Metabolic Syndrome
Conditions
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.
Interventions
DRUGRamipril
Ramipril 20 mg once daily for 6 months
DRUGHCTZ-hydrochlorothiazide
HCTZ 25 mg once daily for 6 months
DRUGRamipril+HCTZ
Ramipril 20 mg and HCTZ 25 mg, both once daily for 6 months
Sponsors
King Pharmaceuticals is now a wholly owned subsidiary of Pfizer
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 65 Years
Healthy volunteers
Yes
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Insulin Sensitivity | 6 months | Measures of change in endogenous glucose production from baseline to final 30 minutes of clamp studies after 6 months of treatment. |
Countries
United States
Participant flow
Recruitment details
Individuals with pre-diabetes (metabolic syndrome) are recruited for a 6 month study intervention.
Participants by arm
| Arm | Count |
|---|---|
| Ramipril Patients randomized to 6 months treatment of Ramipril.
Ramipril: Ramipril 20 mg once daily for 6 months | 9 |
| HCTZ Patients randomized to 6 months treatment of HCTZ.
HCTZ-hydrochlorothiazide: HCTZ 25 mg once daily for 6 months | 4 |
| Ramipril+HCTZ Patients randomized to 6 months treatment of Ramipril+HCTZ.
Ramipril+HCTZ: Ramipril 20 mg and HCTZ 25 mg, both once daily for 6 months | 4 |
| Total | 17 |
Baseline characteristics
| Characteristic | HCTZ | Ramipril+HCTZ | Total | Ramipril |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants | 17 Participants | 9 Participants |
| Age, Continuous | 46 years STANDARD_DEVIATION 9 | 41 years STANDARD_DEVIATION 13 | 46 years STANDARD_DEVIATION 10 | 49 years STANDARD_DEVIATION 8.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 11 Participants | 6 Participants |
| Region of Enrollment United States | 4 participants | 4 participants | 17 participants | 9 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 8 Participants | 3 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 9 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 9 | 0 / 4 | 0 / 4 |
| serious Total, serious adverse events | 0 / 9 | 0 / 4 | 0 / 4 |
Outcome results
Primary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramipril | Changes in Insulin Sensitivity | 0.98 mg/kg/min | Standard Error 0.36 |
| HCTZ | Changes in Insulin Sensitivity | 1.5 mg/kg/min | Standard Error 0.23 |
| Ramipril+HCTZ | Changes in Insulin Sensitivity | 1.2 mg/kg/min | Standard Error 0.17 |