Georgia Anastasiou, George Liamis, Haralampos Milionis, Moses Elisaf, Eliza Christopoulou, Theodora Dimitriou, Evangelos N. Liberopoulos
Department of Internal Medicine, Faculty of Medicine, University of Ioannina, Ioannina, Greece
Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been demonstrated to be safe and effective in low-density lipoprotein cholesterol (LDL-C) lowering and cardiovascular risk reduction. Data on clinical implementation of PCSK9 inhibitors in real life setting in Greece is limited. Thus, we report 2-year experience with PCSK9 inhibitors in clinical practice at a University Hospital Lipid Clinic. Patients and methods: This is a retrospective study of patients who were first prescribed a PCSK9 inhibitor during 2016-2018. Patients had either established cardiovascular disease (CVD) and/or familial hypercholesterolemia (FH) and LDL-C level >100 mg/dL despite maximum tolerated high-intensity statin plus ezetimibe. Patient demographics, medical history, concomitant medications and laboratory results were documented during visits. Results: We included 37 patients (mean age 52 years, 56.8% males). Of patients, 28 (76%) had established CVD and 27 patients (74%) had FH. Concerning treatment, 33 patients (89%) were receiving high-intensity statin, while 35 patients (95%) were also on ezetimibe 10 mg. Addition of PCSK9 inhibitors (51% on evolocumab 140 mg per 2 weeks (Q2W), 22% on alirocumab 75 mg Q2W and 27% on alirocumab 150 mg Q2W) resulted in a reduction of total cholesterol by 42% and LDL-C by 59% after 2 months (p<0.05). These reductions remained unchanged after 1 and 2 years on treatment. Thirty patients (81%) achieved LDL-C treatment goal following PCSK9i treatment. Four patients (11%) developed minor adverse effects. No treatment discontinuation was reported. Conclusion: In real-life setting addition of PCSK9 inhibitors to maximally tolerated lipid-lowering therapy resulted in reductions of LDL-C levels of the magnitude seen in clinical studies. These reductions were sustainable during a 2-year follow-up.
Key words: PCSK9 inhibitors, dyslipidemia, familial hypercholesterolemia, statins, cardiovascular disease, ezetimibe
Corresponding author: Dr Evangelos N. Liberopoulos, MD, Associate Professor of Medicine, Department of Internal Medicine, Faculty of Medicine, University of Ioannina, 45 110 Ioannina, Greece, Tel.: +302651007502, Fax: +302651007016, E-mail: email@example.com
Submission: 19.11.2019, Acceptance: 09.03.2020
Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD) and cardiovascular risk reduction is proportional to low-density lipoprotein cholesterol (LDL-C) lowering1,2. European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) and American College of Cardiology/American Heart Society (ACC/AHA) guidelines impose statin therapy as first line treatment for reducing LDL-C levels and associated cardiovascular risk1,2. Ezetimibe addition to maximum tolerated statin is suggested for further LDL-C lowering1,2. However, a large proportion of patients do not achieve LDL-C goals under maximally tolerated lipid-lowering therapy or are statin intolerant3. This is also the case in Greece4,5.
Monoclonal antibodies inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) have been shown to effectively lower LDL-C levels and associated cardiovascular risk6,7. Two fully human PCSK9 inhibitors (PCSK9i) are available, alirocumab and evolocumab, administered by subcutaneous injection at 75/150 mg every two weeks and 140 mg every 2 weeks/420 mg once a month, respectively. In clinical studies PCSK9i lower LDL-C levels by 50-60% on top of maximally tolerated hypolipidemic treatment8-14. In addition, 3 randomized trials, FOURIER, ODYSSEY OUTCOMES and GLACOV, demonstrated that PCSK9i are associated with significant reductions of major cardiovascular events and atherosclerosis progression with an excellent safety profile6,7,15. Long-term studies have confirmed sustainability of LDL-C lowering up to 4 years16-18.
In Greece PCSK9i are available since 2016 and are reimbursed in patients with either established ASCVD or familiar hypercholesterolemia (FH) and LDL-C level >100 mg/dL despite maximum tolerated high-intensity statin plus ezetimibe19. However, data on the use of PCSK9i in real-life in Greece is limited. We report herein clinical experience with PCSK9i from an outpatient University hospital lipid clinic over 2 year follow-up.
PATIENTS AND METHODS
In the present study, we included consecutive patients attending the lipid clinic at the University Hospital of Ioannina, Ioannina, Greece from 2016 to 2018 who were prescribed a PCSK9i. Reimbursement of PCSK9i treatment was granted to patients with either established ASCVD or FH and LDL-C level ≥100 mg/dL while on maximum tolerated lipid-lowering therapy (rosuvastatin target dose 20-40 mg or atorvastatin target dose 40-80 mg plus ezetimibe) and healthy lifestyle.
All patients prescribed PCSK9i were provided proper subcutaneous injection training. Patient characteristics, family history and concomitant medications were reported, and clinical examination and laboratory tests were performed at baseline visit, as well as after 2 months, 1 year and 2 years following PCSK9i administration. In addition, adverse events and compliance to PCSK9i therapy was reported during follow-up.
Analyses were performed descriptively via the Statistical Package for Social Sciences (SPSS) 21.0 software (SPSS, IBM corp). Continuous numeric variables are expressed as mean ± standard deviation and median (interquartile: IQR) if Gaussian or non-Gaussian distributed, respectively. Categorical data are presented as total number and percentage. An ANOVA with repeated measures was used to compare group means where the participants are the same in each group. Chi square test was used to compare categorical data among the alirocumab and evolocumab treated group. Two-tailed significance was defined as p<0.05.
All participants gave written informed consent and the study protocol was approved by our institutional ethics committee. The research was performed according to the principles of the Declaration of Helsinki (1975).
Baseline patient characteristics (Table 1)
We included 37 patients [56.8% men, age 54 years (IQR: 50-71)]. Of those, 28 (76%) had established CVD [22 (60%) coronary artery disease and 6 (16%) a history of cerebrovascular event], 24 (65%) had HeFH and 3 (8%) had lower extremities arterial disease (LEAD)].
Nineteen individuals initiated evolocumab 140 mg (Q2W) and 18 received alirocumab [8 alirocumab 75 mg (Q2W) and 10 alirocumab 150 mg (Q2W)]. Of the alirocumab treated group, 6 patients maintained the dose of 75 mg (Q2W), while 2 patients were uptitrated to 150 mg (Q2W) after the 2-month follow-up. No significant difference in baseline characteristics was noticed between the 2 groups. Eight patients (5 patients intolerant to statins, 1 with homozygous FH and 2 with heterozygous FH) qualified PCSK9i treatment for primary prevention, while 29 patients for secondary prevention. Prior to initiation of PCSK9i, the vast majority of patients (90%) were on dual maximally tolerated LLT (79% on rosuvastatin 20-40 mg and 11% on atorvastatin 40-80 mg plus ezetimibe), 1 patient was on pitavastatin plus ezetimibe, 1 on pitavastatin monotherapy, 1 on ezetimibe monotherapy and 1 on colesevelam monotherapy (totally intolerable). No significant difference was observed in baseline characteristics among evolocumab and alirocumab treated groups (p=NS).
Lipid profile (Table 2 and Figure)
PCSK9i administration yielded an additional 60% mean reduction in LDL-C and 42% mean reduction in TCHOL after 2 months on treatment (p<0.05). This reduction rate remained sustainable after 1 and 2 years on PCSK9i therapy. The LDL-C and TCHOL lowering rate was similar among evolocumab and alirocumab treated group after 2 months, 1 and 2 years (p=NS for between groups comparison). HDL-C was increased by 3% and triglycerides were decreased by 10% after 2-month PCKS9i treatment (p=NS). The overall percentage of patients attaining LDL-C target according to ESC/EAS 2016 guidelines28 was 81% after 2-month PCSK9i therapy. Excluding homozygous FH patients (n=3), LDL-C was reduced by 63%, TGs by 12%, TCHOL by 42% and HDL-C was increased by 7% after 2 months on PCSK9i treatment. The 3 individuals with homozygous FH experienced a mean LDL-C reduction of 39% over a 2-year follow-up.
Figure 1. Median value of low-density lipoprotein cholesterol level (LDL-C) in all participants, according to treatment assignment and time on proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i).
Safety (Table 3)
The majority of patients (89%) did not report any adverse event during follow-up. One patient complained about backache (evolocumab group), one patient reported diarrhea and abdominal pain (evolocumab group), one patient a non-troublesome reaction at the injection site (alirocumab group) and one patient reported a ‘pruritic rash’ in the upper body which resolved after few days and was not seen with next doses of PCK9i (evolocumab group). The reported adverse events were not different between 2 treated groups. No patient dropped out of treatment. No CVD event was reported during follow-up.
The present study is one of the few investigating the efficacy and safety of PCSK9i administration in a clinical real life setting20-26. Randomized controlled clinical trials frequently enlarge the magnitude of LDL-C lowering rate due to rigorous patient monitoring and intensive lifestyle modifications8-14. Our study indicates a mean LDL-C reduction rate comparable with that of FOURIER and ODYSSEΥ clinical trials (approximately 60%) and similar with that achieved in real-life studies (50-63%)20-26. It also confirms that PSCK9i-related LDL-C reduction was sustained after 1 and 2 years on treatment with both evolocumab and alirocumab having comparable efficacy.
Three individuals (8.1%) with homozygous FH were responsive to PCSK9i on top of dual or triple hypolipidemic therapy and gained a mean percentage LDL-C level reduction of 39% over a 2-year follow-up. This is line with the mean reduction rate of LDL-C reported by one published real-life study (38%)26. In another trial in patients with homozygous FH, LDL-C was reduced by 20-65% after 12 weeks on PCSK9i. The magnitude of reduction was dependent on the underlying genetic defect with the greatest reduction noted in patients with PCSK9 gain of function mutations14.
Of note, 90% of our patients were treated with high-intensity statins. Two previously published real-life cohorts reported treatment rates with high-intensity statin regiments in 49% and 66% of participants, respectively23,26. This discrepancy could be attributed to different PSCK9i approval criteria applicable in each country. In Greece, LDL-C levels above treatment target despite high-intensity statin plus ezetimibe administration or maximally tolerated LLT comprises a precondition for PCSK9i reimbursement19. Of interest, in our study the percentage of LDL-C goal attainment was 81%. This proportion is higher than other cohorts reporting LDL-C target achievement by 55-76%20,22,24,26,29.
Our data verify the favorable safety profile of both evolocumab and alirocumab in daily clinical practice in line with randomized clinical trials. Minor adverse events were manifested by 6% of patients, a lower incidence than that reported in randomized clinical trials; there were no differences between evolocumab and alirocumab treatment groups. These side effects did not lead to treatment discontinuation and resolved spontaneously. Notably, in our study no treatment discontinuation was observed in contrast with other cohorts reporting a discontinuation range of 2.5-15.0%, mainly due to non-adherence20,22,24,26. Interestingly, 8.1% of patients being intolerant to statins due to muscle symptoms did not report any muscle event with PCSK9i administration. In GAUSS-3 there was a higher percentage of muscle symptoms in ezetimibe compared with evolocumab group27.
This study comprises real-life data from a relatively small number of patients attending a university outpatient lipid clinic. In this view, our findings may not be generalizable to other populations particularly to hospitals those without lipid clinics or to the private practice.
In conclusion, PCSK9i administration in a real-life clinical setting was associated with potent LDL-C reductions and a favorable safety profile during a 2-year follow-up comparable to what is reported in randomized clinical trials.
Dr. G. Anastasiou contributed to the conception and design, acquisition, analysis and interpretation of data and been involved in drafting the manuscript. Dr. E. Christopoulou and Dr. T. Dimitriou contributed to the analysis and interpretation of data. Dr. G. Liamis, Dr. H. Milionis and Prof. M. Elisaf have been involved in critically revising the manuscript. Dr. E. Liberopoulos has given the final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
The authors have received no payment in preparation of this manuscript.
Conflict of interest
AG, EC, and TD have nothing to declare; EL has participated in educational, research and advisory activities sponsored by Astra-Zeneca, MSD, Lilly, Bayer, Amgen, Sanofi, Boehringer-Ingelheim, Novartis, Novo Nordisk and Servier; HM reports receiving honoraria, consulting fees and non-financial support from healthcare companies including Amgen, Bayer, MSD, Mylan, Pfizer, Sanofi, and Servier; GL reports personal fees from Angelini, Bayer, Menarini and Sanofi; Professor M. Elisaf reports honoraria from MSD, Novartis, Chiesi, Bayer, Astra-Zeneca, Pfizer, Abbott, Mylan, Sanofi, Amgen, Boheringer-Ingelheim, Lilly, GSK, Angelini, Winmedica and grants and personal fees from MSD and Astra-Zeneca.
1. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College ofCardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019 Jun;73(24):3168-209.
2. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2020 Jan;41(1):111-88.
3. Kotseva K, De Backer G, De Bacquer D, Rydén L, Hoes A, Grobbee D, et al. Lifestyle and impact on cardiovascular risk factor control in coronary patients across 27 countries: Results from the European Society of Cardiology ESC-EORP EUROASPIRE V registry. Eur J Prev Cardiol. 2019 May;26(8):824-35.
4. Liberopoulos E, Rallidis L, Spanoudi F, Elena Xixi, Anselm Gitt, Martin Horack, et al. Attainment of cholesterol target values in Greece: Results from the Dyslipidemia International Study II. Arch Med Sci. 2019 Jul;15(4):821-31.
5. Barkas F, Liberopoulos EN, Kostapanos MS, Liamis G, Tziallas D, Elisaf M. Lipid target achievementamong patientswithvery high and high cardiovascular risk ina lipid clinic. Angiology. 2015 Apr;66(4):346-53.
6. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May;376(18):1713-22.
7. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018 Nov;379(22):2097-107.
8. Koren MJ, Sabatine MS, Giugliano RP, Langslet G, Wiviott SD, Ruzza A, et al. Long-Term Efficacy and Safety of Evolocumab in Patients with Hypercholesterolemia. J Am Coll Cardiol. 2019 Oct;74(17):2132-46.
9. Wasserman SM, Sabatine MS, Koren MJ, Giugliano RP, Legg JC, Emery MG, et al. Comparison of LDL-C Reduction Using Different Evolocumab Doses and Intervals: Biological Insights and Treatment Implications. J Cardiovasc Pharmacol Ther. 2018 Sep;23(5):423-32.
10. Defesche JC, Stefanutti C, Langslet G, Hopkins PN, Seiz W, Baccara-Dinet MT, et al. Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia. J Clin Lipidol. 2017 Nov – Dec;11(6):1338-46.e7.
11. Stroes E, Guyton JR, Lepor N, Civeira F, Gaudet D, Watts GF, et al. Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients with Hypercholesterolemia Not on Statin Therapy: The ODYSSEY CHOICE II Study. J Am Heart Assoc. 2016 Sep;5(9):e003421.
12. Toth PP, Sattar N, Blom DJ, Martin SS, Jones SR, Monsalvo ML, et al. Effect of evolocumab on lipoprotein particles. Am J Cardiol. 2018 Feb;121(3):308-14.
13. Farnier M, Hovingh GK, Langslet G, Dufour R, Baccara-Dinet MT, Din-Bell C, et al. Long-term safety and efficacy of alirocumab in patients with heterozygous familial hypercholesterolemia: An open-label extension of the ODYSSEY program. Atherosclerosis. 2018 Nov;278:307-14.
14. Raal FJ, Hovingh GK, Blom D, Santos RD, Harada-Shiba M, Bruckert E, et al. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis,in patients with homozygous familial hypercholesterolaemia: An interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol. 2017 Apr;5(4):280-90.
15. Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JP, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients, The GLAGOV Randomized Clinical Trial. JAMA. 2016 Dec; 316(22):2373-84.
16. Koren MJ, Sabatine MS, Giugliano RP, Langslet G, Wiviott SD, Kassahun H, et al. Long-term low-density lipoprotein cholesterol–lowering efficacy, persistence, and safety of evolocumab in treatment of hypercholesterolemia. Results up to 4 Years from the open-label OSLER-1 extension study. JAMA Cardiol. 2017 Jun;2(6):598-607.
17. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al.; for the ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr;372(16):1489-99.
18. Hovingh GK, Raal FJ, Dent R, Stefanutti C, Descamps O, Masana L, et al. Long-term safety, tolerability, and efficacy of evolocumab in patients with heterozygous familial hypercholesterolemia. J Clin Lipidol. 2017 Nov – Dec;11(6):1448-57.
19. Achimastos A, Alexandrides T, Alexopoulos D, Athyros V, Bargiota A, Bilianou E, et al. Expert consensus on the rational clinical use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Hormones. 2016 Jan-Mar; 15(1):8-14.
20. Stoekenbroek RM, Hartgers ML, Rutte R, de Wijer DD, Stroes ESG, Hovingh GK, et al. PCSK9 inhibitors in clinical practice: Delivering on the promise? Atherosclerosis. 2018 Mar;270:205-210.
21. Sarsam S, Berry A, Degheim G, Singh R, Zughaib M. Real-world use of PCSK9 inhibitors: A single center experience. J Int Med Res. 2019 Jan;47(1):265-70.
22. Graesdal A, Dybvig A. A real-life PCSK9 experience: efficacy, compliance and side effects afteroneyear treatment in familial hypercholesterolemia patients. J Am Coll Cardiol. 2018 March; 71(11)Suppl DOI: 10.1016/S0735-1097(18)32295-2.
23. Navarro-Hoyas C, Moragrega Raquel M, Delegido-Gómez L, López-Muñoz B, Moreno-Pérez Ó, Picó-Alfonso A, et al. Efficacy and safety of proprotein convertase subtilisin/kexintype nine inhibitors in real life experience. Endocrine In: 20th European Congress of Endocrinology. Vol 56. Bioscientifica. 2018.
24. Zafrir B, Jubran A. A Lipid-lowering therapy with PCSK9-inhibitors in the real-world setting: Two-year experience of a regional lipid clinic. Cardiovasc Ther. 2018 Oct; 36(5):e12439.
25. Jensen JS, Weeke PE, Bang LE, Høfsten DE, Sejersten Ripa M, Schjerning AM, et al. Clinical characteristics and lipid lowering treatment of patients initiated on proprotein convertase subtilisin-kexin type 9 inhibitors: A nationwide cohort study. BMJ Open. 2019 Apr 1;9(4):e022702
26. Galema-Boers AMH, Lenzen MJ, Sijbrands EJ, Roeters van Lennep JE. Proprotein convertase subtilisin/kexin 9 inhibition in patients with familial hypercholesterolemia: Initial clinical experience. J Clin Lipidol. 2017 May – Jun;11(3):674-81.
27. Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial. JAMA. 2016 Apr;315(15):1580-90.
28. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J. 2016 Oct 14; 37(39): 2999-3058.
29. Rallidis LS, Skoumas I, Liberopoulos EN, Vlachopoulos C, Kiouri E, Koutagiar I, et al. PCSK9 inhibitors in clinical practice: Novel directions and new experiences. Hellenic J Cardiol. 2019 Nov 26. pii: S1109-9666(19)30276-3. doi: 10.1016/j.hjc.2019.10.003. [Epub ahead of print]