Elevated Lp(a), Even in Statin-Treated Patients, Linked With Higher CVD Risks

New data from several large-scale statin trials provide yet more evidence that individuals with elevated concentrations of lipoprotein(a), even when treated with LDL cholesterol-lowering therapy, are at an increased risk of cardiovascular events.

Using patient-level data from seven randomized, placebo-controlled studies of statin therapy, investigators observed an “approximately linear” association between Lp(a) and cardiovascular events, suggesting that residual cardiovascular risk is present in patients with elevated Lp(a) and this excess risk is not addressed by statins.

“Our hypothesis is that with LDL reduction, the risk attributable to LDL cholesterol is diminished and this allows other potential risk factors, such as Lp(a), to gain in importance,” lead investigator Peter Willeit, MD, PhD (Medical University of Innsbruck, Austria), told TCTMD. “Specifically, what we think is that people who are on statin treatment and who still are at high risk, there is something else going on. Lp(a) is a really good candidate marker and a potential therapeutic target in this type of population.”

Accumulating epidemiologic and genetic evidence over the past several years has identified an association between Lp(a) concentrations and cardiovascular disease, including data from the Emerging Risk Factors Collaboration. The bulk of research, said Willeit, is based on patients without cardiovascular disease not treated with secondary-prevention therapies.

In the secondary-prevention setting, the magnitude of the association between Lp(a) and clinical events has varied, ranging from significantly positive to no association at all. These studies included limited numbers of patients with elevated Lp(a) levels—such as those greater than 50 mg/dL—which “limited the statistical power to reliably characterize the elevated risk with high Lp(a),” said Willeit.

The new meta-analysis, which was published October 4, 2018, in the Lancet, included 29,069 patients with repeat Lp(a) measurements who were treated with moderate-to-high-dose statin therapy in the AFCAPS, CARDS, 4D, JUPITER, LIPID, MIRACL, and 4S studies. In doing so, the present study helps define the magnitude of “residual risk that remained even under statin treatment,” said Willeit.   

Meta-analysis of Large Statin Trials

The meta-analysis includes patients without cardiovascular disease, those with type 2 diabetes, primary-prevention patients with elevated C-reactive protein levels, and patients with ACS, previous MI or unstable angina. The median baseline Lp(a) concentration was 11 mg/dL and the median follow-up was 3.0 years.   

Compared with baseline levels less than 15 mg/dL, there was an 11% increased risk of cardiovascular events among patients with baseline Lp(a) levels ranging from 30 mg/dL to less than 50 mg/dL and a 31% increased risk among those with Lp(a) 50 mg/dL or greater. When patients were treated with statins, there was a relative 43% increase in risk of cardiovascular events among those with Lp(a) levels 50 mg/dL or greater (compared with an on-statin treatment Lp(a) less than 15 mg/dL). These associations were statistically significant even after adjusting for conventional cardiovascular disease risk factors.

The researchers also compared the predictive value of on-statin versus on-placebo Lp(a) concentrations for incident cardiovascular disease and found that the association was stronger in the on-statin treatment group (P = 0.01).

Michael Miller, MD (University of Maryland School of Medicine, Baltimore), who was not involved in the study, told TCTMD that “Lp(a) is among the most important though underrecognized cardiovascular disease risk factors” and that at his center they will measure and check Lp(a) levels in patients with premature coronary artery disease or a strong family history.

Like Miller, John William McEvoy, MBBCh (National University of Ireland, Galway), measures Lp(a) levels in clinical practice, but noted he has a specialty interest in preventive cardiology and often sees patients with premature heart disease and lipid disorders. “I certainly find Lp(a) is valuable in patients with a family or personal history of premature coronary artery disease who are tolerating sufficient doses of statins,” McEvoy told TCTMD. “I think it’s a worthwhile test to consider with a view to stratifying their future risk. Lp(a) is one of the more common lipid disorders that is genetically driven that isn’t influenced by statin therapy.”

Critical Studies Remain Ahead

In an editorial, Gerald Watts, MBBS, PhD (University of Western Australia, Perth), and Michael Boffa, PhD (University of Western Ontario, London, Canada), call Lp(a) “one of the final frontiers for resolving residual risk for atherosclerotic cardiovascular disease.” Like others, they say, the only thing missing that challenges the “causality of Lp(a) in atherosclerotic cardiovascular disease and the case for routine screening for raised amounts of Lp(a) in plasma is data showing that specific lowering of elevated lipoprotein(a) reduces incident or recurrent atherosclerotic cardiovascular events.”

To TCTMD, Willeit said there are two critical issues when it comes to Lp(a). The first is use of the atherogenic biomarker for risk stratification, and the second is whether lowering Lp(a) reduces clinical events. With risk stratification, several studies have shown that Lp(a) provides additional information beyond conventional risk factors. “But what happens when you intervene, when you selectively reduce Lp(a)?” said Willeit. “The cardiovascular outcomes trial is the next step. We will see what happens in the next couple of years.” 

Niacin lowers Lp(a) levels by roughly 20% and the PCSK9 inhibitors evolocumab (Repatha; Amgen) and alirocumab (Praluent; Sanofi/Regeneron) reduce Lp(a) levels by approximately 30%. More importantly, injectable antisense oligonucleotide, an RNA-based therapy that directly targets apolipoprotein(a) and inhibits the translation of the primary protein of Lp(a), reduces levels by approximately 70% to 90%.

While physicians are not yet targeting Lp(a) to reduce the risk of cardiovascular events, McEvoy said the biomarker provides patients with some information to explain why they might have had a cardiovascular event. “It gives patients some prognostic information and perspective on their overall condition,” said McEvoy. “Oftentimes patients are confused, particularly those who might be coming back with a second event but they’ve been doing what they’ve been asked to do [in terms of lifestyle modification]. When they find they have an elevated Lp(a), it helps provide some perspective.”

McEvoy highlighted the conundrum physicians might face, specifically whether it’s worthwhile to measure Lp(a) if they have no means of treating elevated levels. He noted that statins increase Lp(a), at least to a small extent and said the reduction with PCSK9 inhibitors is too modest to have a clinical impact. While potent RNA-based therapies are promising, McEvoy pointed out that physicians must await the clinical trials testing whether lowering Lp(a) reduces cardiovascular events.

“Many would argue that in the post-PCSK9 inhibitor world, LDL cholesterol is no longer the fine focus of residual risk reduction,” said McEvoy. “We can get LDL levels down as low as we want with statins and PCSK9 inhibitors, but individuals still have excess cardiovascular risk despite doing so.”

Some of the residual cardiovascular risk may be related to inflammation, which was addressed in the CANTOS study with canakinumab, and some relegated to elevated triglycerides, which has been tackled with prescription-dose EPA in the soon-to-be-presented REDUCE-IT study. “And some of it is [related to] Lp(a),” said McEvoy. “Having more tools in the toolbox is certainly good for preventive cardiologists.”