Pharmaco-metabolomic Effects of Statins: METASTATINE (METASTATINE)

Statins are effective in cardio-vascular prevention by lowering LDL-Cholesterol levels but also through other mechanisms poorly understood. Our hypothesis is that some of these effects are mediated by microbiota alteration, leading to diminution of expression of microbiota derived pro-atherogenic metabolites.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Diseases
• Intervention / Treatment: Drug: Atorvastatin 40mg Tablet; Drug: Placebo comparator

Detailed Description

The aim of this prospective double blind placebo-controlled study is to evaluate the acute effects of statins on microbiota and its derived metabolites at 2 and 6 weeks.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Joe Elie SALEM, MD; Phone Number: 33 1 42 17 85 32; Email: joe-elie.salem@aphp.fr
• Study Contact Backup: Name: Alban DANSET, MD; Phone Number: 33 1 42 17 85 33; Email: alban.danset@aphp.fr

Study Locations

• France
  • Paris, France, 75013
    • CIC La Sapétrière
  • Paris, France, 75015
    • CIC HEGP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient with cardiovascular risk requiring statins in primary prevention
• Contraception for women of childbearing age

Exclusion Criteria:

• Previous antibiotics, proton pomp inhibitors, statins or other hypolipidemic drugs intake in the previous three months
• Renal insufficiency with creatinine clearance <40ml/min
• Contra-indication to statins
• Previously known conditions affecting muscles, or digestive system
• Requirement of statins in secondary prevention

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ATORVASTATIN; Atorvastatin 40mg caps: one daily. 3 patient visits: inclusion / week 2 / week 6. At each visit, blood sampling, stool sampling, ECG, to evaluate the pharmaco-metabolomic effects of the Statine	Drug: Atorvastatin 40mg Tablet; Patient participation for 6 weeks of treatment; Other Names: No other name
Placebo Comparator: PLACEBO; Placebo caps: one daily. 3 patient visits: inclusion / week 2 / week 6. At each visit, blood sampling, stool sampling, ECG to compare the pharmaco-metabolomic effects of the Statine between atorvastatin arm and placebo arm	Drug: Placebo comparator; Patient participation for 6 weeks of treatment; Other Names: No other name

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of trimethylamine N-oxide trimethylamine oxide in blood, measured post-prandially at week-6 in atorvastatin arm and placebo arm.	The main objective of the study is to measure the direct effect of Hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors (Atorvastatin) on the production of atherogenic metabolites derived from intestinal microbiota	Week-6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of trimethylamine N-oxide trimethylamine oxide in blood, measured post-prandially at week-2 in atorvastatin arm and placebo arm.	To evaluate the evolution of the whole circulating metabolomic profile linked to the introduction of statins	week-2
Rate of trimethylamine N-oxide trimethylamine oxide in blood, measured pre and post-prandially at week-2 and week-6 in atorvastatin arm.	To evaluate changes in the microbiome related to the introduction of statins	Week-2 and week-6
Comparison between W0, W2 and W6 after initiation of atorvastatin vs placebo of circulating metabolomic profile (pre- and postprandial)	To correlate changes in lipid parameters induced by statins with metabolomic and lipidemic changes and microbiome. Rate of 100 metabolites will be analysed, and gathered as follows: metabolism of acylcarnitine (3), metabolism of bile acids (5), carbohydrate metabolism (1), dietary choline metabolism (3), metabolism of amino acids (34), vitamins and cofactors (7), metabolism of creatine (2), polyamine metabolism (3), purine metabolism (5), pyrimidine metabolism (9), tryptophan / kynurenine metabolism (21), caffeine metabolism (3), Citric Acid cycle (3), urea cycle (1)	Week 2 and Week 6
Comparison between W0, W2 and W6 after initiation of atorvastatin vs placebo of the microbiome	To analyze the influence of the microbiota on the variability of response to atorvastatin. 169/5000 The stool will be analyzed by metagenomic sequencing using the "shot gun" technique, a direct sequencing that quantifies the number of bacterial genes and annotates them.	Week 2 and Week 6

Collaborators and Investigators

• Sponsor: French Cardiology Society
• Collaborators: Fédération Française de Cardiologie; Fondation Cœur et Recherche; ICAN Nutrition Education and Research
• Investigators: Principal Investigator: Joe Elie SALEM, MD, CIC 1421 CHU Pitie Salpetriere

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2019
• Primary Completion (Actual): December 21, 2022
• Study Completion (Actual): December 21, 2022

Study Registration Dates

• First Submitted: February 7, 2019
• First Submitted That Met QC Criteria: February 11, 2019
• First Posted (Actual): February 12, 2019

Study Record Updates

• Last Update Posted (Actual): January 18, 2023
• Last Update Submitted That Met QC Criteria: January 17, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: cardiovascular risk; Statins; metabolomics; primary prevention microbiota
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: 2016-02 (Other Identifier: ap hm)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No