-
The New England Journal of Medicine Apr 2020Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing.
METHODS
We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540.
RESULTS
A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent.
CONCLUSIONS
Reductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo. (Funded by the Medicines Company; ORION-10 and ORION-11 ClinicalTrials.gov numbers, NCT03399370 and NCT03400800.).
Topics: Aged; Aged, 80 and over; Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol, LDL; Coronary Artery Disease; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Injections, Subcutaneous; Liver Function Tests; Male; Middle Aged; PCSK9 Inhibitors; RNA, Small Interfering; Risk Factors
PubMed: 32187462
DOI: 10.1056/NEJMoa1912387 -
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 Apr 2020Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin-kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia.
METHODS
In this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous familial hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540.
RESULTS
The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of -44.3 percentage points (95% CI, -48.5 to -40.1; P<0.001). There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups.
CONCLUSIONS
Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile. (Funded by the Medicines Company; ORION-9 ClinicalTrials.gov number, NCT03397121.).
Topics: Adult; Anticholesteremic Agents; Cholesterol, LDL; Double-Blind Method; Female; Humans; Hyperlipoproteinemia Type II; Injections, Subcutaneous; Male; Middle Aged; PCSK9 Inhibitors; Proprotein Convertase 9; RNA, Small Interfering; Treatment Outcome
PubMed: 32197277
DOI: 10.1056/NEJMoa1913805 -
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 -
Nutrients Jun 2023Atherosclerotic cardiovascular disease (ASCVD) remains the major mortality cause in developed countries with hypercholesterolaemia being one of the primary modifiable... (Review)
Review
Atherosclerotic cardiovascular disease (ASCVD) remains the major mortality cause in developed countries with hypercholesterolaemia being one of the primary modifiable causes. Lifestyle intervention constitutes the first step in cholesterol management and includes dietary modifications along with the use of functional foods and supplements. Functional foods enriched with plant sterols/stanols have become the most widely used nonprescription cholesterol-lowering approach, despite the lack of randomized trials investigating their long-term safety and cardiovascular efficacy. The cholesterol-lowering effect of plant-sterol supplementation is well-established and a potential beneficial impact on other lipoproteins and glucose homeostasis has been described. Nevertheless, experimental and human observational studies investigating the association of phytosterol supplementation or circulating plant sterols with various markers of atherosclerosis and ASCVD events have demonstrated controversial results. Compelling evidence from recent genetic studies have also linked elevated plasma concentrations of circulating plant sterols with ASCVD presence, thus raising concerns about the safety of phytosterol supplementation. Thus, the aim of this review is to provide up-to-date data on the effect of plant sterols/stanols on lipid-modification and cardiovascular outcomes, as well as to discuss any safety issues and practical concerns.
Topics: Humans; Phytosterols; Hypercholesterolemia; Anticholesteremic Agents; Cholesterol; Atherosclerosis; Cardiovascular Diseases
PubMed: 37447172
DOI: 10.3390/nu15132845 -
Reviews in Cardiovascular Medicine 2018Low-density lipoprotein (LDL) receptors on the surface of liver hepatocytes are the primary way that humans regulate serum LDL cholesterol levels. Proprotein convertase... (Review)
Review
Low-density lipoprotein (LDL) receptors on the surface of liver hepatocytes are the primary way that humans regulate serum LDL cholesterol levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a proteolytic enzyme that indirectly regulates serum LDL cholesterol (LDL-C) by causing the destruction of LDL receptors. Less LDL receptors result in increased LDL-C in the bloodstream but inhibiting or binding the circulating PCSK9 results in increased LDL receptors with the resultant decrease in serum LDL-C. Two PCSK9 inhibitors are currently approved for use: alirocumab and evolocumab. Both are fully human monoclonal antibodies that bind free PCSK9. Herein we discuss the mechanism of action, efficacy, and safety of PCSK9 inhibitors. clinical problem.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Biomarkers; Cholesterol, LDL; Dyslipidemias; Humans; PCSK9 Inhibitors; Proprotein Convertase 9; Serine Proteinase Inhibitors; Treatment Outcome
PubMed: 30207556
DOI: 10.3909/ricm19S1S0002 -
Journal of the American College of... Jul 2018Variants in proprotein convertase subtilisin/kexin type 9 (PCSK9) provide insights into mechanisms regulating low-density lipoprotein (LDL) levels. Human monoclonal... (Review)
Review
Variants in proprotein convertase subtilisin/kexin type 9 (PCSK9) provide insights into mechanisms regulating low-density lipoprotein (LDL) levels. Human monoclonal antibodies that target PCSK9 lower LDL cholesterol (LDL-C) levels by 55% to 72% in different high-risk patient groups. Clinical trials with PCSK9 inhibitors have demonstrated reductions in atherosclerotic cardiovascular disease events, particularly in patients with recent acute coronary syndrome, multivessel coronary artery disease, or peripheral arterial disease. Commonly observed profound reductions in LDL-C to levels <25 mg/dl have been accompanied by even lower rates of atherosclerotic cardiovascular disease events, thus supporting the concept that there may be no lower limit for LDL-C. Aggressive LDL-C lowering with fully human PCSK9 monoclonal antibodies has been accompanied by a safety profile that has been very favorable. On the basis of clinical trial evidence, LDL lowering with PCSK9 inhibitors is recommended for high-risk patients with LDL-C levels ≥70 mg/dl on maximally tolerated oral therapies including statins and/or ezetimibe.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol, LDL; Clinical Trials as Topic; Humans; Hypercholesterolemia; PCSK9 Inhibitors; Treatment Outcome
PubMed: 30012326
DOI: 10.1016/j.jacc.2018.04.054 -
Indian Heart Journal Mar 2024Familial hypercholesterolemia is a common genetic disorder of autosomal inheritance associated with elevated LDL-cholesterol. It is estimated to affect 1:250 individuals... (Review)
Review
Familial hypercholesterolemia is a common genetic disorder of autosomal inheritance associated with elevated LDL-cholesterol. It is estimated to affect 1:250 individuals in general population roughly estimated to be 5 million in India. The prevalence of FH is higher in young CAD patients (<55 years in men; <60 years in women). FH is underdiagnosed and undertreated. Screening during childhood and Cascade screening of family members of known FH patients is of utmost importance in order to prevent the burden of CAD. Early identification of FH patients and early initiation of the lifelong lipid lowering therapy is the most effective strategy for managing FH. FH management includes pharmaceutical agents (statins and non statin drugs) and lifestyle modification. Inspite of maximum dose of statin with or without Ezetimibe, if target levels of LDL-C are not achieved, Bempedoic acid, proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibitors/Inclisiran can be added.
Topics: Male; Humans; Female; Proprotein Convertase 9; Anticholesteremic Agents; Cholesterol, LDL; Hyperlipoproteinemia Type II; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 38599725
DOI: 10.1016/j.ihj.2023.12.002