Should Lp(a) Be Measured and Treated? Two Experts Hash Out Its Current Role

Researchers debated the merits of Lp(a)—while one sees the future, another argued in favor of sticking with LDL cholesterol.

Should Lp(a) Be Measured and Treated? Two Experts Hash Out Its Current Role

MAASTRICHT, the Netherlands—Should physicians measure, let alone treat, elevated levels of lipoprotein(a)? Or is it much too early, and the data much too weak, to even consider such a therapeutic track?

Lp(a)’s clinical utility was the question two experts grappled with during a debate closing out the 2019 European Atherosclerosis Society (EAS) Congress, and while they took opposing positions, both agreed it will ultimately be settled with a large-scale cardiovascular outcomes study that is currently being planned.

For time being, there is only one conclusion based on the existing data, according to Brian Ference, MD (University of Cambridge, England). 

“There is absolutely no evidence that lowering Lp(a) with any of the therapies—niacin, CETP inhibitors, and the PCSK9 inhibitors—has any effect on reducing the risk of cardiovascular disease,” said Ference. “At the moment, we should not be recommending treatment with an Lp(a)-lowering therapy, or even aspirin or an antithrombin.”

Sotirios Tsimikas, MD (University of California, San Diego), on the other hand, likened patients with genetically elevated Lp(a) levels to having the sword of Damocles hanging over them. At the moment, there is a real need for developing specific Lp(a)-lowering therapies because there is currently nothing to offer such patients, particularly those who have already had a cardiovascular event.

“There is a lot of anxiety out there about this risk factor,” he said. “Everybody is really waiting for something to offer these patients.” Tsimikas, an employee of Ionis Pharmaceuticals, a company currently developing an antisense oligonucleotide targeting Lp(a), estimates there are 60 million US individuals with Lp(a) levels greater than 60 mg/dL and 32 million with levels exceeding 90 mg/dL.

In the European guidelines, Lp(a) “should be considered” in selected patients at high risk for atherosclerotic cardiovascular disease (ASCVD), those with a family history of premature ASCVD, and for reclassification purposes in patients at borderline risk (IIb recommendation). In the US guidelines, elevated Lp(a)—defined as ≥ 50 mg/dL or ≥ 125 nmol/L—is considered a “risk-enhancing” factor that can be used to determine how aggressively to treat LDL cholesterol levels.

Elevated Lp(a) and Calcific Aortic Valves

Arguing in favor of measurement and treatment, Tsimikas noted that the risk of elevated Lp(a) manifests in all arterial sites, including the aortic valve. “You can explain about one-third of coronary artery disease with elevated Lp(a) and you can explain about 37% of aortic valve disease,” he said. To date, Tsimikas and colleagues have published seven papers showing a connection between the progression of calcific aortic stenosis and elevations in Lp(a) and oxidized phospholipids.

Four studies testing statins in the setting of aortic valve disease showed the drugs failed to halt the progression of calcific aortic valve stenosis, however. Tsimikas pointed to data from the ASTRONOMER trial suggesting researchers might have targeted the wrong molecule by going after LDL cholesterol. He noted that rosuvastatin increased Lp(a) 20% and oxidized phospholipids 46% in the trial.

“We used a therapy to lower LDL, but if the pathophysiological determinant is Lp(a), the particles are going in the wrong direction with statin therapy,” he said.  

With respect to cardiovascular events, Tsimikas highlighted a 2018 study from Peter Willeit, MD, PhD (Medical University of Innsbruck, Austria), showing an almost linear relationship between Lp(a) and clinical outcomes in seven randomized, placebo-controlled trials of statin therapy. Statin-treated patients with Lp(a) levels ≥ 50 mg/dL had a 47% increased risk of cardiovascular events compared with patients with lower Lp(a) levels. The association was independent of established risk factors, he said.   

Taking a pragmatic tact, Ference said a mythology currently surrounds Lp(a), noting that the lipoprotein is considered proinflammatory, proatherogenic, and prothrombotic. And yet the data supporting Lp(a) as a causal risk factor for cardiovascular disease is surprisingly weak. Given the absence of strong evidence, the current focus should be on LDL and other apoB-containing lipoproteins to most effectively reduce risk for the greatest number of people.

“I’m afraid the holes in the evidence begin at the beginning,” said Ference. “Originally, the observational research suggests that Lp(a) is only a weak risk factor for cardiovascular disease. In fact, in the original Emerging Risk Factors Collaboration involving more than 40 studies and 350,000 patients, each standard deviation in Lp(a) only increased the risk of cardiovascular events by about 15%.”

Yet in the same studies, each standard deviation in LDL cholesterol increased the risk of cardiovascular events by 40%. As a result, the Emerging Risk Factors Collaboration concluded that the focus should be directed to lowering LDL cholesterol levels. “One can’t argue that Lp(a) is a dominant risk factor in cardiovascular disease,” said Ference. “It should by no means divert our attention from the important causal risk factors.”

How Big a Reduction Is Needed?

Shifting from the observational data, Ference next turned to the mendelian randomization studies showing that higher levels of Lp(a) were associated with increasing risks of cardiovascular events. Here, however, Ference argued that such studies don’t prove that therapies targeting Lp(a) would lower the risk of future events. “Instead, we have to estimate how much we have to lower that biomarker to produce a clinically meaningful effect, or whether or not it would be useful to pursue it,” said Ference.

Based on the relationship between Lp(a) and coronary heart disease, Ference estimated that a reduction in the range of 80 to 100 mg/dL would be needed to achieve a therapeutic effect akin to a 40 mg/dL reduction in LDL cholesterol. “This strongly implies that we’re going to require extremely large absolute reductions in Lp(a) to reduce the risk of cardiovascular disease,” said Ference. “That assessment is only valid if Lp(a) and LDL cholesterol have similar cumulative effects over time.”

Using data from 486,000 patients included in the UK Biobank, Ference estimated only patients in the 95th to 99th percentile would have sufficiently high enough levels of Lp(a) to warrant treatment. Given that such large reductions might be needed, Ference suggested that very few people may benefit from potential therapies.

Tsimikas, though, was not persuaded and said he remains optimistic about AKCEA-APO(a)-LRx, the antisense oligonucleotide that has been previously shown to reduce Lp(a) levels by as much as 80% depending on the dose. When used at the dose needed to achieve an 80% reduction, nearly 100% of patients in a phase II, dose-ranging study achieved a treatment goal of less than 50 mg/dL. “The way I see this antisense is having Crestor as the very first statin,” he said. “It’s going to get everybody to goal and it’s going to be very potent.”

Ference, for his part, also expressed optimism. Despite taking the opposing side in the EAS debate, he predicted Lp(a) will turn out to play a crucial role in clinical practice. Nonetheless, he cautioned investigators to design clinical trials so that they include patients with very high baseline Lp(a) to achieve very large therapeutic absolute reductions in Lp(a). Only in doing so will they avoid an unexpected null trial result that would throw the field for a loop.        

Sources
  • Ference BA. Don’t treat high Lp(a): at least, not at the moment. Presented at: European Atherosclerosis Society 2019 Congress. May 29, 2019. Maastricht, the Netherlands.

  • Tsimikas S. Treat Lp(a). Presented at: European Atherosclerosis Society 2019 Congress. May 29, 2019. Maastricht, the Netherlands.

Disclosures
  • Ference reports research grants from Merck, Novartis, Amgen, Esperion, Therapeutics, and Ionis Pharmaceuticals; and consulting for/serving on the advisory board of/ receiving honoraria from Merck, Amgen, Regeneron, Sanofi, Novartis, Pfizer, Eli Lilly, Novo Nordisk, Ionis Pharmaceuticals, dalCOR, The Medicines Company, CiVi Pharm, KrKa Pharmaceuticals, Medtronic, Celera, and Quest Diagnostics.
  • Tsimikas holds a dual appointment at UCSD and Ionis Pharmaceuticals.

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