341 Observational multicentre study on effectiveness and tolerability of Alirocumab in real world, the OMERO study: interim data from the first 699 patients

Aims OMERO is a prospective study, aimed to assess the long-term effectiveness, tolerability, and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9-i), in the real life in Italy. The study is planned to include 800 patients, from 40 Italian sites, treated with alirocumab on top of standard lipid lowering therapy. Methods and results This analysis concerns 699 (out of 800) patients with all data available: 65.5% male; mean age 60.6 ± 11.09 years; 29.6% with HeFH in primary prevention; 70.4% in secondary prevention (with/without HeFH). Before ALI administration, 461 patients (66%) were treated with statins while 231 (33%) reported statin intolerance, that resulted in the statin discontinuation. Mean baseline LDL-C was 161.5 ± (53.07) mg/dl. Based on clinical judgement, ALI was initially prescribed at 75 mg Q2W dosing regimen in 60.80% of participants, whereas the remainder received 150 mg Q2W. At V1 57 patients (89.06%) switch from 75 mg Q2W to 150 mg Q2W and 7 patients (10.94%) from 150 mg Q2W to 75 mg Q2W. LDL-C level reduction from baseline (before ALI administration) to 6 months from the study enrolment (V1), was −45% (V1: mean LDL-C was 73.5 ± 45.70 mg/dl). LDL-C levels at V1 by participant category are shown in Figure 1. The rate of patients with at least one adverse event was 25.6% (of which SAE 7.4%); the rate of patients with at least one related adverse reaction to treatment was 3.8% none of them were serious. Conclusions OMERO confirmed in clinical practice the results observed in trials: a significant reduction of LDL-C was observed with ALI 75/150 mg Q2W in participants at high CV risk with or without HeFH. ALI was generally well tolerated.

Case Report: Difficulties in the Treatment of a 12-Year-Old Patient With Homozygous Familial Hypercholesterolemia, Compound Heterozygous Form − 5 Years Follow-Up

The literature review we conducted reveals the limited use of proprotein convertase subtilisin/kexin type 9-inhibitors (PCSK9i) in children with familial hypercholesterolemia (FH). In 2015, a 10-year-old boy presented with round, xanthochromic lesions on his right knee and elbow. The values of total and LDL-cholesterol (LDL-C)−18 and 15 mmol/l, respectively—along with normal triglycerides and HDL-cholesterol (HDL-C) confirmed the lesions were xanthomas. The data suggested a homozygous form of FH. The level of lipoprotein (a) was high: 270 mg/dl. Initial treatment, based on European recommendations, included Atorvastatin 20 mg and Ezetimibe 10 mg and led to a decrease in LDL-C by 46% for 5 months; however, the patient developed severe statin intolerance. Atorvastatin was replaced with Rosuvastatin 10 mg, but the symptoms persisted. Success was achieved by switching to an intermittent regimen: Rosuvastatin 10 mg three times a week with a daily intake of Ezetimibe 10 mg. However, the results were far from the desired LDL target. LDL-apheresis was advisable, but unfortunately, it is not performed in Bulgaria. In May 2017, a genetic analysis [two pathological mutations within the LDLR gene: c.1519A>G; p.(Lys507Glu) and c.2403_2406del; p.(Leu802Alafs*126)] confirmed the initial diagnosis: the patient had homozygous FH with compound heterozygosity indeed. Having turned 12 in September 2017, the patient was eligible for treatment with a PCSK9i: Evolocumab 140 mg. The mean reduction of LDL-C with the triple combination reached a reduction of 52.17% for the whole 2-year period. The LDL target was reached in January 2020. The triple therapy significantly reduced Apolipoprotein B by 29.16%. No statistically significant difference was found in Lp (a) levels (p > 0.05) Our clinical case demonstrates that the triple lipid-lowering combination in a patient with compound heterozygous FH is a good therapeutic option for reaching the LDL-target.

Key aspects of statin intolerance leading to treatment discontinuation: a patient perspective

Background and aims Statins are the standard of care for patients with dyslipidemia, but some patients develop intolerance to treatment. The experience of statin intolerant (SI) patients is poorly understood. The objective of this study was to identify key aspects of SI that may be associated with treatment discontinuation. Methods Using a previously created questionnaire, we conducted a pilot cross-sectional survey to identify items important for describing patient-centric aspects of SI. The study recruited adult (18+) patients with a history of statin-associated side effects from 9 clinics in 6 countries (France, Italy, Norway, Spain, Sweden, and the United Kingdom), who had received statin treatment within the previous two years. Results We surveyed 104 patients (mean age 61.5 SD=11.2 years, 63.5% men, 50% currently on statins). Patients most frequently reported muscle-related symptoms: pain (90.9%), cramps (63.7%), and stiffness (58.2%). Using a 0–10 point scale, significant differences were found between those continuing versus discontinuing their statins for being bothered by side effects (7.5 vs 9.2, p=0.001), for an inability to tolerate side effects (6.7 vs 9.0, p<0.001), and those having too much side effects interference with their daily life (5.7 vs 8.6, p<0.001; see figure). For patients whose doctors worked on adjusting statin regimen, 67% stayed on treatment; for those whose doctors did not, only 10% continued treatment. Conclusions Results of this pilot survey suggest patients who experience greater side effects severity and interference with daily activity, along with lower efforts by clinicians to work with adjusting their statin regimen, are at greater risk for discontinuing treatment. A wider survey and larger study population is needed to confirm the results of this pilot study. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was sponsored by Amgen Inc.

Common Statin Intolerance Variants in ABCB1 and LILRB5 Show Synergistic Effects on Statin Response: An Observational Study Using Electronic Health Records

Background: Statin intolerance impacts approximately 10% of statin users, with side effects ranging from mild myalgia to extreme intolerance resulting in myopathy and rhabdomyolysis. Statin intolerance results in poor adherence to therapy and can impact statin efficacy. Many genetic variants are associated with statin intolerance. The effect of these variants on statin efficacy has not been systematically explored.Methods: Using longitudinal electronic health records and genetic biobank data from Tayside, Scotland, we examined the effect of seven genetic variants with previously reported associations with simvastatin or atorvastatin intolerance on the outcome of statin response. Statin response was measured by the reduction achieved when comparing pre- and post-statin non-high-density lipoprotein-cholesterol (non-HDL-C). Post-treatment statin response was limited to non-HDL-C measured within 6months of therapy initiation. Univariate and multivariable linear regression models were used to assess the main and adjusted effect of the variants on statin efficacy.Results: Around 9,401 statin users met study inclusion criteria, of whom 8,843 were first prescribed simvastatin or atorvastatin. The average difference in post-treatment compared to pre-treatment non-HDL-cholesterol was 1.45 (±1.04) mmol/L. In adjusted analyses, only two variants, one in the gene ATP-binding cassette transporter B1 (ABCB1; rs1045642), and one in leukocyte immunoglobulin like receptor B5 (LILRB5; rs12975366), were associated with statin efficacy. In ABCB1, homozygous carriers of the C allele at rs1045642 had 0.06mmol/L better absolute reduction in non-HDL-cholesterol than carriers of the T allele (95% CI: 0.01, 0.1). In LILRB5 (rs12975366), carriers of the C allele had 0.04mmol/L better absolute reduction compared to those homozygous for the T allele (95% CI: 0.004, 0.08). When combined into a two-variant risk score, individuals with both the rs1045642-CC genotype and the rs12975366-TC or CC genotype had a 0.11mmol/L greater absolute reduction in non-HDL-cholesterol compared to those with rs1045642-TC or TT genotype and the rs12975366-TT genotype (95% CI: 0.05, 0.16; p<0.001).Conclusion: We report two genetic variants for statin adverse drug reactions (ADRs) that are associated with statin efficacy. While the ABCB1 variant has been shown to have an association with statin pharmacokinetics, no similar evidence for LILRB5 has been reported. These findings highlight the value of genetic testing to deliver precision therapeutics to statin users.

Gender differences low-density lipoprotein cholesterol reduction with PCSK9 inhibitors in real world patients

Background Monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDLc) by 55%, regardless of baseline treatments, and are supposed to have a homogenous effect. We tested possible gender differences in a large multicenter registry of real-world patients treated with PCSK9 inhibitors. Methods Multicentre and retrospective registry of patients treated with PCSK9 inhibitors from 14 different hospitals from Spain. Before and on-treatment LDLc cholesterol was recorded as well as medical treatments, clinical indication and clinical features. Results A total of 562 patients were analysed, mean age 60.2 (9.6) years and 79.2% males. Most frequent indication for PCSK9 inhibitor treatment was established cardiovascular disease (CVD) with LDLc >100 mg/dl (58.1%) followed by familial hypercholesterolemia (23.4%) and statin intolerance (18.5%). Indications other than CVD were more frequent in women (53.3% vs. 39.1%; p=0.03). Women were more frequently ezetimibe (67.5% vs. 50.6%; p=0.001) before PCSK9 treatment; although no gender differences in statin use was observed (78.6% vs. 83.6%; p=0.93) in the whole cohort it was significantly lower in patients with coronary heart disease (91.4% vs. 98.9%; p=0.005). Before treatment LDLc was 148.7 (50.1) mg/dl and it was higher women vs. men (160.3 (59.3) vs. 145.6 (47.0); p=0.005). Evolocumab was initiated in 318 (56.6%) patients; 229 (40.7%) alirocumab 75 mg and 15 (2.7%) alirocumab 150 mg. No gender differences in PCSK9 inhibitors drug or dose were observed. Median time to second blood determination were 187.5 (IQR 101–242) days. Mean on-treatment LDLc was 66.7 (46.4) mg/dl and it was also higher in women vs. men (84.4 (58.6) vs. 61.9 (41.3); p<0.001). Mean LDLc reduction was 54.7% but it was higher in men as compared to women (57.0% vs. 46.1%; p=0.0003). Higher LDLc reductions were also observed in patients with CVD as compared to the other 2 indications (57.1% vs. 47.3%; p=0.002). Moreover, LDLc reduction with PCSK9 inhibitors treatment was also higher in men vs women among patients with CVD (58.9% vs. 48.0%; p=0.04) Conclusions This multicentre and retrospective registry of real-world patients treated with PCSK9 inhibitors highlights significant gender differences in LDLc reduction. FUNDunding Acknowledgement Type of funding sources: None.

Novel insights into the management of German patients with very high cardiovascular risk eligible for PCSK9 inhibitor treatment: baseline characteristics from the PERI-DYS study

Background The reasons why patients are treated or not with PCSK9 inhibitors (PCSK9i) are incompletely understood. In Germany, access to PCSK9i is limited by local regulations and many high-risk cardiovascular patients do not receive these therapies. The PERI-DYS study aims to describe and compare two groups of dyslipidaemia patients at very high CV risk: those treated with PCSK9i compared with patients qualifying for but not treated with PCSK9i. Methods Observational study with up to 2000 consented patients, documented mainly by office-based cardiologists or physicians in lipid ambulances with data extracted from patient charts. Lipid lowering treatment (LLT) at enrolment includes ongoing PCSK9i use, newly initiated PCSK9i, statins, ezetimibe, and lipoprotein apheresis. Patients are followed for up to 3 years, with visits every 6±2 months to record LLT (drugs, dosing), other CV medications, lipid and glucose values, blood pressure, clinical events (major adverse cardiac and cerebrovascular events) and adverse drug reactions. Results As of 05 March 2021, 1488 patients have been enrolled across 70 sites. The majority of patients (91.5%) had heterozygous familial or non-familial hypercholesterolemia or mixed dyslipidaemia. At enrolment, 49.4% of patients were receiving PCSK9i (35.4% ongoing and 14.0% newly treated). Among PCSK9i users, the majority were receiving evolocumab 140 mg (n=567, 38.1% of all enrolled patients). There were no major differences in demographics and non-lipid lowering medication, with the exception of more females in the PCSK9i group. The estimated untreated LDL-C based on “back-calculation” was higher in patients who were on ongoing PCSK9i therapy than in those not on PCSK9i or newly treated with PCSK9i (Table 1). Physician-reported statin intolerance was much more common in the two PCSK9i groups compared with the non-PCSK9i group (67% versus 14%). Patients in the PCSK9i groups received fewer concomitant statins. Mean on-treatment total cholesterol and LDL-C were considerably lower in patients who were on ongoing PCSK9i compared to non-PCSK9i. Overall, nicotinic acid, fibrates, cholestagel, and omega-3 fatty acids were rarely used (data not shown). Conclusions Patients treated with PCSK9i and those qualifying for but not treated with PCSK9i had similar baseline characteristics, but the former had higher estimated untreated LDL-C values and a higher rate of statin intolerance. Ongoing follow-up will determine the prognostic importance of these findings. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Amgen GmbH Germany

Clinical features of familial hypercholesterolaemia in children and adults – the PMMHRI Registry

Background Familial hypercholesterolaemia (FH) affects approximately 150,000 people in Poland. However, there are many patients still unaware of this diagnosis. On the other hand, it might lead to early cardiovascular mortality and morbidity due to the lifetime exposure to high levels of LDL-C. Therefore, increased awareness of FH is very important. Purpose We aimed to evaluate the clinical features of FH in children and adults based on the preliminary data from the Polish Mother's Memorial Hospital Research Institute (PMMHRI) Registry. Methods The registry of children and adults with FH conducted in PMMHRI (2nd largest, supra-regional hospital in Poland) was established to investigate the clinical characteristics, management and clinical outcomes data of FH patients. All consecutive patients with diagnosed (genetically and/or phenotypically) FH were included in the study. Results Of 103 patients with FH, there were 16 children aged 9±3 and 87 adults aged 41±16; 59% were female. The diagnosis of FH in adults was late – at the mean age of 41 years. Among children with FH, as compared with adults, the levels of highest TC and LDL-C ever were similar. However, children presented higher mean levels of total cholesterol, LDL-C and HDL-C measured at baseline visit (Table). Interestingly there was no difference in BMI between children and adults (Table). Among adults, chronic coronary syndrome was diagnosed in 11.5% patients, from which 5.7% patients had a history of myocardial infarction and 7% patients required revascularization. The prevalence of chronic coronary disease, peripheral artery disease as well as stroke in family history was definitely higher (in 44 patients – 50%, 17 patients – 20% and 22 patients – 25%, respectively). Most of adult patients at baseline visit were prescribed statins (rosuvastatin or atorvastatin). 14 patients (13.6%) declared statin intolerance, most of them complained of muscle pain, 4.6% patients reported hepatic disturbances. The frequency of statin use in children was lower – 56% children were prescribed statin, 19% declared statin intolerance with muscle pain as the side-effect of treatment. Ezetimibe, as a part of combination therapy, was taken by 29% adult patients. PCSK9 inhibitors were prescribed (within drug program) for 11.5% adult patients. Fibrates were prescribed for 13.7% adult patients, the same was for n-3 fatty acids. Conclusions Despite definitely younger age of FH diagnosis children present higher mean levels of LDL cholesterol than adults. Therefore, the lifetime exposure to LDL cholesterol starts at a very young age. As a result, there is a need to the earlier initiation of therapy and strict monitoring of the atherosclerosis progression. On the other hand, late diagnosis of FH in adults is an unmet need, that might be associated with poorer prognosis. FUNDunding Acknowledgement Type of funding sources: None.