Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have opened a new avenue in the management of dyslipidaemia in patients with familial hypercholesterolaemia (FH), but real-world experience with PCSK9 inhibitors is limited.
We aimed to explore the efficacy and safety of PCSK9 inhibitors in a single-centre study, and to conduct a meta-analysis of the available observational studies to report pooled data on these efficacy and safety parameters.
The Hull PCSK9 inhibitor study consisted of patients from the Lipid Clinic at the Hull Royal Infirmary–Hull University Teaching Hospitals NHS Trust during the period 2016–2018. Patients with FH and atherosclerotic cardiovascular disease (ASCVD) were screened for eligibility and were prescribed PCSK9 inhibitors. Lipid profile, liver function, renal function, and creatine kinase levels were measured at baseline and after a 12-week follow-up. For the meta-analysis, review of the literature identified six additional observational studies for FH, which were used to calculate pooled percentage low-density lipoprotein (LDL)-cholesterol (LDL-C) reduction.
The Hull PCSK9 inhibitor study consisted of 16 patients with definite FH (LDL-receptor mutation-positive), 20 patients with clinical FH and 15 patients with ASCVD with a mean age of 60.6 ± 13.9 years, 60% female. Baseline median (interquartile range) LDL-C levels (mmol/L) in the definite FH, clinical FH and ASCVD were 4.9 (4.6–5.9), 6.7 (5.3–7.1) and 4.4 (4.1–4.7). After 12 weeks, the LDL-C levels (mmol/L) dropped significantly (p<0.0001) in all three groups to 2.0 (1.6–3.4), 2.3 (1.9–2.6) and 2.2 (1.7–2.8) in the definite FH, clinical FH and ASCVD groups, respectively. The meta-analysis of the seven observational studies in 446 patients with FH showed pooled mean reduction of 55.5 ± 18.1% in the LDL-C levels, with 58% of patients reaching treatment targets. Treatment-associated side effects occurred in 6% to 45% of patients, and 0–15% of patients discontinued treatment due to intolerable side effects.
In conclusion, we showed that PCSK9 inhibitors are overall well-tolerated when used in real-world settings, and their efficacy is comparable with that reported in clinical trials. Longitudinal population-based registries are needed to monitor responses to treatment, treatment adherence and side effects of these lipid-lowering agents.
Familial hypercholesterolaemia (FH) is a monogenic disorder characterised by excessive levels of low-density lipoprotein-cholesterol (LDL-C) and associated with significant cardiovascular morbidity and mortality.1 A reduction in LDL-C levels is the mainstay of treatment in FH and evidence-based guidelines have proposed treatment goals for these patients. The National Institute for Health and Care Excellence (NICE) recommends at least a 50% reduction in LDL-C levels from the baseline measurement in patients with FH,2 while the European Atherosclerosis Society and the International FH Foundation suggest target LDL-C levels of <2.5 mmol/L in adults with FH or <1.8 mmol/L in adults with FH and concomitant clinical coronary artery disease or diabetes.1,3 Several studies have shown that reaching these targets with high-intensity statins, ezetimibe or a combination of these two drug classes in patients with FH is difficult.4-6 Recent clinical trials with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have shown promising reductions in LDL-C levels in patients with and without FH, and have suggested that these agents are generally well tolerated.7,8 The ODYSSEY FH I and FH II trials9 showed up to a 57% reduction in LDL-C in patients with heterozygous FH and inadequate LDL-C control at baseline, despite maximally tolerated statin and other lipid-lowering therapy, while the RUTHERFORD (Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder) 2 trial10 showed a 59% reduction in LDL-C levels in patients with heterozygous FH. Similarly, in patients with homozygous FH,10 the PSCK9 inhibitors led to a 39% reduction in LDL-C levels, however, some were non-responders, dependent on mutation class. The FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trial11 and the ODYSSEY trial12-14 have established the usefulness of PSCK9 inhibitors in atherosclerotic cardiovascular disease patients (ASCVD), showing relative hazard reduction and an absolute risk reduction in major cardiovascular events with the use of PCSK9 inhibitors.
Despite the promising findings from clinical trials, there are limited data on the performance of PSCK9 inhibitors in real-world settings,15-19 and no systematic summary of real-world performance of PSCK9 inhibitors in terms of efficacy and safety As such, we aimed to i) explore the efficacy (LDL-C reduction and attainment of target LDL-C levels) and safety (side effects and tolerability) of PCSK9 inhibitors in a single-centre study (the Hull PCSK9 inhibitor study) and ii) conduct a meta-analysis of the available observational studies to report pooled results of these efficacy and safety parameters.
The Hull PCSK9 inhibitor study
This study included patients from the Lipid Clinic at the Hull Royal Infirmary–Hull University Teaching Hospital NHS Trust during the period 2016–2018. During the study period, we initiated 36 patients with genetically proven or clinical FH and 15 ASCVD patients. The diagnosis of clinical FH was based on the Simon Broome Criteria.20,21 Patients with a modified Dutch Lipid Clinic network score22 of ≥6 were offered next generation sequencing for four-panel gene for FH. Those with contraindications for PCSK9 (age <18 years, chronic kidney disease stage 4 and 5, severe hepatic impairment [Child-Pugh C], pregnancy or lactation) were not considered for PCSK9 inhibitor therapy. Patients were started either on PCSK9 inhibitors; evolocumab or alirocumab. Following treatment initiation, all patients had a monthly telephone consultation and a follow-up at 12 weeks where all fasting baseline blood tests were repeated. Satisfactory response to PCSK9 inhibitors in this study was defined as more than a 20% drop in LDL-C from baseline. Adverse effects were recorded and intolerance to treatment was defined as serious adverse effect leading to the withdrawal of PCSK9 treatment. Information about comorbidities, such as diabetes and hypertension, was obtained from electronic patient records and drug summaries.
Study selection and methods for the meta-analysis
We searched PubMed/Medline and Embase until 1 January 2018, for keywords such as PCSK9 antibody/inhibitor, evolocumab, alirocumab, bococizumab, AMG145, REGN727, SAR236553, RN 316, and PF-04950615. Citations were screened at the title and abstract levels and if they were considered potentially relevant, they were retrieved for full-text evaluation. All randomised-controlled trials were excluded from this meta-analysis. Six observational studies were identified and together with the Hull PCSK9 inhibitor study, included for pooled analysis. Pooled mean and standard deviation (SD) were calculated. In studies that reported confidence intervals, these were converted to SD in Excel. The Mann–Whitney U-test was used to compare baseline and post-treatment LDL-C levels. All statistical analysis was done in R3.3.2.
The Hull PCSK9 inhibitor study
Baseline study characteristics
During the two-year study period, 16 patients with definite FH (mean age 55.8 ± 15.6 years, 56% female), 20 patients with clinical FH (mean age 60.6 ± 14.4 years, 80% female) and 15 patients with ASCVD (mean age 65.2 ± 9.7 years, 40% female) were initiated on PCSK9 inhibitors. Table 1 shows the baseline characteristics of the study population. The prevalence of hypertension was 50% in the FH patients, while all ASCVD patients had hypertension. The prevalence of diabetes was up to 11% and 5% in FH and ASCVD patients, respectively.
Table 1. Baseline demographic characteristics of the study population and response to treatment in the Hull PCSK9 inhibitor study
|Variable||Definite FH (n=16)||Clinical FH (n=20)||Definite and clinical FH (n=36)||ASCVD patients (n=15)||Total (n=51)|
|Age (years), mean ± SD||55.8 ± 15.6||60.6 ± 14.4||58.5 ± 14.9||65.2 ± 9.7||60.6 ± 13.9|
|Intolerant to PCSK9||6%||20%||13%||33%||21%|
|Baseline TC (mmol/L), median (IQR)||7.2 (6.5–8.3)||8.65 (7.6–102)||8.2 (6.8–9.6)||6.4 (6.1–6.9)||7.5 (6.5–8.6)|
|Baseline LDL-C (mmol/L), median (IQR)||4.9 (4.6–5.9)||6.7 (5.3–7.1)||5.7 (4.8–6.8)||4.4 (4.1–4.7)||4.9 (4.4–6.1)|
|12 weeks TC (mmol/L), median (IQR)||3.5 (2.6–4.6)||4.5 (4.1–5)||4.3 (3.6–4.8)||4.1 (3.2–4.6)||4.2 (3.4–4.7)|
|12 weeks LDL-C (mmol/L), median (IQR)||2.0 (1.6–3.4)||2.3 (1.9–2.5)||2.2 (1.7–2.8)||2.1 (1.4–2.2)||2.2 (1.6–2.7)|
|Reduction in LDL-C during follow-up, median (IQR)||56% (21.7–69.5)||64% (49–68)||60% (38.5–68%)||43.8 (39–48.4)||53% (38.6–49.9)|
|>20% reduction in LDL-C||68%||90%||80%||93%||84%|
|>50% reduction in LDL-C||56%||65%||61%||20%||50%|
|Key: ASCVD = atherosclerotic cardiovascular disease; FH = familial hypercholesterolaemia; IQR = interquartile range;
LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9; SD = standard deviation; TC = total cholesterol
In patients with definite FH, the LDL-C levels reduced significantly from a median (interquartile range) baseline value of 4.9 (4.6–5.9) mmol/L to 2.0 (1.6–3.4) mmol/L (p<0.0001) accounting for a 56% reduction in LDL-C levels from baseline. In patients with clinical FH, the LDL-C levels reduced significantly from a median baseline of 6.7 (5.3–7.1) mmol/L to 2.3 (1.9–2.5) mmol/L (p<0.0001) resulting in a 64% reduction in LDL-C levels from baseline. Finally, in patients with ASCVD, the LDL-C levels reduced significantly from a median baseline of 4.4 (4.1–4.7) mmol/L to 2.1 (1.4–2.2) mmol/L (p<0.0001), with a 43.8% reduction in LDL-C levels. This drop in each of the patient categories was associated with concomitant reductions in total cholesterol levels (data not shown).
Concomitant use of statins and ezetimibe
In this study, 50% of patients were on maximally tolerated statins and the percentage reduction in LDL-C levels was greater in those with concomitant use of statins than those without statins (62% vs. 50%). There were 37% receiving both maximally tolerated statins and ezetimibe, and the reduction in LDL-C levels was marginally higher (63% vs. 50%) in those with both lipid-lowering agents.
Side effects and discontinuation
In this study, 45% of patients on PCSK9 inhibitors experienced at least one adverse effect (table 2). Specifically, 13% of the patients experienced joint-pain and fatigue, 7% of patients developed a rash and 5% of patients had other flu-like symptoms. Medicines and Healthcare products Regulatory Agency (MHRA) reports were raised for two patients for severe reactions, one with asymptomatic creatinine kinase (CK) elevations to 5,000 U/L, and another for severe generalised maculopapular rash. Most of the adverse effects were transient or tolerated. Five patients with definite and clinical FH and four patients with ASCVD discontinued treatment with PCSK9 inhibitors due to intolerable side effects.
Table 2. Prevalence of adverse effects in patients on proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in Hull study and observational studies **
|Zafrir et al.15||Galema-Boers et al.19||Stokenbroek et al.16||Hull study||Kohli et al.14||Sarsam et al.18|
|Injection site reaction||3%||13%||3.4%||1%||–||5.8%|
|NB: Side effects were not reported in Razek et al.
** Reported side effects in both familial hypercholesterolaemia (FH) and atherosclerotic cardiovascular disease (ASCVD) patients;
*** Treatment discontinued as no significant drop in low-density lipoprotein cholesteral (LDL-C), or side effects
Meta-analysis: pooled estimates from observational studies
Table 3 shows the percentage change in LDL-C levels after PCSK9 inhibitor initiation in seven observational studies from North America, Europe, UK, and Middle-East in 446 patients with genetically proven and clinical FH. The pre-treatment LDL-C (mmol/L) levels across the seven observational studies ranged from 3.60 ± 1.20 to 5.67 ± 2.17, while the post-treatment LDL-C levels (mmol/L) ranged from 1.47 ± 0.82 to 2.4 ± 2.10. The overall pooled percentage reduction in LDL-C following PCSK9 inhibitors across 442 patients was 55.5 ± 18.1%.
Table 3. Percentage LDL-C reduction and achievement of target LDL-C in patients on PCSK9 inhibitors
|Study||Population||Patients with FH||Pre-treatment LDL-C
|LDL-C (% baseline reduction)||Target LDL-C achieved (% patients)|
|Razek et al.17||Canada||36||3.60 ± 1.20||1.82 ± 1.02||65.6 ± 23.2%||85.4%|
|Zafrir et al.15||Israel||36||5.67 ± 2.17||NR||59 ± 22%||64%|
|Galema-Boers et al.19||Netherlands||83||5.0 ± 2.1||2.4 ± 2.1||55 ± 21%||55%|
|Stokenbroek et al.16||Netherlands||160||4.07 (3.02–5.29)||1.71 (1.09–2.52)||55 ± 15.9%*||60.3%|
|Hull study||UK||36||4.25 ± 2.38||1.57 ± 1.18||69 ± 14%||56%|
|Kohli et al.14||UK||78||5.58 ± 1.82||2.29 ± 1.09||43 ± 19%||30%b|
|Sarsam et al.18,a||USA||17||4.01 ± 0.80||1.47 ± 0.83||63 ± 20%||NR|
|Total sample size||446||Pooled mean reduction||55.5 ± 18.1%||58%|
|a Included both FH and ASCVD patients. Did not report SD for % change in LDL-C and assumed to be 20%; b Refers to both FH and ASCVD patients; * Refers to patients with ASCVD and FH (n=238), however, 67% patients had FH
Key: ASCVD = atherosclerotic cardiovascular disease; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol; NR = not reported; PCSK9 = proprotein convertase subtilisin/kexin type 9
In this work, we make important contributions to the available real-world experience with PCSK9 inhibitors in FH patients by presenting efficacy and safety data in a UK population from a tertiary National Health Service (NHS) hospital and by summarising available evidence from observational studies using a meta-analytic approach. We reported pooled estimates of percentage LDL-C levels reduction from seven observational studies and showed that the LDC-C reduction with PCSK9 inhibitors in real-world settings is similar to that reported in clinical trials.9,10 We also showed that PSCK9 inhibitors are generally well tolerated and the prevalence of side effects is comparable with clinical trials.9,23
There are very limited real-world data on the use of PCSK9 inhibitors in FH. An observational study looking at the effect of PCSK9 inhibitors was reported from the British Columbia FH registry in Canada and showed that of the 48 patients in the registry who were started on PCSK9 inhibitors, 85% achieved at least a 50% reduction in LDL-C, while this target was only achieved in 50% of patients who were not on PCSK9 inhibitors. Small observational studies in the US, Israel, and Europe have shown up to a 64% reduction in the LDL-C from baseline and the findings of the Hull study agree with these studies.14,17,19 A pooled estimate of these studies with our study showed a mean 55% reduction in LDL-C from baseline, which is comparable with data from clinical trials.9,10
In clinical trials for PCSK9 inhibitors, 65–85% patients reached the treatment target of LDL-C,9,10,23 however, in our and other observational studies, on average, 50–60% of patients reached the treatment targets. These differences can be attributed to the fact that treatment adherence, follow-up, and dispensation of medicines tend to be better in clinical trials compared with real-world settings. Our study also highlights the fact that despite being on maximally tolerated anti-lipid therapy and PCSK9 inhibitors, approximately 40% of patients are not able to achieve the treatment targets for LDL-C reduction. These inter-individual differences can partially be attributed to genetic heterogeneity in this population, and pharmacogenetic studies for PCSK9 inhibitors can potentially identify non-responders to PCSK9 inhibitor treatment. The prevalence of adverse effects varied across the seven observational studies, with approximately 6–45% of patients experiencing a treatment-associated side effect. The most common side effects were flu-like symptoms, myalgia, joint pains, and fatigue, as would be expected with monoclonal antibody treatment.24 Our study had several limitations. The follow-up period varied among studies, ranging from six weeks to six months, so the average reduction in LDL-C and the frequency and intensity of side effects might not be directly comparable.
To summarise, we presented a single-centre UK-based study on the real-world experience of PCSK9 inhibitors and the first meta-analysis of available observational data. We showed that PCSK9 inhibitors are generally well tolerated and have efficacy comparable with that reported in clinical trials when used in real-world settings. This study highlights the need for population-based registries to monitor efficacy, adherence, side effects and long-term outcomes in FH patients on PCSK9 inhibitors.
- The low-density lipoprotein cholesterol (LDC-C) reduction with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in real-world settings is comparable with that reported in clinical trials
- PSCK9 inhibitors are generally well tolerated and the prevalence of side effects is comparable with clinical trials
- The PCSK9 inhibitors are a useful agent for reduction in LDL-C in patients with familial hypercholesterolaemia and atherosclerotic cardiovascular disease
Conflicts of interest
HD is funded by a NIHR clinical lectureship.
Study approval and consent
This was an audit. The approval for this audit was obtained from the audits approval committee at Hull University Teaching Hospitals NHS Trust.
1. Ito MK, Watts GF. Challenges in the diagnosis and treatment of homozygous familial hypercholesterolemia. Drugs 2015;75:1715–24. https://doi.org/10.1007/s40265-015-0466-y
2. National Institute for Health and Care Excellence. Familial hypercholesterolaemia: identification and management. CG71. London: NICE, 2017. Available from: https://www.nice.org.uk/guidance/cg71
3. Nordestgaard BG, Chapman MJ, Humphries SE et al. 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 2013;34:3478a–3490a. https://doi.org/10.1093/eurheartj/eht273
4. Schmidt N, Dressel A, Grammer TB et al. Lipid-modifying therapy and low-density lipoprotein cholesterol goal attainment in patients with familial hypercholesterolemia in Germany: the CaReHigh registry. Atherosclerosis 2018;277:314–22. https://doi.org/10.1016/j.atherosclerosis.2018.08.050
5. Rizos CV, Elisaf MS, Skoumas I et al. Characteristics and management of 1093 patients with clinical diagnosis of familial hypercholesterolemia in Greece: data from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). Atherosclerosis 2018;277:308–13. https://doi.org/10.1016/j.atherosclerosis.2018.08.017
6. Klaus G, Taylan C, Büscher R et al. Multimodal lipid-lowering treatment in pediatric patients with homozygous familial hypercholesterolemia-target attainment requires further increase of intensity. Pediatr Nephrol 2018;33:1199–208. https://doi.org/10.1007/s00467-018-3906-6
7. Raal FJ, Honarpour N, Blom DJ et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:341–50. https://doi.org/10.1016/S0140-6736(14)61374-X
8. Raal F, Scott R, Somaratne R et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 2012;126:2408–17. https://doi.org/10.1161/CIRCULATIONAHA.112.144055
9. Kastelein JJ, 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;36:2996–3003. https://doi.org/10.1093/eurheartj/ehv370
10. Raal FJ, Stein EA, Dufour R et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:331–40. https://doi.org/10.1016/S0140-6736(14)61399-4
11. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22. https://doi.org/10.1056/NEJMoa1615664
12. Schwartz GG, Steg PG, Szarek M et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–107. https://doi.org/10.1056/NEJMoa1801174
13. Szarek M, White HD, Schwartz GG et al. Alirocumab reduces total nonfatal cardiovascular and fatal events in the ODYSSEY OUTCOMES trial. J Am Coll Cardiol 2019;73:387–96. https://doi.org/10.1016/j.jacc.2018.10.039
14. Kohli M, Patel K, MacMahon Z et al. Pro-protein subtilisin kexin-9 (PCSK9) inhibition in practice: lipid clinic experience in 2 contrasting UK centres. Int J Clin Pract 2017;71:e13032. https://doi.org/10.1111/ijcp.13032
15. Zafrir B, Jubran A. Lipid-lowering therapy with PCSK9-inhibitors in the real-world setting: two-year experience of a regional lipid clinic. Cardiovasc Ther 2018;36:e12439. https://doi.org/10.1111/1755-5922.12439
16. Stoekenbroek RM, Hartgers ML, Rutte R et al. PCSK9 inhibitors in clinical practice: Delivering on the promise? Atherosclerosis 2018;270:205–10. https://doi.org/10.1016/j.atherosclerosis.2017.11.027
17. Razek O, Cermakova L, Armani H et al. Attainment of recommended lipid targets in patients with familial hypercholesterolemia: real-world experience with PCSK9 inhibitors. Can J Cardiol 2018;34:1004–09. https://doi.org/10.1016/j.cjca.2018.04.014
18. 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;47:265–70. https://doi.org/10.1177/0300060518800595
19. 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;11:674–81. https://doi.org/10.1016/j.jacl.2017.02.014
20. Scientific Steering Committee on behalf of the Simon Broome Register Group. Risk of fatal coronary heart disease in familial hypercholesterolaemia. BMJ 1991;303:893–6. https://doi.org/10.1136/bmj.303.6807.893
21. Starr B, Hadfield SG, Hutten BA et al. Development of sensitive and specific age- and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing. Clin Chem Lab Med 2008;46:791–803. https://doi.org/10.1515/CCLM.2008.135
22. Defesche JC, Lansberg PJ, Umans-Eckenhausen MA, Kastelein JJ. Advanced method for the identification of patients with inherited hypercholesterolemia. Semin Vasc Med 2004;4:59–65. https://doi.org/10.1055/s-2004-822987
23. Kastelein JJ, Hovingh GK, Langslet G et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody alirocumab vs placebo in patients with heterozygous familial hypercholesterolemia. J Clin Lipidol 2017;11:195.e4–203.e4. https://doi.org/10.1016/j.jacl.2016.12.004
24. Hansel TT, Kropshofer H, Singer T, Mitchell JA, George AJ. The safety and side effects of monoclonal antibodies. Nat Rev Drug Discov 2010;9:325–38. https://doi.org/10.1038/nrd3003