Hypertension
Conditions
Keywords
blood pressure, insulin sensitivity, beta blockers, randomised double blind crossover trial
Brief summary
The purpose of this study is to conduct a randomised trial to compare the insulin sensitivity, 24 hour blood pressure profile, and tolerability of nebivolol plus a thiazide-like diuretic versus atenolol plus a thiazide-like diuretic.
Detailed description
Retrospective studies of treated hypertensive cohorts have strongly implicated beta blocker therapy as increasing the risk of developing new-onset diabetes. This has led to the latest British Hypertension Society guidelines advising caution when using beta blockers particularly in combination with thiazide-like diuretics. However the National Institute of Clinical Excellence recommends beta-blocker + thiazide combinations as the treatment of choice in patients who are not at increased risk of developing diabetes. Nebivolol is a newer class of beta blocker. Some studies in diabetic hypertensive patients have suggested that nebivolol does not impair insulin sensitivity. The aim of this study is to compare the effect on insulin sensitivity of nebivolol versus atenolol, both in combination with a thiazide-like diuretic, in a group of non-diabetic hypertensive patients.
Interventions
DRUGNebivolol
Nebivolol 2.5mg daily
DRUGAtenolol
Atenolol 25mg daily
Sponsors
Foundation for Circulatory Health
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males or females aged 18 or above * Blood pressure that meets any of the three following criteria: * BP should be \<140/85 mmHg on a maximum of two anti-hypertensive drugs
Exclusion criteria
* contraindications to beta-blockade * contraindications to thiazide use * if there was a history of asthma, diabetes, heart failure, bradycardia, atrial fibrillation, AV conduction disturbances * concurrent treatment with verapamil & dilitiazem * childbearing women * compelling indication for treatment with a beta blocker * any condition that will interfere with the treatment or the patient's ability to complete the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity Index (ISI) | Baseline, 15, 30, 60, 90, 120m following oral glucose load, at baseline and at the end of each phase(8 weeks treatment | Patients were asked to fast for a minimum of 12 hours prior to each oral glucose tolerance test (OGTT). Venous blood was withdrawn for insulin and glucose analysis, 15 minutes and immediately prior to, and 30, 60, 90 and 120 minutes following an oral glucose load. For each OGTT, the Insulin Sensitivity Index (ISI) was calculated using the standard method for oral glucose tolerance testing. For each OGTT, the Insulin Sensitivity Index (ISI) was calculated using the standard method for oral glucose tolerance testing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 24 Hour Systolic Blood Pressure | Before and after 8 weeks of treatment | The 24-h Ambulatory Blood Pressure Monitoring (ABPM) was recorded at the beginning and end of each beta-blocker treatment period. BP was automatically recorded for 24 h at 30 min intervals. The time periods from 0700h to 2200h and from 2200h to 0700h were defined as daytime and night-time, respectively. |
| Total Cholesterol | Before and after 8 weeks of treatment | Fasting blood samples were taken at the beginning and end of each treatment period. |
| HbA1c | Before and after 8 weeks of treatment | Fasting blood samples were taken at the beginning and end of each treatment period. |
| BMI | Before and after 8 weeks of treatment | Body weights and heights were taken at the beginning and end of each treatment period. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants Crossover study design all participants will receive both treatments | 54 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Wash-out (4 Weeks) | Lost to Follow-up | 3 | 7 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 61.1 years STANDARD_DEVIATION 11 |
| BMI | 27.2 kg/m^2 STANDARD_DEVIATION 6.7 |
| Current Smoker | 14 Participants |
| Diastolic Blood Pressure (DBP) | 81.3 mmHg STANDARD_DEVIATION 9 |
| Ex-smoker | 14 Participants |
| HBa1c | 5.7 percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.7 |
| Heart Rate | 71.1 bpm STANDARD_DEVIATION 8.9 |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 25 Participants |
| Systolic Blood Pressure (SBP) | 129.4 mmHg STANDARD_DEVIATION 13.2 |
| Total Cholesterol | 5.1 mmol/L STANDARD_DEVIATION 1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 54 | 0 / 54 |
| other Total, other adverse events | 0 / 54 | 0 / 54 |
| serious Total, serious adverse events | 0 / 54 | 0 / 54 |
Outcome results
Primary
Insulin Sensitivity Index (ISI)
Patients were asked to fast for a minimum of 12 hours prior to each oral glucose tolerance test (OGTT). Venous blood was withdrawn for insulin and glucose analysis, 15 minutes and immediately prior to, and 30, 60, 90 and 120 minutes following an oral glucose load. For each OGTT, the Insulin Sensitivity Index (ISI) was calculated using the standard method for oral glucose tolerance testing. For each OGTT, the Insulin Sensitivity Index (ISI) was calculated using the standard method for oral glucose tolerance testing.
Time frame: Baseline, 15, 30, 60, 90, 120m following oral glucose load, at baseline and at the end of each phase(8 weeks treatment
Population: Patients with mild-to-moderate essential hypertension, aged 18 years or above, with blood pressure controlled to \<140/85 mmHg on a maximum of two antihypertensive drugs, were recruited from the Peart-Rose Hypertension clinic at St Mary's Hospital in West London and from local general practices.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Atenolol | Insulin Sensitivity Index (ISI) | Before | 82.36 factor |
| Atenolol | Insulin Sensitivity Index (ISI) | After | 75.47 factor |
| Nebivolol | Insulin Sensitivity Index (ISI) | Before | 80.70 factor |
| Nebivolol | Insulin Sensitivity Index (ISI) | After | 81.54 factor |
Comparison: Comparing treatment effects on ISIp-value: 0.6Linear Mixed effect Modelling, adjusted
Secondary
24 Hour Systolic Blood Pressure
The 24-h Ambulatory Blood Pressure Monitoring (ABPM) was recorded at the beginning and end of each beta-blocker treatment period. BP was automatically recorded for 24 h at 30 min intervals. The time periods from 0700h to 2200h and from 2200h to 0700h were defined as daytime and night-time, respectively.
Time frame: Before and after 8 weeks of treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atenolol | 24 Hour Systolic Blood Pressure | SBP before | 128.4 mmHg | Standard Deviation 9.7 |
| Atenolol | 24 Hour Systolic Blood Pressure | SBP after | 117.2 mmHg | Standard Deviation 9.2 |
| Nebivolol | 24 Hour Systolic Blood Pressure | SBP before | 130.4 mmHg | Standard Deviation 9.5 |
| Nebivolol | 24 Hour Systolic Blood Pressure | SBP after | 121.2 mmHg | Standard Deviation 8.2 |
Comparison: Comparing treatment effects on ABPMp-value: 0.06Linear Mixed effect Model, adjusted for
Secondary
BMI
Body weights and heights were taken at the beginning and end of each treatment period.
Time frame: Before and after 8 weeks of treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atenolol | BMI | Before | 28.1 kg/m^2 | Standard Deviation 4.6 |
| Atenolol | BMI | After | 28.0 kg/m^2 | Standard Deviation 4.4 |
| Nebivolol | BMI | Before | 28.2 kg/m^2 | Standard Deviation 4.7 |
| Nebivolol | BMI | After | 28.3 kg/m^2 | Standard Deviation 4.7 |
Comparison: Comparing treatment effects on BMIp-value: 0.09Linear Mixed effect Modelling, adjusted
Secondary
HbA1c
Fasting blood samples were taken at the beginning and end of each treatment period.
Time frame: Before and after 8 weeks of treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atenolol | HbA1c | Before | 5.7 percentage of glycosylated hemoglobin | Standard Deviation 0.8 |
| Atenolol | HbA1c | After | 5.7 percentage of glycosylated hemoglobin | Standard Deviation 0.4 |
| Nebivolol | HbA1c | Before | 5.7 percentage of glycosylated hemoglobin | Standard Deviation 0.8 |
| Nebivolol | HbA1c | After | 5.7 percentage of glycosylated hemoglobin | Standard Deviation 0.3 |
Comparison: Comparing treatment effects on HbA1cp-value: 0.48Linear Mixed effect Modelling, adjusted
Secondary
Total Cholesterol
Fasting blood samples were taken at the beginning and end of each treatment period.
Time frame: Before and after 8 weeks of treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atenolol | Total Cholesterol | Before | 5.0 mmol/L | Standard Deviation 1 |
| Atenolol | Total Cholesterol | After | 4.9 mmol/L | Standard Deviation 1 |
| Nebivolol | Total Cholesterol | Before | 5.1 mmol/L | Standard Deviation 0.9 |
| Nebivolol | Total Cholesterol | After | 5.1 mmol/L | Standard Deviation 0.9 |
Comparison: Comparing treatment effects on total cholesterolp-value: 0.51Linear Mixed effect Modelling, adjusted