Mechanisms of Ramipril Reduction in the Onset of Type 2 Diabetes

Early Phase 1TerminatedNCT00574834

University of Maryland, Baltimore17 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

DOUBLE

Enrollment

Conditions

Metabolic Syndrome

Interventions

RamiprilDRUG

Ramipril 20 mg once daily for 6 months

HCTZ-hydrochlorothiazideDRUG

HCTZ 25 mg once daily for 6 months

Ramipril+HCTZDRUG

Ramipril 20 mg and HCTZ 25 mg, both once daily for 6 months

Eligibility

Sex: ALLMin age: 20 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (1)

University of Maryland, Baltimore

Baltimore, Maryland, United States

Outcomes

Primary Outcomes

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.

Time frame: 6 months

Data from ClinicalTrials.gov

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