiovascular risk as a 1 mmol/L reduction in LDL-cholesterol levels, lipoprotein(a) would have to be lowered by 171 nmol/L, or 91 mg/dL.


• There was no significant difference in the impact of a 100 nmol/L reduction in lipoprotein(a) levels in cardiovascular risk between men and women, at odds ratios of 0.72 and 0.68, respectively.


• There was no significant difference in the impact of a 100 nmol/L reduction in lipoprotein(a) levels in cardiovascular risk between men and women, at odds ratios of 0.72 and 0.68, respectively.


• There was also no difference in cardiovascular risk reduction with lipoprotein(a) reduction across deciles of LDL cholesterol, whether assessed by measured LDL-cholesterol levels or 98 exome variant scores.


• No significant difference was found in variants in the guanylate cyclase soluble subunit alpha-3 gene (GUCY1A3), which is involved in regulating vascular tone and platelet activation, the team again found no significant differences.


• Combining Factor II and Factor 5 gene variants into a genetic score that mimicked the effect of an antithrombin therapy showed an increase in venous thromboembolism risk by anticoagulant score, lowering lipoprotein(a) levels by 100 nmol/L had no significant effect on the risk for venous thromboembolism, deep vein thrombosis, or pulmonary embolism.

The risk for the coronary disease increases with increasing lipoprotein(a) levels, the clinical benefit of lowering lipoprotein(a) is likely to be proportional to the absolute reduction in concentrations, Katzmann said.