Pharmaco-metabolomic Effects of Statins: METASTATINE

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Pharmaco-metabolomic Effects of Statins: METASTATINE

Conditions
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Cardiovascular Diseases

Intervention / Treatment
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* Drug: Atorvastatin 40mg Tablet
* Drug: Placebo comparator


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 2 groups of patients having treatment or placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATORVASTATIN<br>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<br>* Patient participation for 6 weeks of treatment<br>* Other names: No other name;|
| Placebo Comparator: PLACEBO<br>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<br>* Patient participation for 6 weeks of treatment<br>* Other names: No other name;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Statins, cardiovascular risk, primary prevention microbiota, metabolomics