-
European Heart Journal Apr 2022
Topics: Anticholesteremic Agents; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Humans
PubMed: 34999786
DOI: 10.1093/eurheartj/ehab889 -
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 -
Journal of the American College of... Apr 2023The routine use of high-intensity statins should be considered carefully in elderly patients because of their higher risk of intolerance or adverse events. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The routine use of high-intensity statins should be considered carefully in elderly patients because of their higher risk of intolerance or adverse events.
OBJECTIVES
We evaluated the impact of moderate-intensity statin with ezetimibe combination therapy compared with high-intensity statin monotherapy in elderly patients with atherosclerotic cardiovascular disease (ASCVD).
METHODS
In this post hoc analysis of the RACING (RAndomized Comparison of Efficacy and Safety of Lipid-lowerING With Statin Monotherapy Versus Statin/Ezetimibe Combination for High-risk Cardiovascular Diseases) trial, patients were stratified by age (≥75 years and <75 years). The primary endpoint was a 3-year composite of cardiovascular death, major cardiovascular events, or nonfatal stroke.
RESULTS
Among the 3,780 enrolled patients, 574 (15.2%) were aged ≥75 years. The rates of the primary endpoint were not different between the moderate-intensity statin with ezetimibe combination therapy group and the high-intensity statin monotherapy group among patients aged ≥75 years (10.6% vs 12.3%; HR: 0.87; 95% CI: 0.54-1.42; P = 0.581) and those <75 years (8.8% vs 9.4%; HR: 0.94; 95% CI: 0.74-1.18; P = 0.570) (P for interaction = 0.797). Moderate-intensity statin with ezetimibe combination therapy was associated with lower rates of intolerance-related drug discontinuation or dose reduction among patients aged ≥75 years (2.3% vs 7.2%; P = 0.010) and those <75 years (5.2% vs 8.4%; P < 0.001) (P for interaction = 0.159).
CONCLUSIONS
Moderate-intensity statin with ezetimibe combination therapy showed similar cardiovascular benefits to those of high-intensity statin monotherapy with lower intolerance-related drug discontinuation or dose reduction in elderly patients with ASCVD having a higher risk of intolerance, nonadherence, and discontinuation with high-intensity statin therapy. (RAndomized Comparison of Efficacy and Safety of Lipid-lowerING With Statin Monotherapy Versus Statin/Ezetimibe Combination for High-risk Cardiovascular Diseases [RACING Trial]; NCT03044665).
Topics: Aged; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ezetimibe; Anticholesteremic Agents; Cardiovascular Diseases; Drug Therapy, Combination; Atherosclerosis; Lipids; Treatment Outcome
PubMed: 37019580
DOI: 10.1016/j.jacc.2023.02.007 -
Pharmacological Research Apr 2023Statins have contributed to the prevention of numerous atherosclerotic cardiovascular (CV) events and cardiovascular deaths in the past three decades. The benefit of...
Statins have contributed to the prevention of numerous atherosclerotic cardiovascular (CV) events and cardiovascular deaths in the past three decades. The benefit of statins is mainly mediated by the lowering of LDLc. According to scientific evidence, the current international guidelines recommend very low LDLc goals in patients at high/very high cardiovascular risk because they are associated with fewer CV events and improvements in atherosclerotic plaques. However, these goals often cannot be obtained with statins alone. Recent RCTs have demonstrated that these CV benefits can also be obtained with nonstatin LDLc-lowering drugs such as PCSK9 inhibitors (alirocumab and evolocumab), ezetimibe and bempedoic acid, while evidence with inclisiran is upcoming. Icosapent ethyl, a lipid metabolism modifier, has also shown an effect on event reduction. Physicians should take advantage of the currently available lipid-lowering therapies, choosing the drug or combination of drugs that is most appropriate for each patient according to his or her CV risk and baseline LDLc concentration. Strategies implementing combination therapies from early stages or even from the outset may increase the number of patients attaining LDLc goals, thereby preventing new CV episodes and improving existing atherosclerotic lesions.
Topics: Humans; Male; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proprotein Convertase 9; Anticholesteremic Agents; Plaque, Atherosclerotic; Cholesterol, LDL; Atherosclerosis; Cardiovascular Diseases
PubMed: 36940892
DOI: 10.1016/j.phrs.2023.106738 -
Cardiovascular Diabetology Jun 2022The Food and Drug Administration has approved Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors for the treatment of dyslipidemia. However, evidence of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The Food and Drug Administration has approved Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors for the treatment of dyslipidemia. However, evidence of the optimal PCSK9 agents targeting PCSK9 for secondary prevention in patients with high-risk of cardiovascular events is lacking. Therefore, this study was conducted to evaluate the benefit and safety of different types of PCSK9 inhibitors.
METHODS
Several databases including Cochrane Central, Ovid Medline, and Ovid Embase were searched from inception until March 30, 2022 without language restriction. Randomized controlled trials (RCTs) comparing administration of PCSK9 inhibitors with placebo or ezetimibe for secondary prevention of cardiovascular events in patients with statin-background therapy were identified. The primary efficacy outcome was all-cause mortality. The primary safety outcome was serious adverse events.
RESULTS
Overall, nine trials totaling 54,311 patients were identified. Three types of PCSK9 inhibitors were evaluated. The use of alirocumab was associated with reductions in all-cause mortality compared with control (RR 0.83, 95% CrI 0.72-0.95). Moreover, evolocumab was associated with increased all-cause mortality compared with alirocumab (RR 1.26, 95% CrI 1.04-1.52). We also found alirocumab was associated with decreased risk of serious adverse events (RR 0.94, 95% CrI 0.90-0.99).
CONCLUSIONS
In consideration of the fact that both PCSK9 monoclonal antibody and inclisiran enable patients to achieve recommended LDL-C target, the findings in this meta-analysis suggest that alirocumab might provide the optimal benefits regarding all-cause mortality with relatively lower SAE risks, and evolocumab might provide the optimal benefits regarding myocardial infarction for secondary prevention in patients with high-risk of cardiovascular events. Further head-to-head trials with longer follow-up and high methodologic quality are warranted to help inform subsequent guidelines for the management of these patients.
Topics: Anticholesteremic Agents; Cardiovascular Diseases; Humans; Network Meta-Analysis; PCSK9 Inhibitors; Proprotein Convertase 9; Secondary Prevention
PubMed: 35706032
DOI: 10.1186/s12933-022-01542-4 -
Drugs Nov 2023Tafolecimab (SINTBILO), a subcutaneously administered anti-proprotein convertase subtilisin/kexin type 9 enzyme (PCSK9) monoclonal antibody, is being developed by... (Review)
Review
Tafolecimab (SINTBILO), a subcutaneously administered anti-proprotein convertase subtilisin/kexin type 9 enzyme (PCSK9) monoclonal antibody, is being developed by Innovent for the treatment of hypercholesterolemia and mixed hyperlipidemia. Tafolecimab was approved in August 2023 in China as an adjunct to diet, in combination with a statin or statin with other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, for the treatment of adults with primary hyperlipidemia [including heterozygous familial hypercholesterolemia (HeFH) and non-familial hypercholesterolemia (non-FH)] and mixed dyslipidemia who have failed to achieve LDL-C goals despite moderate or higher doses of statins, to reduce LDL-C, total cholesterol (TC), and apolipoprotein B (ApoB) levels. This article summarizes the milestones in the development of tafolecimab leading to this first approval for the treatment of adults with primary hyperlipidemia and mixed dyslipidemia.
Topics: Adult; Humans; Proprotein Convertase 9; Cholesterol, LDL; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Antibodies, Monoclonal; Hypercholesterolemia; Dyslipidemias; Anticholesteremic Agents
PubMed: 37847461
DOI: 10.1007/s40265-023-01952-y -
Drugs Jun 2021The recombinant human monoclonal antibody evinacumab (evinacumab-dgnb, EVKEEZA™) is an angiopoietin-like protein three (ANGPTL3) inhibitor that has been developed by... (Review)
Review
The recombinant human monoclonal antibody evinacumab (evinacumab-dgnb, EVKEEZA™) is an angiopoietin-like protein three (ANGPTL3) inhibitor that has been developed by Regeneron Pharmaceuticals for the treatment of homozygous familial hypercholesterolaemia (HoFH), refractory hypercholesterolemia (both familial and non-familial) and severe hypertriglyceridaemia. Based on the results of the phase III ELIPSE HoFH trial, evinacumab was recently approved in the USA as an adjunct to other LDL-C lowering therapies for the treatment of adult and paediatric patients aged 12 years and older with HoFH, and has received a positive opinion in the EU. This article summarizes the milestones in the development of evinacumab leading to this first approval for HoFH.
Topics: Angiopoietin-like Proteins; Antibodies, Monoclonal; Anticholesteremic Agents; Double-Blind Method; Drug Approval; Humans; Hypercholesterolemia; Hypertriglyceridemia; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; United States
PubMed: 34003472
DOI: 10.1007/s40265-021-01516-y -
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 -
The Canadian Journal of Cardiology Dec 2023Depressed low-density lipoprotein cholesterol concentration protects against atherosclerotic cardiovascular disease. Natural hypocholesterolemia states can have a... (Review)
Review
Depressed low-density lipoprotein cholesterol concentration protects against atherosclerotic cardiovascular disease. Natural hypocholesterolemia states can have a monogenic etiology, caused by pathogenic loss of function variants in the PCSK9, ANGPTL3, MTTP, or APOB genes. In this focused review, we discuss development and clinical use of several new therapeutics that inhibit these gene products to target elevated levels of low-density lipoprotein cholesterol. In particular, inhibitors of proprotein convertase subtilisin kexin type 9 (PCSK9) have notably affected clinical practice, followed recently by inhibition of angiopoietin-like 3 (ANGPTL3). Currently used in the clinic are alirocumab and evolocumab, two anti-PCSK9 monoclonal antibodies, inclisiran, a small interfering RNA that prevents PCSK9 translation, evinacumab, an anti-ANGPTL3 monoclonal antibody, and lomitapide, a small-molecule inhibitor of microsomal triglyceride transfer protein. Additional therapies are in preclinical or clinical trial stages of development. These consist of other monoclonal antibodies, antisense oligonucleotides, small-molecule inhibitors, mimetic peptides, adnectins, vaccines, and gene-editing therapies. Vaccines and gene-editing therapies in particular hold great potential to confer active long-term attenuation or provide single-treatment life-long knock-down of PCSK9 or ANGPTL3 activity. Biologic therapies inspired by monogenic hypocholesterolemia states are becoming valuable tools to help protect against atherosclerotic cardiovascular disease.
Topics: Humans; Cholesterol, LDL; Proprotein Convertase 9; PCSK9 Inhibitors; Cardiovascular Diseases; Antibodies, Monoclonal; Atherosclerosis; Biological Therapy; Vaccines; Anticholesteremic Agents; Angiopoietin-Like Protein 3
PubMed: 37562541
DOI: 10.1016/j.cjca.2023.08.003 -
Current Neurology and Neuroscience... Jul 2022We reviewed lipid-modifying therapies and the risk of stroke and other cerebrovascular outcomes, with a focus on newer therapies. (Review)
Review
PURPOSE OF REVIEW
We reviewed lipid-modifying therapies and the risk of stroke and other cerebrovascular outcomes, with a focus on newer therapies.
RECENT FINDINGS
Statins and ezetimibe reduce ischemic stroke risk without increasing hemorrhagic stroke risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors similarly reduce ischemic stroke risk in statin-treated patients with atherosclerosis without increasing hemorrhagic stroke, even with very low achieved low-density lipoprotein cholesterol levels. Icosapent ethyl reduces the risk of total and first ischemic stroke in patients with established cardiovascular disease or diabetes mellitus. Clinical outcome trials are underway for newer lipid-modifying agents, including inclisiran, bempedoic acid, and pemafibrate. New biologic agents including evinacumab, pelacarsen, olpasiran, and SLN360 are also discussed. In addition to statins and ezetimibe, PCSK9 inhibitors and icosapent ethyl reduce the risk of ischemic stroke without increasing the risk of hemorrhagic stroke. These therapies dramatically expand options for reducing stroke in high-risk settings.
Topics: Anticholesteremic Agents; Cardiovascular Diseases; Ezetimibe; Hemorrhagic Stroke; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ischemic Stroke; Lipids; Proprotein Convertase 9; Stroke
PubMed: 35554824
DOI: 10.1007/s11910-022-01197-4