Focus on PCSK9 Inhibitors: From Genetics to Clinical Practice

ABSTRACT

Elevation of low-density lipoprotein cholesterol (LDL-C) is an important cause of atherosclerotic cardiovascular disease (ASCVD). Over the years, clinical outcome studies with LDL-C lowering agents have revealed that reducing LCL-C levels is effective in reducing rates of major ASCVD events. Although secondary factors play a role in clinical expression, severe lipid disorders often have a strong genetic component. Genetic revelations have provided novel targets for improving LDL-C management in high-risk individuals. Most recently, researchers have explored how the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) alters LDL metabolism and lowers LDL-C levels to achieve lipid goals and potentially reduce ASCVD risk in patients with severe lipid disorders, including familial hypercholesterolemia (FH). This CMHC Spotlight article summarizes the clinical evidence demonstrating the safety, tolerability, and efficacy of PCSK9 inhibitors in lowering LDL-C levels. Reductions in LDL-C levels by PCSK9 inhibitors alone in patients who are statin intolerant or combined with maximally tolerated statins in patients with severe lipid disorders demonstrate the potential for reduced morbidity and mortality associated with ASCVD.

KEYWORDS:

• PCSK9 inhibitors
• LDL-C
• lipid disorders
• familial hypercholesterolemia
• statin intolerance

CME/CE Information

Activity Title: Focus on PCSK9 Inhibitors: From Genetics to Clinical Practice Highlights from a CME Symposium held at the Cardiometabolic Health Congress (CMHC), Sheraton Boston Hotel, Boston, MA 23 October 2015

Activity Format: CME/CE Spotlight

Estimated Time to Complete: 1 hour

Release Date: July 11, 2016

Expiration Date: July 11, 2017

Credit Type(s) Available: ACCME, CDR, ANCC, ACPE

Maximum Credits: 1 AMA PRA Category 1 Credit(s)^TM

Provided By: This activity is jointly provided by and Medical Education Resources, Inc (MER) and Tarsus Cardio Inc. dba Cardiometabolic Health Congress.

Commercial Supporter:

This activity is supported by an educational grant from Amgen, Inc.

Program Description:

This article summarizes the clinical evidence demonstrating the safety, tolerability, and efficacy of PCSK9 inhibitors in lowering LDL-C levels. Reductions in LDL-C levels by PCSK9 inhibitors alone in patients who are statin intolerant or combined with maximally tolerated statins in patients with severe lipid disorders demonstrate the potential for reduced morbidity and mortality associated with ASCVD.

Purpose Statement:

To improve patient outcomes through communication and intervention strategies regarding management of patients with lipid disorders.

Intended Audience:

This activity is designed for advanced-level clinicians responsible for the prevention, diagnosis, and management of cardiometabolic risk.

Educational Objectives:

Upon completion of this activity, participants should be able to:

• Describe the importance of lowering LDL-C levels in high-risk patients, including those with residual atherosclerotic cardiovascular disease (ASCVD) risk due to familial hypercholesterolemia (FH) and/or statin intolerance

• Assess the genetic basis and mechanistic rationale for lowering LDL-C through novel pathways and the use of monoclonal antibodies (mAbs)

• Review the efficacy of PCSK9 inhibitors in reducing ASCVD risk based on recent clinical trial data

• Identify the potential use of emerging lipid-lowering agents as replacements or complementary treatments for patients on statins based on future outcomes studies and patient preference

FACULTY INFORMATION:

Corresponding Author:

Marc S. Sabatine, MD, MPH

Chairman, Thrombolysis in Myocardial Infarction (TIMI) Study Group

Division of Cardiovascular Medicine

Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine

Brigham and Women’s Hospital, and the Department of Medicine

Professor of Medicine, Harvard Medical School

Boston, MA

[email protected]

Disclosures:

Grants/Research Support: Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Daiichi Sankyo, Eisai, Gilead,GlaxoSmithKline, Intarcia, Merck, Roche Diagnostics, Sanofi-Aventis, Takeda

Consulting Fees: Alnylam, Amgen, AstraZeneca, Cubist, CVS Caremark, Intarcia, Merck

Co-authors:

James A. Underberg, MD

Clinical Assistant Professor of Medicine

NYU Medical School

NYU Center for CVD Prevention

Director, Bellevue Hospital Lipid Clinic

New York, NY

Disclosures:

Grants/Research Support: Pfizer, Kowa, Aegerion

Consulting Fees: Amgen, Sanofi, Novartis, Esperion, Liposcience, Amarin

Speakers’ Bureau: Merck, Amarin, Sanofi, Genzyme, Kowa, AstraZeneca

Michael Koren, MD

Chief Executive Officer

Jacksonville Center for Clinical Research

Past President, Academy of Physicians in Clinical Research

Jacksonville, FL

Disclosures:

Grants/Research Support: Sanofi, Regeneron, Amgen, Pfizer

Speakers’ Bureau: Sanofi, Regeneron, Amgen

Seth J. Baum, MD, FACC, FAHA, FACPM, FNLA

Chief Medical Officer, MB Clinical Research

President Elect, American Society for Preventive Cardiology

Board of Directors, The FH Foundation

Disclosures:

Consulting Fees: Merck, AstraZeneca, Aegerion Pharmaceuticals Inc., Genzyme, Sanofi

Speakers’ Bureau: Merck, AstraZeneca, Aegerion Pharmaceuticals Inc., Genzyme, Sanofi

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MER: Julie Johnson, PharmD, Veronda Smith, FNP

CMHC: Erin Franceschini, MS, Karin McAdams, Mary Mihalovic, Melissa Wiles

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Participants are expected to read the full activity before attempting to complete the posttest and evaluation. Successful completion will lead to the issuance of a certificate for 1 AMA PRA Category 1 Credit(s)™.

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A natural human experiment: PCSK9 and cholesterol

James A. Underberg, MD

Elevation of low-density lipoprotein cholesterol (LDL-C) is an important determinant in severe lipid disorders that can lead to atherosclerotic cardiovascular disease (ASCVD). Over the years, clinical outcome studies with LDL-C-lowering agents have revealed that reducing LCL-C levels is effective in reducing rates of major ASCVD events [1–3]. Although secondary factors play a role in clinical expression, lipid disorders have a strong genetic component, which is now a target for improving clinical outcomes in high risk individuals.

For the past 20 years, statins used as monotherapy or in combination with other lipid-lowering agents, such as ezetimibe, have been the mainstay therapy for lowering LDL-C levels. Although statins have proven efficacious in patients with high LDL-C levels, there remains a need for alternative lipid lowering agents in the difficult to treat patient populations. To meet this need, researchers have begun exploring other targets in the LDL metabolic pathway. Most recently, researchers have investigated the role of the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), in reducing LDL-C levels in patients with dyslipidemia and severe hypercholesterolemia.

History of PCSK9

When discovered in 2003 [4], PCSK9 was thought to be involved in neural apoptosis and liver regeneration due to its association with the NARC-1 gene [5]. However, Michael Brown, Joseph Goldstein, and Jay Horton began uncovering the role of PCSK9 in the regulation of cholesterol, either through production and/or clearance [5–7]. These investigators worked with a variety of elements involved in the regulation of cholesterol synthesis, called sterol regulatory element-binding proteins (SREBP), and noted that these proteins not only controlled the metabolism of cholesterol, but also impacted the expression of the LDL receptor (LDLR) and PCSK9.

Subsequently, French researchers uncovered the pedigree of a family with familial hypercholesterolemia (FH) in whom genetic sequencing did not reveal a known or identifiable cause based on an abnormality of the LDLR. Gene sequencing revealed that this family had a mutation in the PCSK9 gene [6]. This newly discovered gene was found to cause FH by a gain-of-function mutation, which results in increased expression of the PCSK9 protein, increased serum LDL-C, and the expression of the FH phenotype.

Further investigation with animal models revealed that overexpression of the PCSK9 gene results in a dropout in the LDLR and an increase in LDL-C levels [8]. Researchers hypothesized that a gain-of-function mutation leads to an increase in LDL-C and a loss-of-function mutation leads to a decrease in LDL-C [9]. Epidemiologic analysis has supported this hypothesis, finding that the rates of coronary heart disease (CHD) for populations of individuals that have loss-of-function mutations in PCSK9 are lower than that observed in the general public [9].

But what occurs in individuals who have little or no PCSK9? Investigators were able to answer this question when presented with a 32-year-old woman who had an LDL-C level of 14 mg/dL and complete loss of function of PCSK9. Her parents each had different mutations in the PCSK9 gene, which resulted in complete loss of function of PCSK9 in their offspring. The fact that the woman was a healthy college graduate with normal fertility and development, and had no history of cancer or neurocognitive issues suggested that a loss-of-function mutation in the PCSK9 gene is benign. Other individuals with very low LDL-C levels and no obvious abnormalities have since been identified.

Role of the LDL receptor

The LDLR is produced within the endoplasmic reticulum and 8excreted to the surface of the hepatocyte where it binds LDL-C (Figure 1a). The LDL-C/LDLR complex is then endocytosed into an endosome, which fuses with the lysosome [8–12]. A variety of lipases are involved in breaking down the content of LDL-C and the LDLR can be recirculated to the surface of the hepatocyte. At the same time that the receptor is produced, PCSK9 is also produced and secreted by the hepatocyte into the extracellular space where it binds to the LDL-C/LDLR complex (Figure 1b). Binding of PCSK9 creates a tight affinity for LDL-C with the LDLR. As the complex is internalized into the endosome and fused with the lysosome, the residence time for the LDLR is increased significantly within the lysosome. This leads to its degradation and inability to recirculate back to the surface. Increased levels of PCSK9 lead to decreased availability of the LDLR, and thus, higher LDL-C levels [12].

Figure 1. (a) and (b). Normal function of PCSK9 is to promote degradation of LDL receptors. Adapted from reference [8].

LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; mRNA, messenger ribonucleic acid; PCSK9, proprotein convertase subtilisin/kexin type 9.

Therapeutic approaches to PCSK9 inhibition

Animal, genetic, and human modeling support PCSK9 inhibition strategies. Human monoclonal antibodies (mAbs) bind to PCSK9 in the extracellular space preventing the binding of PCSK9 to the LDL/LDLR complex. Other therapeutic approaches include the inhibition of PCSK9 synthesis at the messenger RNA level, or with small molecules that block PCSK9 or interfere with SREPs that are involved in the regulation of PCSK9.

In summary, the discovery of PCSK9 represents a major milestone in the understanding of LDL metabolism. Gain-of-function mutations shed new light on FH and mechanisms of LDL-C clearance. Loss-of-function mutations are associated with low PCSK9 levels, increase in the density of LDLR, and very low LDL-C levels in otherwise healthy individuals. As a result, PCSK9 inhibition has implications for clinicians who manage patients with dyslipidemia or severe hypercholesterolemia through reduction of LDL-C levels and potential reduction of the risk of ASCVD events.

PCSK9 monoclonal antibodies in clinical practice: unique mechanisms and safety

Michael Koren, MD

To understand the role of mAbs in clinical practice, it is helpful to review basic information about the role of antibodies in human physiology. Antibodies are produced by B lymphocytes. Antibody structure includes light and heavy chains. There are five isoforms of antibodies [13]:

• Immunoglobulin (Ig) M is structurally the largest antibody and exists as a pentamer (five heavy and light chains) or a hexamer (six heavy and light chains). It participates in the immediate immune reaction.

• IgA consists of two heavy and light chains. It is secreted in saliva and breast milk.

• IgE is found in the lungs and skin. It mediates hypersensitivity responses in many forms of allergy.

• IgD is expressed on naïve B-cells.

• IgG is the most abundant antibody in humans (80% of all antibodies). It consists of four subclasses. Therapeutic mAbs are IgG.

Currently, manufacturers use two major techniques to create human mAbs: (1) a phage display platform which involves the insertion of human genes into viruses and (2) the utilization of transgenic mice. Both PCSK9 mAbs currently approved by the Food and Drug Administration (FDA), alirocumab and evolocumab, are derived from transgenic mice.

Advantages and disadvantages of PCSK9 inhibitor therapy

Although statins remain the first-line drug therapy for lowering elevated cholesterol levels, the emergence of PCSK9 inhibitors provides a breakthrough alternative in the treatment of patients who require additional LDL-C reduction. Although outcomes trials are still in progress, current mAb PCSK9 inhibitors may offer advantages in LDL-C treatment. mAbs have a high specificity and affinity, and reduce free PCSK9 to extremely low levels within hours [14]. Additionally, mAb PCSK9 inhibitors may have a synergistic effect with statins. In addition to upregulating LDLR activity, statins also upregulate the production of PCSK9. When used concurrently with statins, PCSK9 inhibitors negate this effect [15]. mAbs circulate throughout the body for several days or even weeks. Because of this characteristic, physicians can dose the current PCSK9 mAbs biweekly or monthly [14]. Furthermore, elimination of mAbs from the body occurs via an antigen-specific target mediated disposition or the reticuloendothelial system. From a clinician’s perspective, patients may benefit in that these mAbs do not require elimination by the kidneys or liver.

Possible disadvantages of using mAb PCSK9 inhibitors for the treatment of patients with high LDL-C levels relate to their high costs due to a complex and expensive manufacturing process. Patients and clinicians may also have concerns about using parenteral therapy versus oral therapy for hypercholesterolemia [15]. Further, while PCSK9 inhibitors lower LDL-C levels by 50% or more, their effects on HDL-C and triglycerides are modest. These agents do, however, have an effect on lipoprotein (a) (Lp (a)), which has not been observed with statin therapy. Finally, the long-term effects of these therapeutic agents on cardiovascular outcomes are not yet known.

Safety and tolerability of PCSK9 inhibitors

Concerns regarding the safety and tolerability of mAb PCSK9 inhibitors include immunogenicity and possible adverse effects of very low LDL-C. Direct immunogenicity of PCSK9 antibodies does not occur because the mAbs are very specific for PCSK9 and do not have direct immune effects.

Antidrug antibodies can develop over a period of patient exposure to a biologic agent. Even fully human therapeutic antibodies can produce antidrug antibodies either through different posttranslational changes in the molecule or other parts of the manufacturing process that may introduce impurities. To date, alirocumab and evolocumab demonstrated 4.8% and 0.1% rates of new antidrug antibodies and 0.3% and 0% neutralizing antibodies, respectively. Neutralizing antibodies are more concerning since they may neutralize the therapeutic effect of the mAb. For bococizumab, which is still in Phase 3 clinical trials, an incidence of 7% for binding antibodies and only 1 out of 251 patients with neutralizing antibodies has been reported. Since each manufacturer uses a different assay to assess antidrug antibodies, comparisons between products should be made cautiously.

Other possible adverse effects (AEs) of these new agents were addressed in the ODYSSEY Long Term Trial [16] which found that serious adverse events (SAEs) were balanced between the active and placebo arms of this double-blind study. Fewer nonfatal MIs and adjudicated CV events were noted in those treated with alirocumab. However, the incidence of myalgias and local injection site reactions were greater (though they did not reach statistical significance) in alirocumab-treated patients compared to placebo-treated patients. Lab abnormalities affecting the kidneys or the liver were balanced between the two groups.

In the OSLER program [17] which studied the longer-term effects of evolocumab on safety, LDL-C, and other lipids, investigators documented a sustained decrease in LDL-C over 12 months. The study evaluated participants with LDL-C levels of less than 25 mg/dL, less than 50 mg/dL, and greater than 50 mg/dL. Results showed no significant differences in AEs among the three groups, although neurocognitive events were reported more frequently in the evolocumab group.

In summary, the introduction of mAbs for preventive cardiology represents a new approach. Two PCSK9 inhibitors, alirocumab and evolocumab, have received FDA approval in the U.S. for the treatment of hypercholesterolemia. Safety and tolerability appear favorable to date and ongoing studies will assess the long-term benefits and risks of PCSK9 mAb in hypercholesterolemic patients.

PCSK9 inhibitors in practice: efficacy, barriers and benefits

Marc Sabatine, MD, MPH

Three PCSK9 inhibitors, evolocumab, alirocumab, and bococizumab, of which evolocumab and alirocumab are FDA-approved for treatment of adults with (1) heterozygous familial hypercholesterolemia (HeFH) and (2) clinical ASCVD who require additional lowering of LDL-C as an adjunct to diet and maximally tolerated statin therapy (evolocumab is also indicated for homozygous familial hypercholesterolemia [HoFH]), have been studied to varying degrees in clinical trials.

The FDA approvals of evolocumab and alirocumab were based on results from multiple clinical trials. For example, LAPLACE-TIMI 57 evaluated patients with hypercholesterolemia who were taking maximal doses of statins and were randomly assigned to evolocumab at doses of 70, 105, or 140 mg or matching placebo every 2 weeks or evolocumab at doses of 145, 280, 350, or 420 mg or matching placebo every 4 weeks. Results showed that evolocumab lowered LDL-C by as much as 66.1% when compared to placebo at week 12 [18]. It was also observed that at the highest doses evolocumab reduced Lp(a), another proatherogenic lipoprotein that has been linked in Mendelian randomization studies to atherosclerosis and appears to play a causative role, by 25–30% [18]. The ODYSSEY COMBO II Study [19] also evaluated patients with hypercholesterolemia who were taking maximal statin therapy. Patients were randomized to either alirocumab at a dose of 75 mg every 2 weeks, plus oral placebo, or oral ezetimibe 10 mg daily, plus subcutaneous placebo, along with statin therapy. Results showed approximately a 60% reduction in LDL-C levels at the highest doses, and LDL-C reductions were sustained long term. Equally important and as previously mentioned, when alirocumab or evolocumab is given over time with repeat injections, no neutralizing antibodies at any appreciable frequency were observed. Further, in a 24-week, multicenter, double-blind, placebo-controlled, dose-ranging study, Ballantyne et al. found evidence that indicates bococizumab reduced LDL-C levels by approximately 52% [20].

The effects of PCSK9 inhibitors in specific patient populations

There are data available on the role of PCSK9 inhibitors in the management of specific patient populations, including FH. HeFH is typically attributable to a heterozygous pathogenic variant in one of three genes, APOB, LDLR, and PCSK9, that can lead to reduced LDLR function. It occurs in 1 of 200–500 persons in the general population, and if untreated, the risk for CHD is increased greatly [21]. Data from the RUTHERFORD-2 trial [22], which evaluated the efficacy and safety of evolocumab as add-on therapy to maximally tolerated statin and/or other lipid-lowering therapy compared with placebo over 12 weeks among patients (N = 331) with HeFH, demonstrated a reduction in LDL-C levels by approximately 60%. Other studies, ODYSSEY FH I and II, which also consisted of patients (N = 735) with HeFH having inadequate LDL-C control on maximally tolerated lipid-lowering therapy, showed alirocumab reduced LDL-C levels by 50–60% [23]. Based upon this data, both evolocumab and alirocumab received an indication for both HeFH [24,25]. As previously mentioned, evolocumab was also indicated for treatment of HoFH based on results from the TESLA clinical trial [26,27]. TESLA evaluated evolocumab versus placebo in patients with HoFH receiving stable background lipid-lowering therapy who were not on apheresis. Compared with placebo, evolocumab significantly reduced LCL-C at 12 weeks by 30.9% [27].

Individuals intolerant of statin therapy are another population to consider for PCSK9 inhibition. There has been much debate as to the true incidence of statin intolerance, but in a generalized population, it is estimated to be approximately 5–10% [28,29].

If a patient cannot tolerate a statin, what other therapies can a clinician offer? In GAUSS-2 [30], which evaluated 307 statin-intolerant patients, evolocumab was compared to ezetimibe. Results showed a 56% decrease in LDL-C levels from baseline with evolocumab over 12 weeks, which translated into 37% more reduction compared to ezetimibe. The incidence of muscle AEs was relatively low: 12% for evolocumab versus 23% for ezetimibe. Again, data are similar with alirocumab, where a 45% reduction in LDL-C was noted at 24 weeks in the ODYSSEY ALTERNATIVE study among 251 high CV risk patients with a history of intolerance to two or more statins, compared to a 15% reduction with ezetimibe [31].

CV outcomes are also important to consider. As previously stated, the OSLER trial demonstrated that evolocumab plus standard of care reduced the composite end point of death, MI, unstable angina, revascularization, stroke, TIA, or heart failure by approximately 50%. The cumulative incidence of these end points over one year was 0.95% in the PCSK9 group (n = 2976), compared to 2.18% in patients receiving standard care alone (n = 1489) [17].

There are dedicated CV outcomes trials underway: ODYSSEY OUTCOMES Trial with alirocumab [32]; the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) Trial with evolocumab [33]; and The Evaluation of Bococizumab (PF-04950615; RN316) in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects (SPIRE-1) [34] and SPIRE-2 trials [35] for bococizumab. These large trials will provide further insight into the effect of PCSK9 inhibitors on CV outcomes since the aforementioned trials were not specifically designed to measure these end points.

In summary, the introduction of mAb PCSK9 inhibitors represents a new approach for clinicians to put into clinical practice, especially in patients with FH and who are resistant to statin therapy.

Evolved understanding of the genetic basis of familial hypercholesterolemia

Seth Baum, MD

Previously, FH was ‘hiding in the shadows’, but awareness has increased and there are now pharmacotherapies available to treat both HeFH and HoFH. Clinicians need to recognize how to identify and diagnose FH in order to appropriately manage their patients.

The historical view of FH has changed quite dramatically over the last three years. In an initial paper on FH in 1972, Goldstein and Brown first described the cause of FH as dysfunction in HMG-CoA reductase. But very rapidly, they recognized the problem was due to a mutation of the LDLR [36]. To date more than 1,700 mutations in the LDLR have been identified. Additional genes such as PCSK9 and APOB100 that affect LDLR functionality have also been identified in playing a role in the cause of FH.

There are two forms of FH: HeFH and HoFH. The prevalence of HoFH is estimated at approximately 1 in 160,000 based upon estimates using the Hardy–Weinberg Equilibrium, which determines the expected frequencies of genotypes based upon the absence or presence of alleles. The prevalence of HeFH is much higher. Originally, the prevalence of HeFH was felt to be 1 in 500. Results from major studies have revealed the prevalence of HeFH is most likely closer to 1 in 200 [21]. Despite this increase in prevalence, fewer than 10% of FH patients have been identified; therefore, at least 90% of individuals with FH remain undiagnosed. Thus, there is a desperate need for clinicians to better recognize the signs and symptoms of FH in their patients as well as in specific patient populations who may be located in their region. For example, Founder groups, which include French Canadians, Ashkenazi Jews, South African Afrikaners, and Christian Lebanese, have a much higher prevalence of FH.

Screening and diagnosing FH

Diagnosis is multifaceted, relying on family history, patient history, physical examination, LDL-C level, and response to lipid lowering therapy [37,38]. Nonpaternity, possible de novo mutations, and the genetic impact of double heterozygosity also make the diagnosis of HoFH more difficult.

There are three terms used to define HoFH. The first is simple HoFH, in which a person inherits one mutated allele from the mother and the exact same mutation from the father. This individual harbors a single gene possessing the same mutation from both parents—a very rare occurrence.

Compound heterozygous HoFH is the second and far more common form of the disease. The compound heterozygote is a homozygote that has a single gene involved with two different mutations, one from the mother and one from the father. It is the most common form of HoFH. Finally, there is double heterozygous HoFH in which two different genes are involved, for instance, mutations of LDLR and either ApoB or PCSK9. One mutation comes from mother, the other from the father.

Previously, it was believed that homozygotes were marked by LDL-C levels greater than 450–500 mg/dL. Recently, it has been recognized that an untreated population of true pathogenic HoFH patients may have LDL-C readings of 170–900 mg/dL, an amazingly large range.

Although FH is predominantly an LDL-C disorder, other lipid abnormalities can also occur. As a result, FH is persistently under-diagnosed and thus under-treated.

The National Lipid Association (NLA) [37] acknowledges the genetics and urgency associated with FH. It recommends universal screening for serum cholesterol levels. The NLA suggests that cholesterol screening should be considered starting at age 2 for children with a family history of FH, premature cardiovascular disease or high cholesterol levels, and that all children should be screened between the ages of 9 and 11 regardless of family history.

During a physical examination, when clinicians assess pedal pulses they should always remember to evaluate the thickness of the Achilles tendon(s) [39]. Tendon xanthomas occur because of accelerated cholesterol deposition within both vascular and extravascular tissues, and are specific for FH. The Achilles tendon is a common location for such deposition extravascular of cholesterol. The Achilles tendon may be thickened but without the usual ‘bumpy’ presentation. It is unknown why some FH subjects develop xanthomas while others do not. Clinicians should also assess the superior and inferior aspects of the cornea, where the majority of the blood supply enters and where lipids may accumulate to cause a corneal arcus. It should be understood that the corneal arcus need not be circumferential; it can simply be present in either the superior or inferior regions.

FH screening in the future

The FH Foundation, a nonprofit research and advocacy organization focused on FH, has as their mission to save lives by increasing the rate of early diagnosis and encouraging proactive treatment of FH. FIND FH® is a multipronged initiative utilizing machine-learning technology to analyze lab data, patient claims, and electronic health record data, in order to create algorithms which forecast U.S individuals with probable FH. The goal of FIND FH® is to support clinicians in identifying the more than 90% of undiagnosed FH patients in the U.S.

The FH Foundation will be starting an active cascade screening program in the very near future. This active cascade screening system will be appropriate for a country with the geographic and population size of America. It will start with a pilot to assess feasibility and subsequently scale up upon success.

In summary, approximately 90% of individuals with FH remain undiagnosed. It is critical that clinicians are aware of the history and genetic basis of FH, screening and diagnostic strategies, and methods to distinguish between HeFH and HoFH. The NLA recommends universal screening for serum cholesterol levels, and clinicians should also assess the thickness of the Achilles tendon of FH as well as the entire cornea, including its superior and inferior aspects during the physical examination in patients suspected to have FH. In the future, the FH Foundation will launch an active cascade screening program to support clinicians in identifying the undiagnosed FH patients in the U.S.

Expert case presentation and panel discussion on practicalities of PCSK9 inhibitors

The following clinical cases presented by the faculty panel include severe FH or HoFH and HeFH.

Patient case one

A 40-year-old male presents with a family history of severe hyperlipidemia and ASCVD in both parents.

Medical history:

• Baseline LDL-C: 505 mg/dL

• First myocardial infarction occurred in his early 20s

• 14 stents inserted since the age of 29

• History of hypertension, diabetes, and obesity

Current medications and interventions:

• Several lipid-lowering medications

• Apheresis, which caused wide swings in LDL-C levels over time.

  • ∘ Pre-apheresis LDL-C level was between of 150 and 250 mg/dL.

Question: how would you manage this patient?

According to the opinion of the members of the faculty panel, this patient would be a good candidate for a PCSK9 inhibitor. It must first be taken into consideration if the patient is a homozygote or heterozygote. If the patient is a heterozygote, he will demonstrate a response to a PCSK9 inhibitor; however, more assessment must take place if the patient is a homozygote. In the homozygous population, there are generally two different types of mutations in the PCSK9 gene: defective or null. The defective mutation results in 2–25% efficacy of the LDLR and the null mutation results in less than 2% efficacy of the receptor. In a null/null patient, which is very rare, a PCSK9 inhibitor will have no impact on the reduction of LDL-C. However, in a patient who has a defective/null mutation, there will be a mid-range response in the reduction of LDL-C levels to PCSK9 inhibition while a patient with a defective/defective mutation will demonstrate the most robust response.

It is a distinct possibility that this patient is a homozygote based on his baseline LDL-C initially over 500 mg/dL; however, because the patient is on several lipid-lowering medications, it can be assumed that he has demonstrated some type of response involving the manipulation of the LDLR. Therefore, this patient may benefit from treatment with evolocumab, which is indicated for HoFH and has demonstrated variability in response, with some patients having a good response and some a fairly modest response.

Patient case two

A 23-year-old woman presents with LDL-C level of 137 mg/dL. She is on 20 mg of simvastatin, but she has been opposed to taking statins. She agrees to take rosuvastatin 10 mg. After being on the statin, her LDL-C level drops to 79 mg/dL.

Medical history:

• LDL-C at age 14: 200 mg/dL

• Father—hyperlipidemia; vascular disease

• Mother—normal; no history of CVD

Laboratory results:

• Normal coronary CT; very small bilateral carotid plaques demonstrating increased risk

• Genotyping revealed an intronic mutation in the LDLR, which has never been described earlier.

What is the best next step in the management of this patient?

As this patient is of child-bearing age and statins are contraindicated in pregnancy (the effect of PCSK9 inhibitors in pregnant women remains unknown), the main question to consider in the management of her treatment is whether or not she should remain on a statin, switch her treatment to a PCSK9 inhibitor, or even be treated at this time due to the risks if she becomes pregnant? The faculty panel agrees that before changing her treatment plan, extensive patient counseling is required to understand the patient’s preferences and understanding of the CV risks if she were to delay treatment and pregnancy risks if she decided to continue treatment.

If the clinician believes that the patient may not be able to control the timing of the pregnancy, he or she may suggest avoiding statins. However, the discomfort level of the clinician might grow with the delay in treatment as the patient’s CV risk increases over time. In this situation, adding ezetimibe would be a reasonable choice. Clinicians may also find it appropriate to prescribe a PCSK9 inhibitor to a nonpregnant woman of child-bearing age; it is too early to make any recommendation about its use in pregnancy. In this patient’s current situation, she must weigh the benefits versus risks of treatment with the counsel of her physician to determine a treatment plan.

Declaration of interest

This paper was funded by Amgen, through support provided to the 2015 Cardiometabolic Health Congress (CMHC); editorial support was arranged by CMHC. Editorial support was provided by Paul Cerrato, Robert E. Lamb, and Erin Franceschini. MS Sabatine has received grants/research support from Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Daiichi Sankyo, Eisai, Gilead,GlaxoSmithKline, Intarcia, Merck, Roche Diagnostics, Sanofi-Aventis and Takeda, as well as consulting fees from Alnylam, Amgen, AstraZeneca, Cubist, CVS Caremark, Intarcia and Merck. JA Underberg has received grants/research support from Pfizer, Kowa and Aegerion, as well as consulting fees from Amgen, Sanofi, Novartis, Esperion, Liposcience and Amarin, and he has been on the Speakers’ Bureau for Merck, Amarin, Sanofi, Genzyme, Kowa and AstraZeneca. M Koren has received grants/research support from Sanofi, Regeneron, Amgen and Pfizer, and been on the Speakers’ Bureau for Sanofi, Regeneron and Amgen. SJ Baum has received consulting fees from Merck, AstraZeneca, Aegerion Pharmaceuticals Inc., Genzyme and Sanofi, and been on the Speakers’ Bureau for Merck, AstraZeneca, Aegerion Pharmaceuticals Inc., Genzyme and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.