The potential next pathway to target in CVD prevention: ‘Common’ elevated Lp(a)
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About 20% of the global population and one in five U.S. adults have elevated levels of lipoprotein(a), a complex form of LDL that strongly predicts risk for coronary disease and aortic valve stenosis.
Evidence for a causal association between Lp(a) concentration, which is primarily genetically determined, and CV outcomes across ethnicities continues to build. Data published in the Journal of the American College of Cardiology in July show that, among patients with elevated Lp(a), the cumulative incidence rate of major adverse CV events, including all-cause and CV death, and major adverse limb events were nearly two times and four times higher, respectively, compared with patients with lower Lp(a) concentrations. The associations were not influenced by LDL levels or statin administration.
Recent breakthroughs have shifted Lp(a) from a biomarker of atherosclerotic CVD risk to a potential target of novel therapy. Several Lp(a) inhibitors are currently in phase 1, 2 and 3 testing, with at least three promising candidates emerging.
The next step, according to experts, is to raise awareness that Lp(a) should be measured once for every patient, ideally as early as possible.
“The problem is that only 13% of people who have known ASCVD have a known Lp(a) level,” Cardiology Today Editorial Board Member Steven E. Nissen, MD, MACC, chief academic officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic, said in an interview. “Physicians have not been obtaining Lp(a) levels. I understand why; there has never been a treatment. I happen to think that, even without a treatment, patients and their providers need to know this: All vascular disease and aortic stenosis are accelerated by high levels of Lp(a).”
The updated 2018 ACC/American Heart Association/Multisociety Guideline on the Management of Blood Cholesterol states that elevated Lp(a), defined as a level of at least 50 mg/dL or higher, constitutes a risk-enhancing factor, especially at higher levels, and notes a relative indication for its measurement is family history of premature ASCVD. However, U.S. guidelines do not universally recommend routine measurement, though the latest European Atherosclerosis Society consensus statement recommends a routine one-time Lp(a) measurement. For those who do have their Lp(a) measured, clinicians must determine how to manage patients who have very high Lp(a) concentrations when there are no approved drugs for treatment, according to Michelle L. O’Donoghue, MD, MPH, cardiovascular medicine specialist and senior investigator of the TIMI Study Group at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School.
“I get phone calls where someone will say, ‘My LDL is 45 mg/dL, but my Lp(a) is 400 nmol/L. What do I do?’” O’Donoghue told Cardiology Today. “That is a real clinical challenge, without a firm answer.”
Genetic data: ‘The targets have shifted’
Lp(a) was discovered in human serum in 1963 during a study of variation in LDL antigenicity. The LPA gene makes messenger RNA, which then makes apolipoprotein (Apo)a, which then forms Lp(a) particles by binding covalently to the apolipoprotein B moiety of LDL. There has been interest in the lipoprotein since its discovery, but the relationship between Lp(a) and CVD has only recently become more firmly established, according to Christie M. Ballantyne, MD, FACC, FACP, FAHA, FNLA, chief of the section of cardiovascular research and professor of medicine at Baylor College of Medicine.
“Interest in Lp(a) goes back a while, but recently, several things have happened,” Ballantyne told Cardiology Today. “One is the genetic data are now conclusive that genetic variants associated with high Lp(a) levels predict increased ASCVD risk and also risk for aortic stenosis. Whenever we have epidemiology and now, Mendelian randomization data showing risk for increased events, that tells us, OK, this is important: Lp(a) is in the causal pathway. The targets have shifted to things that have the genetic data to support them.”
Lp(a) contains ApoB, which can cause atherosclerosis and plaque formation, but also contains Apo(a), which structurally resembles plasminogen, which can inhibit the degradation of blood clots, Patrick M. Moriarty, MD, FACC, FACP, FNLA, FESC, professor of medicine and director of clinical pharmacology and the Atherosclerosis/Lipoprotein-Apheresis Center at the University of Kansas Medical Center, told Cardiology Today. Lp(a) is also the preferential lipoprotein carrier for oxidized phospholipids, a proatherogenic and proinflammatory biomarker.
“We think now that the most important parts of Lp(a) are the inflammatory molecules that are bound to the Lp(a), particularly oxidized phospholipids, shown to potentially degrade the plaque to make it susceptible to rupture,” Moriarty said. “So, Lp(a) is a triple threat.”
Attenuating risk without approved treatment
There are currently no approved pharmacological therapies for targeted treatment of Lp(a). However, there are promising candidates in development. Current treatments are primarily aimed at risk factor modification.
“We have PCSK9 inhibitors that do lower Lp(a) by about 25% to 30%, though there is substantial variability in how much it is lowered,” O’Donoghue said. “We may need to see a much larger absolute reduction for it to translate into meaningful clinical benefit.”
In the U.S., lipoprotein apheresis therapy is approved for patients with familial hypercholesterolemia. In Germany, apheresis therapy is used for patients with an Lp(a) of 60 mg/dL or higher with normal LDL and CVD.
Diet and exercise have no meaningful effect on Lp(a) concentration; however, lifestyle modification should still be recommended along with medications to intensify risk factor management, Nissen said.
“I will more intensively treat LDL and other risk factors if I know the Lp(a) is high,” Nissen said. “I will target a much lower LDL because I want to take the other risk factors off the table. That is a reasonable approach.”
Ballantyne agreed.
“It makes sense that if someone is at increased risk, you treat their BP, introduce lifestyle modifications like smoking cessation and regular exercise,” Ballantyne said. “These things work.”
New research suggests that low-dose aspirin for primary prevention of CV events may benefit some adults with elevated Lp(a)-associated genotypes. In a new analysis of the ASPREE trial published in September that assessed participants who carry genotypes associated with elevated Lp(a) levels, in rs3798220-C and high Lp(a) genomic risk score subgroups, aspirin reduced major adverse CV events by 11.4 and 3.3 events per 1,000 person-years, respectively, without significantly increasing bleeding risk.
“There is also some data to suggest that unlike other primary prevention patients, people with an elevated Lp(a) benefit from aspirin,” Nissen said. “We do not give aspirin for primary prevention, but it makes sense if the Lp(a) is high.”
Without an FDA-approved treatment, clinicians generally try to attenuate CV risks by offering statin therapy, O’Donoghue said.
“Statins do not lower Lp(a), but it is well established that statins reduce CV risk profile,” O’Donoghue said. “It is only now that there are so many therapeutics emerging in the pipeline that have shined an intense spotlight on this topic. The feeling is that, once and for all, we will get definitive answers soon.”
Promising drug candidates
There are three therapies targeting Lp(a) in phase 2 or 3 development: pelacarsen (Novartis/Ionis), an antisense therapy, and olpasiran (Amgen) and LY3819469 (Eli Lilly), which are small interfering RNA (siRNA) therapies (Table).
Pelacarsen, given by self-injection once monthly, is being tested in the ongoing phase 3 Lp(a) HORIZON study, which is now fully enrolled with more than 8,000 participants with prior ASCVD events, Nissen said. The drug is a single-stranded DNA connected to N-Acetylgalactosamine (GalNAc), which has a receptor in the liver.
“It is a remarkable approach to drug delivery; the hepatocytes take up that sugar, GalNAc, but attached to it is a small piece of DNA, short sequence, that is complementary to messenger RNA for Apo(a), an essential component of Lp(a),” said Nissen, who is the HORIZON study chair. “It blocks the message by degrading the messenger RNA that codes for the critical protein in Lp(a). In a medium-sized phase 2 trial, Lp(a) levels were reduced by 80% with pelacarsen.”
Olpasiran, an siRNA also directed to the liver, yielded similarly substantial and sustained reductions in Lp(a) concentrations among patients with established ASCVD in the phase 2 OCEAN(a)-DOSE study.
“The higher doses of olpasiran studied in phase 2 led to a more than 95% reduction in Lp(a) concentration, so certainly a very robust effect,” said O’Donoghue, who presented the OCEAN(a)-DOSE findings at the AHA Scientific Sessions in November. “Both classes of drugs, so far, appear safe.”
Eli Lilly also has a siRNA drug, LY3819469, in development moving through phases 2 and 3, Nissen said. “It appears to be an effective therapy, with results hopefully to be published in the near future,” he said.
“What we have here, essentially, is three shots on goal,” Nissen said. “Our hope is that at least one of them will get to the back of the net, and maybe all three.”
At an earlier stage is SLN360 (Silence Therapeutics), a siRNA drug that in the phase 1 APOLLO study, published in JAMA in April, produced Lp(a) reductions of more than 90% for 300 mg and 600 mg doses.
Measure Lp(a) for everyone ‘at least once’
Lp(a) levels greater than 50 mg/dL contribute to a higher risk for heart disease. Lp(a) levels differ across race groups and people of sub-Saharan descent are more genetically predisposed to this risk factor, Moriarty said.
However, Lp(a) is still not routinely measured in the U.S.
“With many patients having elevated Lp(a), particularly African Americans, it is a marker for disease and there should be universal testing for it,” Moriarty said. “Europe does it. Canada does it. It is not that far away for the U.S.; I guarantee it. The guidelines are catching up with the new drugs in the pipeline.”
Even without approved drugs, it is important for a person to know if they are at greater risk for heart disease, Ballantyne said.
“We don’t have a target for calcium, either, yet everyone says a coronary artery calcium score is a great test,” Ballantyne said. “You don’t need a specific therapy to reduce CV events. If the major cause of morbidity and mortality is CVD, why not get a one-time test to see if someone has a high Lp(a)? It is in the European guidelines and it makes sense. The lipid profile will not show this.”
O’Donoghue said if someone has elevated Lp(a), immediate family members should also receive priority screening.
“For people on the high end of the Lp(a) spectrum, we have definitely seen that when family members are screened, a similar pattern may exist,” O’Donoghue said. “Screening is important because it helps to identify someone who might be a good candidate for aggressive, good primary prevention who might not otherwise seek medical attention until they are much older.”
‘A future primary prevention drug’
Lp(a) therapies in the pipeline are currently being tested only in secondary prevention populations; most participants have extremely high Lp(a) levels so that a dramatic decline can be demonstrated. But much like the initial statin trials, that will likely change with time, Moriarty said.
“High Lp(a) is associated with the initiation, but not the progression, of aortic valve stenosis,” Moriarty said. “If I have a patient with high Lp(a), am I going to wait until they develop aortic valve stenosis? No. I see this as being a future primary prevention drug.”
Different studies suggest wide-ranging estimates for how much of an absolute drop in Lp(a) is needed to translate to meaningful clinical benefit. The consensus among most researchers: a very large reduction, O’Donoghue said.
“One important question raised is: Are there any beneficial physiologic functions to Lp(a)?” O’Donoghue said. “That remains incompletely understood. The only adverse finding for people with seemingly low Lp(a) is a higher risk for diabetes. It is unknown whether or not these therapies will increase risk for diabetes; that will be closely watched. But individuals who have very low Lp(a) concentrations appear to be very healthy.”
Moriarty, who suggested humans have “evolved beyond” a need for Lp(a), said drugs that target Lp(a) could be the future for the one-quarter of the world’s population that has elevated levels.
“Lp(a) only has negative connotations,” Moriarty said. “Getting rid of it — getting it as low as you can — is the future.”
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