Mechanisms of Ramipril Reduction in the Onset of Type 2 Diabetes

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Mechanisms of Reduced Ramipril on the Onset of Type 2 Diabetes Mellitis

Conditions
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Metabolic Syndrome

Intervention / Treatment
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* Drug: Ramipril
* Drug: HCTZ-hydrochlorothiazide
* Drug: Ramipril+HCTZ


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ramipril<br>Patients randomized to 6 months treatment of Ramipril. | Drug: Ramipril<br>* Ramipril 20 mg once daily for 6 months<br>* Other names: Altace;|
| Active Comparator: HCTZ<br>PAtients randomized to 6 months treatment of HCTZ. | Drug: HCTZ-hydrochlorothiazide<br>* HCTZ 25 mg once daily for 6 months<br>* Other names: Brand Names: HydroDIURIL, Microzide;|
| Active Comparator: Ramipril+HCTZ<br>Patients randomized to 6 months treatment of Ramipril+HCTZ. | Drug: Ramipril+HCTZ<br>* Ramipril 20 mg and HCTZ 25 mg, both once daily for 6 months<br>* Other names: Altace and HydroDIURIL, Microzide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Insulin Sensitivity | Measures of change in endogenous glucose production from baseline to final 30 minutes of clamp studies after 6 months of treatment. | 6 months |