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Citrulline Efficacy to Improve Carbohydrate Metabolism Abnormalities in the Patient Treated With High Doses of Statin (STATIMPROVE)

Primary Purpose

Atorvastatin

Status

Completed

Phase

Not Applicable

Locations

France

Study Type

Interventional

Intervention

citrulline supplementation

placebo supplementation

glucose tolerance test

About this trial

This is an interventional prevention trial for Atorvastatin focused on measuring Carbohydrate Metabolism, Citrulline, Statine

Eligibility Criteria

40 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

40 years old < Age <75 years old
men and women who are menopausal or who benefit from effective contraception
treatment with atorvastatin at 40 or 80 mg / d for more than 3 months for primary prevention or secondary prevention at more than 3 months of the acute event (stroke, acute coronary syndrome) with or without ezetimibe (Ezetrol® monotherapy or in the form of associated with atorvastatin Liptruzet® 10/40 or 10/80)
with a Body Mass Index (BMI) ≥28 kg / m2 and at least one other risk factor for statin-dependent diabetes among the following 4:
- Blood pressure ≥ 140/90 mmHg or hypotensive treatment
- Triglyceridemia ≥ 150 mg / l
- Fasting blood glucose ≥ 100 mg / dl
- HDL-cholesterol <40 mg / dL in men, <50 mg / dL in women
affiliated to a social security scheme
signed informed consent

Exclusion Criteria:

- General criteria:

Subject with unstable medical or psychological conditions that, in the opinion of the investigator, could lead the subject to be non-compliant or uncooperative during the study or could compromise the safety or participation of the subject under study L.1121-6, L.1121-8, L.1121-9 and L1122-1-2 of the Public Health Code).
Major subjects under guardianship or deprived of their liberty by judicial or administrative decision.
Plan for weight loss during the previous 3 months, current or future
Dietary supplements for weight loss (based on plant extracts, algae, pre- and probiotics) in the previous 3 months or in progress

Biological criteria:

Aspartate Amino Transferase (ASAT), Alanine Amino Transferase (ALAT)> 2 times the normal values
HbA1c> 6.5%
Creatin Phospho Kinase (CPK)> 2 times normal
Triglycerid > 5g / L
Renal insufficiency (clearance <60 mL / min)
Demonstration of a biological abnormality deemed by the investigator to be clinically significant

Medical and therapeutic criteria:

Diabetes type 1 or 2
Subjects treated with a drug that may interfere with the metabolism of citrulline and glucose (vitamin K antagonists, corticosteroids for more than 8 days before the study, anorexigenic drugs (Anorex, Fenproporex Deglaude AP, Moderatan, Prefamone Chronules), drugs (Orlistat, Lioresal)
Any associated or uncontrolled progressive pathology (cardiac pathology, myocardial infarction of less than 6 months, arterial hypertension, psychiatric, renal or hepatic, cancer).
pregnant or lactating woman
Consumption of more than 3 glasses of alcohol per day.
Subjects who express any reluctance to consume a food supplement morning and evening.
eating disorders.
Weight variation of +/- 5% during the previous 3 months
Severe, progressive affection.
Depressive or psychiatric state (antidepressant or psychotropic treatment).
Medical or surgical history deemed by the investigator to be incompatible with this study.
Blood donation in the 2 months prior to inclusion.

Sites / Locations

Endocrinology and diabetology service, Louis Pradel Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

citrulline

Placebo

Arm Description

citrulline 5g/d

pure mixture of amino acids: alanine, aspartate, glycine, proline, serine, histidine

Outcomes

Primary Outcome Measures

difference in the area under the curve of the glycemic response during a 75 g glucose tolerance test between the end and the beginning of citrulline supplementation versus placebo

Secondary Outcome Measures

Difference in the index of insulin sensitivity determined during Oral Glucose Tolerance Test (OGTT) performed at the end and before the supplementation in citrulline versus placebo

Difference in the index of insulin secretion determined during OGTT performed at the end and before the supplementation in citrulline versus placebo

occurrence of adverse events and serious adverse events for assessment of tolerability

Full Information

NCT ID

NCT03596684

First Posted

June 4, 2018

Last Updated

April 7, 2023

Sponsor

Hospices Civils de Lyon

1. Study Identification

Unique Protocol Identification Number

NCT03596684

Brief Title

Citrulline Efficacy to Improve Carbohydrate Metabolism Abnormalities in the Patient Treated With High Doses of Statin

Acronym

STATIMPROVE

Official Title

Citrulline Efficacy to Improve Carbohydrate Metabolism Abnormalities in the Patient Treated With High Doses of Statin

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Completed

Study Start Date

February 26, 2020 (Actual)

Primary Completion Date

June 7, 2022 (Actual)

Study Completion Date

June 7, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hospices Civils de Lyon

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Hypercholesterolemia is a major cardiovascular risk factor. Statins are the first-line drug treatment for hypercholesterolemia and have been shown to be effective in both primary and secondary prevention of cardiovascular disease. However, long-term statin therapy is associated with impaired carbohydrate metabolism and increased risk of developing type 2 diabetes (T2D), particularly in patients with metabolic syndrome. The risk of developing T2D is higher with high doses of statins. Currently the benefits of statins on the reduction of major cardiovascular events and mortality are considered superior to the risk of statin-induced diabetes T2D, and no change in clinical practice has been recommended to date. However, it now appears necessary to develop strategies to reduce the adverse effects of statins on carbohydrate metabolism and maintain the carbohydrate tolerance of patients on statins, especially in those at risk of developing T2D under statins. Statins are able to induce the expression and activity of an enzyme synthesizing nitric oxide (NO), the endothelial NO synthase (eNOS), which helps improving insulin sensitivity and insulin secretion. However, availability and metabolism of its substrate arginine is impaired in obesity and T2D. The investigators thus hypothesized that providing citrulline to statin treated patients, the arginine precursor with better gastrointestinal tolerance and bioavailability than arginine, would beneficially impact their glucose homeostasis. Tested in vivo by Béatrice Morio, a member of the CarMeN laboratory, combining citrulline to atorvastatin improved glucose tolerance and insulin sensitivity in mice fed a high fat-high sucrose diet. These data therefore suggest that combining citrulline to atorvastatin may improve glucose tolerance in statin-treated patients at high risk of developing T2D. The objective of the study is therefore to investigate the impact of citrulline supplementation (5g/d) vs. placebo for 4 weeks on glucose tolerance assessed during an oral glucose tolerance test in patients at risk for developing T2D and treated with atorvastatin (40 or 80 mg / day).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Atorvastatin

Keywords

Carbohydrate Metabolism, Citrulline, Statine

7. Study Design

Primary Purpose

Prevention

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

2 (Actual)

8. Arms, Groups, and Interventions

Arm Title

citrulline

Arm Type

Experimental

Arm Description

citrulline 5g/d

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

pure mixture of amino acids: alanine, aspartate, glycine, proline, serine, histidine

Intervention Type

Dietary Supplement

Intervention Name(s)

citrulline supplementation

Intervention Description

2.5 g per os of citrulline on the morning and the evening (5 g/ jour) during 4 weeks.

Intervention Type

Dietary Supplement

Intervention Name(s)

placebo supplementation

Intervention Description

2.5 g of the product in the morning and in the evening during 4 weeks.

Intervention Type

Procedure

Intervention Name(s)

glucose tolerance test

Intervention Description

2 exploration mornings distant from 28 days (before and after citrulline) will allow carrying out an oral glucose tolerance test of 2 hours (75 g glucose per os)

Primary Outcome Measure Information:

Title

difference in the area under the curve of the glycemic response during a 75 g glucose tolerance test between the end and the beginning of citrulline supplementation versus placebo

Time Frame

4 weeks

Secondary Outcome Measure Information:

Title

Difference in the index of insulin sensitivity determined during Oral Glucose Tolerance Test (OGTT) performed at the end and before the supplementation in citrulline versus placebo

Time Frame

4 weeks

Title

Difference in the index of insulin secretion determined during OGTT performed at the end and before the supplementation in citrulline versus placebo

Time Frame

4 weeks

Title

occurrence of adverse events and serious adverse events for assessment of tolerability

Time Frame

assessed up 8 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

40 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 40 years old < Age <75 years old men and women who are menopausal or who benefit from effective contraception treatment with atorvastatin at 40 or 80 mg / d for more than 3 months for primary prevention or secondary prevention at more than 3 months of the acute event (stroke, acute coronary syndrome) with or without ezetimibe (Ezetrol® monotherapy or in the form of associated with atorvastatin Liptruzet® 10/40 or 10/80) with a Body Mass Index (BMI) ≥28 kg / m2 and at least one other risk factor for statin-dependent diabetes among the following 4: Blood pressure ≥ 140/90 mmHg or hypotensive treatment Triglyceridemia ≥ 150 mg / l Fasting blood glucose ≥ 100 mg / dl HDL-cholesterol <40 mg / dL in men, <50 mg / dL in women affiliated to a social security scheme signed informed consent Exclusion Criteria: - General criteria: Subject with unstable medical or psychological conditions that, in the opinion of the investigator, could lead the subject to be non-compliant or uncooperative during the study or could compromise the safety or participation of the subject under study L.1121-6, L.1121-8, L.1121-9 and L1122-1-2 of the Public Health Code). Major subjects under guardianship or deprived of their liberty by judicial or administrative decision. Plan for weight loss during the previous 3 months, current or future Dietary supplements for weight loss (based on plant extracts, algae, pre- and probiotics) in the previous 3 months or in progress Biological criteria: Aspartate Amino Transferase (ASAT), Alanine Amino Transferase (ALAT)> 2 times the normal values HbA1c> 6.5% Creatin Phospho Kinase (CPK)> 2 times normal Triglycerid > 5g / L Renal insufficiency (clearance <60 mL / min) Demonstration of a biological abnormality deemed by the investigator to be clinically significant Medical and therapeutic criteria: Diabetes type 1 or 2 Subjects treated with a drug that may interfere with the metabolism of citrulline and glucose (vitamin K antagonists, corticosteroids for more than 8 days before the study, anorexigenic drugs (Anorex, Fenproporex Deglaude AP, Moderatan, Prefamone Chronules), drugs (Orlistat, Lioresal) Any associated or uncontrolled progressive pathology (cardiac pathology, myocardial infarction of less than 6 months, arterial hypertension, psychiatric, renal or hepatic, cancer). pregnant or lactating woman Consumption of more than 3 glasses of alcohol per day. Subjects who express any reluctance to consume a food supplement morning and evening. eating disorders. Weight variation of +/- 5% during the previous 3 months Severe, progressive affection. Depressive or psychiatric state (antidepressant or psychotropic treatment). Medical or surgical history deemed by the investigator to be incompatible with this study. Blood donation in the 2 months prior to inclusion.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sybil Charriere, MD

Organizational Affiliation

Hospices Civils de Lyon Endocrinology and diabetology service, Louis Pradel Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Endocrinology and diabetology service, Louis Pradel Hospital

City

Bron

ZIP/Postal Code

69500

Country

France

12. IPD Sharing Statement

Learn more about this trial

Citrulline Efficacy to Improve Carbohydrate Metabolism Abnormalities in the Patient Treated With High Doses of Statin

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