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Journal of Clinical Lipidology 2023Inclisiran is the first-in-class small interfering RNA (siRNA) proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor. In clinical trials inclisiran showed...
BACKGROUND AND OBJECTIVE
Inclisiran is the first-in-class small interfering RNA (siRNA) proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor. In clinical trials inclisiran showed effective and sustained low-density lipoprotein cholesterol (LDL-C) reduction of ± 50 %. As data in clinical setting are scarce, we aim to investigate the efficacy and safety in clinical practice.
METHODS
We describe a registry of consecutive patients who started with inclisiran at a lipid clinic of a university hospital. Patients were eligible if they fulfilled the reimbursement criteria in the Netherlands. Patients were included if they started with inclisiran as first line (group 1) or switched from PCSK9 monoclonal antibody (mAbs) to inclisiran (group 2). LDL-C levels were measured at 3 and 9 months after initiation of inclisiran. Median change of LDL-C levels was calculated on an individual and group level.
RESULTS
We analysed 65 patients (36 women), median [25 percentile; 75 percentile] age of 63 [54; 68] years. Of these, 44 patients had both a 3 month and 9 month visit. At 3 months, patients who newly started inclisiran (group 1, n = 45) showed a LDL-C decrease of 38 [-49;-33] %. Patients who used statins as co-medication (n = 15) had a higher median LDL-C decrease compared to those without statin use (n=30; 45 % vs 38 %). However, patients who switched from mAbs to inclisiran (group 2, n = 20) had an increase in LDL-C of 38 [+4; +97] %. Adverse effects associated with inclisiran were mild and consisted of mild injection site reactions. Efficacy was slightly less whereas safety results were similar at 9 months.
CONCLUSION
Our initial experience of inclisiran in a clinical setting showed less reduction in LDL-C levels compared to clinical trials but a similar safety profile. Moreover, patients who switched from PCSK9 mAbs to inclisiran generally showed an increase in LDL-C levels implying that inclisiran is less potent in LDL-C reduction compared to PCSK9 mAbs.
Topics: Humans; Female; Cholesterol, LDL; Proprotein Convertase 9; RNA, Small Interfering; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Anticholesteremic Agents
PubMed: 37775462
DOI: 10.1016/j.jacl.2023.09.005 -
Circulation Jul 2023Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small...
BACKGROUND
Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design.
METHODS
Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (change in low density lipoprotein cholesterol).
RESULTS
MK-0616 displayed high affinity ( = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84-103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple-oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43-85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616.
CONCLUSIONS
This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.
Topics: Adult; Humans; Anticholesteremic Agents; Cholesterol; Cholesterol, LDL; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Peptides; Proprotein Convertase 9; Receptors, LDL
PubMed: 37125593
DOI: 10.1161/CIRCULATIONAHA.122.063372 -
Journal of Atherosclerosis and... Nov 2023The study aimed to investigate low-density lipoprotein cholesterol (LDL-C) goal achievement rates in patients receiving LDL-C-lowering therapy using recent real-world...
AIMS
The study aimed to investigate low-density lipoprotein cholesterol (LDL-C) goal achievement rates in patients receiving LDL-C-lowering therapy using recent real-world data, following the 2017 revision of the Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases (JAS GL2017).
METHODS
Patients with documented LDL-C test results were extracted from the Medical Data Vision claims database between July 2018 and June 2021 and divided into three groups according to JAS GL2017: primary prevention high risk (Group I, LDL-C goal <120 mg/dL), secondary prevention (Group II, LDL-C goal <100 mg/dL), and secondary prevention high risk (Group III, LDL-C goal <70 mg/dL).
RESULTS
The mean LDL-C value was 108.7 mg/dL (n=125,235), 94.4 mg/dL (n=57,910), and 90.6 mg/dL (n=33,850) in Groups I, II, and III, respectively. Intensive statin monotherapy (pitavastatin, rosuvastatin, or atorvastatin) was the most frequently prescribed lipid-lowering treatment (21.6%, 30.8%, and 42.7% in Groups I, II, and III, respectively), followed by ezetimibe (2.5%, 7.1%, and 8.5% in Groups I, II, and III, respectively). LDL-C goals were achieved by 65.5%, 60.6%, and 25.4% of patients overall in Groups I, II, and III, respectively. Achievement rates were 83.9%, 75.3%, and 29.5% in patients prescribed intensive statin monotherapy and 82.3%, 86.4%, and 46.4% in those prescribed statin and ezetimibe combinations in Groups I, II, and III, respectively. In Group III, the proportion of patients with familial hypercholesterolemia prescribed statin and ezetimibe combinations achieving LDL-C goals was low (32.5%).
CONCLUSIONS
The proportion of patients achieving LDL-C goals for secondary prevention in the high-risk group remains low even with statin and ezetimibe combination therapy.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Goals; Cardiovascular Diseases; Japan; Treatment Outcome; Ezetimibe; Atherosclerosis; Anticholesteremic Agents
PubMed: 36928267
DOI: 10.5551/jat.63940 -
Journal of Clinical Lipidology 2023Obicetrapib, a selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Obicetrapib, a selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein particles, and apolipoproteins, when added to high-intensity statin in patients with dyslipidemia.
OBJECTIVE
To evaluate the safety and lipid-altering efficacy of obicetrapib plus ezetimibe combination therapy as an adjunct to high-intensity statin therapy.
METHODS
This double-blind, randomized, phase 2 trial administered 10 mg obicetrapib plus 10 mg ezetimibe (n = 40), 10 mg obicetrapib (n = 39), or placebo (n = 40) for 12 weeks to patients with LDL-C >70 mg/dL and triglycerides (TG) <400 mg/dL, on stable high-intensity statin. Endpoints included concentrations of lipids, apolipoproteins, lipoprotein particles, and proprotein convertase subtilisin kexin type 9 (PCSK9), safety, and tolerability.
RESULTS
Ninety-seven patients were included in the primary analysis (mean age 62.6 years, 63.9% male, 84.5% white, average body mass index of 30.9 kg/m). LDL-C decreased from baseline to week 12 by 63.4%, 43.5%, and 6.35% in combination, monotherapy, and placebo groups, respectively (p<0.0001 vs. placebo). LDL-C levels of <100, <70, and <55 mg/dL were achieved by 100%, 93.5%, and 87.1%, respectively, of patients taking the combination. Both active treatments also significantly reduced concentrations of non-HDL-C, apolipoprotein B, and total and small LDL particles. Obicetrapib was well tolerated and no safety issues were identified.
CONCLUSION
The combination of obicetrapib plus ezetimibe significantly lowered atherogenic lipid and lipoprotein parameters, and was safe and well tolerated when administered on top of high-intensity statin to patients with elevated LDL-C.
Topics: Humans; Male; Middle Aged; Female; Ezetimibe; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proprotein Convertase 9; Anticholesteremic Agents; Cholesterol, LDL; Antibodies, Monoclonal, Humanized; Cholesterol; Drug Therapy, Combination; Apolipoproteins; Double-Blind Method; Treatment Outcome
PubMed: 37277261
DOI: 10.1016/j.jacl.2023.05.098 -
Progress in Cardiovascular Diseases 2023Cardiovascular disease (CVD) is a chronic non-communicable disease (NCD) and the predominant cause of morbidity and mortality worldwide. Substantial reductions in the... (Review)
Review
Cardiovascular disease (CVD) is a chronic non-communicable disease (NCD) and the predominant cause of morbidity and mortality worldwide. Substantial reductions in the CVD prevalence have been achieved in recent years by the attenuation of risk factors (particularly hypertension and dyslipidaemias) in primary and secondary prevention. Despite the remarkable success of lipid lowering treatments, and of statins in particular, in reducing the risk of CVD, there is still an unmet clinical need for the attainment of guideline lipid-targets in even 2/3 of patients. Bempedoic acid, the first in-class inhibitor of ATP-citrate lyase presents a new approach to lipid-lowering therapy. By reducing the endogenous production of cholesterol, upstream of the rate-limiting enzyme HMG-CoA-reductase, i.e., the target of statins, bempedoic acid reduces circulating plasma concentrations of low-density lipoprotein cholesterol (LDL-C), and major adverse CVD events (MACE). Bempedoic acid has the potential to contribute to the reduction of CVD risk not only as monotherapy, but even further as part of a lipid-lowering combination therapy with ezetimibe, reducing LDL-C cholesterol up to 40%. This position paper of the International Lipid Expert Panel (ILEP) summarises the recent evidence around the efficacy and safety of bempedoic acid and presents practical recommendations for its use, which complement the 'lower-is-better-for-longer' approach to lipid management, which is applied across international guidelines for the management of CVD risk. Practical evidence-based guidance is provided relating to the use of bempedoic acid in atherosclerotic CVD, familial hypercholesterolaemia, and statin intolerance. Although there are still no sufficient data avilable for the role of bempedoic acid in the primary prevention of CVD, its favourable effects on plasma glucose and inflammatory markers makes this drug a rational choice in the patient-centred care of specific groups of primary prevention.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Cardiovascular Diseases; Risk Factors; Cholesterol; Heart Disease Risk Factors; Anticholesteremic Agents
PubMed: 36889490
DOI: 10.1016/j.pcad.2023.03.001 -
Circulation Jan 2024Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) and a high risk of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular events. The proof-of-concept study ORION-2 (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) showed that inclisiran, a small interfering RNA that prevents production of the hepatic PCSK9 protein (proprotein convertase subtilisin/kexin type 9), could lead to durable reductions in LDL-C levels when added to statins and ezetimibe in patients with homozygous familial hypercholesterolemia.
METHODS
ORION-5 was a phase 3, 2-part, multicenter study in 56 patients with homozygous familial hypercholesterolemia and elevated LDL-C levels despite maximum tolerated doses of LDL-C-lowering therapies with or without lipoprotein apheresis. Patients eligible for part 1 (double-blind, 6 months) were randomized 2:1 to receive either 300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or placebo. Placebo-treated patients from part 1 were transitioned to inclisiran in part 2 (open-label, 18 months). The primary end point was the percentage change in LDL-C levels from baseline to day 150.
RESULTS
The mean age of the patients was 42.7 years, and 60.7% were women. The mean baseline LDL-C levels were 294.0 mg/dL and 356.7 mg/dL in the inclisiran and placebo groups, respectively. The placebo-corrected percentage change in LDL-C level from baseline to day 150 was -1.68% (95% CI, -29.19% to 25.83%; =0.90), and the difference was not statistically significant between the inclisiran and placebo groups. The placebo-corrected percentage change in PCSK9 levels from baseline to day 150 was -60.6% with inclisiran treatment (<0.0001); this was sustained throughout the study, confirming the effect of inclisiran on its biological target of PCSK9. No statistically significant differences between the inclisiran and placebo groups were observed in the levels of other lipids and lipoproteins (apolipoprotein B, total cholesterol, and non-high-density lipoprotein cholesterol). Adverse events and serious adverse events did not differ between the inclisiran and placebo groups throughout the study.
CONCLUSIONS
Inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia despite substantial lowering of PCSK9 levels. Inclisiran was well-tolerated, and the safety findings were consistent with previously reported studies and the overall safety profile.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03851705.
Topics: Humans; Female; Adult; Male; Proprotein Convertase 9; Cholesterol, LDL; Homozygous Familial Hypercholesterolemia; Hydroxymethylglutaryl-CoA Reductase Inhibitors; RNA, Small Interfering; Cholesterol; Anticholesteremic Agents
PubMed: 37850379
DOI: 10.1161/CIRCULATIONAHA.122.063460 -
Arteriosclerosis, Thrombosis, and... Oct 2023The objective of this scientific statement is to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive low-density lipoprotein... (Review)
Review
The objective of this scientific statement is to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive low-density lipoprotein cholesterol lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke. The writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize existing evidence and to identify gaps in current knowledge. Although some retrospective, case control, and prospective longitudinal studies suggest that statins and low-density lipoprotein cholesterol lowering are associated with cognitive impairment or dementia, the preponderance of observational studies and data from randomized trials do not support this conclusion. The risk of a hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is nonsignificant, and achieving very low levels of low-density lipoprotein cholesterol does not increase that risk. Data reflecting the risk of hemorrhagic stroke with lipid-lowering treatment among patients with a history of hemorrhagic stroke are not robust and require additional focused study.
Topics: Humans; American Heart Association; Anticholesteremic Agents; Brain; Cholesterol, LDL; Dementia; Ezetimibe; Hemorrhagic Stroke; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Prospective Studies; Retrospective Studies; Stroke
PubMed: 37706297
DOI: 10.1161/ATV.0000000000000164 -
Journal of the American College of... Dec 2023Inclisiran is a small interfering RNA agent to lower low-density lipoprotein cholesterol.
BACKGROUND
Inclisiran is a small interfering RNA agent to lower low-density lipoprotein cholesterol.
OBJECTIVES
The purpose of this study was to provide reliable evidence to date on the long-term safety profile of inclisiran.
METHODS
This post hoc analysis comprised patients treated with 300 mg inclisiran sodium or placebo in the completed (ORION-1, -3, -5, -9, -10, and -11) and ongoing (ORION-8) trials. Exposure-adjusted incidence rates and Kaplan-Meier estimates of cumulative incidence of reported treatment-emergent adverse events (TEAE), abnormal laboratory measurements, and incidence of antidrug antibodies were analyzed.
RESULTS
This analysis included 3,576 patients treated with inclisiran for up to 6 years and 1,968 patients treated with placebo for up to 1.5 years, with 9,982.1 and 2,647.7 patient-years of exposure, respectively. Baseline characteristics were balanced between groups. Kaplan-Meier analyses showed that TEAEs that were serious or led to discontinuation; hepatic, muscle, and kidney events; incident diabetes; and elevations of creatine kinase or creatinine accrued at a comparable rate between groups for up to 1.5 years, with similar trends continuing for inclisiran beyond this period. Numerically fewer major cardiovascular events reported as TEAEs occurred with inclisiran during this period. Treatment-induced antidrug antibodies were uncommon with inclisiran (4.6%), with few of these persistent (1.4%) and not associated with greater incidence of TEAEs leading to study drug discontinuation or serious TEAEs.
CONCLUSIONS
Long-term treatment with inclisiran was well tolerated in a diverse population, without new safety signals, supporting the safety of inclisiran in patients with dyslipidemia.
Topics: Humans; Hypercholesterolemia; Cholesterol, LDL; RNA, Small Interfering; Dyslipidemias; Anticholesteremic Agents; Proprotein Convertase 9
PubMed: 38057066
DOI: 10.1016/j.jacc.2023.10.007 -
Current Atherosclerosis Reports Oct 2023It is clear from epidemiological studies that patients at high and very-high risk of atherosclerotic cardiovascular diseases (ASCVD) risk do not reach lipid... (Review)
Review
PURPOSE OF REVIEW
It is clear from epidemiological studies that patients at high and very-high risk of atherosclerotic cardiovascular diseases (ASCVD) risk do not reach lipid guideline-recommended targets. Thus, fixed-dose combinations of statins/ezetimibe, bempedoic acid/ezetimibe and statins/fibrates may represent a further armamentarium in the field of lipid-lowering approaches in these individuals.
RECENT FINDINGS
The combination therapy of moderate-intensity statin with ezetimibe is not inferior to high-intensity statin monotherapy in reducing cardiovascular outcomes. Drug discontinuation or dose reduction is inferior with fixed-dose combination. The fixed-dose combination of bempedoic acid with ezetimibe is superior to bempedoic acid in monotherapy in lowering LDL-C and in reducing high-sensitivity C-reactive protein concentrations. The combination fenofibrate with atorvastatin is superior to monotherapies in lowering triglycerides. Lipid-lowering fixed-dose combinations may guarantee a higher therapy adherence, representing a better approach to control plasma lipids and thus ameliorate ASCVD burden. Additional studies will define the advantages on cardiovascular outcomes in high and very high-risk patients.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Ezetimibe; Dyslipidemias; Drug Therapy, Combination; Atherosclerosis; Anticholesteremic Agents; Treatment Outcome
PubMed: 37715044
DOI: 10.1007/s11883-023-01142-x -
Frontiers in Endocrinology 2023The relationship between dyslipidemia and female reproductive endocrine diseases has been increasingly studied. The use of lipid-lowering drugs in treating various...
PURPOSE
The relationship between dyslipidemia and female reproductive endocrine diseases has been increasingly studied. The use of lipid-lowering drugs in treating various related diseases, including coronary heart disease, may affect female reproductive endocrine diseases. Therefore, our study aims to investigate the effects of lipid-lowering drugs on female reproductive endocrine diseases and provide a basis for the appropriate selection of drugs.
METHODS
In this study, we focused on three drug targets of statins, namely HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase kexin 9 (PCSK9) inhibitors, and Niemann-Pick C1-Like 1 (NPC1L1) inhibitors. To identify potential inhibitors for these targets, we collected single nucleotide polymorphisms (SNPs) associated with HMGCR, PCSK9, and NPC1L1 from published genome-wide association study statistics. Subsequently, we conducted a drug target Mendelian randomization (MR) analysis to investigate the effects of these inhibitors on reproductive endocrine diseases mediated by low-density lipoprotein cholesterol (LDL-C) levels. Alongside coronary heart disease as a positive control, our main outcomes of interest included the risk of polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), premenstrual syndrome (PMS), abnormal uterine bleeding (including menorrhagia and oligomenorrhea), and infertility.
RESULTS
PCSK9 inhibitors significantly increased the risk of infertility in patients (OR [95%CI] = 1.14 [1.06, 1.23], p<0.05). In contrast, HMGCR inhibitors significantly reduced the risk of menorrhagia in female patients (OR [95%CI] = 0.85 [0.75, 0.97], p<0.05), but had no statistical impact on patients with oligomenorrhea.
CONCLUSION
The findings suggest that PCSK9 inhibitors may significantly increase the risk of infertility in patients. On the other hand, HMGCR inhibitors could potentially offer protection against menorrhagia in women. However, no effects of lipid-lowering drugs have been observed on other reproductive endocrine disorders, such as PCOS, POF, PMS and oligomenorrhea.
Topics: Humans; Female; Proprotein Convertase 9; Polycystic Ovary Syndrome; Genome-Wide Association Study; Mendelian Randomization Analysis; Menorrhagia; Oligomenorrhea; PCSK9 Inhibitors; Hypolipidemic Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Coronary Disease; Lipids; Infertility
PubMed: 38027179
DOI: 10.3389/fendo.2023.1295412