Mechanisms of Ramipril Reduction in the Onset of Type 2 Diabetes

University of Maryland Baltimore (UMB)

Status and phase: Terminated; Early Phase 1

Conditions: Metabolic Syndrome

Treatments: Drug: HCTZ-hydrochlorothiazide; Drug: Ramipril+HCTZ; Drug: Ramipril

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT00574834

HP-00044872-Ramipril

Details and patient eligibility

About

The study will be focused on determining the integrated in-vivo mechanisms responsible for Ramipril's effects on delaying type 2 diabetes and restoring normal (blood sugar levels) glycemia in patients with impaired glucose tolerance.

Hypothesis - Ramipril effects will delay the onset of type 2 diabetes and restore normal glycemia in patients with impaired glucose tolerance.

Full description

Several studies have demonstrated that therapeutic agents used to reduce glucose levels and/or weight can delay the onset of type 2 diabetes. Intriguingly, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) also result in reduction in the onset of type 2 DM. The most striking effect was found with Ramipril in the HOPE study. The onset of new type 2 DM was reduced by 34% (p<0.001) as compared to placebo. Furthermore, the results of the DREAM trial demonstrate that Ramipril at a dose of 15 mg can significantly reverse impaired glucose tolerance. However, the mechanisms underlying Ramipril effects to delay type 2 diabetes are not known.

The proposal will be focused on determining the integrated in-vivo mechanisms responsible for Ramipril's effects on delaying type 2 DM and restoring normal glycemia in patients with impaired glucose tolerance.

The specific aims of the project are:

to determine the effect of Ramipril on insulin resistance at the level of the liver and peripheral tissues, to determine the effect of Ramipril on endothelial function, to determine the effects of Ramipril on insulin secretion, and to determine the effects of Ramipril on substrate flux, lipolysis and inflammatory cytokines.

Enrollment: 17 patients

Sex: All

Ages: 20 to 65 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Inclusion:

• 48 (24 male / 24 female) with impaired glucose tolerance.
• Impaired blood glucose values as outlined by the American Diabetes Association guideline. Fasting plasma glucose between 100 and 126 mg/dl or 2 hour post prandial glucose between 140 and 200 mg/dl
• BMI > 25 kgM2
• Age: 20-65 years
• Treated or Untreated hypertension defined as measurement of seated BP at screening visit of systolic BP 120 to 150 and/ or diastolic BP 80 to 100.

Exclusion:

• Patients receiving agents that can increase or lower blood glucose, i.e., metformin, thiazolidinediones, sulfonylureas, glitinides, acarbose, GLP-1 receptor agonists
• Untreated or treated while seated Systolic Blood pressure >150and/or Diastolic Blood pressure >100
• Taking hypertensive medications of HCTZ or ACE/ARB
• Allergy to HCTZ, heparin, nitroglycerin or lidocaine
• History of allergy or unacceptable side effects from ACE inhibitors
• Pregnancy or intent to become pregnant during the study
• Smoking
• Subject unable to give voluntary informed consent

Physical Exam Exclusion Criteria

• Clinically significant Cardiac Abnormalities (e.g. Heart Failure, Arrhythmia) from history or ECG in subjects > 40 years old
• Pneumonia
• Hepatic Failure/Jaundice
• Renal Failure
• Acute Cerebrovascular/ Neurological deficit
• Fever greater than 38.0 C

Screening Laboratory Tests Exclusion Criteria according to protocol

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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17 participants in 3 patient groups

Ramipril

Active Comparator group

Description:

Patients randomized to 6 months treatment of Ramipril.

Treatment:

Drug: Ramipril

HCTZ

Active Comparator group

Description:

PAtients randomized to 6 months treatment of HCTZ.

Treatment:

Drug: HCTZ-hydrochlorothiazide

Ramipril+HCTZ

Active Comparator group

Description:

Patients randomized to 6 months treatment of Ramipril+HCTZ.

Treatment:

Drug: Ramipril+HCTZ