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Background and AimHigh levels of Low Density Lipoprotein-C (LDL-C) have been associated with increased cardiovascular mortality. The introduction of Inclisiran in recent years have provided an alternative for patients on maximal dose of statins or intolerant to statins and not achieving their target LDL-C level. This study aims to determine the baseline LDL-C level as a predictor in determining the percentage of patients achieving LDL-C level less than 1.8 mmol/l at day 90 after the first dose of Inclisiran with or without statins.MethodThis is a retrospective observational study using real world data which we collected the data electronically by looking at patients who received Inclisiran as an addon to their usual lipid lowering therapy with an initial level of below 2.6 mmol/l. Their baseline LDL-C levels were then grouped into different categories and their percentage of achieving target below 1.8 mmol/l were determined and analysed. This target is the cutoff point for high cardiovascular risk as per ESC guidance.ResultsA total of 69 patients were included in the study. The greatest percentage achieving the target were those with a baseline between 2–3 mmol/l, which was 74%. Of those between 3–4 mmol/l, the percentage reduction was 44%, with 4–5 mmol/l 23% and with 1–2 mmol/l 71%. The analysis showed that none of those with a level above 5 mmol had achieved a target below 1.8 mmol/l.In addition, the percentage reduction in LDL-C in these subgroups were also determined. Those with a baseline between 2–3 mmol/l have the highest percentage reduction of 53% ±11 (95% CI), followed by those between 4–5 mmol/l with 50% ±10 (95% CI), between 3–4 mmol/l 44% ±8 (95% CI). In those with level above 5 mmol/l, they had a reduction of 32% ±11 (95% CI). Surprisingly in those with levels between 1–2 mmol/l, 3 patients had an increase in LDL-C level of 7%, 117% and 197%.ConclusionBaseline LDL-C level can potentially be used as a predictor to determine if patients may achieve the target of below 1.8 mmol/l following the first dose of Inclisiran at day 90, with the best baseline level being 2–3 mmol/l. Our study showed that adding Inclisiran in patients with baseline levels of more than 5 mmol/l did not reach target and the effect can be mitigated in those with low level of 1–2 mmol/l, both of which will need further exploration.Abstract 232 Figure 1Abstract 232 Figure 2Conflict of InterestNone

IntroductionHypercholesterolaemia is a major modifiable risk factor for acute coronary syndromes (ACS). In October 2021, the National Institute for Health and Care Excellence (NICE) recommended that the small interfering ribonucleic acid against proprotein convertase subtilisin/kexin type 9, inclisiran, be offered to certain patients, including those with a history of ACS and low-density lipoprotein cholesterol (LDL-C) level of ≥2.6 mmol/L despite maximum tolerated statin or other lipid-lowering therapy. We aimed to estimate the proportion of our recently treated ACS patients who are likely to have a NICE-defined indication for inclisiran. MethodsA systematically selected sample of records from patients treated for ACS at our centre from 2019–2021 were reviewed (n=370). Data on demographics, diagnoses, treatments and biochemistry results were collected. Proportion of patients with a NICE-defined indication for inclisiran was determined and 95% confidence interval calculated. Where required and valid, LDL-C was calculated using the Friedewald equation.ResultsPatients included had a median age of 67 (IQR 58–79) and 74.1% were male. The index diagnosis was ST-elevation myocardial infarction (STEMI) in 46.2% and non-STE-ACS in 53.8%. 97.3% were receiving a statin at time of follow-up, 4.1% ezetimibe and 0.3% a fibrate. Documented reasons for statin avoidance included previous adverse drug reactions and perceived futility in extreme frailty.Post-discharge measurement of lipid profile was performed in 319 (86.2%) of the cohort. Lack of measurement appeared influenced by changes related to the COVID-19 pandemic (20.3% after March 2020 vs. 7.0% before, odds ratio [OR] 3.4, 95% CI 1.7 to 6.7, p=0.0002). There was evidence of significant improvement in lipid profile between admission and first post-discharge measurement (e.g. total cholesterol 4.8 ±1.4 vs 3.5 ±1.1 mmol/L, p<0.0001).Of those patients with a post-discharge measurement, 29 (9.1%) had LDL-C ≥2.6 mmol/L. Of these, 24 were receiving maximum intensity statin therapy whilst 2 were receiving statin but not at maximum dose. 3 were statin intolerant and receiving ezetimibe but with the potential to add another non-statin lipid-lowering drug. At least 24 (7.5%, 95% CI 4.6 to 10.4) would therefore have a clear indication for inclisiran based on current NICE guidance.A diagnosis of STEMI was associated with increased likelihood of LDL-C ≥2.6 mmol/L (OR 2.6, 1.1 to 6.1, p=0.024). No other significant relationships with other characteristics were seen.ConclusionsBased on these data, approximately 5 to 10% of patients with recent ACS treated in a typical UK centre can be expected to have an indication for inclisiran treatment. Having an accurate estimate in this population can help local resource planning and communication with primary care. We should ensure that monitoring of lipid profile after hospitalisation for ACS is not impacted long-term by the COVID-19 pandemic.Conflict of InterestNone

Background and aimsLow-density lipoprotein cholesterol (LDL-C) is the main therapeutic target in the treatment of hypercholesterolemia. Small interfering RNA (siRNA) inclisiran is a new drug, which targets PCSK9 mRNA in the liver, reducing concentrations of circulating LDL-C. In randomized trials, inclisiran demonstrated a substantial reduction in LDL-C. The German Inclisiran Network (GIN) aims to evaluate LDL-C reductions in a real-world cohort of patients treated with inclisiran in Germany.MethodsPatients who received inclisiran in 14 lipid clinics in Germany for elevated LDL-C levels between February 2021 and July 2022 were included in this analysis. We described baseline characteristics, individual LDL-C changes (%) and side effects in 153 patients 3 months (n = 153) and 9 months (n = 79) after inclisiran administration.ResultsSince all patients were referred to specialized lipid clinics, only one-third were on statin therapy due to statin intolerance. The median LDL-C reduction was 35.5% at 3 months and 26.5% at 9 months. In patients previously treated with PCSK9 antibody (PCSK9-mAb), LDL-C reductions were less effective than in PCSK9-mAb-naïve patients (23.6% vs. 41.1% at 3 months). Concomitant statin treatment was associated with more effective LDL-C lowering. There was a high interindividual variability in LDL-C changes from baseline. Altogether, inclisiran was well-tolerated, and side effects were rare (5.9%).ConclusionIn this real-world patient population referred to German lipid clinics for elevated LDL-C levels, inclisiran demonstrated a high interindividual variability in LDL-C reductions. Further research is warranted to elucidate reasons for the interindividual variability in drug efficacy.

PurposePatients with polyvascular disease (PVD) are at very high cardiovascular risk and require intensive lipid-lowering therapy. This analysis describes the lipid-lowering efficacy and safety of inclisiran versus placebo in patients with and without PVD.MethodsIn this post hoc analysis of the ORION-9, ORION-10, and ORION-11 trials, patients were randomized 1:1 to receive 284 mg inclisiran (300 mg inclisiran sodium) or placebo on day 1, day 90, and 6-monthly thereafter. Percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to day 510 and corresponding time-adjusted change from day 90 and up to day 540 were evaluated per patients’ PVD status. Safety was assessed over 540 days.ResultsOf 3454 patients, 470 (13.6%) had PVD, and 2984 (86.4%) did not. Baseline characteristics were generally balanced between the treatment arms in both cohorts. A greater proportion of patients with PVD had comorbidities versus those without. The mean (95% confidence interval [CI]) placebo-corrected LDL-C percentage change from baseline to day 510 was −48.9% (−55.6 to −42.2) in patients with PVD and −51.5% (−53.9 to −49.1) in patients without. Proportions of patients with reported treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events were similar between treatment arms, irrespective of PVD status, except for an excess of mild or moderate clinically relevant TEAEs at the injection site with inclisiran.ConclusionTwice-yearly inclisiran dosing (after the initial and 3-month doses) was well tolerated and provided effective and sustained lipid-lowering in patients, irrespective of PVD status.

From the medical, pharmaceutical, and social perspectives, 2021 has been a year dominated by the COVID-19 pandemic. However, despite this global health crisis, the pharmaceutical industry has continued its endeavors, and 2021 could be considered an excellent year in terms of the drugs accepted by the US Food and Drug Administration (FDA). Thus, during this year, the FDA has approved 50 novel drugs, of which 36 are new chemical entities and 14 biologics. It has also authorized 10 TIDES (8 peptides, 2 oligonucleotides), in addition to 2 antibody-drug conjugates (ADCs) whose structures contain peptides. Thus, TIDES have accounted for about 24% of the approvals in the various drug categories. Importantly, this percentage has surpassed the figure in 2020 (10%), thus reflecting the remarkable success of TIDES. In this review, the approved TIDE-based drugs are analyzed on the basis of their chemical structure, medical target, mode of action, administration route, and adverse effects.

Dyslipidemia treatment is of major importance in reducing the risk of atherosclerotic cardiovascular disease (ASCVD), which is still the most common cause of death worldwide. During the last decade, a novel lipid-lowering drug category has emerged, i.e., proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Apart from the two available anti-PCSK9 monoclonal antibodies (alirocumab and evolocumab), other nucleic acid-based therapies that inhibit or “silence” the expression of PCSK9 are being developed. Among them, inclisiran is the first-in-class small interfering RNA (siRNA) against PCSK9 that has been approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of hypercholesterolemia. Importantly, inclisiran therapy may improve low-density lipoprotein cholesterol (LDL-C) target achievement by offering a prolonged and significant LDL-C-lowering effect with the administration of only two doses per year. The present narrative review discusses the ORION/VICTORION clinical trial program that has been designed to investigate the impact of inclisiran on atherogenic lipoproteins and major adverse cardiac events in different patient populations. The results of the completed clinical trials are presented, focusing on the effects of inclisiran on LDL-C and lipoprotein (a) (Lp(a)) levels as well as on other lipid parameters such as apolipoprotein B and non-high-density lipoprotein cholesterol (non-HDL-C). Ongoing clinical trials with inclisiran are also discussed.

Purpose of Review Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries consistently show that many people with dyslipidemia do not achieve optimal management, and many of them are treated with low-intensity lipid-lowering therapies. Beyond the well-known association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular prevention, the atherogenicity of lipoprotein(a) and the impact of triglyceride (TG)-rich lipoproteins cannot be overlooked. Within this landscape, the use of RNA-based therapies can help the treatment of difficult to target lipid disorders. Recent Findings The safety and efficacy of LDL-C lowering with the siRNA inclisiran has been documented in the open-label ORION-3 trial, with a follow-up of 4 years. While the outcome trial is pending, a pooled analysis of ORION-9, ORION-10, and ORION-11 has shown the potential of inclisiran to reduce composite major adverse cardiovascular events. Concerning lipoprotein(a), data of OCEAN(a)-DOSE trial with olpasiran show a dose-dependent drop in lipoprotein(a) levels with an optimal pharmacodynamic profile when administered every 12 weeks. Concerning TG lowering, although ARO-APOC3 and ARO-ANG3 are effective to lower apolipoprotein(apo)C-III and angiopoietin-like 3 (ANGPTL3) levels, these drugs are still in their infancy. Summary In the era moving toward a personalized risk management, the use of siRNA represents a blossoming armamentarium to tackle dyslipidaemias for ASCVD risk reduction.

Despite the availability of effective therapies that lower low‐density lipoprotein cholesterol (LDL‐C) levels in patients with atherosclerotic cardiovascular disease, many eligible patients are inadequately treated and their LDL‐C levels remain suboptimal. Patient nonadherence to lipid‐lowering therapy (LLT) is a major contributor to the failure of LDL‐C goal attainment. Several factors have been identified as contributing to LLT nonadherence, including healthcare disparities due to socioeconomic status, age, race, sex, and cost; limited access to healthcare; perceived side effects associated with LLT; health literacy; and the presence of comorbidities. Suboptimal LLT use has also been associated with clinician factors, including failure to identify patients who require LDL‐C reassessment, insufficient LDL‐C monitoring, and clinical inertia such as a lack of therapy intensification. Several strategies to enhance LLT adherence have been shown to be effective, including the implementation of educational initiatives and tools for both patients and physicians, the use of clinical protocols and algorithms to identify patients at risk and optimize treatment, and improvements in electronic healthcare records. Pharmacy‐based programs designed to help patients with prescription refills, including reminders or the use of prescription delivery by mail, have also proven effective. Drugs requiring frequent administration can represent a barrier to treatment adherence; therefore, newer, more effective LLTs with lower frequency of administration and lower potential for polypharmacy may improve patient adherence to LLT. Implementation of strategies to identify patients at risk for LLT nonadherence and the use of flexible tools such as telemedicine to overcome geographical barriers may improve LLT adherence.

Inclisiran is a novel drug that inhibits PCSK9 synthesis specifically in the liver, harnessing the natural mechanism of RNAi. Phase I and II data show that inclisiran lowers low-density lipoprotein cholesterol levels on average by >50% with a duration of effect that enables twice-yearly dosing. Phases I, II and emerging Phase III data support inclisiran's safety, tolerability and risk-benefit profile. The ongoing ORION program includes Phase III trials that will provide robust evidence of inclisiran's safety and efficacy in individuals at high risk of atherosclerotic cardiovascular disease (ASCVD), including established ASCVD and familial hypercholesterolemia. In addition, the ORION-4 trial will assess the impact of inclisiran on cardiovascular outcomes in approximately 15,000 ASCVD subjects.