Clinical trial NCT00574834: Mechanisms of Ramipril Reduction in the Onset of Type 2 Diabetes
Official title: Mechanisms of Reduced Ramipril on the Onset of Type 2 Diabetes Mellitis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: EARLY_PHASE1
Conditions: Metabolic Syndrome
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
Collaborators: name: King Pharmaceuticals is now a wholly owned subsidiary of Pfizer
First posted: 2007-12-17
Enrollment: 17
Sex: ALL
Minimum age (years): 20
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility 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

Primary outcomes:
measure: Changes in Insulin Sensitivity
timeFrame: 6 months
Secondary outcomes:
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: University of Maryland, Baltimore
state: Maryland
Study officials:
affiliation: University of Maryland, Baltimore
name: Stephen N. Davis, MD, FRCP
role: PRINCIPAL_INVESTIGATOR
References: