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

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).

Conditions

• Atorvastatin

Interventions

DIETARY_SUPPLEMENT

citrulline supplementation

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

DIETARY_SUPPLEMENT

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)

Sponsors & Collaborators

• Hospices Civils de Lyon

  lead OTHER

Principal Investigators

• Sybil Charriere, MD · Hospices Civils de Lyon Endocrinology and diabetology service, Louis Pradel Hospital

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

40 Years

Max Age

75 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-02-26

Primary Completion

2022-06-07

Completion

2022-06-07

Countries

• France

Study Locations