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

Atorvastatin Clinical Trial

— STATIMPROVE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03596684
• Other study ID #: 69HCL17_0754
• Secondary ID: 2018-A00575-50
• Status: Completed
• Phase: N/A
• Start date: February 26, 2020
• Est. completion date: June 7, 2022

Study information

• Verified date: April 2023
• Source: Hospices Civils de Lyon
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2
• Est. completion date: June 7, 2022
• Est. primary completion date: June 7, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Atorvastatin
• Congenital Abnormalities

Intervention

Dietary Supplement:
• citrulline supplementation
2.5 g per os of citrulline on the morning and the evening (5 g/ jour) during 4 weeks.
• placebo supplementation
2.5 g of the product in the morning and in the evening during 4 weeks.

Procedure:
• glucose tolerance test
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)

Locations

Country	Name	City	State
France	Endocrinology and diabetology service, Louis Pradel Hospital	Bron

Sponsors (1)

Lead Sponsor	Collaborator
Hospices Civils de Lyon

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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		4 weeks
Secondary	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		4 weeks
Secondary	Difference in the index of insulin secretion determined during OGTT performed at the end and before the supplementation in citrulline versus placebo		4 weeks
Secondary	occurrence of adverse events and serious adverse events for assessment of tolerability		assessed up 8 weeks