Issue: October 2017
October 09, 2017
17 min read

Beyond LDL: CV experts working to combat residual lipid-related risk

Issue: October 2017
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In recent years, the cardiology community has made great strides in lowering the LDL in high-risk patients to prevent CV events. Many patients in various risk categories have been placed on statins, and those whose LDL cannot be lowered sufficiently by statins alone have been given ezetimibe and/or PCSK9 inhibitors.

Unfortunately, some patients whose LDL levels reach acceptable levels — less than 70 mg/dL, sometimes substantially less — continue to have events. This, experts told Cardiology Today, indicates that some patients have residual risk for CVD, often due to genetics or other risk factors, and have lipids and proteins beyond LDL that must be targeted.

“What we’re learning is that we are going to be wringing the towel dry from how much benefit we are going to get when we get LDL under 50 mg/dL, and we are going to have to look at other genetic components of risk that are not addressed by LDL,” Sotirios Tsimikas, MD, FACC, FAHA, FSCAI, vice president of global cardiovascular development at Ionis Pharmaceuticals and professor of medicine and director of vascular medicine at the University of California, San Diego School of Medicine, told Cardiology Today.

The research community and industry have been working to identify these risk components and targets, and are thus developing agents to address them.

Christie M. Ballantyne, MD, FACC, FACP, FAHA, FNLA, said genetic and population studies have identified targets for new therapies to help patients with residual CV risk.
Christie M. Ballantyne, MD, FACC, FACP, FAHA, FNLA, said genetic and population studies have identified targets for new therapies to help patients with residual CV risk.

Source: Baylor College of Medicine; reprinted with permission.

In several years, treatments for various forms of residual risk could become available, bringing hope to patients who remain at risk despite achieving optimal LDL levels.

The LDL story

Many cardiologists have hypothesized that lower LDL is better for patients, and there now appears to be enough evidence to confirm that hypothesis. The link between LDL lowering via statin therapy and reduction in CV events has been established for some time, but the same effect has now been observed in the IMPROVE-IT trial of ezetimibe and the FOURIER trial of the PCSK9 inhibitor evolocumab (Repatha, Amgen). Results from the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab (Praluent, Sanofi/Regeneron) are still to come.

“At this point, with three classes of drugs — PCSK9 inhibitors, ezetimibe and statins — we can get almost everybody else to an acceptable LDL, except in patients with homozygous familial hypercholesterolemia,” Steven E. Nissen, MD, MACC, chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at the Cleveland Clinic’s Sydell and Arnold Miller Family Heart and Vascular Institute and Cardiology Today Editorial Board Member, said in an interview. “So I think we’ve probably solved the equation.”

A challenge remains, however, surrounding what to do about patients who are intolerant to statin therapy, most commonly due to muscle-related symptoms.

“If you lower LDL levels early in life and keep them low, then you have a tremendous impact,” Christie M. Ballantyne, MD, FACC, FACP, FAHA, FNLA, professor of medicine, chief of the section of cardiovascular research and director of the Center for Cardiovascular Disease Prevention at Baylor College of Medicine in Houston, and diplomate for the American Board of Clinical Lipidology, told Cardiology Today. “If everybody could take a high dose of a generic and inexpensive statin, we wouldn’t need all the other drugs. We’ve seen for many years that, in fact, the maximal dose of drugs is hardly used. There is some increase in side effects at the highest dose [of statins], so having alternatives is wonderful.”

A treatment switch to PCSK9 inhibitors may not be an option because these therapies carry a high cost (as high as $14,000 per year) and many insurance companies have resisted paying for them, experts told Cardiology Today.

Therefore, researchers are continuing to search for ways to lower LDL despite the variety of existing therapies.

One strategy is bempedoic acid (Esperion Therapeutics).


“Bempedoic acid is an LDL-lowering drug that works in a similar pathway to statins, but it has to be activated in the liver, so it has no effect on muscles,” Nissen said. “The idea is to have a drug that does what statins do but doesn’t cause any muscle adverse effects.”

CLEAR Outcomes, an outcomes trial of bempedoic acid vs. placebo in more than 10,000 patients, is underway (see Table below for list of ongoing trials of lipid-lowering therapies).

An important avenue of research will be “additional ways to lower LDL that don’t involve the LDL receptor,” Tsimikas said.

ANGPTL3 has been identified as a target for lowering LDL through “non-canonical receptor pathways,” he said. Companies including Ionis/Akcea Therapeutics and Regeneron are working on agents to target ANGPLT3.

“There is interest in looking at additional pathways to lower LDL in very high-risk patients that I think will still be worked on by drug companies over the next decade until we eventually get all patents off apheresis and get the LDL as low as possible in pretty much everybody,” Tsimikas said.

The influence of genetic risk

There are hints that genetic risk influences residual risk, but exactly how remains unclear.

“Genetics is everything,” Henry N. Ginsburg, MD, director emeritus of the Irving Institute and Herbert and Florence Irving Professor of Medicine at Columbia University Medical Center, told Cardiology Today. “Single nucleotide polymorphisms in genome-wide association studies have been associated with coronary artery disease and myocardial infarction, but they haven’t been nailed down to any molecule. The mechanisms for these genes are often very difficult to figure out.”

What is known, Nissen said, is that “family history is an incredibly powerful risk factor. We don’t know all the genes yet, but there is clearly something there beyond lipids that is driving risk. It has been more elusive than a lot of efforts.”

Peter P. Toth, MD, PhD, FAHA, FESC, FACC, director of preventive cardiology at CGH Medical Center in Sperling, Illinois; professor of clinical family and community medicine at University of Illinois College of Medicine in Peoria; and professor of medicine at Michigan State University College of Osteopathic Medicine in East Lansing, agreed that “residual risk does not just boil down to lipids. It’s the entire risk factor spectrum, so if there are risk factors that are inadequately controlled, they will contribute to residual risk. We are still groping our way to finding the most important, but, to date, they include age, lipids, BP, inflammation, smoking status and diabetes.” Beyond LDL, he said, triglyceride-enriched lipoproteins are likely culprits, especially in patients with metabolic syndrome, diabetes or genetically high serum triglycerides.

Population-based studies have enabled researchers to identify people with elevated CVD risk and tie genetic variants and lipid traits to atherosclerotic CV events, Ballantyne said.

Daniel J. Rader, MD
Daniel J. Rader

“Looking at large panels of genes, you can identify some people who have increasing risk,” he said. “We’ve had tremendous numbers in population studies and it’s been easy to look at the genetics. You can look at all the different variants associated with many different genes and lipid traits, and you can figure out which ones are associated with atherosclerotic CVD events. Lipoprotein(a) is in that group. Apolipoprotein C-III is in that group. It turns out NPC1L1, which ezetimibe works on, is in that group, as is HMG CoA-reductase, where statins work, and PCSK9. The exciting part is using population plus genetics plus Mendelian randomization to identify targets in humans.”

Daniel J. Rader, MD, Seymour Gray Professor of Molecular Medicine and chair of the department of genetics at Perelman School of Medicine, University of Pennsylvania, agreed. “This whole area is a great example of how human genetics can lead to new validated targets for common diseases,” he said.

Triglycerides as a target

Patients with low LDL but high triglycerides remain at risk for CVD, so finding ways to lower triglycerides has been a priority, experts told Cardiology Today.

“Triglyceride levels are associated with risk for heart disease based on data from both observational and genetic studies,” James A. Underberg, MD, MS, FACPM, FACP, FASH, FNLA, FASPC, clinical assistant professor of the department of medicine at NYU Langone Health and president of the National Lipid Association, told Cardiology Today. “Triglycerides, when elevated, are often associated with increased levels of apolipoprotein B, low HDL and increased levels of circulating atherogenic lipoproteins. This requires treatment beyond lowering LDL cholesterol and targeting ApoB, non-HDL or LDL particle number.”

Henry N. Ginsburg, MD
Henry N. Ginsberg

Triglycerides “don’t flow freely in the serum because they are hydrophobic,” Ginsberg said. “They are carried on lipoproteins like VLDL. I believe the principal reason why triglycerides correlate with risk is because they indirectly reflect remnant lipoprotein levels. Remnant lipoproteins carry more cholesterol per particle than LDL, can enter the artery wall and are clearly atherogenic. The triglycerides in the remnants are hydrolyzed after the particle is taken up, so you don’t find them in the atherosclerotic plaque, but triglyceride-rich lipoproteins are atherogenic, promoting an influx of inflammatory white cells.”

People with hypertriglyceridemia are usually insulin-resistant and have the metabolic syndrome, so they have a cluster of CV risk factors, Ginsberg said.

Often, ezetimibe, fish oils and/or fibrates are prescribed for patients with high triglycerides, but other therapies are also being investigated, experts said.

James A. Underberg, MD, MS, FACPM, FACP, FASH, FNLA, FASPC
James A. Underberg

“We have two large clinical trials [STRENGTH and REDUCE-IT] in progress looking at the addition of high-dose fish oils on top of a statin in patients with high triglycerides to see if they can further reduce the risk for CVD events,” Underberg said. “There’s a fibrate trial [PROMINENT] going on looking at the exact same concept. Finally, there are new drugs in development. One that’s probably closest is ApoC-III inhibitors, which also lower triglycerides and may potentially play a role in reducing cardiovascular risk when added to a statin in patients with atherogenic dyslipidemia.”

Christopher P. Cannon, MD
Christopher P. Cannon

Nissen said he is working on the STRENGTH trial of more than 10,000 patients to assess the effect of a modified form of fish oil (Epanova, AstraZeneca) on CV outcomes. “Our goal is to take people who have high triglycerides and low HDL on statins and find out whether reducing their triglycerides will reduce morbidity and mortality,” he said.

“Fish oil will probably be the next thing out of the box,” Christopher P. Cannon, MD, senior physician at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, told Cardiology Today. The REDUCE-IT CV outcomes study of icosapent ethyl (Vascepa, Amarin) has completed enrollment, he said.


Apolipoprotein C-III as a target

ApoC-III appears to be closely related to triglycerides, but its exact effect on CV risk is not yet known. There is interest in it as a target, however.

“If you can reduce the secretion of VLDL from the liver, you will lower triglycerides. If you can improve lipoprotein lipase activity, you will lower triglycerides,” Ginsberg said. “ApoC-III is an inhibitor of lipoprotein lipase and it appears that people with insulin resistance, metabolic syndrome and diabetes synthesize and secrete more ApoC-III, and it circulates much longer because it sits on the VLDL packages, which are increased. It’s blocking the exit of the triglycerides from the plasma. If you knock out ApoC-III, you will have very low triglyceride levels, not because you’re secreting less, but because it’s cleared very efficiently.”

Genomic datasets have shown that “patients with increased ApoC-III have higher rates of cardiovascular events, and patients with inherited lower levels of ApoC-III have lower risk,” Underberg told Cardiology Today. “Observational data sets looking at ApoC-III levels also track cardiovascular risk. That seems to be a triglyceride-related risk and its impact on atherogenic lipoproteins. Simply lowering triglycerides and reducing atherogenic lipoprotein burden may ultimately be the best thing that ApoC-III inhibitors can achieve.”

Two studies published in The New England Journal of Medicine in July 2014 showed loss-of-function mutations of APOC3 were associated with reduced risk for CVD.

Ionis and its affiliate Akcea are developing volanesorsen, an antisense oligonucleotide drug designed to reduce the production of ApoC-III and lower triglycerides. The initial patient populations being studied are those with familial chylomicronemia syndrome and those with familial partial lipodystrophy. In the COMPASS study, presented at the NLA Scientific Sessions in May, volanesorsen significantly safely lowered triglyceride levels and reduced pancreatitis events in those with severe hyperglyceridemia, including a small cohort with familial chylomicronemia syndrome. Results of the APPROACH trial reported in March 2017 indicated volanesorsen was associated with a 77% reduction in triglyceride levels as well as reductions in pancreatitis and pain in patients with familial chylomicronemia syndrome.

“Its initial approval will probably only be in the cohort of patients with very high triglycerides at risk for pancreatitis, not for cardiovascular risk reduction or lower triglyceride levels,” Underberg said. “That will have to wait for an outcome trial.”

Lipoprotein(a) as a target

Many people with elevated Lp(a) are at particularly high risk for CVD events, but there is little that can be done for them at this time.

Peter P. Toth, MD, PhD, FAHA, FESC, FACC
Peter P. Toth

“Lp(a) is a bad actor,” Toth said. “Lp(a) in prospective longitudinal cohorts around the world correlates with heightened risk for future cardiovascular events, but also, because it has some amino acid sequence homology with plasminogen, it appears to be prothrombotic. Those are two very bad things.”

While it is known that elevated Lp(a) is harmful, it is not exactly clear to what extent, Ballantyne said.

“We know from population studies and genetic studies that high levels of Lp(a) increase risk for MI and stroke,” he said. “There’s a question mark about after you use a high dose of a high-efficacy statin and, particularly after ACS, dual antiplatelet therapy, how much risk there is with high levels of Lp(a). That’s not totally clear right now. For primary prevention, the data are straightforward. There are some question marks in the secondary prevention setting around using more intensive therapies. Since Lp(a) is thought to confer thrombotic risk, aspirin may be of benefit.”

Niacin and PCSK9 inhibitors lower Lp(a) by approximately 25%, but “that’s not enough to make a difference, because people that have high levels have levels that are about 10 times normal,” Nissen said.


Unfortunately, he said, elevated Lp(a) is underdiagnosed because most clinicians do not order tests for it, and more effective therapies are desperately needed.

People with elevated Lp(a) “have often had multiple events by the time they’re in their 40s, and we have nothing for them right now,” he said.

Another problem, Underberg said, is that “we don’t have any data to date telling us that lowering lipoprotein(a) reduces the risk for events. No drugs used for lipoprotein(a) lowering have been shown to independently reduce the risk for events, so it’s unclear whether lowering lipoprotein(a) is a reasonable thing to do.”

Cannon agreed. “Teasing out the contribution of the lipoprotein(a) reduction compared with LDL reduction is difficult,” he said. “You don’t know from the benefit that was seen how much is attributable to one or the other. Apheresis works for lipoprotein(a) reduction and one study suggested improvements in angina. This is an active area.”

Ionis and Akcea are developing AKCEA APO(a)-LRx, an antisense oligonucleotide targeting apolipoprotein(a) in a ligand-conjugated formulation enabling a small dose. A first-in-human study showed the compound lowered Lp(a) concentrations by a mean of 66% for the 10-mg dose, 80% for the 20-mg dose and 92% for the 40-mg dose.

Sotirios Tsimikas, MD, FACC, FAHA, FSCAI
Sotirios Tsimikas

“When you have a potent drug like that, you can basically reduce Lp(a) to normal in just about everybody,” Tsimikas said. “That’s very exciting, because it’s going to be easy to test the Lp(a) hypothesis, which is that if you randomly assign patients with high Lp(a) to a therapy that lowers Lp(a) to normal vs. placebo, you can now look at their outcomes and assess whether this is a potential therapeutic approach.”

Also of note, he said, is that elevated Lp(a) is associated with aortic stenosis and is present in 30% to 40% of that population. “It would be interesting to find a patient 5 years before they need surgery and put them on a drug to lower their Lp(a),” he said. “Then maybe their valve disease doesn’t progress and you save them an operation when they get older.”

ANGPTL3 as a target

Also emerging as targets are ANGPTL3 and ANGPTL4, which may be related to triglycerides.

“They seem to impact lipoprotein lipase and inhibition of them seems to improve triglyceride metabolism and removal,” Underberg said. “Anything that seems to help with clearance of triglycerides and lowers levels of triglycerides and atherogenic lipoproteins may have a benefit in cardiovascular risk reduction.”

Both proteins became targets of interest after genetic studies implicated ANGPTL3 and ANGPTL4 as associated with CVD risk. Several agents targeting ANGPTL3 are underway, including an antisense agent (AKCEA-ANGPTL3-LRx, Ionis/Akcea) and a monoclonal antibody (evinacumab, Regeneron).

“The data presented show, like ApoC-III, remarkable reductions” in triglycerides, Ginsberg said. “The difference compared to ApoC-III inhibition is that inhibition to ANGPTL3 has been shown to also lower LDL, including in people with homozygous familial hypercholesterolemia who don’t have any LDL receptors. These patients have responded poorly or not at all to statins and PCSK9 inhibitors, and they are being treated with approaches like liver transplant or LDL apheresis, or expensive drugs like lomitapide (Juxtapid, Aegerion) and mipomersen (Kynamro, Genzyme). It appears the ANGPTL3 monoclonal antibody lowers their LDL about 40%. That’s very promising.”

In a phase 1 study of evinacumab published in NEJM, it reduced triglycerides up to 76% and LDL up to 23%.


Ionis and Akcea’s antisense agent is targeting ANGPTL3 in patients with rare hyperlipidemias, metabolic complications and nonalcoholic fatty liver disease. A phase 1/2 study of the agent presented at the American Heart Association Scientific Sessions in November 2016 showed patients given the agent had ANGPTL3 reductions up to 83% and triglyceride reductions up to 66%, as well as LDL reductions up to 35%.

“This looks like a viable approach to get additional benefit above and beyond all the drugs that are lowering LDL through the LDL receptor,” Tsimikas told Cardiology Today.

While ANGPTL4 is also involved in triglyceride metabolism, preclinical data suggested that inhibiting it with the antibody conferred enlargement of intestinal and menenteric lymph nodes, he said. “With drugs targeting ANGPTL3 available that lack this side effect, it may be the preferable protein to target.”

The HDL puzzle

While many targets look promising for reduction of residual risk, HDL remains a puzzle.

Steven E. Nissen, MD, MACC
Steven Nissen

Several agents developed to raise HDL failed in clinical trials, including the CETP inhibitors torcetrapib (Pfizer), dalcetrapib (Roche) and evacetrapib (Eli Lilly) and the HDL mimetics MDCO-216 (The Medicines Company) and CER-001 (Cerenis).

“I’m throwing in the towel,” Nissen said. “I think HDL is a marker, not a target. I know there are people who will never give up on HDL. I’m ready to move on.”

Ballantyne agreed that elevated HDL is best considered as a risk marker. He noted that Wolfgang Patsch, MD, and Josef R. Patsch, MD, found that “people with low levels of HDL had increases in postprandial triglyceride-rich lipoproteins, which were what was really causing the atherosclerosis. Maybe HDL is the integrator of your genes plus your diet plus your environment.”

In the REVEAL study presented at the European Society of Cardiology Congress in August, a fourth CETP inhibitor, anacetrapib (Merck), was found to reduce major coronary events by 9% vs. placebo when added to statin therapy (read more on the REVEAL study here).

However, experts said, the effect may be explained by the agent also lowering LDL, and the effect size may not be large enough to warrant continued development.

“Anacetrapib has problems in that it accumulates in fat cells and stays there and leaks out slowly for years,” Ginsberg said. “That might be enough of a downside, added to the very modest effect on outcomes, that Merck may not even go ahead with it.”

An exciting time

While no one knows how residual risk will best be reduced in the long term, experts agreed that a major flurry of research and development activity is warranted.

The CANTOS trial, also presented at ESC, may inspire further development, as it identified inflammation as a culprit in the risk for CV events (read more on the CANTOS trial here). Patients with MI and an elevated high-sensitivity C-reactive protein level assigned canakinumab (Novartis), which inhibits inflammation caused by overproduction of interleukin-1 beta, had reduced risk for recurrent CV events compared with patients assigned a placebo.


“The CANTOS trial suggests that if you [are taking other medications] and your CRP is still high, an anti-inflammatory agent or approach would be useful,” Ginsberg said. “This trial is a major step forward conceptually, proving what we all knew for years, that inflammation plays an important role in the progression of atherosclerosis.”

“If the price were the same as it is currently,” Cannon said, “it wouldn’t be cost-effective. But that’s OK, it gave a clear answer. That opens up the door for other anti-inflammatory agents to be looked at. I think we’re at the dawn of a whole new field of anti-inflammatory therapy.”

Ballantyne said much research will need to be done to identify which patients should get which therapies.

“How do we identify the population of people with very high residual risk that are going to get the greatest bang for the buck from these therapies?” he said. “You’re going to have to use some combination of traditional risk factors and other measurements to get a quantitative estimation of who needs what.”

Clinicians can take heart that some of their most difficult-to-treat patients may soon have therapies that can greatly reduce their CVD risk.

“After all the statin trials were done and were positive, there wasn’t much going on until PCSK9 antibodies came along and got everybody excited in the cardiology world,” Tsimikas said. “But what we’re realizing is that we probably need to go beyond LDL to have a bigger impact. The reason why there is a lot of excitement now is that there are a lot of new ways to make drug for targets previously undruggable. I anticipate an exciting time for the next 10 to 20 years in terms of development and research on pathways we could not previously target. I envision any pathway mediating cardiovascular disease where a protein is overexpressed will be targeted.” – by Erik Swain, with reporting by Darlene Dobkowski, Katie Kalvaitis and Dave Quaile

Editor’s Note: This article was updated on Oct. 17, 2017. The article misstated the status of the APPROACH trial of volanesorsen. Results reported in March 2017 indicated volanesorsen was associated with a 77% reduction in triglyceride levels as well as reductions in pancreatitis and pain in patients with familial chylomicronemia syndrome. The article also may have incorrectly implied an outcomes trial exists for volanesorsen. The article was further updated on November 3, 2017 to correct the relationship between Ionis Pharmaceuticals and Akcea Therapeutics, and to clarify the patient population in the COMPASS study. The Editors regret the errors.

Disclosures: Ballantyne reports he has consulted for and/or received grant and research support from Abbott Diagnostics, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Esperion, Ionis Pharmaceuticals, Matinas BioPharma, Novartis, Pfizer, Regeneron, Roche Diagnostics and Sanofi-Synthelabo. Cannon reports he has consulted for and/or received research grants from Alnylam, Amarin, Amgen, Arisaph, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, GlaxoSmithKline, Janssen, Kowa, Lipimedix, Merck, Pfizer, Regeneron, Sanofi and Takeda. Ginsberg reports he is a consultant for Amgen, Bristol Myers-Squibb/Pfizer, Ionis Pharmaceuticals, Kowa, Merck, Novartis and Sanofi/Regeneron and has received research grants from Ionis, Merck and Sanofi/Regeneron. Nissen reports that the Cleveland Clinic Center for Clinical Research has received funding in recent years to perform clinical trials from Abbvie, AstraZeneca, Amgen, Cerenis, Eli Lilly, Esperion, Orexigen, Pfizer, Takeda and The Medicines Company; he is involved in these clinical trials, but receives no personal remuneration for his participation. Nissen also reports he consults for many pharmaceutical companies, but requires them to donate all honoraria or consultant fees directly to charity so that he receives neither income nor a tax deduction. Rader reports he is the founder of Staten Biotechnology and consults for Alnylam, Novartis and Pfizer. Toth reports he is a consultant and speaker for Amgen and Regeneron, and has a relationship with Amarin, Kowa and Merck. Tsimikas reports he is an employee of and receives personal fees from Ionis Pharmaceuticals and is named as inventor in patents held by UCSD related to assessment of atherogenesis, risk prediction and therapy. Underberg reports he has consulted for Akcea Therapeutics, Amgen, Regeneron and Sanofi.