Prevention of Type 2 Diabetes Mellitus by L-Arginine in Patients With Metabolic Syndrome

NCT ID: NCT00917449

Last Updated: 2009-06-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 142 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-12-31
• Study Completion Date: 2009-06-30

Brief Summary

Aim

The principal objective of this project is:

• To evaluate the efficacy of long term (18 months) L-Arginine therapy in preventing or delaying clinical onset of type 2 diabetes mellitus in subjects with impaired glucose tolerance (IGT) and Metabolic Syndrome.

Secondary end points are:

1. To define if a long term treatment with L-arginine is able to ameliorate insulin sensitivity and endothelial dysfunction in this population.

2. To find new risk profiles and candidate genes able to define the sub-group of patients at higher risk to develop type 2 diabetes mellitus.

Methodology This is a double blind, parallel, one centre study to determine if long term oral L-arginine administration is able to delay or prevent type 2 diabetes mellitus in patients with Metabolic Syndrome. Two hundred and ninety four subjects were recruited at the Cardio-Metabolic and Clinical Trials Unit of the San Raffaele Scientific Institute. One hundred and forty two patients were randomized to enter the study and assigned to two arms: oral L-arginine (6.4 g/die) or placebo, in addition to diet and physical exercise. The treatment were maintained for 18 months. Visits were performed every 3 months for clinical evaluation, blood samples, treatment supply and collection of data on adverse events. Furthermore, patients were contacted every month by telephone to evaluate the accurate continuation of the study and they were instructed to phone to the centre in case of possible adverse events.

An OGTT were performed before the enter into the study and at the end of the study period. An additional OGTT were performed at an intermediate visit if fasting glucose levels were more than 126 mg/dl. A diabetic response caused the end-point of the patient. Metabolic, hormonal and endothelial activation and inflammation parameters were measured. Evaluation of endothelium-mediated and non-endothelium-mediated vasodilatation were performed by strain gauche plethysmography evaluating forearm blood at the basal state. in post-ischemic conditions and after nitroglycerine administration.

Before the enter into the study, an additional blood sample were drawn for DNA extraction and candidate genes variants evaluation. Before the enter into the study and at the end of the study period, gene expression for inflammation were measured on mRNA extraction on endothelial progenitor cells.

Detailed Description

This is a double blind, parallel, one centre study to determine if long term oral L-arginine administration is able to delay or prevent type 2 diabetes mellitus in patients with IGT and Metabolic Syndrome. Two hundred and ninety four subjects were recruited at the CardioMetabolic and Clinical Trials Unit of the San Raffaele Scientific Institute. One hundred and fourty two patients were randomized to enter the study. Patients were randomly assigned to two arms: oral L-arginine (6.4 g/die) or placebo in blind scheme. The treatment were maintained for 18 months. Visits will be performed every 3 months for clinical evaluation, blood samples, treatment supply and collect data on adverse events, if any. Furthermore, patients were contacted every month by telephone to evaluate the accurate continuation of the study and they were instructed to phone to the centre in case of possible adverse events.

Inclusion criteria

• Written informed consent must be obtained before any procedure of the study is done.
• Male or Female aged more than 35 years.
• Diagnosis of IGT after a standard Glucose Tolerance Test (OGTT, 75 g)
• Moreover, in order to be considered affected by Metabolic Syndrome, they must have two or more of the following criteria:
• Abdominal obesity (waist>120 cm for man, >88 cm for women)
• Hypertriglyceridemia (>150 mg/dl)
• Low HDL cholesterol (<40mg/dl in man, <50 mg/dl in woman)
• Hypertension (>130 / >85 mmHg) Exclusion criteria
• Presence of type 1 or type 2 diabetes mellitus
• Fasting glucose levels >126 mg/dl
• Sitting Systolic Arterial Pressure >140mmHg, and Sitting Diastolic Arterial Pressure >90mmHg
• Pregnancy
• Known renal insufficiency or creatinine levels more than 1.8 mg/dl,
• Presence of chronic hepatopathy or levels of ALT and AST more than two standard deviations from normality levels
• Presence of malignancy
• Abuse of alcohol or abuse substances
• Psychiatric disorders

Conditions

Metabolic Syndrome; Impaired Glucose Tolerance; Insulin Resistance; Endothelial Dysfunction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

L-arginine

L-arginine (3.2 gr bid) plus lifestyle counselling vs placebo plus lifestyle counselling

Group Type: ACTIVE_COMPARATOR

L-arginine

Intervention Type: DRUG

Oral L-arginine (3.2 gr bid)for 18 months

placebo

placebo plus lifestyle counselling for 18 months

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Oral Placebo BID for 18 months

Interventions

L-arginine

Oral L-arginine (3.2 gr bid)for 18 months

Intervention Type: DRUG

Placebo

Oral Placebo BID for 18 months

Intervention Type: DRUG

Other Intervention Names

bioarginine

Eligibility Criteria

Inclusion Criteria

• Written informed consent must be obtained before any procedure of the study is done.
• Male or Female aged more than 35 years.
• Diagnosis of IGT after a standard Glucose Tolerance Test (OGTT, 75 g)
• Moreover, in order to be considered affected by Metabolic Syndrome, they must have two or more of the following criteria:
• Abdominal obesity (waist>120 cm for man, >88 cm for women)
• Hypertriglyceridemia (>150 mg/dl)
• Low HDL cholesterol (<40mg/dl in man, <50 mg/dl in woman)
• Hypertension (>130 / >85 mmHg)

Exclusion Criteria

• Presence of type 1 or type 2 diabetes mellitus
• Fasting glucose levels >126 mg/dl
• Sitting Systolic Arterial Pressure >140mmHg, and Sitting Diastolic Arterial Pressure >90mmHg
• Pregnancy
• Known renal insufficiency or creatinine levels more than 1.8 mg/dl,
• Presence of chronic hepatopathy or levels of ALT and AST more than two standard deviations from normality levels
• Presence of malignancy
• Abuse of alcohol or abuse substances
• Psychiatric disorders

• Minimum Eligible Age: 35 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

IRCCS San Raffaele

OTHER

Sponsor Role: lead

Responsible Party

San Raffaele Scientific Institute

Principal Investigators

PierMarco Piatti, MD

Role: PRINCIPAL_INVESTIGATOR

Scientific Institute San Raffaele

Locations

Scientific Institute San Raffaele

Milan, Milan, Italy

Countries

Italy

References

Monti LD, Galluccio E, Villa V, Fontana B, Spadoni S, Piatti PM. Decreased diabetes risk over 9 year after 18-month oral L-arginine treatment in middle-aged subjects with impaired glucose tolerance and metabolic syndrome (extension evaluation of L-arginine study). Eur J Nutr. 2018 Dec;57(8):2805-2817. doi: 10.1007/s00394-017-1548-2. Epub 2017 Oct 20.

Reference Type: DERIVED

PMID: 29052766 (View on PubMed)

Monti LD, Galluccio E, Fontana B, Spadoni S, Comola M, Marrocco Trischitta MM, Chiesa R, Comi G, Bosi E, Piatti P. Pharmacogenetic influence of eNOS gene variant on endothelial and glucose metabolism responses to L-arginine supplementation: Post hoc analysis of the L-arginine trial. Metabolism. 2015 Nov;64(11):1582-91. doi: 10.1016/j.metabol.2015.08.015. Epub 2015 Aug 28.

Reference Type: DERIVED

PMID: 26385052 (View on PubMed)

Other Identifiers

2005-004639-24

Identifier Type: -

Identifier Source: org_study_id