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American Journal of Cardiovascular... Mar 2023Inclisiran (Leqvio) is a first-in-class, subcutaneously administered, small interfering RNA (siRNA) that prevents hepatic synthesis of proprotein convertase... (Review)
Review
Inclisiran (Leqvio) is a first-in-class, subcutaneously administered, small interfering RNA (siRNA) that prevents hepatic synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9), thereby decreasing circulating low-density lipoprotein cholesterol (LDL-C). In the EU, inclisiran is indicated in adults with primary hypercholesterolemia or mixed dyslipidemia, as an adjunct to diet. It is intended for use in patients unable to reach LDL-C goals on maximally tolerated statin therapy, with or without other lipid-lowering therapies (LLTs). In patients who are statin intolerant or for whom a statin is contraindicated, it can be used with or without other LLTs. In clinical trials, twice-yearly injections of inclisiran (after initial doses at days 1 and 90) approximately halved LDL-C levels in patients with, or at high risk of developing, atherosclerotic cardiovascular disease (ASCVD) who had hypercholesterolemia, irrespective of whether or not their existing treatment included a statin. The safety and tolerability profile of the drug was similar to placebo, although mild to moderate, transient injection-site adverse reactions were more frequent with inclisiran. Pending confirmation of the expected reduction in cardiovascular (CV) events with inclisiran, it is a valuable additional/alternative antihyperlipidemic agent to a statin, as its infrequent maintenance dosing regimen confers a convenience advantage over other non-statin LLTs.
Topics: Humans; Hypercholesterolemia; Proprotein Convertase 9; Cholesterol, LDL; RNA, Small Interfering; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Anticholesteremic Agents
PubMed: 36869996
DOI: 10.1007/s40256-023-00568-7 -
Journal of the American College of... Oct 2022
2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Solution Set Oversight Committee.
Topics: Anticholesteremic Agents; Cardiology; Cardiovascular Diseases; Cholesterol, LDL; Consensus; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; United States
PubMed: 36031461
DOI: 10.1016/j.jacc.2022.07.006 -
Current Atherosclerosis Reports Oct 2022The aim of creating an orally active non-statin cholesterol-lowering drug was achieved with bempedoic acid, a small linear molecule providing both a significant... (Review)
Review
PURPOSE OF REVIEW
The aim of creating an orally active non-statin cholesterol-lowering drug was achieved with bempedoic acid, a small linear molecule providing both a significant low-density lipoprotein cholesterol (LDL-C) reduction and an anti-inflammatory effect by decreasing high-sensitivity C-reactive protein. Bempedoic acid antagonizes ATP citrate-lyase, a cytosolic enzyme upstream of HMGCoA reductase which is the rate-limiting step of cholesterol biosynthesis. Bempedoic acid is a pro-drug converted to its active metabolite by very-long-chain acyl-CoA synthetase 1 which is present mostly in the liver and absent in skeletal muscles. This limits the risk of myalgia and myopathy. The remit of this review is to give clinical insights on the safety and efficacy of bempedoic acid and to understand for whom it should be prescribed.
RECENT FINDINGS
Bempedoic acid with a single daily dose (180 mg) reduces LDL-C by a mean 24.5% when given alone, by 18% when given on top of a major statin and by 38-40% when given in a fixed-dose combination with ezetimibe. Bempedoic acid does not lead to the risk of new-onset diabetes, and moderately improves the glycaemic profile. The extensive knowledge on bempedoic acid mechanism, metabolism and side effects has led to an improved understanding of the potential benefits of this agent and offers a possible alternative to cardiologists and clinical practitioners somewhat worn out today by the occurrence of the muscular side effects of statins.
Topics: Anticholesteremic Agents; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 35900636
DOI: 10.1007/s11883-022-01054-2 -
Drugs Feb 2021Inclisiran (Leqvio; Novartis) is a first-in-class, cholesterol-lowering small interfering RNA (siRNA) conjugated to triantennary N-acetylgalactosamine carbohydrates... (Review)
Review
Inclisiran (Leqvio; Novartis) is a first-in-class, cholesterol-lowering small interfering RNA (siRNA) conjugated to triantennary N-acetylgalactosamine carbohydrates (GalNAc). Inclisiran received its first approval in December 2020 in the EU for use in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet. It is intended for use in combination with a statin or a statin with other lipid-lowering therapies in patients unable to reach low-density lipoprotein cholesterol goals with the maximum tolerated statin dose. In patients who are statin-intolerant or for whom a statin is contraindicated, inclisiran can be used alone or in combination with other lipid-lowering therapies. Inclisiran is administered as a twice-yearly subcutaneous injection. This article summarizes the milestones in the development of inclisiran leading to this first approval for primary hypercholesterolaemia or mixed dyslipidaemia.
Topics: Anticholesteremic Agents; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Injections, Subcutaneous; RNA, Small Interfering
PubMed: 33620677
DOI: 10.1007/s40265-021-01473-6 -
The New England Journal of Medicine Nov 2022Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver.
METHODS
We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed.
RESULTS
Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain.
CONCLUSIONS
Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.).
Topics: Humans; Anticholesteremic Agents; Atherosclerosis; Cardiovascular Diseases; Double-Blind Method; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipoprotein(a); RNA, Small Interfering; Liver; PCSK9 Inhibitors; Ezetimibe
PubMed: 36342163
DOI: 10.1056/NEJMoa2211023 -
The Journal of Clinical Endocrinology... Apr 2022Primary hyperlipidemias include a heterogeneous set of monogenic and polygenic conditions characterized by a strong family aggregation, severe forms of...
Primary hyperlipidemias include a heterogeneous set of monogenic and polygenic conditions characterized by a strong family aggregation, severe forms of hypercholesterolemia and/or hypertriglyceridemia, appearance early on life, and a high risk of cardiovascular events and/or recurrent pancreatitis. In real life, a small proportion of the primary hyperlipidemia cases is recognized and treated properly. Our goal is to present an update of current and upcoming therapies for patients with primary hyperlipidemia. Recently, new lipid-lowering medications have obtained authorization from the U.S. Food and Drug Administration and the European Medicines Agency. These drugs target metabolic pathways, including (adenosine 5'-triphosphates)-citrate lyase (bempedoic acid), proprotein convertase subtilisin/kexin 9 (inclisiran), apolipoprotein CIII (volanesorsen), and angiopoietin-like 3 (volanesorsen), that have additive effects with the actions of the currently available therapies (i.e., statins, ezetimibe or fibrates). We discuss the potential clinical indications for the novel medications. To conclude, the addition of these new medications to the therapeutic options for primary hyperlipidemia patients may increase the likelihood of achieving the treatment targets. Also, it could be a safer alternative for patients with side effects for the currently available drugs.
Topics: Anticholesteremic Agents; Cholesterol, LDL; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Proprotein Convertase 9
PubMed: 34888679
DOI: 10.1210/clinem/dgab876 -
Current Atherosclerosis Reports Jul 2022Despite the elevation of lipid values during pregnancy is mostly physiological, evidence suggest that it may be associated with adverse events. This article reviews the... (Review)
Review
PURPOSE OF REVIEW
Despite the elevation of lipid values during pregnancy is mostly physiological, evidence suggest that it may be associated with adverse events. This article reviews the characteristics of lipid disorders and the possible management with dyslipidemia in pregnant women.
RECENT FINDINGS
Among many available groups of lipid-lowering drugs, only bile acid sequestrants are approved for the treatment of dyslipidemia during pregnancy. Ezetimibe and fenofibrate might be considered if benefits outweigh the potential risk. Statins are still contraindicated due to the results mainly from animal studies and series of human cases. However, recent systematic reviews and meta-analyses showed that their use may not be detrimental, and in some selected cases may be beneficial. Especially, in some groups of pregnant patients with very high cardiovascular risk-those already after an event, or with established cardiovascular disease, with homozygous familial hypercholesterolemia; in such cases the final decision should weight the potential risk of discontinuation of therapy. Finally, we need to wait for the data with new drugs, including PCSK9 inhibitors and especially inclisiran, which (still hypothetically) might be a very interesting option as it may be used just before the pregnancy and immediately after with the duration of about 9 months between injections. The decisions on lipid-lowering therapy in pregnant patients should be individualized. Despite design and ethical difficulties with such studies, further investigations on dyslipidemia treatment during pregnancy are highly awaited.
Topics: Animals; Anticholesteremic Agents; Cholesterol, LDL; Dyslipidemias; Ezetimibe; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications; Proprotein Convertase 9
PubMed: 35499807
DOI: 10.1007/s11883-022-01030-w -
Kardiologia Polska 2023Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in low-density lipoprotein (LDL) metabolism. Pharmacological PCSK9 inhibitors have been... (Review)
Review
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in low-density lipoprotein (LDL) metabolism. Pharmacological PCSK9 inhibitors have been developed as a novel approach to treating dyslipidemia. This article reviews the spectrum of evidence implicating the role of PCSK9 in lipid metabolism and the clinical impact of PCSK9 inhibitors on lipid parameters and cardiovascular risk. Biochemical and genomic studies have established the role that PCSK9 plays in lipid metabolism and potential protection from cardiovascular disease observed in the setting of PCSK9 deficiency. This led to the development of inhibitory monoclonal antibodies (evolocumab, alirocumab) that produce dose-dependent lowering of LDL cholesterol up to 60%, with evidence of regression and stabilization of coronary atherosclerosis (GLAGOV, HUYGENS, PACMAN-AMI) and reduction in cardiovascular risk in large clinical outcomes trials (FOURIER, ODYSSEY Outcomes). More recent developments have witnessed alternative approaches to PCSK9 inhibition such as RNA interference (inclisiran), vaccines, and gene editing, which are currently undergoing clinical evaluation. PCSK9 inhibition has emerged as an important component of treatment approaches to lowering LDL cholesterol and plays an increasing role in preventive strategies.
Topics: Humans; PCSK9 Inhibitors; Cholesterol, LDL; Proprotein Convertase 9; Cardiovascular Diseases; Anticholesteremic Agents
PubMed: 36739653
DOI: 10.33963/KP.a2023.0030 -
European Heart Journal Feb 2022
Topics: Anticholesteremic Agents; Cholesterol, LDL; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents
PubMed: 34636884
DOI: 10.1093/eurheartj/ehab718 -
Current Medical Research and Opinion May 2022Network meta-analysis was used to derive estimates of the relative efficacy of inclisiran, evolocumab, alirocumab, bempedoic acid, and ezetimibe in patients with... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Network meta-analysis was used to derive estimates of the relative efficacy of inclisiran, evolocumab, alirocumab, bempedoic acid, and ezetimibe in patients with hypercholesterolemia and/or at increased cardiovascular risk due to elevated low-density lipoprotein cholesterol taking maximum tolerated dose statins.
METHODS
Clinical trials published through February 2021 comparing percent change from baseline in low-density lipoprotein cholesterol were identified a systematic review. Bayesian network meta-analyses were performed for patients with atherosclerotic cardiovascular disease and/or high cardiovascular risk on maximally tolerated statins in the base case, which included 23 trials.
RESULTS
Results from the base-case analyses demonstrated that inclisiran, evolocumab, and alirocumab provide superior efficacy over placebo, bempedoic acid, and ezetimibe in terms of reduction in low-density lipoprotein cholesterol. Inclisiran was also comparable to alirocumab (mean difference: 0.78% [95% CrI: -8.35, 9.88]) and evolocumab (8.16%, [95% CrI: -1.82, 18.49]). Findings of a scenario which also included trials conducted in patients with heterozygous familial hypercholesterolemia were consistent with the base case. There was evidence of statistical heterogeneity across the included trials, roughly equivalent to variation of 5-10% change in low-density lipoprotein cholesterol, suggesting that any differences between treatments that were greater than 5-10% are generalizable.
CONCLUSIONS
This study provides insight regarding the comparative efficacy of drugs for which no head-to-head trials exist and suggests that inclisiran, alirocumab, and evolocumab are expected to provide similar clinically meaningful improvements in low-density lipoprotein cholesterol in patients with hypercholesterolemia on maximally tolerated statins who are at increased cardiovascular risk.
Topics: Anticholesteremic Agents; Bayes Theorem; Cardiovascular Diseases; Cholesterol; Cholesterol, LDL; Ezetimibe; Heart Disease Risk Factors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipidemias; Network Meta-Analysis; Risk Factors; Treatment Outcome
PubMed: 35262430
DOI: 10.1080/03007995.2022.2049164