The Experts below are selected from a list of 174 Experts worldwide ranked by ideXlab platform

Harold E Bays - One of the best experts on this subject based on the ideXlab platform.

  • Correction to: Assessment of the 1% of Patients with Consistent < 15% Reduction in Low-Density Lipoprotein Cholesterol: Pooled Analysis of 10 Phase 3 ODYSSEY Alirocumab Trials (Cardiovasc Drugs Ther, 10.1007/s10557-018-6784-z)
    Cardiovascular Drugs and Therapy, 2018
    Co-Authors: Harold E Bays, Robert S. Rosenson, Marie T. Baccara-dinet, Michael J. Louie, Desmond Thompson, G. Kees Hovingh
    Abstract:

    The original version of this article unfortunately contained a mistake in the Discussion section. The line that currently reads "During this 4-week period while off PCSK9 monoclonal antibody therapy, the medical staff should ensure an accurate 4-week pill count of concurrently administered statin and/ or other Lipid-Altering Drugs." should be changed to "During this 4-week stabilization period (while off PCSK9 monoclonal antibody therapy for at least 8 weeks), the medical staff should ensure an accurate 4-week pill count of concurrently administered statin and/or other Lipid-Altering Drugs.".

  • National Lipid Association Annual Summary of Clinical Lipidology 2016
    Journal of Clinical Lipidology, 2016
    Co-Authors: Harold E Bays, Peter H. Jones, W Virgil Brown, Carl E. Orringer, Terry A Jacobson
    Abstract:

    The National Lipid Association (NLA) Annual Summary of Clinical Lipidology is a yearly updated summary of principles important to the patient-centered evaluation, management, and care of patients with dysLipidemia. This summary is intended to be a "living document," with future annual updates based on emerging science, clinical considerations, and new NLA Position, Consensus, and Scientific Statements, thus providing an ongoing resource that applies the latest in medical science towards the clinical management of patients with dysLipidemia. Topics include the NLA Recommendations for Patient-Centered Management of DysLipidemia, genetics, Familial Hypercholesterolemia, secondary causes of dysLipidemia, biomarkers and advanced Lipid testing, nutrition, physical activity, obesity, adiposopathy, metabolic syndrome, diabetes mellitus, Lipid pharmacotherapy, Lipid-Altering drug interactions, lipoprotein apheresis, dysLipidemia management and treatment based upon age (children, adolescents, and older individuals), dysLipidemia considerations based upon race, ethnicity and gender, dysLipidemia and human immune virus infection, dysLipidemia and immune disorders, adherence strategies and collaborative care, and Lipid-Altering Drugs in development. Hyperlinks direct the reader to sentinel online tables, charts, and figures relevant to Lipidology, access to online atherosclerotic cardiovascular disease risk calculators, worldwide Lipid guidelines, recommendations, and position/scientific statements, as well as links to online audio files, websites, slide shows, applications, continuing medical education opportunities, and patient information.

  • National Lipid Association Annual Summary of Clinical Lipidology 2015.
    Journal of clinical lipidology, 2014
    Co-Authors: Harold E Bays, Peter H. Jones, W Virgil Brown, Terry A Jacobson
    Abstract:

    The National Lipid Association (NLA) Annual Summary of Clinical Lipidology 2015 is a summary of principles important to the patient-centered evaluation, management, and care of patients with dysLipidemia. This summary is intended to be a "living document," with future annual updates based on emerging science, clinical considerations, and new NLA Position and Consensus Statements. The goal is to provide clinicians an ongoing resource that translates the latest advances in medical science toward the evaluation and treatment of patients with dysLipidemia. The 2015 NLA Annual Summary of Clinical Lipidology was founded on the principles of evidence-based medicine and is generally consistent with established national and international Lipid guidelines. Topics include a general discussion of the 2014 NLA Recommendations for Patient-Centered Management of DysLipidemia, genetics, secondary causes of dysLipidemia, biomarkers and "advanced Lipid testing," medical nutrition, physical activity, obesity, pharmacotherapy, statin safety, Lipid-Altering drug interactions, lipoprotein apheresis, dysLipidemia in children and adolescence, dysLipidemia in older individuals, race/ethnicity, and women, health information technology and electronic medical records, as well as investigational Lipid-Altering Drugs in development.

  • Lowering low-density lipoprotein cholesterol levels in patients with type 2 diabetes mellitus.
    International journal of general medicine, 2014
    Co-Authors: Harold E Bays
    Abstract:

    Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia, insulin resistance, and/or progressive loss of β-cell function. T2DM patients are at increased risk of micro- and macrovascular disease, and are often considered as representing an atherosclerotic coronary heart disease (CHD) risk equivalent. Interventions directed at glucose and Lipid level control in T2DM patients may reduce micro- and macrovascular disease. The optimal T2DM agent is one that lowers glucose levels with limited risk for hypoglycemia, and with no clinical trial evidence of worsening CHD risk. Lipid-Altering Drugs should preferably reduce low-density lipoprotein cholesterol and apolipoprotein B (apo B) and have evidence that the mechanism of action reduces CHD risk. Statins reduce low-density lipoprotein cholesterol and apo B and have evidence of improving CHD outcomes, and are thus first-line therapy for the treatment of hypercholesterolemia. In patients who do not achieve optimal Lipid levels with statin therapy, or who are intolerant to statin therapy, add-on therapy or alternative therapies may be indicated. Additional available agents to treat hypercholesterolemic patients with T2DM include bile acid sequestrants, fibrates, niacin, and ezetimibe. This review discusses the use of these alternative agents to treat hypercholesterolemia in patients with T2DM, either as monotherapy or in combination with statin therapy.

  • National Lipid Association Annual Summary of Clinical Lipidology 2015
    Journal of Clinical Lipidology, 2014
    Co-Authors: Harold E Bays, Peter H. Jones, W Virgil Brown, Terry A Jacobson
    Abstract:

    The National Lipid Association (NLA) Annual Summary of Clinical Lipidology 2015 is a summary of principles important to the patient-centered evaluation, management, and care of patients with dysLipidemia. This summary is intended to be a ''living document,'' with future annual updates based on emerging science, clinical considerations, and new NLA Position and Consensus Statements. The goal is to provide clinicians an ongoing resource that translates the latest advances in medical science toward the evaluation and treatment of patients with dysLipidemia. The 2015 NLA Annual Summary of Clinical Lipidology was founded on the principles of evidence-based medicine and is generally consistent with established national and international Lipid guidelines. Topics include a general discussion of the 2014 NLA Recommendations for Patient-Centered Management of DysLipidemia, genetics, secondary causes of dysLipidemia, biomarkers and ''advanced Lipid testing,'' medical nutrition, physical activity, obesity, pharmacotherapy, statin safety, Lipid-Altering drug interactions, lipoprotein apheresis, dysLipidemia in children and adolescence, dysLipidemia in older individuals, race/ethnicity, and women, health information technology and electronic medical records, as well as investigational Lipid-Altering Drugs in development. 2014 National Lipid Association. All rights reserved.

Michael H Davidson - One of the best experts on this subject based on the ideXlab platform.

  • Prescription omega-3 fatty acids and their Lipid effects: physiologic mechanisms of action and clinical implications
    Expert review of cardiovascular therapy, 2008
    Co-Authors: Harold E Bays, Ann P. Tighe, Richard Sadovsky, Michael H Davidson
    Abstract:

    Hypertriglyceridemia is a risk factor for atherosclerotic coronary heart disease. Very high triglyceride (TG) levels (> or =500 mg/dl [5.65 mmol/l]) increase the risk of pancreatitis. One therapeutic option to lower TG levels is omega-3 fatty acids, which are derived from the oil of fish and other seafood. The American Heart Association has acknowledged that fish oils may decrease dysrhythmias, decrease sudden death, decrease the rate of atherosclerosis and slightly lower blood pressure, and has recommended fish consumption or fish oil supplementation as a therapeutic strategy to reduce cardiovascular disease. A prescription omega-3-acid ethyl esters (P-OM3) preparation has been available in many European nations for at least a decade, and was approved by the US FDA in 2004 to reduce very high TG levels (> or =500 mg/dl [5.65 mmol/l]). Mechanistically, most evidence suggests that omega-3 fatty acids reduce the synthesis and secretion of very-low-density lipoprotein (VLDL) particles, and increase TG removal from VLDL and chylomicron particles through the upregulation of enzymes, such as lipoprotein lipase. Omega-3 fatty acids differ mechanistically from other Lipid-Altering Drugs, which helps to explain why therapies such as P-OM3 have complementary mechanisms of action and, thus, complementary Lipid benefits when administered with statins. Additional human studies are needed to define more clearly the cellular and molecular basis for the TG-lowering effects of omega-3 fatty acids and their favorable cardiovascular effects, particularly in patients with hypertriglyceridemia.

  • torcetrapib atorvastatin combination therapy
    Expert Review of Cardiovascular Therapy, 2005
    Co-Authors: Harold E Bays, James M Mckenney, Michael H Davidson
    Abstract:

    Elevated blood levels of low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk for atherosclerotic coronary heart disease (CHD). Atorvastatin is a statin drug that inhibits 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (the rate-limiting step of cholesterol production) and primarily lowers LDL-C levels. Atorvastatin has also been shown to significantly reduce CHD events. However, as with all statins (and all other monotherapy Lipid-Altering Drugs), atorvastatin alone reduces the risk of CHD in only a minority of patients relative to placebo. Conversely, it is low levels of high-density lipoprotein cholesterol that are associated with increased CHD risk. Torcetrapib is a cholesteryl ester transfer protein inhibitor that primarily raises high-density lipoprotein cholesterol levels, and cholesteryl ester transfer protein inhibition has generally been shown to reduce atherosclerosis in rabbits. Taken together, atorvastatin and torcetrapib provide striking improvements in Lipid levels, and complementary actions upon important Lipid parameters. This review examines the chemistry, mechanism of action, pharmacokinetics, metabolism, safety/tolerability and efficacy of the combination torcetrapib/atorvastatin agent that is currently in development and that provides complementary Lipid benefits towards the goal of reducing CHD risk beyond that of atorvastatin alone.

  • Torcetrapib/atorvastatin combination therapy.
    Expert review of cardiovascular therapy, 2005
    Co-Authors: Harold E Bays, James M Mckenney, Michael H Davidson
    Abstract:

    Elevated blood levels of low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk for atherosclerotic coronary heart disease (CHD). Atorvastatin is a statin drug that inhibits 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (the rate-limiting step of cholesterol production) and primarily lowers LDL-C levels. Atorvastatin has also been shown to significantly reduce CHD events. However, as with all statins (and all other monotherapy Lipid-Altering Drugs), atorvastatin alone reduces the risk of CHD in only a minority of patients relative to placebo. Conversely, it is low levels of high-density lipoprotein cholesterol that are associated with increased CHD risk. Torcetrapib is a cholesteryl ester transfer protein inhibitor that primarily raises high-density lipoprotein cholesterol levels, and cholesteryl ester transfer protein inhibition has generally been shown to reduce atherosclerosis in rabbits. Taken together, atorvastatin and torcetrapib provide striking improvements in Lipid levels, and complementary actions upon important Lipid parameters. This review examines the chemistry, mechanism of action, pharmacokinetics, metabolism, safety/tolerability and efficacy of the combination torcetrapib/atorvastatin agent that is currently in development and that provides complementary Lipid benefits towards the goal of reducing CHD risk beyond that of atorvastatin alone.

  • Non-high-density lipoprotein cholesterol: the forgotten therapeutic target.
    The American Journal of Cardiology, 2005
    Co-Authors: Kevin C. Maki, Ron Galant, Michael H Davidson
    Abstract:

    The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) has acknowledged mounting evidence of an independent association between hypertriglyceridemia and coronary artery disease risk by issuing guidelines that identify non–high-density lipoprotein (HDL) cholesterol as a secondary target for therapy in patients with elevated triglyceride levels. In 2003, a national survey of outpatient Lipid management was conducted for patients undergoing treatment by physicians who were high prescribers of Lipid-Altering Drugs. Results of the NCEP Evaluation Project Utilizing Novel E-Technology II (NEPTUNE II) survey indicated much higher frequencies of low-density lipoprotein (LDL) cholesterol goal achievement compared with frequencies observed in a similarly designed survey in 1997. However, non–HDL cholesterol treatment success in the NEPTUNE II survey was markedly lower than that for LDL cholesterol overall and across risk categories. More aggressive therapy is therefore needed to achieve non–HDL cholesterol goals than LDL cholesterol goals. After achievement of LDL cholesterol goals, non–HDL cholesterol can be managed more aggressively by lowering LDL cholesterol or by using strategies that target a reduction in very-low-density lipoprotein cholesterol. Because the prevalence of hypertriglyceridemia in the United States is high and increasing, enhanced efforts to improve non–HDL cholesterol goal achievement have the potential to produce a substantial effect on public health.

  • Combination therapy for dysLipidemia: safety and regulatory considerations.
    American Journal of Cardiology, 2002
    Co-Authors: Michael H Davidson
    Abstract:

    The use of combination therapy is an effective way to manage dysLipidemia in patients with coronary artery disease (CAD). However, combination therapy is not a frequently used strategy in the treatment of CAD. Aggressive Lipid-Altering therapy often requires the use of combination therapy involving statins in conjunction with niacin, fibric-acid derivatives, ezetimibe, or bile acid resins. Yet, safety concerns regarding the combination of statins with other Lipid-Altering Drugs and patient acceptance of combination therapy have influenced its application in the treatment of CAD. This article discusses several safety and regulatory considerations for the use of combination therapy for dysLipidemia.

Carlos A. Dujovne - One of the best experts on this subject based on the ideXlab platform.

  • colesevelam hcl a non systemic Lipid Altering drug
    Expert Opinion on Pharmacotherapy, 2003
    Co-Authors: Harold E Bays, Carlos A. Dujovne
    Abstract:

    Colesevelam HCl (WelChol®, Sankyo Pharmaceuticals Inc.) is a bile acid sequestrant polymer, which has been shown to significantly lower low density lipoprotein cholesterol and favourably affect high-density lipoprotein cholesterol blood levels in monotherapy and in combination with statins (HMG-CoA reductase inhibitors). Although it is similar to other bile acid sequestrants in that it binds bile acids and is non-systemic, colesevelam HCl differs in that it has a unique polymer structure that allows for greater tolerability with less potential drug interactions than with resins. Currently, statins are the most commonly prescribed Lipid-Altering Drugs. However, it is not uncommon that patients demonstrate true or perceived intolerances to statin therapy, that are often dose-related and may include elevations in liver or muscle enzyme blood levels, or myalgias or muscle weakness without muscle enzyme elevation. In rare circumstances, myopathy and even rhabdomyolysis can occur with statins. In addition, many...

  • Colesevelam HCl: a non-systemic Lipid-Altering drug.
    Expert opinion on pharmacotherapy, 2003
    Co-Authors: Harold E Bays, Carlos A. Dujovne
    Abstract:

    Colesevelam HCl (WelChol, Sankyo Pharmaceuticals Inc.) is a bile acid sequestrant polymer, which has been shown to significantly lower low density lipoprotein cholesterol and favourably affect high-density lipoprotein cholesterol blood levels in monotherapy and in combination with statins (HMG-CoA reductase inhibitors). Although it is similar to other bile acid sequestrants in that it binds bile acids and is non-systemic, colesevelam HCl differs in that it has a unique polymer structure that allows for greater tolerability with less potential drug interactions than with resins. Currently, statins are the most commonly prescribed Lipid-Altering Drugs. However, it is not uncommon that patients demonstrate true or perceived intolerances to statin therapy, that are often dose-related and may include elevations in liver or muscle enzyme blood levels, or myalgias or muscle weakness without muscle enzyme elevation. In rare circumstances, myopathy and even rhabdomyolysis can occur with statins. In addition, many statins also have important potential drug interactions. Finally, statin monotherapy is often not sufficient in achieving Lipid treatment goals in many severely dysLipidaemic patients and the availability of colesevelam HCl provides a Lipid-Altering treatment addition to other Lipid-Altering Drugs. From a clinical perspective, such combination therapy is often required to achieve treatment goals [1] in patients with more complicated or severe dysLipidaemia. Colesevelam HCl may also be an alternative in monotherapy for many patients with mild-to-moderate hypercholesterolaemia, as well as in some patients at potential risk from systemic exposure to alternative Lipid-Altering Drugs (such as young children and fertile women).

  • effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia pooled analysis of two phase ii studies
    Clinical Therapeutics, 2001
    Co-Authors: Harold E Bays, Carlos A. Dujovne, Leslie Lipka, Alexandre Lebeaut, Paul B Moore, Margaret Drehobl, Sidney Rosenblatt, Phillip Toth, Robert H Knopp, Bo Yang
    Abstract:

    Background: Ezetimibe (SCH 58235) is a novel cholesterol absorption inhibitor that selectively and potently blocks intestinal absorption of dietary and biliary cholesterol. Objective: Data from 2 multicenter, placebo-controlled, double-blind, randomized, parallel-group, 12-week studies of ezetimibe were pooled to evaluate the drug's effect on Lipid parameters in patients with primary hypercholesterolemia. Methods: After dietary stabilization (National Cholesterol Education Program Step I diet or a stricter diet), washout of Lipid-Altering Drugs, and a 6-week placebo lead-in period, patients with baseline plasma low-density lipoprotein cholesterol (LDL-C) levels ≥130 and ≤250 mg/dL and plasma triglyceride (TG) levels ≤300 mg/dL were randomized to receive either ezetimibe 0.25, 1, 5, or 10 mg, or placebo administered once daily before the morning meal in study A (dose-response study) or ezetimibe 5 or 10 mg or placebo administered once daily before the morning meal or at bedtime in study B (dose-regimen study). Results: A total of 432 patients were included in this pooled analysis, 243 in study A and 189 in study B. The 5- and 10-mg doses of ezetimibe significantly reduced LDL-C levels by 15.7% and 18.5%, respectively (P < 0.01 vs placebo) and significantly increased high-density lipoprotein cholesterol (HDL-C) levels by 2.9% and 3.5%, respectively (P < 0.05 vs placebo). A reduction in plasma TG levels was observed (P = NS). With the 10-mg dose of ezetimibe, 67.8% of patients achieved ≥15% reduction in plasma LDL-C levels, and 22.0% achieved ≥25% reduction. With the 5-mg dose, 54.0% of patients achieved ≥15% reduction in plasma LDL-C levels, and 15.3% achieved ≥25% reduction. The decrease in plasma LDL-C levels was significantly greater with ezetimibe 10 mg compared with ezetimibe 5 mg (P < 0.05). Ezetimibe was well tolerated, with an adverse event profile similar to that of placebo. Conclusions: In these two 12-week studies, ezetimibe significantly decreased plasma LDL-C levels and increased plasma HDL-C levels, with a tolerability profile similar to that of placebo.

  • Lipid-Altering Drugs in Development
    Drugs in R & D, 1999
    Co-Authors: Harold E Bays, Carlos A. Dujovne
    Abstract:

    Although currently available Lipid lowering therapies are effective and well tolerated, the search continues for additional treatments with even better efficacy and tolerability profiles. As well as refinements to existing strategies (new HMG-CoA reductase inhibitors, fibrates and combination therapies) new avenues are being explored. These include inhibitors of enzymes other thanHMG-CoA reductase involved in cholesterol regulation and Drugs which affect absorption of Lipids from the gastrointestinal tract. In the case of the latter, it has been shown that the new antiobesity treatment orlistat can favourably affect the blood Lipid profile. In line with an increasing emphasis on improving high density lipoprotein-cholesterol (HDL-C) levels, the potential therapeutic roles of niacin and Drugs which inhibit enzymes involved in the metabolism of HDL-C are also being researched.

  • Drug Interactions of Lipid-Altering Drugs
    Drug Safety, 1998
    Co-Authors: Harold E Bays, Carlos A. Dujovne
    Abstract:

    The use of Lipid-Altering Drugs has been shown to reduce the progression of atherosclerotic lesions and reduce the risk of atherosclerotic events (such as myocardial infarction and stroke). In general, these Lipid-Altering Drugs are well tolerated but there is the potential for drug interactions. For example, HMG-CoA reductase inhibitors may interact with macrolides, azalides, azole antifungals and cyclosporin. Resins (such as cholestyramine and colestipol) may impair the absorption of many concurrent medications. Fibrates have potential drug interactions with warfarin, furosemide (frusemide), oral hypoglycaemics and probenecid. Nicotinic acid (niacin) may have potential drug interactions with high dose aspirin (acetylsalicylic acid), uricosuric agents (such as sulfapyrazone) and alcohol (ethanol). Finally, probucol may have potential drug interactions with antidysrhythmics, tricyclic antidepressants and phenothiazines. In addition, Lipid-Altering Drugs, used in combination, may have the potential for drug interactions, enhancing some of the risks of adverse effects, such as myositis and hepatotoxicity. Therefore, in order to use Lipid-Altering Drugs in the most effective, and safest manner, it is important for the clinician to have an understanding of the mechanisms of potential drug interactions, which drug interactions may theoretically occur, and specifically, which specific drug interactions have already been described.

Evan A Stein - One of the best experts on this subject based on the ideXlab platform.

  • lapaquistat acetate development of a squalene synthase inhibitor for the treatment of hypercholesterolemia
    Circulation, 2011
    Co-Authors: Evan A Stein, Jim Pedicano, Dennis P Obrien, Edward Piper, Harold E Bays, Andrea Spezzi
    Abstract:

    Background— Lapaquistat acetate is a squalene synthase inhibitor investigated for the treatment of hypercholesterolemia. Methods and Results— This report summarizes the phase 2 and 3 results from the lapaquistat clinical program, which was halted at an advanced stage as a result of potential hepatic safety issues. Efficacy and safety data were pooled from 12 studies (n=6151). These were 6- to 96-week randomized, double-blind, parallel, placebo- or active-controlled trials with lapaquistat monotherapy or coadministration with other Lipid-Altering Drugs in dysLipidemic patients, including a large (n=2121) 96-week safety study. All studies included lapaquistat 100 mg daily; 5 included 50 mg; and 1 included 25 mg. The main outcome measures were the percent change in low-density lipoprotein cholesterol, secondary Lipid/metabolic parameters, and overall safety. Lapaquistat 100 mg significantly decreased low-density lipoprotein cholesterol by 21.6% in monotherapy and by 18.0% in combination with a statin. It also reduced other cardiovascular risk markers, such as C-reactive protein. Total adverse events were higher for lapaquistat than placebo, although individual events were generally similar. At 100 mg, there was an increase in alanine aminotransferase value ≥3 times the upper limit of normal on ≥2 consecutive visits (2.0% versus 0.3% for placebo in the pooled efficacy studies; 2.7% versus 0.7% for low-dose atorvastatin in the long-term study). Two patients receiving lapaquistat 100 mg met the Hy Law criteria of alanine aminotransferase elevation plus increased total bilirubin. Conclusions— Squalene synthase inhibition with lapaquistat acetate, alone or in combination with statins, effectively lowered low-density lipoprotein cholesterol in a dose-dependent manner. Elevations in alanine aminotransferase, combined with a rare increase in bilirubin, presented potential hepatic safety issues, resulting in termination of development. The lapaquistat experience illustrates the current challenges in Lipid-Altering drug development. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00487994, NCT00143663, NCT00143676, NCT00864643, NCT00263081, NCT00286481, NCT00249899, NCT00249912, NCT00813527, NCT00256178, NCT00268697, and NCT00251680.

  • lapaquistat acetateclinical perspective development of a squalene synthase inhibitor for the treatment of hypercholesterolemia
    Circulation, 2011
    Co-Authors: Evan A Stein, Jim Pedicano, Dennis P Obrien, Edward Piper, Harold E Bays, Andrea Spezzi
    Abstract:

    Background— Lapaquistat acetate is a squalene synthase inhibitor investigated for the treatment of hypercholesterolemia. Methods and Results— This report summarizes the phase 2 and 3 results from the lapaquistat clinical program, which was halted at an advanced stage as a result of potential hepatic safety issues. Efficacy and safety data were pooled from 12 studies (n=6151). These were 6- to 96-week randomized, double-blind, parallel, placebo- or active-controlled trials with lapaquistat monotherapy or coadministration with other Lipid-Altering Drugs in dysLipidemic patients, including a large (n=2121) 96-week safety study. All studies included lapaquistat 100 mg daily; 5 included 50 mg; and 1 included 25 mg. The main outcome measures were the percent change in low-density lipoprotein cholesterol, secondary Lipid/metabolic parameters, and overall safety. Lapaquistat 100 mg significantly decreased low-density lipoprotein cholesterol by 21.6% in monotherapy and by 18.0% in combination with a statin. It also reduced other cardiovascular risk markers, such as C-reactive protein. Total adverse events were higher for lapaquistat than placebo, although individual events were generally similar. At 100 mg, there was an increase in alanine aminotransferase value ≥3 times the upper limit of normal on ≥2 consecutive visits (2.0% versus 0.3% for placebo in the pooled efficacy studies; 2.7% versus 0.7% for low-dose atorvastatin in the long-term study). Two patients receiving lapaquistat 100 mg met the Hy Law criteria of alanine aminotransferase elevation plus increased total bilirubin. Conclusions— Squalene synthase inhibition with lapaquistat acetate, alone or in combination with statins, effectively lowered low-density lipoprotein cholesterol in a dose-dependent manner. Elevations in alanine aminotransferase, combined with a rare increase in bilirubin, presented potential hepatic safety issues, resulting in termination of development. The lapaquistat experience illustrates the current challenges in Lipid-Altering drug development. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00487994, NCT00143663, NCT00143676, NCT00864643, NCT00263081, NCT00286481, NCT00249899, NCT00249912, NCT00813527, NCT00256178, NCT00268697, and NCT00251680.

  • Pharmacotherapy for dysLipidaemia – current therapies and future agents
    Expert opinion on pharmacotherapy, 2003
    Co-Authors: Harold E Bays, Evan A Stein
    Abstract:

    Current Lipid-Altering agents that lower low density lipoprotein cholesterol (LDL-C) primarily through increased hepatic LDL receptor activity include statins, bile acid sequestrants/resins and cholesterol absorption inhibitors such as ezetimibe, plant stanols/sterols, polyphenols, as well as nutraceuticals such as oat bran, psyllium and soy proteins; those currently in development include newer statins, phytostanol analogues, squalene synthase inhibitors, bile acid transport inhibitors and SREBP cleavage-activating protein (SCAP) activating ligands. Other current agents that affect Lipid metabolism include nicotinic acid (niacin), acipimox, high-dose fish oils, antioxidants and policosanol, whilst those in development include microsomal triglyceride transfer protein (MTP) inhibitors, acylcoenzyme A: cholesterol acyltransferase (ACAT) inhibitors, gemcabene, lifibrol, pantothenic acid analogues, nicotinic acid-receptor agonists, anti-inflammatory agents (such as Lp-PLA(2) antagonists and AGI1067) and functional oils. Current agents that affect nuclear receptors include PPAR-alpha and -gamma agonists, while in development are newer PPAR-alpha, -gamma and -delta agonists, as well as dual PPAR-alpha/gamma and 'pan' PPAR-alpha/gamma/delta agonists. Liver X receptor (LXR), farnesoid X receptor (FXR) and sterol-regulatory element binding protein (SREBP) are also nuclear receptor targets of investigational agents. Agents in development also may affect high density lipoprotein cholesterol (HDL-C) blood levels or flux and include cholesteryl ester transfer protein (CETP) inhibitors (such as torcetrapib), CETP vaccines, various HDL 'therapies' and upregulators of ATP-binding cassette transporter (ABC) A1, lecithin cholesterol acyltransferase (LCAT) and scavenger receptor class B Type 1 (SRB1), as well as synthetic apolipoprotein (Apo)E-related peptides. Fixed-dose combination Lipid-Altering Drugs are currently available such as extended-release niacin/lovastatin, whilst atorvastatin/amlodipine, ezetimibe/simvastatin, atorvastatin/CETP inhibitor, statin/PPAR agonist, extended-release niacin/simvastatin and pravastatin/aspirin are under development. Finally, current and future Lipid-Altering Drugs may include anti-obesity agents which could favourably affect Lipid levels.

Andrea Spezzi - One of the best experts on this subject based on the ideXlab platform.

  • lapaquistat acetate development of a squalene synthase inhibitor for the treatment of hypercholesterolemia
    Circulation, 2011
    Co-Authors: Evan A Stein, Jim Pedicano, Dennis P Obrien, Edward Piper, Harold E Bays, Andrea Spezzi
    Abstract:

    Background— Lapaquistat acetate is a squalene synthase inhibitor investigated for the treatment of hypercholesterolemia. Methods and Results— This report summarizes the phase 2 and 3 results from the lapaquistat clinical program, which was halted at an advanced stage as a result of potential hepatic safety issues. Efficacy and safety data were pooled from 12 studies (n=6151). These were 6- to 96-week randomized, double-blind, parallel, placebo- or active-controlled trials with lapaquistat monotherapy or coadministration with other Lipid-Altering Drugs in dysLipidemic patients, including a large (n=2121) 96-week safety study. All studies included lapaquistat 100 mg daily; 5 included 50 mg; and 1 included 25 mg. The main outcome measures were the percent change in low-density lipoprotein cholesterol, secondary Lipid/metabolic parameters, and overall safety. Lapaquistat 100 mg significantly decreased low-density lipoprotein cholesterol by 21.6% in monotherapy and by 18.0% in combination with a statin. It also reduced other cardiovascular risk markers, such as C-reactive protein. Total adverse events were higher for lapaquistat than placebo, although individual events were generally similar. At 100 mg, there was an increase in alanine aminotransferase value ≥3 times the upper limit of normal on ≥2 consecutive visits (2.0% versus 0.3% for placebo in the pooled efficacy studies; 2.7% versus 0.7% for low-dose atorvastatin in the long-term study). Two patients receiving lapaquistat 100 mg met the Hy Law criteria of alanine aminotransferase elevation plus increased total bilirubin. Conclusions— Squalene synthase inhibition with lapaquistat acetate, alone or in combination with statins, effectively lowered low-density lipoprotein cholesterol in a dose-dependent manner. Elevations in alanine aminotransferase, combined with a rare increase in bilirubin, presented potential hepatic safety issues, resulting in termination of development. The lapaquistat experience illustrates the current challenges in Lipid-Altering drug development. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00487994, NCT00143663, NCT00143676, NCT00864643, NCT00263081, NCT00286481, NCT00249899, NCT00249912, NCT00813527, NCT00256178, NCT00268697, and NCT00251680.

  • lapaquistat acetateclinical perspective development of a squalene synthase inhibitor for the treatment of hypercholesterolemia
    Circulation, 2011
    Co-Authors: Evan A Stein, Jim Pedicano, Dennis P Obrien, Edward Piper, Harold E Bays, Andrea Spezzi
    Abstract:

    Background— Lapaquistat acetate is a squalene synthase inhibitor investigated for the treatment of hypercholesterolemia. Methods and Results— This report summarizes the phase 2 and 3 results from the lapaquistat clinical program, which was halted at an advanced stage as a result of potential hepatic safety issues. Efficacy and safety data were pooled from 12 studies (n=6151). These were 6- to 96-week randomized, double-blind, parallel, placebo- or active-controlled trials with lapaquistat monotherapy or coadministration with other Lipid-Altering Drugs in dysLipidemic patients, including a large (n=2121) 96-week safety study. All studies included lapaquistat 100 mg daily; 5 included 50 mg; and 1 included 25 mg. The main outcome measures were the percent change in low-density lipoprotein cholesterol, secondary Lipid/metabolic parameters, and overall safety. Lapaquistat 100 mg significantly decreased low-density lipoprotein cholesterol by 21.6% in monotherapy and by 18.0% in combination with a statin. It also reduced other cardiovascular risk markers, such as C-reactive protein. Total adverse events were higher for lapaquistat than placebo, although individual events were generally similar. At 100 mg, there was an increase in alanine aminotransferase value ≥3 times the upper limit of normal on ≥2 consecutive visits (2.0% versus 0.3% for placebo in the pooled efficacy studies; 2.7% versus 0.7% for low-dose atorvastatin in the long-term study). Two patients receiving lapaquistat 100 mg met the Hy Law criteria of alanine aminotransferase elevation plus increased total bilirubin. Conclusions— Squalene synthase inhibition with lapaquistat acetate, alone or in combination with statins, effectively lowered low-density lipoprotein cholesterol in a dose-dependent manner. Elevations in alanine aminotransferase, combined with a rare increase in bilirubin, presented potential hepatic safety issues, resulting in termination of development. The lapaquistat experience illustrates the current challenges in Lipid-Altering drug development. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00487994, NCT00143663, NCT00143676, NCT00864643, NCT00263081, NCT00286481, NCT00249899, NCT00249912, NCT00813527, NCT00256178, NCT00268697, and NCT00251680.