Mechanisms of Ramipril Reduction in the Onset of Type 2 Diabetes

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.

• Drug: Ramipril
  Ramipril 20 mg once daily for 6 months
  Other Name: Altace
• Drug: HCTZ-hydrochlorothiazide
  HCTZ 25 mg once daily for 6 months
  Other Name: Brand Names: HydroDIURIL, Microzide
• Drug: Ramipril+HCTZ
  Ramipril 20 mg and HCTZ 25 mg, both once daily for 6 months
  Other Name: Altace and HydroDIURIL, Microzide

• Active Comparator: Ramipril
  Patients randomized to 6 months treatment of Ramipril.
  Intervention: Drug: Ramipril
• Active Comparator: HCTZ
  PAtients randomized to 6 months treatment of HCTZ.
  Intervention: Drug: HCTZ-hydrochlorothiazide
• Active Comparator: Ramipril+HCTZ
  Patients randomized to 6 months treatment of Ramipril+HCTZ.
  Intervention: Drug: Ramipril+HCTZ

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