The First Report of a Real-World Experience With a PCSK9 Inhibitor in a Large Familial Hyperlipidemia and Very-High-Risk Middle Eastern Population

Purpose: Evolocumab, a monoclonal inhibitor of proprotein convertase subtilisin/kexin 9, has been shown to reduce proatherogenic lipoproteins in patients with or without familial hypercholesterolemia (FH), diabetes mellitus, or atherosclerotic cardiovascular disease (ASCVD). We explored the safety profile and clinical effectiveness of evolocumab in an outpatient population of Emirati individuals with FH diagnosed per Dutch Lipid Clinic Network criteria, previous ASCVD, or statin intolerance. Methods: This study was a retrospective review of patients initiating evolocumab treatment for any indication at Imperial College London Diabetes Centre between 2017 and 2020. All individuals followed up for at least 90 days or with at least one lipid panel postinitiation were included. Participants were subclassified into primary prevention (no previous ASCVD event, n = 81) and secondary prevention (any prior clinical ASCVD event, n = 102) groups. Findings: Evolocumab was initiated in 183 individuals (mean [SD] age, 51.5 [12.4] years; 51% male); 108 (59%) population, consistent with previous safety reports for evolocumab. Notable strengths of this study include a relatively large cohort, patient heterogeneity and high retention, and a minimum follow-up of 1 year. Despite these strengths, the study has some limitations, including the selection bias due to the retrospective design and absence of comparative group. ( Clin Ther . 2022;44:XXX–XXX)

Implications: This study is the first from the Middle East and North Africa region that reports the real-world efficacy of evolocumab in a mixed risk population of individuals with FH and other non-FH indications. Clinically meaningful and sustained reductions in LDL-C, TG, and cholesterol ratios were observed after evolocumab initiation. Few adverse events were reported in this predominantly Arabic

INTRODUCTION
LDL-C is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Recent evidence supports intensive LDL-C reduction in patients with ASCVD, but many individuals do not achieve their target LDL-C despite maximal conventional lipidlowering therapy (LLT). 1 , 2 This has been attributed to factors such as pharmacogenetic effects on statin response, very high baseline LDL-C concentrations as seen in familial hypercholesterolemia (FH), and lack of adherence to therapies. 3 The proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor family is approved for use in patients with established ASCVD who require intensification of lipid reduction to meet American College of Cardiology/American Heart Association (ACC/AHA) 4 and/or European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) 5 treatment targets for secondary prevention, as well as for the primary prevention of ASCVD in people with inherited hypercholesterolemia (homozygous and heterozygous) and in patients unable to tolerate a statin. [6][7][8][9][10] In clinical trials, the PCSK9 inhibitor evolocumab as monotherapy reduced LDL-C levels up to 60% in patients with and without FH, diabetes mellitus, and/or ASCVD and was well tolerated. 1 , 3 , 11 Current ESC/EAS guidelines estimate LDL-C reductions of up to 85% when PCSK9 inhibitors are used in combination with a statin and ezetimibe. 5

PARTICIPANTS AND METHODS Participants and Study Design
This study followed an observational retrospective cohort design and was conducted at the Imperial College London Diabetes Centre (ICLDC), Abu Dhabi, United Arab Emirates. ICLDC is an outpatient facility that operates specialist Diabetology, Endocrinology, Cardiology, Nephrology, Ophthalmology, Internal Medicine, and General Practice clinics. Individuals enrolling for treatment at ICLDC are given the option to consent for the use of their anonymized data in clinical research. Anonymized patient data were retrieved from the ICLDC electronic medical record (EMR) covering the time period between January 2017 and October 2020. The study protocol was approved by the Institutional Research Ethics Committee (IREC054). The study included all patients aged between 18 and 85 years who initiated PCSK9 inhibitor treatment at ICLDC and who attended follow-up with repetition of the lipid panel on at least one subsequent occasion. The time frame to each follow-up visit postinitiation of evolocumab was ≤3 months. Median follow-up was 359 (79-639) days. Evolocumab was administered at the licensed doses of 140 mg once every 2 weeks or 420 mg once monthly. Information on LLTs used to treat each individual before evolocumab initiation was retrieved from the EMR. Overall, 97% of participants were prescribed a statin before evolocumab initiation, 89% used ezetimibe, and 23% were prescribed omega-3 products. The lipid profile before initiation of evolocumab was considered as baseline. Preexisting or first visit JID: CLITHE [mNS; 13:37 ] ASCVD and/or cardiovascular events were reported as ASCVD prevalence, and subsequent ASCVD and/or cardiovascular events were reported as incidence. The cohort was subdivided into primary and secondary prevention groups based on the absence or presence of clinical ASCVD events at initiation of evolocumab, as per the ACC/AHA guidelines (2018-2019). 4 Clinical ASCVD includes acute coronary syndrome, those with a history of myocardial infarction, stable or unstable angina or coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral artery disease, including aortic aneurysm, all of atherosclerotic origin. All patients with no previous clinical ASCVD event/history were grouped into primary prevention and all patients with clinical ASCVD event/history prior to initiation of evolocumab were grouped into secondary prevention. For patients in the primary prevention group, 10-year ASCVD risk scores were computed before initiation of evolocumab by using pooled cohort equations. 12 In those without a previous ASCVD or FH diagnosis, individuals with absolute 10-year ASCVD risk scores of < 5%, 5% to 7.5%, 7.5% to 20%, and > 20% were classified as low, borderline, intermediate, and high risk, respectively. 4 Secondary prevention patients, conventionally recognized as high or very high secondary ASCVD risk according to the latest ESC/EAS guidelines, 5 were further stratified by using the ESC SMART score ASCVD risk calculator 13 (scores ≥5% to < 10% and ≥10% categorizing patients as high risk and very high risk, respectively). Untreated LDL-C was estimated by dividing the on-treatment LDL-C values by the reciprocal of the expected percentage per the algorithm proposed by Ruel et al 14 to control for the effect of concomitant statin therapy. The estimated likelihood of an underlying diagnosis of FH was calculated by using the Dutch Lipid Clinic Network score (DLCNS) criteria. 15 FH status was considered definitive in individuals with a DLCNS score ≥8 or a genetic diagnosis.

Study Outcome Measures
The primary outcome was defined as attainment of ACC/AHA guidelines-recommended LDL-C targets of ≥30% reduction or LDL-C < 2.6 mmol/L in primary prevention or ≥50% reduction or LDL-C < 1.8 mmol/L in secondary prevention. 4 Participants were further analyzed using new the LDL-C value of < 1.4 mmol/L as recommended in recent ESC/EAS guidelines. 5 The secondary outcome was incidence of new cardiovascular events after evolocumab initiation, expressed as a composite of myocardial infarction, coronary revascularization, stroke, and unstable angina. Safety was assessed according to AEs (injection site reaction, myalgia, worsening of liver enzyme, nausea, and vomiting) recorded in the EMR. Adherence to treatment was assessed by manual review of clinician entries in the EMR and pharmacy records.
The standard of care at ICLDC for follow-up of patients with hyperlipidemia is to perform clinical review and relevant laboratory investigations every 3 months. Prescribing and dispensing of medication in the United Arab Emirates follows a 3-month schedule, and hence individuals who did not collect their prescribed medication during one 3-month cycle were considered to have lapsed treatment. The median follow-up period of the study individuals was 359 (79-639) days; except where indicated, this was the full duration since initiation of therapy at the time of data collection.

Statistical Analysis
Data are expressed as mean (SD) where normally distributed or as median (interquartile range [IQR]) if not. The Wilcoxon signed-rank test was performed to assess change in lipid parameters (LDL-C, TG, and total cholesterol [TC]:HDL-C ratio) following initiation of evolocumab. Where applicable, this test was also performed to assess the significance of differences among baseline and/or postbaseline characteristics in primary and secondary prevention groups. Cox proportional hazards model and Kaplan-Meier curve analysis were performed to measure the hazard ratio and its significance for the secondary outcome measures of the study. Where data were missing, mean values were imputed, amounting to < 2% of the data. Statistical analysis was performed by using R version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria) with the survival, survminer, coin, psych, and tidyverse packages. Significance was assessed at P < 0.05 and at 95% of CI. No correction for multiple comparisons was performed.

Primary Outcome Measure
A total of 121 (66.1%) patients achieved their individualized LDL-C target determined by following the ACC/AHA guidelines (ie, ≥30% reduction or LDL-C < 2.6 mmol/L in primary prevention or ≥50% reduction or LDL-C < 1.8 mmol/L in secondary prevention) within 90 days of evolocumab initiation; of these, 114 (94.2%) sustained these results at each subsequent visit over an average follow-up period of 359 (280) days. Changes in LDL-C after initiation of evolocumab over a follow-up period ≥366 days are shown in Figure 1 . Figure 2 shows patient study flow according to sustained or nonsustained LDL-C reduction during follow-up. Sixty-nine (37.7%) individuals did not attain target LDL-C at more than one review. Nonattainment of the LDL-C target at follow-up was attributed to nonadherence in 36 (52.2%), discontinuation of treatment in 14 (20.3%), and interruption of funding or drug supply limitations in 11 (15.9%). Fourteen patients discontinued treatment, 4 due to AEs, 4 prior to surgical procedures, 2 due to pregnancy, and 4 due to concerns regarding potential side effects (eg, nausea, vomiting, injection site reaction).

Secondary Outcome Measure
In the primary prevention group (n = 81), 26 (32.1%) and 9 (11.1%) individuals were classified as at intermediate and high risk of ASCVD, respectively. In the secondary prevention group (n = 102), 92 (90.2%) were considered as very high risk and 10 (9.8%) as high risk according to the ESC Smart SCORE. Six (7.4%) of 81 individuals in the primary prevention group and 35 (34.3%) of 102 individuals in the secondary prevention group were diagnosed with a new cardiovascular event following initiation of evolocumab. The hazard of new ASCVD event corrected for age, sex, smoking status, diabetes status, and FH status was 6 times higher in the secondary prevention group than in the primary prevention group (hazard ratio, 5.8; 95% CI, 2.3-14.4; P < 0.0001). Moreover, the estimated hazard adjusted for age, sex, smoking status, diabetes status, and FH status for individuals who achieved their ACC/AHA/ESC/EAS LDL-C targets (LDL-C target achievers) versus those who did not achieve these targets (LDL-C target nonachievers) was 0.46 (95% CI, 0.24-0.89; P < 0.02). Figure 4 presents the hazard function among LDL-C target achievers versus nonachievers.

Statin Background
A robust path for LLT combinations was used before the clinical decision to initiate evolocumab; 70.4% (n = 57) of patients in the primary prevention group and 81.4% (n = 83) in the secondary prevention group received at least one statin therapy since the diagnosis of hyperlipidemia. Median duration of statin usage for patients treated with a statin before

Safety
Four (2.2%) patients presented with AEs attributed to evolocumab, including injection site reaction in two (1.1%), one (0.6%) with myalgia, and one (0.6%) with elevation of liver enzymes. Table III provides a summary of the treatment-emergent AEs.

DISCUSSION
In our experience, countries in the MENA region rely on data from North American and European authorities for new drug approvals, and data regarding the safety and effectiveness of new therapies in Arabic populations are lacking. To our knowledge, the present study is the first real-world study describing experience with evolocumab in the MENA region in a large cohort of patients who were followed up for at least 1 year. Overall, evolocumab was well tolerated and provided robust and sustained reductions in proatherogenic lipids.
Real-world experience reports, including the ones of Nanchen et al, 16 Gürgöze et al, 17 Waldmann et al, 18 and Sbrana et al, 19      very high ASCVD risk, and statin intolerance were the leading indications for the use of evolocumab. Evolocumab was effective in lowering LDL-C levels to within individualized target ranges in the majority of participants, particularly in those with statin intolerance. Although significant LDL-C reductions were noted after evolocumab prescription in both the primary and secondary prevention groups, these reductions were more pronounced in the secondary prevention group. The most likely explanation is the higher number of FH patients in the primary prevention cohort who usually have higher baseline LDL-C levels. The high number of FH individuals with elevated LDL-C levels is difficult to treat, in case the induction of PCSK9 inhibitor with other LLT may benefit. 22 Other potential factors include a higher proportion of female patients, younger age, and higher baseline HDL-C and TG levels in the primary prevention group, which have been reported to independently affect the likelihood of achieving LDL-C targets. 23 We observed sustained reductions in LDL-C during evolocumab treatment comparable with those reported by Wasserman et al, 24 who also reported more stability of lipid lowering in those receiving standard doses of evolocumab.
Although up to a 70% reduction in LDL-C was reported in Phase III clinical trials, 25 and an expected up to 85% in triple LLT combination as stated in the ESC/EAS guidelines, 5 other real-world experience studies performed following regulatory approval of evolocumab reported LDL-C reductions averaging from 40% to 60%, [27][28][29][30][31][32][33] which is comparable to our findings. LDL-C reductions of 39%, 52.3%, 54.9%, and 60% were observed in PCSK9 treatment groups in reports by Sarsam et al, 26 Koren et al, 27 Santos et al, 28 and Desai et al. 29 In the present study, introduction pf evolocumab helped attain the ACC/AHA guidelines-recommended reduction in LDL-C ( ≥30% reduction or LDL-C < 2.6 mmol/L in primary prevention or ≥50% reduction or LDL-C < 1.8 mmol/L in secondary prevention) not only as add-on therapy to statins but also as a combination with other LLTs in statin-intolerant patients. Voutyritsa et al 34 reported greater (up to 70%) reductions in LDL-C with evolocumab when administered with other LLTs. Desai et al 29 observed an LDL-C reduction of up to 60% in a real-world setting. Gürgöze et al 17 reported that the addition of evolocumab to other LLTs lowered LDL-C levels by ∼60%.
The secondary outcome measure of the present study was the incidence of ASCVD and/or cardiac events postinitiation of evolocumab. The incidence of new ASCVD events in patients at a minimum followup of 366 days was 8.6% and 29.4%, respectively, in the primary and secondary prevention groups. These findings clearly highlight the elevated ASCVD risk and great unmet need of the studied population. How much the use of evolocumab in our population has had an impact on the risk of these events remains to be determined. Previously, Dixon et al 30 reported a 9.8% reduction in the incidence of ASCVD events after initiation of evolocumab in patients at high risk of ASCVD already treated with statins. In contrast, among the secondary prevention patients, only the FOURIER trial reported a 15% reduction in ASCVD incidence (hazard ratios of 0.83 and 0.87 in patients with diabetes and without diabetes, respectively). 31 Due to the lack of a comparison group in our study, we are unable to comment on relative risk reduction in ASCVD incidence.
Evolocumab was well tolerated, with few documented AEs in our patients. Similar good tolerability has also been shown in the GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3) randomized clinical trial, 32 which reported a significant reduction in LDL-C levels with evolocumab and also fewer AEs compared with other LLTs. Based on our findings, we suggest that evolocumab is a well-tolerated, safe drug for the treatment of hyperlipidemia in patients with or without cardiac comorbidities.
Gürgöze et al 17 noted that drug discontinuation was responsible for a nonsustained LDL-C reduction in 7% of participants. We observed comparable rates of evolocumab discontinuation but a smaller proportion was attributed to AEs (2.2%). In contrast, the OSLER-1 (Open Label Study of Long Term Evaluation Against LDL-C Trial) extension study 33 reported discontinuation of evolocumab in 21% of participants.
The current study is the first from the MENA region that reports the real-world efficacy of evolocumab in a mixed risk population of individuals with FH and other non-FH indications. Notable strengths of our study include a relatively large cohort, patient heterogeneity and high retention, and a minimum follow-up of 1 year. Despite these strengths, our study has some limitations,