¹Professor of Internal Medicine, Medical School, National and Kapodistrian University of Athens, ²Professor of Internal Medicine-Endocrinology, Medical School, University of Patras, ³Professor of Cardiology, Medical School, University of Patras, ⁴Associate Professor of Internal Medicine, Past President of the Hellenic Atherosclerosis Society Aristotle University of Thessaloniki, ⁵Assistant Professor of Internal Medicine-Endocrinology, Medical School, University of Thessaly, ⁶Consultant-Cardiology, Head of Lipid Outpatient Clinic, “Tzaneio” General Hospital of Piraeus, ⁷Consultant Cardiology, 1st University Cardiology Clinic, “Hippokratio” General Hospital of Athens, ⁸Assistant Professor of Metabolic Pediatrics, Medical School, National and Kapodistrian University of Athens, ⁹Professor of Internal Medicine, Medical School, Past President of the Hellenic Atherosclerosis Society, University of Ioannina, ¹⁰Professor of Internal Medicine, Medical School, Past President of the Hellenic Atherosclerosis Society, University of Crete, ¹¹Professor of Cardiology, Medical School, University of Ioannina, ¹²Consultant-Internal Medicine, Head of the Diabetes and Obesity Outpatient Clinics, General Hospital of Nea Ionia “Konstantopouleio-Patission”, ¹³Consultant-Cardiology, Head of LDL Apheresis Unit and Lipid Outpatient Clinics, Past President of the Hellenic Atherosclerosis Society, President of the Hellenic College of Treatment of Atherosclerosis, Onassis Cardiac Surgery Center, ¹⁴Assistant Professor of Internal Medicine, Aristotle University of Thessaloniki, ¹⁵Professor of Cardiology, Medical School, National and Kapodistrian University of Athens, ¹⁶Assistant Professor of Internal Medicine, Medical School, University of Ioannina, ¹⁷Consultant-Internal Medicine, Coordinator-Director of 1st Internal Medicine Clinic, “Tzaneio” General Hospital of Piraeus, ¹⁸Consultant-Cardiology, “Korgialenio Benakio” “HRC” Hospital, Athens, ¹⁹Assistant Professor of Internal Medicine, Medical School, University of Thessaly, ²⁰Associate Professor of Internal Medicine, Medical School, Democritus University of Thrace, ²¹Internist-Diabetologist, President of the Institute for the Study, Research and Training on Diabetes Mellitus and Metabolic Diseases, Athens, ²²Emeritus Professor of Cardiology, Medical School, National and Kapodistrian University of Athens, ²³Associate Professor of Cardiology, Medical School, University of Athens, ²⁴Director of Cardiology Department, Athens Euroclinic, President of the Hellenic Society of Lipidology and Atherosclerosis, Athens, ²⁵Cosultant-Cardiology, Head of the Lipid Unit of the 1st University Clinic, “Hippokratio” General Hospital of Athens, ²⁶Associate Professor of Internal Medicine, Medical School, National and Kapodistrian University of Athens, ²⁷Professor of Cardiology, Medical School, National and Kapodistrian University of Athens, ²⁸Professor of Biochemistry-Clinical Chemistry, President of the Hellenic Atherosclerosis Society, University of Ioannina, ²⁹Associate Professor of Cardiology, National and Kapodistrian University of Athens, ³⁰Professor of Cardiology, Medical School, Democritus University of Thrace, ³¹Assistant Professor of Medicine, Medical School, Aristotle University of Thessaloniki, ³²Professor of Cardiology, Medical School, Past President of the European Cardiology Society, University of Crete, ³³Associate Professor of Cardiology, President of the European Society of Cardiology working Group for Peripheral Circulation, National and Kapodistrian University of Athens, ³⁴Associate Professor of Nephrology, National and Kapodistrian University of Athens; Greece

Two proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab and alirocumab, have recently been approved by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of hypercholesterolemia. These fully human monoclonal antibodies selectively block PCSK9, thus permitting the low-density lipoprotein (LDL) receptor to effectively recycle to the surface of liver cells. The administration of these antibodies leads to robust LDL cholesterol (LDL-C) lowering by 50-60% on top of maximum hypolipidemic treatment. At least 4 randomized, placebo-controlled studies are under way and will address the question of whether the administration of these PCSK9 inhibitors is associated with a significant reduction of cardiovascular events. Because of the high cost associated with the use of these medications it is very important to consider which patients may gain the most benefit, at least until the results of outcome studies are available. In this Consensus paper, 34 clinicians/scientists define 3 groups of patients that should be currently considered as candidates for the use of these novel drugs. These include: 1a. Adults with established cardiovascular disease and LDL-C≥100 mg/dL while on lifestyle modifications and maximally tolerated hypolipidemic treatment, i.e. high-intensity statin + ezetimibe, 1b. Adults with diabetes and established cardiovascular disease or chronic kidney disease or target organ damage and LDL-C ≥100 mg/dL while on lifestyle modifications and maximally tolerated hypolipidemic treatment, i.e. high-intensity statin + ezetimibe, 2. Adults with familial hypercholesterolemia (FH) without established cardiovascular disease and LDL-C ≥130 mg/dL while on lifestyle modifications and maximally tolerated hypolipidemic treatment, i.e. high-intensity statin + ezetimibe (evolocumab is also indicated in children above 12 years with homozygous FH), and 3. Adults at high or very high cardiovascular risk who are statin intolerant and have an LDL-C ≥100 and ≥130 mg/dL, respectively, while on any tolerated hypolipidemic treatment.

Cardiovascular disease, Diabetes, Ezetimibe, Familial hypercholesterolemia, High-risk, LDL cholesterol, PCSK9, Statin intolerance, Statins

---

---

INTRODUCTION

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in lipoprotein metabolism because it binds and accelerates the cellular degradation of low-density lipoprotein (LDL) receptors, thus preventing their recycling to the hepatocyte surface. This effect results in the increase of plasma LDL cholesterol (LDL-C) levels.^1-7

The administration of fully human monoclonal antibodies that bind plasma PCSK9 of patients treated with statins (with or without ezetimibe) results in an additional reduction of LDL-C by 50-60% and the achievement of lipid-lowering therapy goals in the vast majority of high-risk patients.^7-19 Clinical and experimental data have shown that statins, as opposed to their ability to reduce LDL-C levels, increase PCSK9 levels.¹ This increase is due to the activation of the Sterol Regulatory Element-Binding-Protein-2 (SREBP-2), a transcription factor that induces gene expression and therefore increases the levels of LDL receptors as well as of PCSK9.¹ These findings reinforce the clinical trial data showing that inhibition of PCSK9 with monoclonal antibodies enhances the lipid-lowering effect of statins. Moreover, it has been shown that PCSK9 inhibitors decrease levels of lipoprotein (a) [Lp(a)] by approximately 25%, triglycerides by 9%, non-high density lipoprotein (HDL) cholesterol by 52% and apolipoprotein B by 43% as well as increase HDL cholesterol (HDL-C) levels by 9% and apolipoprotein AI by 5%.^8-20

Three large meta-analyses of PCSK9 inhibitors, evolocumab and alirocumab (meta-analysis of 24 randomized studies by Navarese et al, 25 randomized studies by Zhang et al and 17 randomized studies by Lipinski et al), confirmed the efficacy and safety of both drugs, without differences regarding serious adverse events among patients treated with evolocumab or alirocumab and placebo.^8-10 Of note, injection-site reactions and neurocognitive adverse events were more frequent in patients on PCSK9 inhibitors compared with placebo.¹⁰ The possible association of PCSK9 inhibitors with neurocognitive adverse events is under scrutiny in ongoing studies.

It is of particular interest that two studies recently published (ODYSSEY LONG TERM & OSLER studies) showed that administration of both drugs, apart from the well tolerated reduction in LDL-C, resulted in a significant (50%) reduction in cardiovascular (CV) events (treatment duration 1 year, starting LDL-C levels of ~120 mg/dL).^19,20 However, these studies were not designed to evaluate the effect of the drugs on CV events, while the number of CV events recorded during treatment was low and the time of prospective follow-up of patients was limited. Ongoing studies will answer the question whether the reduction of LDL-C through PCSK9 inhibition leads to a proportional reduction of CV events in cases of long-term administration, without adverse events.

Regulatory authorities in the USA and Europe [Food and Drug Administration (FDA) and European Medicines Agency (EMA)] have approved the administration of these drugs to adult patients with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, as adjunct treatment to diet:

In combination with a statin or statin with other lipid lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin, or,

Alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant or for whom a statin is contraindicated.

Evolocumab has received an additional indication in adolescents over 12 years old with homozygous familial hypercholesterolemia (FH) in combination with other lipid-lowering treatments.

The drugs are administered as subcutaneous injections every 2 weeks (evolocumab 140 mg and alirocumab 75 or 150 mg) or 4 weeks (evolocumab 420 mg).

Patients who could benefit from treatment with PCSK9 inhibitors

Until the announcement-publication of the prospective randomized clinical trials that will confirm the effect of these drugs on CV morbidity and mortality, it is proposed that their prescription be limited to specific patient groups at very high risk who are expected to benefit from the treatment.

The following guidelines are consistent with the recent recommendations of the US National Lipid Association (NLA) and are summarized in Table 1.¹¹ It is to be noted that patient adherence with already administered lipid-lowering therapy should always be examined first. The patient groups that are expected to benefit from treatment are: (1) patients with FH, (2) patients with established vascular disease and very high-risk diabetic patients who do not achieve the hypolipidemic treatment goals with the maximum available lipid-lowering therapy (high doses of effective statins + ezetimibe), and (3) patients intolerant to statins. Patients with FH are at high CV risk because of very high levels of LDL-C. These patients often do not achieve the goals of hypolipidemic treatment in daily clinical practice. It must be underlined that a percentage of patients display intolerance to statins, i.e. myalgia with or without an increase in muscle enzymes, which makes it difficult to continue treatment with statins or to administer high doses of these drugs.^21-25

Diagnosis of FH

The diagnosis of heterozygous FH is set clinically using the Dutch criteria (Table 2 and FH score in App Store (https://appsto.re/gr/wF4Q7.i), FH score in Google Store (https://play.google.com/store/apps/details ?id=com.ajjumax.helleniccalculat) and Download in desktop (http://web.alphabit.gr/FHCalculator/index.html) and when the patient has a score ≥6 (probable or definite FH).^26-38

The Hellenic Atherosclerosis Society has already initiated a nationwide registry of patients with FH (HELLAS FH Registry - Hellenic Registry of Patients with FH). The inclusion of any patient in this registry also confirms its diagnosis.

Diagnosis of statin intolerance

The diagnosis of statin intolerance is set in patients who: (a) display significant increases in creatine kinase (CK) >5 times of the upper limit reference values, and/or, (b) irrespective of any increase in CK, display muscle symptoms which may be attributed to statins (pain, fatigue, weakness, cramps) and after the exclusion of any other factors which could cause similar symptoms (Table 3) and/or any possible interactions of the co-administered drugs have been excluded (Table 4).

In order to confirm possible statin intolerance, a sequential administration of at least 2 different statins starting at low doses followed by a careful dosage up-titration over a few weeks is required (Table 5). The improvement of symptoms following statin treatment discontinuation and their reappearance with the re-administration of the same or a different statin reinforce the diagnosis of statin intolerance. The therapeutic options in patients intolerant to statins before administration of the PCSK9 inhibitors are shown in Table 6.^21-25

FINANCIAL AND COMPETING INTEREST DISCLOSURE

This consensus was written independently and was not financed by the pharmaceutical industry. Some authors have given lectures and participated in congresses and advisory boards of various pharmaceutical companies; however, they have no conflict of interest in terms of employment, stock ownership or options, grants, or patents received or pending, or royalties. No writing assistance was utilized in the production of this consensus.

ACKNOWLEDGEMENT

This consensus was published in Greek in the Hellenic Journal of Atherosclerosis (Hellenic J Atheroscler 2015, 6(Suppl): 3-8). After agreement of the two Editors-in-Chief it is published in English in an extended form in Hormones.

REFERENCES

1. Careskey HE, Davis RA, Alborn WE, Troutt JS, Cao G, Konrad RJ, 2008 Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J Lipid Res 49: 394-398.
2. Elisaf M, Liberopoulos E, Pitsavos C, et al, 2014 Updated guidelines of the Hellenic Society of Atherosclerosis for the diagnosis and treatment of dyslipidemia-2014. Hellenic J Atheroscler 5: 151-163 [in Greek]
3. European Association for Cardiovascular Prevention & Rehabilitaiton,Reiner Z, Catapano AL, De Backer G, et al, 2011 ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 32: 1769-1818.
4. Stone NJ, Robinson JG, Lichtenstein AH, et al, 2014 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. Circulation 129: Supple 2: 1-45.
5. Anderson TJ, Gregoire J, Hegele RA, et al, 2013 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 29: 151-167.
6. Grundy SM, Arai H, Barter P, et al, 2014 An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia-full report. J Clin Lipidol 8: 29-60.
7. American Diabetes Association, 2015 Standards of Medical Care in Diabetes - 2015. Diabetes Care 38: Suppl 1: 49-57.
8. Navarese EP, Kolodziejczak M, Schulze V, et al, 2015 Effects of Proprotein Convertase Subtilisin/ KexinType 9. Antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med 163: 40-51
9. Zhang XL, et al, 2015 Safety and efficacy of anti-PCSK9 antibodies: a metaanalysis of 25 randomized, controlled trials. BMC Med 13: 123.
10. Lipinski MJ, Benedetto U, Escarcega RO, et al, 2016 The impact of proprotein convertase subtilisinkexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis. Eur Heart J 37: 536-545
11. Jacobson TA, Maki KC, Orringer CE, et al, 2015 National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2. J Clin Lipidol 9: Suppl 1: 1-122
12. Robinson JG, Nedergaard BS, Rogers WJ, et al, 2014 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 311: 1870-1882.
13. Stein EA, Mellis S, Yancopoulos GD, et al, 2012 Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 366: 1108-1118.
14. Blom DJ, Hala T, Bolognese M, et al, 2014 A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 370: 1809-1819.
15. Stroes E, Colquhoun D, Sullivan D, et al, 2014 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 63: 2541-2548.
16. Koren MJ, Lundqvist P, Bolognese M, et al, 2014 Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol 63: 2531-2540.
17. Koren MJ, Giugliano RP, Raal FJ, et al, 2014 Efficacy and safety of longer term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 129: 234-243.
18. Raal FJ, Honarpour N, Blom DJ, et al, 2015 Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 385: 341-350.
19. Sabatine MS, Giugliano RP, Wiviott SD et al, Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators 2015 Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 372: 1500-1509
20. Robinson JG, Farnier M, Krempf M, et al, ODYSSEY LONG TERM Investigators, 2015 Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 372: 1489-1499.
21. Stroes ES, Thompson PD, Corsini A, et al, European Atherosclerosis Society Consensus Panel, 2015 Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 36: 1012-1022.
22. Guyton JR, Bays HE, Grundy SM, Jacobson TA, 2014 The National Lipid Association Statin Intolerance Panel. An assessment by the Statin Intolerance Panel: 2014 update. J Clin Lipidol 8: Suppl: 72-81.
23. Rosenson RS, Baker SK, Jacobson TA, et al, 2014 The National Lipid Association’s Muscle Safety Expert Panel. An assessment by the Statin Muscle Safety Task Force: 2014 update. J Clin Lipidol 8: Suppl: 58-71.
24. Mancini GB, Tashakkor AY, Baker S, et al, 2013 Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update. Can J Cardiol 29: 1553-1568.
25. Banach M, Rizzo M, Toth PP, et al, 2015 Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci 11: 1-23.
26. Raal FJ, Stein EA, Dufour R et al, RUTHERFORD-2 Investigators, 2015 PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 385: 331-340
27. Nordestgaard BG, Chapman MJ, Humphries SE, et al, European Atherosclerosis Society Consensus Panel, 2013 Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 34: 3478-3490.
28. Roth EM, Taskinen MR, Ginsberg HN, et al, 2014 Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol 176: 55-61.
29. Boekholdt SM, Hovingh GK, Mora S et al, 2014 Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol 64: 485-494.
30. Everett BM, Smith RJ, Hiatt WR, 2015 Reducing LDL with PCSK9 Inhibitors - The Clinical Benefit of Lipid Drugs. N Engl J Med 373: 1588-1591.
31. Giugliano RP, Sabatine MS, 2015 Are PCSK9 inhibitors the next breakthrough in the cardiovascular field? J Am Coll Cardiol 65: 2638-2651.
32. Kastelein JJ, Ginsberg HN, Langslet G, et al, 2015 ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 36: 2996-3003.
33. Bays H, Gaudet D, Weiss R, et al, 2015 Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I Randomized Trial. J Clin Endocrinol Metab 100: 3140-3148.
34. Kereiakes DJ, Robinson JG, Cannon CP, et al, 2015 Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J 169: 906-915.e13.
35. Verbeek R, Stoekenbroek RM, Hovingh GK, 2015 PCSK9 inhibitors: Novel therapeutic agents for the treatment of hypercholesterolemia. Eur J Pharmacol 7 63(Pt A): 38-44.
36. Cannon CP, Cariou B, Blom D et al, ODYSSEY COMBO II Investigators, 2015 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 36: 1186-1194.
37. Schwartz GG, Bessac L, Berdan LG, et al, 2014 Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J 168: 682-689.
38. Panagiotakos DB, Fitzgerald AP, Pitsavos C, et al, 2007 Statistical modeling of 10-year fatal cardiovascular disease risk in Greece: the Hellenic SCORE (a calibration of the ESC Score project). Hellenic J Cardiol 48: 55-63.

---

Address for correspondence:
Moses Elisaf, Professor of Internal Medicine, Medical School, University of Ioannina, 451 10 Ioannina, Greece; Tel.: +30 2651-007 509, Fax: +30 2651-007 016, E-mail: melisaf54@gmail.com

Received: 04-12-2015, Accepted: 09-12-2015