SynthesisCirculation2011
Lapaquistat acetate: development of a squalene synthase inhibitor for the treatment of hypercholesterolemia.
Synthesis in Circulation, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It reports registered trial NCT00487994. Cited by 31 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Double-Blind, Randomized, Parallel Group Study to Evaluate the Safety, Tolerability and Efficacy of Lapaquistat Acetate Alone or Coadministered With Atorvastatin in Subjects With Primary Dyslipidemia
Open the trial in the graphA Double-blind, Randomized Study to Evaluate the Efficacy and Safety of TAK-475 100 mg Versus Placebo in Subjects With Primary Hypercholesterolemia
A Double-blind, Randomized Placebo-controlled Study to Evaluate the Efficacy and Safety of TAK-475 50 mg, 100 mg, or Placebo When Co-administered With Atorvastatin (10 mg to 40 mg) in Subjects With Primary Hypercholesterolemia
A Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of Lapaquistat or Placebo When Co-Administered With High Dose Statin Therapy in Subjects With Primary Hypercholesterolemia
A Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of Lapaquistat Acetate 50 mg, 100 mg or Placebo When Coadministered With Rosuvastatin 10 mg or 20 mg in Subjects With Primary Hypercholesterolemia
A Placebo-Controlled, Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of Lapaquistat Acetate 100 mg in Subjects With Type 2 Diabetes Currently Treated With Lipid-Lowering Therapy
A Placebo-controlled, Double-blind, Randomized Study to Evaluate the Efficacy and Safety of TAK-475 50 mg and 100 mg Versus Placebo, When Co-administered With Simvastatin 20 mg or 40 mg in Subjects With Primary Dyslipidemia.
A Double-blind, Placebo-controlled, Randomized Study to Evaluate the Efficacy and Safety of TAK-475 or Placebo When Co-administered With Current Lipid-lowering Therapy in Subjects With Homozygous Familial Hypercholesterolemia.
A Double-Blind, Double-Dummy, Randomized, Parallel Group, Multicenter, Phase 3 Study to Evaluate the Efficacy and Safety of Lapaquistat Acetate 100 mg and Lapaquistat Acetate 100 mg Administered in Combination With Ezetimibe 10 mg vs Ezetimibe 10 mg in Subjects With Primary Dyslipidemia
A Double-Blind, Randomized, Placebo-Controlled Factorial Study to Evaluate the Efficacy and Safety of Lapaquistat and Simvastatin Alone and in Combination in Subjects With Hypercholesterolemia
A Double-blind, Randomized Study to Evaluate the Efficacy and Safety of TAK-475 or Placebo When Coadministered With Fenofibrate in Subjects With Combined Hyperlipidemia
A Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of TAK-475 (100 mg) Vs Placebo When Coadministered With Atorvastatin (10 or 20 mg) in Subjects With Primary Hypercholesterolemia
Who cites it
31 citing papers in PubMed.
- Article
- Unraveling the Potential Pathogenic Role of Squalene Synthase (SQS) in Lung Cancer Using Enzyme Inhibitors as Molecular Tools.ACS medicinal chemistry letters · 2025Article
- Targeting the isoprenoid pathway in choleste biosynthesis: An approach to identify isoprenoid biosynthesis inhibitors.Archiv der Pharmazie · 2025Article
- Innovations in Antifungal Drug Discovery among Cell Envelope Synthesis Enzymes through Structural Insights.Journal of fungi (Basel, Switzerland) · 2024Review
- Impact of De Novo Cholesterol Biosynthesis on the Initiation and Progression of Breast Cancer.Biomolecules · 2024Review
- Crosstalk between cholesterol metabolism and psoriatic inflammation.Frontiers in immunology · 2023Review
- The potential role and mechanism of circRNA/miRNA axis in cholesterol synthesis.International journal of biological sciences · 2023Review
- A Structural and Bioinformatics Investigation of a Fungal Squalene Synthase and Comparisons with Other Membrane Proteins.ACS omega · 2022Article
- Squalene synthase predicts poor prognosis in stage I-III colon adenocarcinoma and synergizes squalene epoxidase to promote tumor progression.Cancer science · 2022Article
- Article
- Bioactivity of Dietary Polyphenols: The Role in LDL-C Lowering.Foods (Basel, Switzerland) · 2021Review
- Compromised Protein Prenylation as Pathogenic Mechanism in Mevalonate Kinase Deficiency.Frontiers in immunology · 2021Review
- Cholesterol-Lowering Action of a Novel Nutraceutical Combination in Uremic Rats: Insights into the Molecular Mechanism in a Hepatoma Cell Line.Nutrients · 2020Article
- The history of proprotein convertase subtilisin kexin-9 inhibitors and their role in the treatment of cardiovascular disease.Therapeutic advances in chronic disease · 2020Review
- Discovery of Potential Inhibitors of Squalene Synthase from Traditional Chinese Medicine Based on Virtual Screening and In Vitro Evaluation of Lipid-Lowering Effect.Molecules (Basel, Switzerland) · 2018Article
- Systems Pharmacology Dissection of Cholesterol Regulation Reveals Determinants of Large Pharmacodynamic Variability between Cell Lines.Cell systems · 2017Article
- Statins, Muscle Disease and Mitochondria.Journal of clinical medicine · 2017Review
- A Genomic DNA Reporter Screen Identifies Squalene Synthase Inhibitors That Act Cooperatively with Statins to Upregulate the Low-Density Lipoprotein Receptor.The Journal of pharmacology and experimental therapeutics · 2017Article
- Differential Regulation of Gene Expression by Cholesterol Biosynthesis Inhibitors That Reduce (Pravastatin) or Enhance (Squalestatin 1) Nonsterol Isoprenoid Levels in Primary Cultured Mouse and Rat Hepatocytes.The Journal of pharmacology and experimental therapeutics · 2016Article
- Bivariate genome-wide association study identifies novel pleiotropic loci for lipids and inflammation.BMC genomics · 2016Article
Corrections and comments
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundLapaquistat acetate is a squalene synthase inhibitor investigated for the treatment of hypercholesterolemia. METHODS AND
resultsThis 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.
conclusionsSqualene 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 registrationURL: http://www.clinicaltrials.gov. Unique identifiers: NCT00487994, NCT00143663, NCT00143676, NCT00864643, NCT00263081, NCT00286481, NCT00249899, NCT00249912, NCT00813527, NCT00256178, NCT00268697, and NCT00251680.
Indexed as
Identifiers
21518985What Socratic holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.