Causal Effect of Lp(a) on CVD Not Modified by LDL

Liam Davenport

June 17, 2019

MAASTRICHT, The Netherlands — Results of a Mendelian randomization analysis suggest lifetime exposure to lower levels of lipoprotein(a) is associated with lower cardiovascular risk, an effect that was not modified by lower levels of low-density-lipoprotein (LDL) cholesterol, gender, or the presence of genetic variants that mimic the effects of antiplatelet therapy.

"Therefore, in randomized clinical trials, the effect of lipoprotein(a)-lowering therapies is unlikely to be attenuated by treatment with LDL-C-lowering drugs or by treatment with antiplatelet agents," the researchers, led by Julius L. Katzmann, MD, Department of Cardiology, University of Leipzig, Germany, conclude.

Katzmann and colleagues looked at data on almost 370,000 participants in the UK Biobank who had plasma lipoprotein(a) measurements to determine the effect of gene variants that result in lower lifetime proteins levels on cardiovascular disease risk.

Their results, presented here at the European Atherosclerosis Society (EAS) 2019 Congress, showed that, to achieve a reduction in disease risk comparable to a 1 mmol/L reduction in LDL cholesterol, lipoprotein(a) levels would have to be lowered by around 170 mol/L.

Katzmann told the audience that 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)."

"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.

Pia R. Kamstrup, MD, PhD, head of the Department of Clinical Biochemistry, Copenhagen University Hospital, Denmark, who was not involved in the research, described the results as "very positive."

She told theheart.org | Medscape Cardiology that the findings, along with those from other large studies, document "without a doubt" that lipoprotein(a) "is a very common and strong risk factor for cardiovascular disease, and that the genetic evidence is very strong that it is indeed causal."

Kamstrup said that the findings are also "very important in moving the field forward" toward a large, randomized trial.

"Specifically for this study, it was very reassuring to see that...with 375,000 individuals who had lipoprotein(a) plasma measurements performed, there did not seem to be issues in planning a clinical trial with participants being on antiplatelet therapy, the fear being that, if participants were on antiplatelet therapy, that could somehow ameliorate the risk associated with high Lp(a) levels [and] sabotage a clinical trial," she said.

Increasing Risk

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

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

The researchers calculated that lifelong exposure to 100 nmol/L lower lipoprotein(a) levels resulted in an odds ratio of the composite end point 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.

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

Consequently, it was determined that to achieve the same effect on 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 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.

When looking at 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.

Next, they combined Factor II and Factor 5 gene variants into a genetic score that mimicked the effect of an antithrombin therapy.

Although this, as expected, 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.

Kamstrup said that this contrasts with what they saw in their Copenhagen studies, which involved more than 100,000 participants.

Despite the overall findings in the two studies being "very much in line," the Danish group found "a small signal for thrombotic disease, deep vein thrombosis [DVT], and pulmonary embolism for extremely high levels of lipoprotein(a)."

She said: "So if you have levels above the 95th percentile of the concentration distribution, in our studies at least in the general population, we see a slight, perhaps 30%, increased risk of the combined end point of DVT and pulmonary embolism."

Kamstrup and colleagues also examined the number of kringle IV repeats in lipoprotein(a), increasing numbers of which increase the size of the protein.

They found the same association with DVT and pulmonary embolism, "indicating that it is indeed a causal effect."

Kamstrup noted, however: "It is important to stress that the risk is marginally increased, and...it should not invalidate or endanger the planning of a large randomized trial."

When asked during the postpresentation discussion whether the number of kringle repeats could affect the anti- or prothrombotic effects of lipoprotein(a), Katzmann conceded that they didn't have the relevant information in the dataset.

Nevertheless, he said that because the number of kringle repeats also influences lipoprotein(a) levels, it is "hard to distinguish" their effects, "so I'm not sure how we can pull this apart."

No conflicts of interest or funding declared.

European Atherosclerosis Society (EAS) 2019 Congress: Abstract EAS19-0777. Presented May 27, 2019.

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