Hypertension
Conditions
Brief summary
This study will measure and compare changes in insulin production and sensitivity using the hyperglycemic clamp technique in obese patients with impaired glucose tolerance and hypertension treated with placebo, isosorbide mononitrate (ISMN) or hydrochlorothiazide (HCTZ).
Interventions
HCTZ 50 mg (two 25 mg capsules) once daily for 4 weeks per treatment period.
DRUGComparator: Placebo to HCTZ
Placebo to HCTZ two 0 mg capsules once daily for 4 weeks per treatment period
ISMN 60 mg extended release capsule once daily for 4 weeks per treatment period
DRUGComparator: Placebo to ISMN
Placebo to ISMN 0 mg capsule once daily for 4 weeks per treatment period
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
35 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Female participants must be post-menopausal * Body Mass Index (BMI) of at least 29 kg/m\^2 * Weight has been stable over the past 3 months * Has never been treated for hypertension or is diagnosed with hypertension taking up to 2 anti-hypertensive medications * Willing to stop hypertension treatment for 14 days prior to randomization and throughout the study * Does not have a history of diabetes * In good health with the exception of hypertension * No history of abnormal heart rhythms * Part I only: willing to comply with high potassium/low sodium diet for the duration of the study * Willing to avoid strenuous physical activity during the study * Nonsmoker and/or has not used nicotine for at least 3 months and agrees to refrain from use of tobacco-containing products throughout the study * Agrees to refrain from consuming alcohol and caffeine during in-patient periods and to limit consumption at all other times during the study * Agrees not to consume grapefruit, grapefruit products, and citrus, apple, and pineapple juices 2 weeks prior to administration of the first dose of study drug
Exclusion criteria
* History of any illness that may make their participation in the study unsafe or confuse the study results * Taking spironolactone or eplerenone * Cannot refrain from using any prescription or non-prescription drugs during the study * On a weight loss program and is not in the maintenance phase * Started a weight loss drug within 8 weeks of the first study visit * Consumes excessive amounts of alcohol or caffeine * Has had major surgery, donated or lost 1 unit of blood within 4 weeks of the first study visit * History of multiple and/or severe allergies to drugs or food * Is dehydrated
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Glucose Tolerance (IGT) | 90 -120 minutes post-dose | Steady state was defined as 90-120 minutes post-dose. IGT was defined as a 2 hour plasma glucose \>= 140 and \<= 199 mg/dL during a 75g oral glucose tolerance test at screening. |
| Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Fasting Glucose (IFG) | 90 -120 minutes post-dose | Steady state was defined as 90-120 minutes post-dose. IFG was defined as fasting plasma glucose (FPG) between 100 and 125 mg/dL at screening. |
| Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants Who Had Normal Glucose Tolerance (NGT) | 90 -120 minutes post-dose | Steady state was defined as 90-120 minutes post-dose. NGT participants (FPG \<100 mg/dL & 2 hour plasma glucose (PG) \<140 mg/dL during a 75g oral glucose tolerance test (OGTT) at screening) were neither Impaired Glucose Tolerant (IGT) nor Impaired Fasting Glucose (IFG). IGT was defined as a 2 hour plasma glucose \>= 140 and \<= 199 mg/dL during a 75g oral glucose tolerance test at screening. IFG was defined as FPG between 100 and 125 mg/dL at screening. |
| Part II: Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady-state | 90 -120 minutes post-dose | Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Fasting Glucose (IFG) | 90 -120 minutes post-dose | Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes. IFG was defined as fasting plasma glucose (FPG) between 100 and 125 mg/dL at screening. |
| Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Normal Glucose Tolerant (NGT) | 90 -120 minutes post-dose | Steady state was defined as 90-120 minutes post-dose. The ratio was the measure of the quantity of glucose disposed per unit of plasma insulin concentration (PIC). Approximate PIC was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals, time = 90, 100, 110, and 120 minutes. NGT participants (FPG \<100 mg/dL & 2 hour PG \<140 mg/dL during a 75g OGTT at screening) were neither IGT nor IFG at screening. IGT - defined as a 2 hour PG \>= 140 and \<= 199 mg/dL during a 75g OGTT at screening. IFG - defined as FPG between 100 and 125 mg/dL at screening. |
| Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Glucose Tolerant (IGT) | 90 -120 minutes post-dose | Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes. IGT was defined as a 2 hour plasma glucose \>= 140 and \<= 199 mg/dL during a 75g oral glucose tolerance test at screening. |
Participant flow
Pre-assignment details
Enrolled participants were place into two periods. 36 Part I participants received Hydrochlorothiazide (HCTZ) first, then placebo or placebo first, then HCTZ. A new group of 28 Part II participants received Isosorbide Mononitrate (ISMN) first, then placebo or placebo first, then ISMN.
Participants by arm
| Arm | Count |
|---|---|
| All Part I Participants Part I Overall: Hydrochlorothiazide (HCTZ) in Period 1 followed by Placebo in Period 2 or Placebo in Period 1, followed by HCTZ in Period 2 | 36 |
| All Part II Participants Part II Overall: Isosorbide mononitrate (ISMN)in Period 1, followed by placebo in Period 2 or placebo in Period 1, followed by ISMN in Period 2 | 28 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part I | Adverse Event | 0 | 2 | 0 | 0 |
| Part I | Laboratory abnormality | 0 | 1 | 0 | 0 |
| Part I | Withdrawal by Subject | 3 | 0 | 0 | 0 |
| Part II | Adverse Event | 0 | 0 | 1 | 2 |
| Part II | Lack of Efficacy | 0 | 0 | 1 | 0 |
| Part II | Protocol Violation | 0 | 0 | 0 | 1 |
| Part II | Withdrawal by Subject | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | All Part I Participants | All Part II Participants | Total |
|---|---|---|---|
| Age, Continuous | 57 years | 54 years | 55 years |
| Sex: Female, Male Female | 20 Participants | 13 Participants | 33 Participants |
| Sex: Female, Male Male | 16 Participants | 15 Participants | 31 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 29 / 36 | 25 / 36 | 26 / 28 | 17 / 28 |
| serious Total, serious adverse events | 0 / 36 | 0 / 36 | 0 / 28 | 0 / 28 |
Outcome results
Primary
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants Who Had Normal Glucose Tolerance (NGT)
Steady state was defined as 90-120 minutes post-dose. NGT participants (FPG \<100 mg/dL & 2 hour plasma glucose (PG) \<140 mg/dL during a 75g oral glucose tolerance test (OGTT) at screening) were neither Impaired Glucose Tolerant (IGT) nor Impaired Fasting Glucose (IFG). IGT was defined as a 2 hour plasma glucose \>= 140 and \<= 199 mg/dL during a 75g oral glucose tolerance test at screening. IFG was defined as FPG between 100 and 125 mg/dL at screening.
Time frame: 90 -120 minutes post-dose
Population: Number of participants with NGT.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Hydrochlorothiazide (HCTZ) | Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants Who Had Normal Glucose Tolerance (NGT) | 5.54 ng/minute | Standard Deviation 2.15 |
| Hydrochlorothiazide (HCTZ) Placebo | Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants Who Had Normal Glucose Tolerance (NGT) | 5.01 ng/minute | Standard Deviation 1.63 |
p-value: >0.590% CI: [0.4, 0.67]ANCOVA
Primary
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Fasting Glucose (IFG)
Steady state was defined as 90-120 minutes post-dose. IFG was defined as fasting plasma glucose (FPG) between 100 and 125 mg/dL at screening.
Time frame: 90 -120 minutes post-dose
Population: Number of participants with IFG.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Hydrochlorothiazide (HCTZ) | Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Fasting Glucose (IFG) | 5.60 ng/minute | Standard Deviation 1.45 |
| Hydrochlorothiazide (HCTZ) Placebo | Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Fasting Glucose (IFG) | 4.50 ng/minute | Standard Deviation 0.95 |
p-value: >0.590% CI: [0.86, 1.34]ANCOVA
Primary
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Glucose Tolerance (IGT)
Steady state was defined as 90-120 minutes post-dose. IGT was defined as a 2 hour plasma glucose \>= 140 and \<= 199 mg/dL during a 75g oral glucose tolerance test at screening.
Time frame: 90 -120 minutes post-dose
Population: Number of participants with IGT.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Hydrochlorothiazide (HCTZ) | Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Glucose Tolerance (IGT) | 3.44 ng/minute | Standard Deviation 1.03 |
| Hydrochlorothiazide (HCTZ) Placebo | Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Glucose Tolerance (IGT) | 3.55 ng/minute | Standard Deviation 1.03 |
p-value: 0.06790% CI: [-0.22, 0.01]ANCOVA
Primary
Part II: Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady-state
Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes.
Time frame: 90 -120 minutes post-dose
Population: Number of participants who took ISMN/placebo.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Hydrochlorothiazide (HCTZ) | Part II: Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady-state | 0.040 (mg/kg/minute)/(µIU/mL) | Standard Deviation 0.027 |
| Hydrochlorothiazide (HCTZ) Placebo | Part II: Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady-state | 0.044 (mg/kg/minute)/(µIU/mL) | Standard Deviation 0.041 |
p-value: 0.34290% CI: [-0.023, 0.014]ANOVA
Secondary
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Fasting Glucose (IFG)
Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes. IFG was defined as fasting plasma glucose (FPG) between 100 and 125 mg/dL at screening.
Time frame: 90 -120 minutes post-dose
Population: Number of participants with IFG.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Hydrochlorothiazide (HCTZ) | Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Fasting Glucose (IFG) | 0.038 (mg/kg/minute)/(µIU/mL) | Standard Deviation 0.019 |
| Hydrochlorothiazide (HCTZ) Placebo | Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Fasting Glucose (IFG) | 0.037 (mg/kg/minute)/(µIU/mL) | Standard Deviation 0.109 |
p-value: >0.590% CI: [-0.008, 0.011]ANOVA
Secondary
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Glucose Tolerant (IGT)
Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes. IGT was defined as a 2 hour plasma glucose \>= 140 and \<= 199 mg/dL during a 75g oral glucose tolerance test at screening.
Time frame: 90 -120 minutes post-dose
Population: Number of participants with IGT.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Hydrochlorothiazide (HCTZ) | Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Glucose Tolerant (IGT) | 0.061 (mg/kg/minute)/(µIU/mL) | Standard Deviation 0.044 |
| Hydrochlorothiazide (HCTZ) Placebo | Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Glucose Tolerant (IGT) | 0.045 (mg/kg/minute)/(µIU/mL) | Standard Deviation 0.041 |
p-value: 0.1390% CI: [-0.012, 0.044]ANOVA
Secondary
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Normal Glucose Tolerant (NGT)
Steady state was defined as 90-120 minutes post-dose. The ratio was the measure of the quantity of glucose disposed per unit of plasma insulin concentration (PIC). Approximate PIC was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals, time = 90, 100, 110, and 120 minutes. NGT participants (FPG \<100 mg/dL & 2 hour PG \<140 mg/dL during a 75g OGTT at screening) were neither IGT nor IFG at screening. IGT - defined as a 2 hour PG \>= 140 and \<= 199 mg/dL during a 75g OGTT at screening. IFG - defined as FPG between 100 and 125 mg/dL at screening.
Time frame: 90 -120 minutes post-dose
Population: Number of participants with NGT.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Hydrochlorothiazide (HCTZ) | Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Normal Glucose Tolerant (NGT) | 0.045 (mg/kg/minute)/(µIU/mL) | Standard Deviation 0.028 |
| Hydrochlorothiazide (HCTZ) Placebo | Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Normal Glucose Tolerant (NGT) | 0.042 (mg/kg/minute)/(µIU/mL) | Standard Deviation 0.024 |
p-value: >0.590% CI: [-0.003, 0.01]ANOVA