PCSK9 Inhibitors for LDL Cholesterol Reduction: Emerging Clinical Perspectives

Michael J. Bloch, MD
B. Alan Bottenberg, DO
Volume 56 - Issue 4 - April 2016

ABSTRACT: Morbidity and mortality from cardiovascular disease in the United States has trended lower over the past several decades. Much of this risk reduction can be attributed to the use of statin therapies to lower low-density lipoprotein cholesterol (LDL-C). Despite this, coronary heart disease remains the leading cause of death in men and women. Residual risk may persist in patients who fail to achieve LDL-C targets or in those who are unable to tolerate moderate- or high-dose statins. Patients with familial hypercholesterolemia (FH) may be unable to achieve LDL-C targets despite high-dose statin therapy. Recently, monoclonal antibody therapy to reduce PCSK9 activity at the surface of the hepatocyte has been approved for use in those with FH or cardiovascular disease who require additional LDL-C lowering despite the use of maximally tolerated statins. PCSK9 blocking antibodies may reduce LDL-C up to 70% beyond levels achieved with statin therapies alone.

KEYWORDS: PCSK9, familial hypercholesterolemia, low-density lipoprotein cholesterol, coronary heart disease, statins, monoclonal antibody therapy

Cardiovascular disease remains one of the worldwide leading causes of morbidity and mortality. The incidence of cardiovascular diseases is expected to increase over the next several decades. Increased levels of low-density lipoprotein cholesterol (LDL-C) remain one of the most powerful modifiable risk factors. Deposition of oxidized LDL-C in the vascular wall leads to atherosclerotic cardiovascular disease (ASCVD) and the potential for a cardiovascular event.

Reduction of LDL-C has been one of the mainstays of cardiovascular disease prevention. Statin drugs remain the cornerstone of therapy. Treatment with moderate- and high-dose statins has been shown to reduce cardiovascular events by 30% to 50%. Despite aggressive statin therapy, many patients have persistently elevated LDL-C levels, leading to an increased residual risk of cardiovascular disease. These patients often have a very high LDL-C at baseline, including those with genetic defects such as familial hypercholesterolemia (FH). Also, many high-risk patients are unable to tolerate moderate- or high-dose statins due to various potential adverse effects, the most common of which are myalgias.

PCSK9 Biology

Proprotein convertase subtilisin-like kexin type 9 (PCSK9) is a 692 amino acid serine protease. It is expressed primarily in the liver, kidney, and intestine. It has a very short plasma half-life of less than 10 minutes. It is a key regulator of LDL receptor expression on the hepatocyte as well as of LDL receptor degradation inside the hepatocyte. Through these mechanisms, PCSK9 plays a large role in the regulation of circulating LDL-C.1

The PCSK9 gene was discovered in 2003. The crystalline structure of the PCSK9 proprotein was published in 2007. Loss-of-function mutations in PCSK9 have been shown to drastically reduce circulating levels of LDL-C. These mutations have been shown to reduce the frequency of coronary heart disease by as much as 88% due to the very low circulating levels of LDL-C.2

In response to decreased intracellular cholesterol, hepatocytes express LDL receptors on the cell surface. The LDL receptor then binds LDL particles in the plasma. This complex is then brought into the cell via endocytosis. Inside the endosome, LDL particles dissociate from the LDL receptor. The LDL particle subsequently is degraded by catalytic enzymes. The LDL receptor is then recycled to the cell surface, where the process repeats itself. The LDL receptor is capable of repeating this cycle approximately 150 times on average.

When LDL receptors are produced, PCSK9 is also generated. Once released into the plasma, PCSK9 binds to the epidermal growth factor–like repeat A domain of the LDL receptor. The LDL receptor, complexed with PCSK9, will bind an LDL particle within the circulation. The LDL receptor/LDL particle is then taken into the hepatocyte via endocytosis. The presence of PCSK9 targets the LDL receptor for degradation along with the LDL particle. This leaves fewer LDL receptors to recirculate to the hepatocyte surface, which leads to less LDL clearance and elevated plasma LDL-C.

The use of statin therapy reduces intracellular cholesterol and increases the production of LDL receptors. However, this mechanism also upregulates the expression and production of PCSK9. This feedback mechanism helps to explain why some patients do not reach LDL-C targets despite aggressive statin therapy.

Mechanism of PCSK9 Inhibitors

As shown in Figure 1, PCSK9 antibodies have been designed to strongly bind to PCSK9, rendering it unable to complex with the LDL receptor. Once injected into the subcutaneous tissue, PCSK9 antibodies enter the lymphatic circulation and are delivered to the venous circulation. Maximum suppression of free PCSK9 in the bloodstream occurs within 4 hours. In the absence of PCSK9, the LDL receptors are free to recirculate to the surface of the hepatocyte and capture more LDL particles, thereby lowering circulating levels of LDL-C. The antibody-bound PCSK9 is then removed from the circulation through various mechanisms, including phagocytic cells of the immune system. There is no hepatic or renal clearance, and the pharmacokinetics are not affected by age, sex, race, or creatinine clearance. There is no drug-drug interaction seen with high-intensity statin therapy.


Figure 1. PCSK9 Inhibitors Mechanism of Action. Monoclonal antibodies bind to PCSK9 to prevent the association between PCSK9 and the LDL receptor (LDL-R). The LDL-R binds the LDL particle and is internalized; then the LDL particle is degraded in the lysosome, with the LDL-R being recycled back to the plasma membrane. (Reprinted/adapted with permission from: Lambert G, Sjouke B, Choque B, Kastelein JJP, Hovingh GK. The PCSK9 decade: thematic review series: new lipid and lipoprotein targets for the treatment of cardiometabolic diseases. J Lipid Res. 2012;53(12):2515-2524.)

Monoclonal antibodies remain an attractive therapeutic modality, because they are extremely specific for their targets, have a low incidence of adverse effects, and are relatively easily produced. Immunoglobulin G (IgG) antibodies are constructed of paired heavy and light polypeptide chains. The 3 globular regions form a Y-shaped structure. The arms of the structure are involved in the antigen binding. The stem of the structure interacts with the effector cells and molecules. Because these monoclonal antibodies would be quickly degraded in the gastrointestinal system, they require subcutaneous administration.

Evolocumab (Repatha, Amgen Inc) and alirocumab (Paraluent, Sanofi US and Regeneron Pharmaceuticals Inc) are both fully human IgG monoclonal antibodies. Bococizumab (Pfizer Inc) is another monoclonal antibody in development and is in phase 3 clinical trials. ALN-PCS (Alnylam Pharmaceuticals Inc) is a small interfering RNA designed to inhibit the production of PCSK9 in the hepatocyte; it recently has completed phase 1 clinical trials. A peptide-based vaccine (Affiris AG) is in a preclinical stage of development.

Phase 3 Study Results: Effects on LDL-C

Phase 3 clinical trials are those in which the investigational treatment is compared with either placebo or other approved therapies to confirm the safety and efficacy of a medication. Phase 3 studies commonly are designed in collaboration with the U.S. Food and Drug Administration (FDA) and usually provide the pivotal data that help the FDA make decisions about approval for specific clinical indications. Both alirocumab and evolocumab, the 2 PCSK9 inhibitors currently approved in the United States, were subject to extensive phase 3 clinical trial programs prior to FDA approval. Most studies performed prior to approval examined the effects on LDL-C compared with placebo or with other lipid-lowering therapy in patients with established ASCVD, FH, or statin intolerance and suboptimally controlled LDL-C levels.

The global family of studies for alirocumab is known as the ODYSSEY program. Overall, the ODYSSEY program enrolled more than 23,000 patients worldwide. An example of the pre​approval phase 3 studies included in the ODYSSEY program is the COMBO II study.3 In this trial, 720 patients with high cardiovascular risk and elevated LDL-C despite maximal doses of statin therapy were randomly assigned to receive either alirocumab or ezetimibe in addition to a maximum tolerated dose of a statin. The initial dose of alirocumab was 75 mg every 2 weeks, which was then titrated up to 150 mg every 2 weeks if the LDL-C remained greater than 70 mg/dL after 8 weeks. Baseline LDL-C in this study was 108 to 109 mg/dL in both groups despite a maximally tolerated statin. After 24 weeks of therapy, the LDL-C level was reduced by 50.6% to 50.6 mg/dL in the alirocumab group, compared with a 20.7% reduction to an achieved LDL-C of 82.5 mg/dL in the ezetimibe group.

Alirocumab also was evaluated in 2 studies of patients meeting the clinical criteria for heterozygous FH, the ODYSSEY FH I and FH II studies.4 In these trials, patients were randomly assigned to alirocumab, 75 to 150 mg every 2 weeks, on top of a background of maximally tolerated statin therapy and other lipid-lowering drugs. Compared with placebo, after 24 weeks alirocumab decreased LDL-C by 57.9% and 51.4% in the 2 studies, respectively. In the ODYSSEY ALTERNATIVE study,5 248 patients with documented statin intolerance were randomly assigned to alirocumab 75 to 150 mg every 2 weeks or to ezetimibe. Alirocumab use was associated with a 45% reduction in LDL-C from baseline compared with a 14.6% reduction with the use of ezetimibe.

The phase 3 clinical trial program for evolocumab is known as the Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 in Different Populations (PROFICIO). PROFICIO includes 14 trials that evaluated evolocumab in multiple patient populations. One of the phase 3 studies with evolocumab is the LAPLACE-2 study.6 In this trial, 2067 patients with primary hypercholesterolemia were initially randomly assigned to 1 of 5 different moderate- or high-intensity statin groups and then were randomly assigned to receive different doses of evolocumab, ezetimibe, or placebo in addition to statin therapy. Overall, the use of evolocumab reduced LDL-C by 66% from baseline and by 73% compared with placebo. Adverse events were reported in 36%, 40%, and 39% of patients receiving evolocumab, ezetimibe, and placebo, respectively.

In The GAUSS-2 trial,7 307 participants with hypercholesterolemia who were unable to tolerate effective doses of statins (at least 2 attempts) were randomly assigned to varying doses of evolocumab, ezetimibe, or placebo. In this study, the mean baseline LDL-C of 193 mg/dL was decreased by 53% to 56% from baseline with evolocumab dosed once or twice a month, which was a 37% to 39% greater reduction than was seen in those treated with ezetimibe. Finally, the RUTHERFORD 2 study8 randomly assigned 329 patients meeting the clinical criteria for heterozygous FH and who were on background therapy that usually included statins, to evolocumab or placebo. In this study, the use of evolocumab decreased LDL-C by 59% to 66% over and above statin and/or other lipid-lowering therapy.

While not yet approved by the FDA, bococizumab also is being evaluated in a large phase 3 clinical trial program. Known as the SPIRE program, these clinical trials have enrolled patients at high cardiovascular risk or with heterozygous FH and randomly assigned them to either bococizumab every 2 weeks or placebo.9 Results of the studies examining the effects on LDL-C were to have been available in early 2016. One unique planned study with bococizumab will enroll patients with HIV disease at high risk for ASCVD events.10

Pooled Phase 3 Data Investigating Cardiovascular Effects

Pooled long-term cardiovascular outcome data have been published from the results of phase 3 studies of alirocumab and evolocumab (Figure 2). It is important to note that these data are from post hoc exploratory analyses and should be considered hypothesis-generating rather than definitive.


Figure 2. Post hoc exploratory analysis of cardiovascular events in available phase 3 clinical trials of PCSK9 inhibitors. Difference between PCSK9 inhibitor group and usual care.

 

In the pooled OSLER program data,11 which included 4465 patients who completed 1 of 12 phase 2 or 3 trials, the use of evolocumab was associated with a 61% reduction of LDL-C levels and a 53% reduction in a composite of multiple cardiovascular events. The incidence of serious adverse events was 7.5% in both the evolocumab group and the standard therapy group. Neurocognitive adverse events occurred in 0.9% of evolocumab and 0.3% of standard therapy patients. Muscle-related events occurred in 6.4% of evolocumab and 6.0% of standard therapy groups; creatinine kinase elevation was rare and had similar rates of occurrence in both groups.

In the ODYSSEY LONG TERM study,12 which included 2341 patients, the use of alirocumab was associated with a 61.9% reduction in LDL-C compared with standard therapy, which led to a 48% reduction in a composite of multiple cardiovascular events. The incidence of serious adverse events was 18.7% in the alirocumab group and 19.5% in the standard therapy group. Neurocognitive adverse events occurred in 1.2% of alirocumab and 0.5% of standard therapy patients. Muscle-related events occurred in 5.4% of alirocumab and 2.9% of standard therapy groups; creatinine kinase elevation was rare with similar rates in both groups.

A systematic review and meta-analysis13 involving 24 phase 2 and 3 randomized, controlled studies enrolling 10,159 patients showed a 47.5% lower achieved LDL-C in those on PCSK9 inhibitors vs placebo or other therapies (eg, ezetimibe). This reduction in LDL-C was associated with a statistically significant 55% reduction in cardiovascular mortality and a borderline statistically significant 50% reduction in all-cause mortality. No difference in serious adverse events was noted between those taking PCSK9 inhibitors and those who were not.

While these data must be interpreted with caution due to the exploratory nature of the analyses and the low number of events, the consistency of the findings with both agents lends considerable weight to the as yet unproven hypothesis that PCSK9 inhibition will decrease cardiovascular events.

Planned Outcome Studies

While the surrogate endpoint data (LDL-C) and post hoc phase 3 data are encouraging, only well-powered clinical outcomes studies can determine whether or not there is a statistically significant benefit, and more importantly, a clinically significant benefit to this class. The medical literature is replete with examples of interventions that seemed promising based on surrogate endpoints only to fail when rigorously tested.

Fortunately, a number of clinical outcome studies with PCSK9 inhibitors are planned, and many are already enrolling patients (Table 1). For instance, the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study14 is a secondary outcomes study planning to enroll at least 27,500 patients to test whether evolocumab, used in addition to “effective” statin therapy (defined as atorvastatin at least 20 mg daily or equivalent) will reduce the risk of cardiovascular death, myocardial infarction, hospitalization for unstable angina, or coronary revascularization in patients with a history of established ASCVD. The ODYSSEY OUTCOMES study15 also is a secondary prevention trial that will enroll at least 18,000 patients with a history of acute coronary syndromes (ACS) already on statin therapy and will compare the effect of alirocumab and placebo on the occurrence of cardiovascular events. And the SPIRE-1 and SPIRE-2 trials16,17 will examine the effect of bococizumab compared with placebo in more than 26,000 patients at high risk for cardiovascular events who are already on appropriate lipid-lowering agents, including statins.


 

It is important to note that the FOURIER and ODYSSEY cardiovascular outcomes studies require use of moderate- to high-dose statin therapy at baseline and a history of ASCVD. Uniquely, the SPIRE studies will include high-risk primary prevention patients and do not specify the agent or dose of background lipid-lowering therapy.

However, 2 important patient populations will not be adequately included in these studies. First, the planned studies will not help us to determine whether PCSK9 inhibitors are effective in reducing events in high-risk patients who are truly intolerant of moderate- to high-intensity statins. Second, these studies will not include primary prevention patients with heterozygous FH with poor LDL-C control despite high-intensity statin therapy. The failure to include these important groups of patients who have limited treatment options may represent a crucial misstep in our understanding of where to use these novel medications. If events rates in the usual care group of the planned studies are low, we may end up in the situation where there is a statistically significant relative risk reduction, but not a clinically significant absolute reduction in events, and uncertainty about the true clinical utility and cost-effectiveness of these expensive medications.

FDA-Approved Indications

In the fall of 2015, the first 2 PCSK9 inhibitors, alirocumab and evolocumab, were approved for use in patients with clinical ASCVD or heterozygous FH who require further LDL lowering despite lifestyle changes and use of maximally tolerated statins. As defined in the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines,18 established clinical ASCVD includes a history of coronary artery disease (including myocardial infarction, chronic or unstable angina, or history of coronary revascularization), significant carotid disease, peripheral arterial disease, or atherothrombotic stroke or transient ischemic attack.

FH is characterized by severely elevated LDL-C levels due to mutations in genes involved with LDL metabolism, including the LDL receptor or, less commonly, gain-of-function mutations in PCSK9. Patients with homozygous FH have very little LDL receptor activity and commonly have LDL-C levels greater than 500 mg/dL. These patients commonly are diagnosed with cardiovascular disease by age 20. Luckily, homozygous FH is uncommon, occurring in approximately 1 in 1 million individuals. Heterozygous FH is far more common, occurring in 1 in 200 to 1 in 500 individuals. Heterozygous FH is diagnosed based on elevated LDL-C, usually greater than 190 mg/dL, in the setting of a family history of premature cardiovascular events and/or a personal or family history of physical findings such as tendon xanthoma.

While the diagnosis of FH usually is made based on the mere presence of the above criteria, several published diagnostic algorithms are designed to help make the diagnosis more definitively. These include the Simon Broome criteria, the Dutch Lipid Clinic Network criteria, the US MEDPED criteria, and others. These criteria each have specific advantages and disadvantages regarding sensitivity, specificity, and ease of use. Genetic screening also is available but is not widely used in clinical practice; more than 1600 identified LDL receptor mutations have been identified, but still a large number of patients with clinical criteria consistent with FH have negative genetic test results, suggesting that many genetic abnormalities remain to be discovered.19

The FDA-approved starting dose of alirocumab is 75 mg every 2 weeks; up-titration to 150 mg every 2 weeks is approved for those who do not have adequate response in LDL-C to the starting dose. Evolocumab is dosed at 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly. Evolocumab also is indicated for homozygous FH at the 420 mg monthly dose. Both agents are administered via a single-use auto-injector that does require refrigeration.

Based on the available data, it appears that adverse effects are generally mild and most often include upper respiratory tract symptoms. Injection site reactions generally are quite mild and rarely lead to discontinuation of therapy. During clinical trials, many patients on PCSK9 therapy achieved LDL-C levels of less than 25 mg/dL. In the analyses available to date, there was no difference in the incidence of adverse effects in those achieving very low LDL-C levels compared with the remainder of the study population; however, longer-term clinical trials are needed to confirm the safety of very low achieved LDL-C levels. Larger and longer studies also are needed to determine whether these agents increase the risk of neurocognitive problems and other less common adverse effects of lipid-lowering therapy.

Clinical Implications and Conclusions

Recently published ACC/AHA guidelines18 recommend that high-risk patients achieve a 50% reduction in LDL-C by using moderate- to high-dose statin therapy. Recommendations from  other groups, such as the National Lipid Association (NLA),20 recommend an LDL target of less than 70 mg/dL in high-risk patients. For the majority of patients at heightened cardiovascular risk, moderate- or high-intensity statin therapy will continue to be the mainstay of treatment. While most patients are able to achieve appropriate LDL-C lowering with statin therapy, many such statin-eligible individuals may be intolerant to the agents and to doses of statin recommended in the guidelines. Moreover, many patients with high baseline LDL-C, including those with heterozygous FH, may not be able to achieve an optimal LDL-C level even on high-intensity statin therapy. These patients appear to have residual risk that could potentially be managed by novel lipid-lowering agents such as PCSK9 inhibitors.

The evidence from phase 3 clinical trials suggests that high-risk patients with suboptimal control of LDL-C despite maximum tolerated statin therapy be considered for PCSK9 inhibitors. A subset of these patients, namely those with established ASCVD and heterozygous FH, with suboptimal control of LDL-C despite maximum tolerated statin therapy, are included in the current FDA-approved indication for evolocumab and alirocumab. Notably absent from the approved indications is the high-risk primary prevention in statin-intolerant patients—a population with few other available treatment options. Further clinical trials with PCSK9 inhibitors in patients who are truly intolerant to evidence-based doses of statin therapy should be encouraged.

The excellent safety and tolerability profile of PCSK9 inhibitors demonstrated so far is promising. However, further long-term safety data are needed, particularly in patients with very low achieved LDL-C (in many cases < 25 mg/dL). Data from the recently published IMPROVE-IT study21 with ezetimibe for the first time have definitively shown that the addition of a nonstatin LDL-C lowering strategy can reduce events. And, the post hoc data demonstrating a reduction in cardiovascular events with evolocumab and alirocumab also are encouraging but certainly are not definitive. Large-scale, prospective, long-term outcome studies are under way, and data should be available in the next few years.

Balanced against the demonstrated efficacy of PCSK9 inhibitors are the issues of cost and access that may lead to significant limitations in their use. The average wholesale cost of the 2 approved PCSK9 inhibitors is more than $10,000 per year. Obtaining approval for coverage from third-party payers generally requires significant commitment on the part of patient and provider office staff. Even when approval is obtained, copayments may be high for certain patients, particularly older patients. Moreover, the need for refrigeration and appropriate sharps disposal also are potential barriers for some patients.

While the approved labeling for alirocumab and evolocumab does not define a specific LDL-C above which PCSK9 inhibitors should be considered, the NLA has suggested a conservative approach pending the results of outcome studies.22 According to the NLA recommendations, PCSK9 inhibitors should be considered primarily in those who despite maximally tolerated statin therapy have (1) ASCVD with LDL-C at least 100 mg/dL (or non-HDL-C at least 130 mg/dL) or (2) clinically apparent heterozygous FH with LDL-C greater than 130 mg/dL (or non-HDL-C at least 160 mg/dL) (Table 2).

Although the evidence is less strong, PCSK9 inhibitors also may be considered in highly selective high-risk patients with ASCVD (particularly those with recurrent events) who have LDL-C greater than 70 mg/dL despite maximally tolerated statin therapy or those who meet a strict definition of statin intolerance and who require substantial additional lipid lowering despite use of other lipid-lowering therapies.  

A recent ACC expert consensus document on the role of nonstatin therapies also suggests a similar role for PCSK9 inhibitors,23 stating that PCSK9 inhibitors should be considered in the following patients groups: (1) ASCVD without comorbidities with a less than 50% LDL-C reduction or who do not reach an LDL-C below 100 mg/dL on maximally tolerated statin therapy (usually after adding or considering ezetimibe); (2) ASCVD with comorbidities or a baseline LDL-C above 190 mg/dL who do not have a greater than 50% LDL-C reduction or who do not reach an LDL-C below 70 mg/dL on maximally tolerated statin therapy (usually after adding or considering ezetimibe); or (3) in patients without ASCVD with a baseline LDL-C above 190 mg/dL who do not have a greater than 50% reduction in LDL-C or reach an LDL-C below 100 mg/dL on maximally tolerated statin therapy (with or without ezetimibe).  This document does not recommend consideration of PCSK9 inhibitors in patients without ASCVD or baseline LDL-C above 190 mg/dL.

Statins are life-saving medications, and the absolute event rate in the standard therapy arms of the planned endpoint studies may be quite low. Given the cost associated with the 2 approved agents, it will be important to examine not only the relative risk reduction, but also the number needed to treat and the projected cost per event saved. As mentioned above, it is concerning that some of the patient populations who might be expected to derive the greatest absolute benefit from PCSK9 inhibitors, such as high-risk statin-intolerant patients or those with FH, are not well-represented in the currently planned endpoint studies.

In summary, PCSK9 inhibitors have thus far demonstrated tremendous efficacy in lowering LDL-C with an excellent safety and tolerability profile. Based on these results and the proof of concept supplied by naturally occurring genetic mutations, these products appear to be uniquely positioned to become an important part of our armamentarium in the treatment of dyslipidemia and cardiovascular risk. Importantly, in just a few years, the results of clinical outcomes studies should be available to help us determine the true value of this innovative class of lipid-lowering medications.

B. Alan Bottenberg, DO, is a physician at Northern Nevada Lipidology, Internal Medicine Associates, in Carson City, Nevada.

Michael J. Bloch, MD, is an associate professor in the Department of Medicine at the University of Nevada School of Medicine and medical director of Vascular Care at the Renown Institute for Heart and Vascular Health in Reno, Nevada.

Financial Disclosure

Dr Bottenberg reports serving on the speakers bureau for Amgen Inc.

Dr Bloch reports serving as a consultant for and on the speakers bureau for Amgen Inc.

References:

  1. Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci. 2007;32(2):71-77.
  2. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272.
  3. Cannon CP, Cariou B, Blom D, et al; ODYSSEY COMBO II Investigators. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36(19):1186-1194.
  4. Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36(43):2996-3003.
  5. Moriarty PM, Thompson PD, Cannon CP, et al. ODYSSEY ALTERNATIVE: efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody, alirocumab, versus ezetimibe, in patients with statin intolerance as defined by a placebo run-in and statin rechallenge arm. Presented at: American Heart Association Scientific Sessions; November 17, 2014; Chicago, IL. https://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469597.pdf. Accessed March 31, 2016.
  6. Robinson JG, Nedergaard BS, Rogers WJ, et al; LAPLACE-2 Investigators. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-1883.
  7. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2541-2548.
  8. Raal FJ, Stein EA, Dufour R, et al; RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):331-340.
  9. Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol. 2014;11(10): 563-575.
  10. Bococizumab HIV Evaluation (B-HIVE) Study (B-HIVE). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02524106. Accessed March 31, 2016.
  11. Sabatine MS, Giugliano RP, Wiviott SD, et al; Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500-1509.
  12. Robinson JG, Farnier M, Krempf M, et al; ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489-1499.
  13. Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med. 2015;163(1):40-51.
  14. Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/study/NCT01764633. Accessed March 31, 2016.
  15. ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01663402. Accessed March 31, 2016.
  16. The Evaluation of Bococizumab (PF-04950615;RN316) in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects (SPIRE-1). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01975376.Accessed March 31, 2016.
  17. The Evaluation of Bococizumab (PF-04950615; RN316) in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects (SPIRE-2). ClinicalTrial.gov. https://clinicaltrials.gov/ct2/show/NCT01975389. Accessed March 31, 2016.
  18. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25):2889-2934.
  19. Al-Rasadi K, Al-Waili K, Al-Sabti HA, et al. Criteria for diagnosis of familial hypercholesterolemia: a comprehensive analysis of the different guidelines, appraising their suitability in the Omani Arab population. Oman Med J. 2014;29(2):85-91.
  20. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1- – executive summary. J Clin Lipidol. 2014;8(5):473-488.
  21. Cannon CP, Blazing MA, Giugliano RP, et al; IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397.
  22. Jacobson TA, Maki KC, Orringer CE, et al; NLA Expert Panel. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 2. J Clin Lipidol. 2015;9(6 suppl):S1-S122.e1.
  23. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of athersclerotic cardiovascular disease risk [published online April 1, 2016]. J Am Coll Cardiol. doi:10.1016/j.jacc.2016.03.519.