February 06, 2015
14 min read

Familial hypercholesterolemia: Underdiagnosed, risks underappreciated; new treatments on horizon

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If untreated, familial hypercholesterolemia confers a greatly elevated risk for CVD. Yet, familial hypercholesterolemia is routinely underdiagnosed in much of the world, including the United States.

It is estimated that without treatment a man with heterozygous familial hypercholesterolemia (HeFH) has a 50% chance of having an MI by age 50 years and a woman has a 30% chance by age 60 years. The odds for those individuals with homozygous familial hypercholesterolemia (HoFH) are even worse; it is not uncommon for those patients to have CVD as teenagers.

However, many people with FH never receive a formal diagnosis and, thus, while many may be treated for high cholesterol, their risk for CV events can be underappreciated.

“FH tends to be lumped together with all other kinds of elevated cholesterol levels. That’s wrong for two reasons,” Joshua W. Knowles, MD, PhD, FAHA, FACC, assistant professor of cardiovascular medicine at Stanford University; attending physician at the Stanford Center for Inherited Cardiovascular Disease, Familial Hypercholesterolemia Clinic; and chief medical officer of the FH Foundation, South Pasadena, Calif., told Cardiology Today.

Joshua Knowles

Joshua W. Knowles, MD, PhD, FAHA, FACC, is chief medical officer of the FH Foundation, an organization dedicated to raising awareness of all forms of familial hypercholesterolemia.

Photo: Norbert von der Groeben/Stanford Health Care; printed with permission.

“One, patients with FH have a much higher risk for heart disease because they have a much higher lifelong burden of high cholesterol. Two, FH is an autosomal-dominant condition, so if one individual in a family has it that means each first-degree relative has a 50% chance of also having FH, so family screening needs to be much more rigorous.”

Treatment of FH often requires a number of different therapies in combination, and these patients are expected to be among the first to benefit from proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors after approval from the FDA.

“We have many patients with FH and severe vascular disease who are on four drugs to control their cholesterol, yet their LDL levels are still more than 130 mg/dL,” Knowles said. “There is going to be a role for those PCSK9 inhibitors.”

Prevalence and phenotypes

The prevalence of FH has been traditionally estimated at one in 500 for HeFH and one in 1 million for HoFH in white individuals of European descent. However, recent research indicates that FH may be even more common.

A study published online in Nature in December by Ron Do, PhD, and Sekar Kathiresan, MD, from Massachusetts General Hospital, and colleagues reported a prevalence of one in 217 for pathologic LDL receptor mutations, which was consistent with some other recent estimates from Europe.

Certain populations, including South African Afrikaaners, French Canadians, Christian Lebanese and Ashkenazi Jews, have higher rates of FH than the general population, so “it becomes important for practicing physicians to know their environment,” Seth J. Baum, MD, FACC, FACPM, FAHA, FNLA, president of Preventive Cardiology Inc., Boca Raton, Fla.; medical director of women’s preventive cardiology at Christine E. Lynn Women’s Health and Wellness Institute, Boca Raton Regional Hospital; voluntary associate professor of medicine at the University of Miami Miller School of Medicine; and president-elect of the American Society of Preventive Cardiology, said in an interview.


Seth J. Baum

The expression of FH is also more complex than previously believed. When FH was first described in 1973, it was strictly defined as a mutation of the LDL receptor. But it is now known that mutations of other genes can produce the same effects, Baum and colleagues wrote in an editorial published in the Journal of Clinical Lipidology in December.

Similarly, although the consensus had been that very high LDL thresholds needed to be met for a diagnosis of FH to be made, new research suggests it is not that simple. People with untreated HoFH typically have LDL >500 mg/dL, but one woman with genetically proven HoFH was documented with untreated LDL 170 mg/dL.

“In terms of the different phenotypes, there is a giant spectrum, and it can be extraordinarily confusing,” said Baum, a member of the FH Foundation’s board of directors. “You can have people with a given mutation who have a very high LDL or not as high LDL. You can have the same mutation and respond nicely to LDL-lowering drugs or terribly to LDL-lowering drugs. You can have a MI or not have an infarction. You have to treat the individual patient, whatever that patient’s phenotypic expression may be.”



A consensus statement from the European Atherosclerosis Society published in 2013 estimated that the diagnosis rate for FH was less than 1% in 12 of the 22 countries for which data were available, including the United States. Experts interviewed by Cardiology Today said the US diagnosis rate may not be as low as less than 1%, but is likely no greater than 10%.

There are several theories about why the condition is so underdiagnosed. A common theory has to do with the way doctors are trained.

“The difficulty arose from what we were all taught in medical school,” Baum said. “You learn about FH, you’re shown an image of a small child with terrible tendon xanthomas and subcutaneous xanthomas and corneal arcus, and horrible coronary disease at the age of 5, which is a homozygous FH patient. You say, ‘That’s one in a million, I’m never going to see that patient,’ and promptly forget about it. We are now fighting against that, educationally.”

Another issue, according to Knowles, is the lack of ICD-9 diagnostic codes for FH, so there is no system in place to prompt doctors to consider FH as a diagnosis. The FH Foundation has lobbied for FH to be included in the ICD-10 coding system when it comes out, he said.

Patrick M. Moriarty, MD, FACC, FACP

Patrick M. Moriarty

There are other systemic reasons, Patrick M. Moriarty, MD, FACC, FACP, director of the division of clinical pharmacology and the lipoprotein apheresis center at the University of Kansas Medical Center, Kansas City, Kan., told Cardiology Today. “Until recently, measuring total cholesterol and LDL in young people had not been a major priority in preventive disease activity by pediatricians and general practitioners. But even when it becomes diagnosed, treatment can be sustained until a further date based on pediatricians fearful of using lipid-lowering therapy in a young population that is asymptomatic, or even primary care physicians [not wanting to prescribe medical therapy to] 20- to 30-year-olds who are asymptomatic despite having high cholesterol.”

Diagnosis of patients with HoFH is considered easier because of extreme factors such as family history of very early CVD and death, extremely high LDL levels in childhood, and presence of xanthomas and corneal arcus. HoFH, on the other hand, is often misinterpreted as poor adherence to a healthy lifestyle, experts said.

“Many patients with heterozygous FH do not express the full phenotype until they get older,” Karol E. Watson, MD, PhD, FACC, professor of medicine and cardiology at the David Geffen School of Medicine, University of California, Los Angeles; co-director of the UCLA program in preventive cardiology; and director of the UCLA Barbra Streisand Women’s Heart Health Program, said in an interview. “As they age, each year their cholesterol will go up slightly, so it may not strike alarms. Once LDL gets above 190 mg/dL, the diagnosis is often familial. It is very hard to eat your way to an LDL that high. There is often a genetic abnormality.”

Most diagnoses are made on clinical grounds, and health care professionals can use any of three systems — Simon Broome, Dutch Lipid Clinic Network or Make Early Diagnosis to Prevent Early Death (MEDPED) — to determine whether a patient meets the criteria for FH.

Debate surrounds to what extent genetic screening should be used to diagnose patients with FH. Genetic screening is common in some countries in Europe, most notably the Netherlands, but is rarely used in the United States outside of research settings.

At the American Heart Association Scientific Sessions in November, one session featured experts from around the world who “went over evidence showing that, in the proper setting, the use of genetic testing helps our ability to find FH, to distinguish it from other forms of heart disease and to potentially motivate patients,” said Knowles, who co-moderated the session. “It was eye-opening for the audience to hear that this is a place where genetic medicine might play an important role, and needs to be explored further.”

Karol E. Watson, MD, PhD, FACC

Karol E. Watson

“A genetic test can often nail the diagnosis,” Watson said, noting that she primarily uses it in the children of people with FH.

However, “there are, just in the LDL receptor mutations, the most prominent form of FH, more than 1,700 known mutations that could cause FH. You can still have FH and miss it with one of those genetic tests because many people with FH do not have mutations in these genes. Not only that, but we now know that defects in the apolipoprotein B molecule, defects in PCSK9, and many other things that we call FH-like phenotypes, are indistinguishable from FH, so it doesn’t make sense not to treat them like it, and they will be missed with the standard FH genetic panel,” Watson said.

Because current genetic screening methods only diagnose about 70% of FH cases, alternative diagnostic methods may be necessary, Moriarty said. He often uses carotid intima-media thickness, which can show signs of disease long before symptoms present.

However, he said his guiding principle is that “if a patient has high LDL, regardless of whether it is genetically proven FH, and is a young person with no other reason for these comorbidity problems, there is a strong chance that patient has FH and a strong chance he or she needs to be treated.”

The FH Foundation has established the Cascade FH Registry, which aims to encourage screening for FH among all parents, siblings and children of anyone diagnosed with the condition.


Available treatments

Many patients with FH receive multiple therapies to help lower LDL and prevent CVD, experts said. As with all patients tasked with lowering cholesterol, the first step is lifestyle changes including diet, exercise and weight management. “Unfortunately with FH, those steps have less of an impact on lowering LDL numbers,” Baum said.

Statins are the first step in medical therapy, as most now have generic versions. Statin therapy “has the most potent ability to reduce LDL, and the most positive possibility of reducing CV events,” Moriarty said.

For many patients with FH, however, statins are not enough, and there is a higher rate of statin intolerance in the FH population than in the general population, experts said.

The most common second-line therapy is ezetimibe (Zetia, Merck). The efficacy of ezetimibe as an add-on therapy to statins was demonstrated in the IMPROVE-IT trial, in which patients assigned simvastatin plus ezetimibe (Vytorin, Merck) achieved lower LDL levels and had a lower rate of CV events compared with those assigned simvastatin (Zocor, Merck) monotherapy.

Sometimes therapies for which there is less clinical evidence, such as bile acid binding resins and niacin, are used. Moriarty noted that in a few cases, he will use coenzyme Q10 or omega-3 fatty acids. Fibric acid derivatives are sometimes used, but generally not in the United States because their use is not supported in guidelines, Knowles said.

Michael J. Koren, MD, FACC, CPI

Michael J. Koren

For adults with HoFH whose LDL cannot be controlled with any combination of available therapies, two drugs approved about 2 years ago are available: lomitapide (Juxtapid, Aegerion) and mipomersen (Kynamro, Isis Pharmaceutical/Genzyme). Although they are associated with significant reductions in LDL, “they are not widely used, are quite expensive and are associated with a number of side effects,” Michael J. Koren, MD, FACC, CPI, chief medical officer of the Jacksonville Center for Clinical Research, Jacksonville, Fla., told Cardiology Today. “This is an area where there is room for improvement.”

Patients whose LDL levels remain dangerously high despite optimal pharmacotherapy may be referred for lipoprotein apheresis, in which LDL particles are removed from the bloodstream. To qualify, “you have to fail pharmacotherapy … and your LDL needs to still be above 200 mg/dL with known CVD or above 300 mg/dL without known CVD,” Moriarty said. “But there is a gray zone. Many centers are starting therapies for patients with LDLs in the 180s or 190s, based on ongoing symptomatic disease.”

The process can lower LDL by more than 70%, but must be repeated approximately every 2 weeks, Baum said. Additionally, some insurers are trying to restrict access to the treatment, which the FH Foundation, the National Lipid Association and others are fighting.

The promise of PCSK9 inhibitors

The treatment strategy for FH is anticipated to be transformed by PCSK9 inhibitors, many of which are currently in development and under investigation. Experts predict FDA approval sometime in 2015. Amgen in August filed a biologics license application for its PCSK9 inhibitor evolocumab. Sanofi and Regeneron in July acquired a priority review voucher for $67.5 million, which will cut the regulatory review time for its PCSK9 inhibitor alirocumab by approximately 4 months, and in the fourth quarter of 2014 filed a BLA for alirocumab. (Amgen in October sued Sanofi and Regeneron for patent infringement.)

Clinical data released thus far for alirocumab and evolocumab demonstrate substantial reductions in LDL in patients with FH, without increased serious adverse events.

“The PCSK9 inhibitors appear to be remarkably consistent in their ability to lower LDL by 40% to 60%,” Knowles said. “It doesn’t seem to matter what other drugs a patient is on. The evidence continues to accumulate that … any way you are able to lower the LDL is going to be better. I am rather confident that the long-term outcome studies will show benefit.”

The drugs’ mechanism of action is the key to the positive results so far, according to Koren, an investigator involved in clinical trials for several PCSK9 inhibitors, including evolocumab and alirocumab. “When you block PCSK9, the LDL receptor is enabled, which is a safe and effective mechanism for LDL lowering that statins also use. This mechanism is anticipated to make a difference in CV outcomes,” he said. “In addition, there is a synergy between PCKS9 inhibitors and statins: While statins upregulate the LDL receptor, they also upregulate the production of PCSK9, which offsets some of the effects of statins.”

Response to PCSK9 inhibitors by patients with FH may vary by genotype and metabolic issues, Baum said. “The homozygous FH patient with two null LDL receptor mutations is not going to respond well,” he said. “But on the other end of the spectrum, some heterozygous FH patients can achieve a 60% reduction in LDL, which is remarkable.”

However, Koren said, results of the TESLA study of evolocumab in patients with HoFH were encouraging. “It showed that even homozygotes, who theoretically do not have any LDL receptors or have two genes for deficient LDL receptors, still seem to respond to a PCSK9 inhibitor to some degree,” he said. “The study raises some issues as to whether or not PCSK9 works in other places than just the LDL receptor in these types of patients.” Knowles noted, however, that patients with 0% LDL receptor activity did not respond.

Table. Developmental stages of PCSK9 inhibitors

Source: Ballantyne CM. Late-Breaking Clinical Trials and FDA update. Presented at: Cardiometabolic Health Congress; Oct. 22-25, 2014; Boston. Adapted from: Stein EA. Curr Atheroscler Rep. 2013;15:310.

Patients with FH, whether involved in the trials or not, have been enthusiastic about the prospects of PCSK9 inhibitors, even to the point where they are not bothered by the injectable delivery system, experts said.

“There has not been a lot of pushback in getting the injections,” Koren said. “Interestingly, if you get an injection every 2 weeks or once a month, there may be some compliance benefits. Some patients might actually prefer that regimen rather than having to remember to take a pill every day.”

Experts noted that cost will be a major factor in how quickly and widespread the PCSK9 inhibitors are adopted once approved.

Moriarty, an investigator on some trials for alirocumab, said that drug will soon be tested in patients on apheresis. “The goal is to try to, if not wean them off of apheresis, at least decrease the intervals of therapy,” he said.

Many phase 3 studies for alirocumab and evolocumab have been completed. Phase 3 studies have begun for another PCSK9 inhibitor, bococizumab (Pfizer/Rinat), and research for other PCSK9 inhibitors is in earlier stages (see Table). However, the most anticipated studies are those assessing long-term clinical outcomes: ODYSSEY OUTCOMES for alirocumab, FOURIER for evolocumab, and SPIRE-1 and SPIRE-2 for bococizumab.


Others in the pipeline

Other therapies for patients with FH may come along after PCSK9 inhibitors, but none are expected to be available on the market in the near future.

A few years ago, there was enthusiasm about CETP inhibitors. Two, anacetrapib (Merck) and evacetrapib (Eli Lilly), remain in development, but two others, torcetrapib (Pfizer) and dalcetrapib (Hoffmann-La Roche), failed in clinical studies.

Watson said the concern with CETP inhibitors is that, unlike with PCSK9 inhibitors, where natural PCSK9 loss-of-function mutations were known to be associated with better CV outcomes, “the CETP natural polymorphisms that lower CETP function and availability have not demonstrated a consistent lowering of vascular events. So it kind of made sense to me that that therapy would not necessarily work.”

Another approach that may help patients with FH is lowering of lipoprotein(a); patients with controlled LDL but elevated Lp(a) remain at risk for CV events, according to Moriarty. Although PCSK9 inhibitors have been shown to lower Lp(a), the same has not been shown for other currently available therapies, except mipomersen and lipoprotein apheresis, he said.

Isis Pharmaceuticals is developing an antisense oligonucleotide Lp(a) that has shown the ability to lower Lp(a) by as much as 90% in early studies, according to Moriarty. That development process could produce “the landmark study that is needed to validate, first, that Lp(a) is an independent risk factor for CVD, and second, that treating it by this drug class can have a significant benefit,” he said.

‘Time is plaque’

Many available therapies can help reverse the effects of FH, and PCSK9 inhibitors have the potential to become one of the most effective therapies to do so, but the benefits will be mitigated if physicians and the public are not aware of FH and do not keep it in mind as a potential diagnosis.

“Education is the key,” Baum said. “If you don’t have FH on the tip of your tongue when you create a differential diagnosis, you are never going to diagnose it and people will go untreated.”

The stakes are particularly high because missing one diagnosis can mean missing many diagnoses.

“We don’t find individuals with FH, we only find families with FH,” Knowles said. “If we forget to screen family members, we miss the most important public health benefit for looking for FH: finding people before they have events. We need to continue to stress that.”

Although FH is a chronic condition, the odds of having a CV event because of it being left untreated are so high that it might well be considered an acute condition.

“Time is of the essence in managing these patients,” Baum said. “We used to say that time is muscle, now we should be saying time is plaque. We need to treat them aggressively and quickly.” – by Erik Swain

Baum SJ. J Clin Lipidol. 2014;8:542-549.
Cannon CP. LBCT.02: Anti-lipid therapy and prevention of CAD. Presented at: American Heart Association Scientific Sessions; Nov. 15-19, 2014; Chicago.
Do R. Nature. 2014;doi:10.1038/nature13917.
Nordestgaard BG. Eur Heart J. 2013;34:3478-3490.
Raal FJ. Clinical and Late-Breaking Session I: Abstract 1177. Presented at: the 82nd Congress of the European Atherosclerosis Society; May 31-June 3, 2014; Madrid.

For more information:
Seth J. Baum, MD, FACC, FACPM, FAHA, FNLA, can be reached at 7900 Glades Road, Suite 400, Boca Raton, FL 33434; email: sjbaum@fpim.org.
Joshua W. Knowles, MD, PhD, FAHA, FACC, can be reached at 300 Pasteur Drive, Rm CV273, Falk CVRC MC 5406, Stanford, CA 94305; email: knowlej@stanford.edu.
Michael J. Koren, MD, FACC, CPI, can be reached at 4085 University Blvd. South, Jacksonville, FL 32216; email: mkoren@encoredocs.com.
Patrick M. Moriarty, MD, FACC, FACP, can be reached at 3901 Rainbow Blvd., Mail Stop 3008, Kansas City, KS 66160; email: pmoriart@kumc.edu.
Karol E. Watson, MD, PhD, FACC, can be reached at Geffen School of Medicine at UCLA, Division of Cardiology, 650 Charles E. Young Drive South, A2-237 CHS MC: 167917, Los Angeles, CA 90095; email: kwatson@mednet.ucla.edu.
Disclosures: Baum reports serving on the board of directors for the FH Foundation and advisory boards for Aegerion, AstraZeneca, Genzyme and Kowa, and lecturing for Merck. Knowles reports serving as chief medical officer of the FH Foundation, which receives support from several pharmaceutical companies, but receives no financial compensation. Koren is an employee of a clinical research center that receives research support from numerous industry and government sources. Moriarty reports receiving research grants from Amgen, B. Braun, Catabasis, Eli Lilly, Espirion, Genzyme, Kaneka, Kowa, Novartis, Pfizer, Regeneron and Sanofi; consulting for B. Braun, Catabasis, Duke Clinical Research Institute, Genzyme, Kaneka and Regeneron; and receiving honoraria from Aegerion, Amarin and Kowa. Watson reports consulting for Daiichi Sankyo and Merck.