Metabolic Diseases, Diabetes Mellitus, Endocrine System Diseases, Glucose Metabolism Disorders
Conditions
Keywords
Glucose, Insulin
Brief summary
The purpose of this study is to determine the effects of mineralocorticoid receptor (MR) antagonism and renin inhibition on glucose metabolism in humans.
Detailed description
The purpose of this study is to determine the effects of mineralocorticoid receptor (MR) antagonism and renin inhibition on fasting blood glucose and glucose-stimulated insulin secretion in humans.
Interventions
DRUGAliskiren 300 mg (ALI 300)
Aliskiren 300mg daily
DRUGSpironolactone 50 mg (SPL 50)
Spironolactone 50 mg daily
HCTZ 12.5mg daily
DRUGAliskiren 150 mg (ALI 150)
Aliskiren 150mg daily
DRUGSpironolactone (SPL 25)
spironolactone 25mg daily
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Subjects meeting all of the following conditions will be included in the study: 1. Ambulatory subjects, 18 to 70 years of age, inclusive 2. For female subjects, the following conditions must be met: 1. postmenopausal status for at least 1 year, or 2. status-post surgical sterilization, or 3. if of childbearing potential, utilization of adequate birth control and willingness to undergo urine beta-hcg testing prior to drug treatment and on every study day. 3. A seated or supine systolic blood pressure greater than 130/85 on three separate measurements at least 15 minutes apart 4. Metabolic Syndrome as defined by the presence of \> 3 of the following: 1. Hypertension as characterized by having Systolic Blood Pressure \> 140 mm Hg and Diastolic Blood Pressure \> 90 mm Hg. 2. Impaired Glucose Tolerance (Fasting Plasma Glucose \> 100 mg/dL) 3. Increased triglyceride level \> 150mg/dL 4. Decreased levels of High-Density Lipoprotein (HDL) cholesterol 1. For males, less than 30 mg/dL 2. For females, less than 40 mg/dL 5. Waist circumference 1. For males, greater than 40 inches. 2. For females, greater than 35 inches.
Exclusion criteria
* Subjects presenting with any of the following will not be included in the study: 1. Diabetes type 1 or type 2, a fasting glucose of greater than 110 mg/dL or the use of anti-diabetic medication 2. Use of hormone replacement therapy 3. Statin therapy 4. Pregnancy 5. Breast-feeding 6. Cardiovascular disease such as prior myocardial infarction, presence of angina pectoris, significant arrhythmia, congestive heart failure \[Left Ventricular (LV) hypertrophy acceptable\], deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy 7. Treatment with anticoagulants 8. History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack 9. History or presence of immunological or hematological disorders 10. Diagnosis of asthma requiring use of inhaled beta agonist \>1 time per week 11. Clinically significant gastrointestinal impairment that could interfere with drug absorption 12. Impaired hepatic function \[aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) \>1.5 x upper limit of normal range\] 13. Impaired renal function \[estimated glomerular filtration rate (eGFR) of \<60ml/min\] as determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine (Scr) is expressed in mg/dl and age in years: eGFR (ml/min/1.73m2)=175 • Scr-1.154 • age-0.203 • (1.212 if black) • (0.742 if female) 14. Hematocrit \<35% 15. Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult, such as arthritis treated with non-steroidal antiinflammatory drugs 16. Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month) 17. Treatment with lithium salts 18. History of alcohol or drug abuse 19. Treatment with any investigational drug in the 1 month preceding the study 20. Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study 21. Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study 22. Screening plasma potassium \<3.2 mmol/L or use of chronic potassium supplements for the treatment of hypokalemia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Insulin | at the end of each 1 month study period ( 3 times in total) | A Hyperglycemic clamp was performed once during each study period to assess glucose stimulated insulin secretion. Glucose is infused intravenously to maintain blood glucose near 200 mg/dL to stimulate insulin secretion. During this time plasma insulin levels were measured and the insulin response is reported as the incremental increase over the first 10 minutes of glucose administration. |
| Plasma Glucose | at the end of each 1 month study period ( 3 times in total) | Fasting plasma glucose, measured during hyperglycemic clamp |
Countries
United States
Participant flow
Pre-assignment details
31 of the consented participants did not meet inclusion criteria and did not participate in the study
Participants by arm
| Arm | Count |
|---|---|
| HCTZ Plus ALI 150 Then ALI 300 Baseline: HCTZ 12.5mg daily for 1 month (Baseline, HCTZ only), then Period 1: HCTZ 12.5mg daily plus Aliskiren 150 mg daily for 1 month (HCTZ + ALI 150), then Period 2: HCTZ 12.5mg daily plus Aliskiren 300mg for 1 month (HCTZ + ALI 300) | 13 |
| HCTZ Plus ALI 150 Then ALI 150 and SPL 25 Baseline: HCTZ 12.5mg HCTZ daily for 1 month (Baseline, HCTZ only), then Period 1: HCTZ 12.5mg daily plus Aliskiren 150 mg daily for 1 month (HCTZ + ALI 150), then Period 2: HCTZ 12.5mg daily plus Aliskiren 150 mg daily and Spironolactone 25 mg daily for one month (HCTZ + ALI 150 and SPL 25) | 7 |
| HCTZ Plus SPL 25 Then SPL 50 Baseline: HCTZ 12.5mg HCTZ daily for 1 month (Baseline, HCTZ only), then Period 1: HCTZ 12.5mg daily plus Spironolactone 25 mg daily for 1 month (HCTZ + SPL 25), then Period 2: HCTZ 12.5mg daily plus Spironolactone 50 mg daily for one month (HCTZ + SPL 50) | 12 |
| HCTZ Plus SPL 25 Then ALI 150 and SPL 25 Baseline: HCTZ 12.5mg HCTZ daily for 1 month (Baseline, HCTZ only) Period 1: HCTZ 12.5mg daily plus Spironolactone 25 mg daily for 1 month (HCTZ + SPL 25) Period 2: HCTZ 12.5mg daily plus Aliskiren 150 mg daily and Spironolactone 25 mg daily for one month (HCTZ + ALI 150 and SPL 25) | 6 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 1 | 0 |
| Overall Study | Inadequate IV access | 1 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 3 | 0 |
Baseline characteristics
| Characteristic | HCTZ Plus ALI 150 Then ALI 150 and SPL 25 | HCTZ Plus SPL 25 Then SPL 50 | HCTZ Plus ALI 150 Then ALI 300 | HCTZ Plus SPL 25 Then ALI 150 and SPL 25 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 12 Participants | 13 Participants | 6 Participants | 38 Participants |
| Age, Continuous | 46.8 years STANDARD_DEVIATION 8.4 | 44.0 years STANDARD_DEVIATION 11.6 | 46.8 years STANDARD_DEVIATION 11.8 | 42.8 years STANDARD_DEVIATION 13.8 | 45.3 years STANDARD_DEVIATION 11.2 |
| Region of Enrollment United States | 7 Participants | 12 Participants | 13 Participants | 6 Participants | 38 Participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 9 Participants | 1 Participants | 19 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 4 Participants | 5 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 7 | 0 / 12 | 0 / 6 |
| other Total, other adverse events | 6 / 13 | 7 / 7 | 5 / 12 | 1 / 6 |
| serious Total, serious adverse events | 0 / 13 | 0 / 7 | 0 / 12 | 0 / 6 |
Outcome results
Primary
Plasma Glucose
Fasting plasma glucose, measured during hyperglycemic clamp
Time frame: at the end of each 1 month study period ( 3 times in total)
Population: 2 participants were excluded from the final analysis because they did not complete any of the Hyperglycemic clamps:1 from the HCTZ plus ALI150 then ALI 300 group and 1 participant from the HCTZ plus SPL 25 then ALI 150 and SPL 25 group
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HCTZ Plus ALI 150 Then ALI 300 | Plasma Glucose | Baseline, HCTZ Only | 108.6 mg/dl | Standard Deviation 24.1 |
| HCTZ Plus ALI 150 Then ALI 300 | Plasma Glucose | HCTZ + ALI 150 | 119.7 mg/dl | Standard Deviation 39.7 |
| HCTZ Plus ALI 150 Then ALI 300 | Plasma Glucose | HCTZ + ALI 300 | 111.4 mg/dl | Standard Deviation 25.3 |
| HCTZ Plus ALI 150 Then ALI 150 and SPL 25 | Plasma Glucose | Baseline, HCTZ Only | 106.1 mg/dl | Standard Deviation 18.1 |
| HCTZ Plus ALI 150 Then ALI 150 and SPL 25 | Plasma Glucose | HCTZ + ALI 150 and SPL 25 | 102.1 mg/dl | Standard Deviation 10.9 |
| HCTZ Plus ALI 150 Then ALI 150 and SPL 25 | Plasma Glucose | HCTZ + ALI 150 | 105.7 mg/dl | Standard Deviation 20.4 |
| HCTZ Plus SPL 25 Then SPL 50 | Plasma Glucose | Baseline, HCTZ Only | 96.4 mg/dl | Standard Deviation 10.1 |
| HCTZ Plus SPL 25 Then SPL 50 | Plasma Glucose | HCTZ + SPL 50 | 105.9 mg/dl | Standard Deviation 10.7 |
| HCTZ Plus SPL 25 Then SPL 50 | Plasma Glucose | HCTZ + SPL 25 | 104.8 mg/dl | Standard Deviation 10.7 |
| HCTZ Plus SPL 25 Then ALI 150 and SPL 25 | Plasma Glucose | Baseline, HCTZ Only | 102.2 mg/dl | Standard Deviation 18.4 |
| HCTZ Plus SPL 25 Then ALI 150 and SPL 25 | Plasma Glucose | HCTZ + SPL 25 | 101.7 mg/dl | Standard Deviation 11.5 |
| HCTZ Plus SPL 25 Then ALI 150 and SPL 25 | Plasma Glucose | HCTZ + ALI 150 and SPL 25 | 107.2 mg/dl | Standard Deviation 17.3 |
Primary
Plasma Insulin
A Hyperglycemic clamp was performed once during each study period to assess glucose stimulated insulin secretion. Glucose is infused intravenously to maintain blood glucose near 200 mg/dL to stimulate insulin secretion. During this time plasma insulin levels were measured and the insulin response is reported as the incremental increase over the first 10 minutes of glucose administration.
Time frame: at the end of each 1 month study period ( 3 times in total)
Population: 2 participants were excluded from the final analysis because they did not complete any of the Hyperglycemic clamps:1 from the HCTZ plus ALI150 then ALI 300 group and 1 participant from the HCTZ plus SPL 25 then ALI 150 and SPL 25 group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HCTZ Plus ALI 150 Then ALI 300 | Plasma Insulin | HCTZ + ALI 300 | 75.7 uU/ml | Standard Deviation 76.6 |
| HCTZ Plus ALI 150 Then ALI 300 | Plasma Insulin | Baseline, HCTZ Only | 75.4 uU/ml | Standard Deviation 82.7 |
| HCTZ Plus ALI 150 Then ALI 300 | Plasma Insulin | HCTZ + ALI 150 | 54.8 uU/ml | Standard Deviation 50.2 |
| HCTZ Plus ALI 150 Then ALI 150 and SPL 25 | Plasma Insulin | HCTZ + ALI 150 | 43.3 uU/ml | Standard Deviation 33 |
| HCTZ Plus ALI 150 Then ALI 150 and SPL 25 | Plasma Insulin | Baseline, HCTZ Only | 50.1 uU/ml | Standard Deviation 40.1 |
| HCTZ Plus ALI 150 Then ALI 150 and SPL 25 | Plasma Insulin | HCTZ + ALI 150 and SPL 25 | 69.1 uU/ml | Standard Deviation 37.3 |
| HCTZ Plus SPL 25 Then SPL 50 | Plasma Insulin | HCTZ + SPL 50 | 44.3 uU/ml | Standard Deviation 18.3 |
| HCTZ Plus SPL 25 Then SPL 50 | Plasma Insulin | Baseline, HCTZ Only | 43.5 uU/ml | Standard Deviation 23.9 |
| HCTZ Plus SPL 25 Then SPL 50 | Plasma Insulin | HCTZ + SPL 25 | 53.4 uU/ml | Standard Deviation 36.6 |
| HCTZ Plus SPL 25 Then ALI 150 and SPL 25 | Plasma Insulin | HCTZ + ALI 150 and SPL 25 | 99.9 uU/ml | Standard Deviation 32 |
| HCTZ Plus SPL 25 Then ALI 150 and SPL 25 | Plasma Insulin | HCTZ + SPL 25 | 113.2 uU/ml | Standard Deviation 99.7 |
| HCTZ Plus SPL 25 Then ALI 150 and SPL 25 | Plasma Insulin | Baseline, HCTZ Only | 114.0 uU/ml | Standard Deviation 93.1 |