Abdominal Obesity, Hypertension
Conditions
Brief summary
The purpose of this study is to compare the effects of two different combination therapies for high blood pressure on vascular health.
Detailed description
Hydrochlorothiazide (HCTZ) has been a popular choice for the treatment of hypertension mainly due to its efficacy in lowering blood pressure, safety, and cost-effectiveness. Similarly, angiotensin converting enzyme inhibitors (ACE-I), because of their neutral to positive impact on glycemic control, have been a popular choice for addressing hypertension in abdominally obese patients. Furthermore, the ACE-I drug class has been shown to improve vascular endothelial function and inflammation in addition to its blood pressure lowering effects. Conversely, beta-adrenergic receptor blockers (b-blockers) have generally been avoided as first line anti-hypertensive therapy in pre-diabetic patients due to concerns about worsening glycemic control and potential hastening of progression to type 2 diabetes mellitus (T2DM). However, recent data have shown that the 3rd generation b-blocker carvedilol does not negatively affect glucose metabolism and therefore may be a safe and effective choice for blood pressure control in these patients. This neutral glycemic effect is likely due to the fact that carvedilol is a non-selective b-receptor antagonist (blocks both b1 and b2 receptors) with alpha1-receptor blocking properties. In addition, carvedilol possesses anti-oxidant properties and improves endothelial function, potentially making it an attractive anti-hypertensive treatment strategy in patients with abdominal obesity. The combination of carvedilol and lisinopril may be especially effective in reducing blood pressure and may act synergistically to address the impaired vascular function and increased inflammation and oxidative stress present in patients with the metabolic syndrome phenotype. Therefore the primary objective of the current study will be to evaluate the effects of carvedilol CR + lisinopril compared to lisinopril + HCTZ on vascular function in a head to head trial in abdominally obese, hypertensive patients. The secondary objective will be to compare the effects of these two anti-hypertensive therapies on plasma biomarkers of endothelial activation, inflammation, and oxidative stress in these patients.
Interventions
DRUGCarvedilol CR + Lisinopril
Participants were given Carvedilol CR + Lisinopril for three months. Oral medication. Carvedilol CR and Lisinopril combination therapy was initiated at 20 mg and 10 mg, respectively. Patients returned one week later and doses of carvedilol CR and lisinopril were increased to 40 mg and 20 mg, respectively, depending on blood pressure.
DRUGLisinopril + HCTZ
Participants were given Lisinopril + HCTZ for three months. Oral medication. Lisinopril + HCTZ combination therapy was initiated at 12.5 mg and 10 mg, respectively. Patients returned 1 week later and doses of hydrochlorothiazide and lisinopril were increased to 25 mg and 20 mg, respectively, depending on blood pressure levels.
Sponsors
GlaxoSmithKline
St. Paul Heart Clinic
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* \>18 years old * Systolic blood pressure (SBP) \>130 and/or diastolic blood pressure (DBP) \>85 (or currently taking anti-hypertensive medication) * Waist circumference \>102 cm (men) and \>88 cm (women) * Stable cardiovascular medication regimen (or other medications known to affect endothelial function) at least 1 month prior to enrollment and throughout the study
Exclusion criteria
* Use of anti-hypertensive medications within one month of randomization (patients may be washed-out from anti-hypertensive medications) * Unstable angina * History of angina symptoms within 3 months of screening * Decompensated heart failure * History of myocardial infarction * Stroke or coronary artery bypass graft within 3 months of screening * Standard clinical contraindications to beta-blocker therapy * Standard clinical contraindications to ACE-I therapy * Women who are currently pregnant or planning to become pregnant (pregnancy testing will occur at specific intervals throughout study and women will be informed of potential risks during the consenting process; information specific to this risk will be detailed in the consent form) * Breastfeeding women * Clinically significant liver disease * Creatinine \> 2.5 mg/dL * Hepatic function greater than 3 times upper limit of normal
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Reactive Hyperemic Index by Period (Carvedilol CR + Lisinopril vs. Lisinopril + HCTZ) | Change from three months to seven months | Reactive hyperemic index is a measure of endothelial function. This is measured by the ratio of post-occlusion blood volume flow versus the baseline blood volume flow. The outcome reported is the change in this ratio after the first intervention phase compared to after the second intervention phase. |
Countries
United States
Participant flow
Recruitment details
patients were recruited from medical clinics
Pre-assignment details
Patients using anti-hypertensive medication(s) at baseline were allowed to undergo a 1-month washout prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Carvedilol CR + Lisinopril, Then Lisinopril + HCTZ Participants were randomized to Carvedilol CR + Lisinopril for the first three months, then had a washout period for one month, and then were given Lisinopril + HCTZ for the final three months. | 10 |
| Lisinopril + HCTZ, Then Carvedilol CR + Lisinopril Participants were randomized to Lisinopril + HCTZ for the first three months, then had a washout period for one month, and then were given Carvedilol CR + Lisinopril for the final three months. | 15 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (First Three Months) | Lost to Follow-up | 1 | 1 |
Baseline characteristics
| Characteristic | Lisinopril + HCTZ, Then Carvedilol CR + Lisinopril | Carvedilol CR + Lisinopril, Then Lisinopril + HCTZ | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 10 Participants | 25 Participants |
| Age Continuous | 54.9 years STANDARD_DEVIATION 6.39 | 52.7 years STANDARD_DEVIATION 9.21 | 54.0 years STANDARD_DEVIATION 7.5 |
| Region of Enrollment United States | 15 participants | 10 participants | 25 participants |
| Sex: Female, Male Female | 7 Participants | 6 Participants | 13 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 10 | 0 / 15 |
| serious Total, serious adverse events | 0 / 10 | 0 / 15 |
Outcome results
Primary
Change in Reactive Hyperemic Index by Period (Carvedilol CR + Lisinopril vs. Lisinopril + HCTZ)
Reactive hyperemic index is a measure of endothelial function. This is measured by the ratio of post-occlusion blood volume flow versus the baseline blood volume flow. The outcome reported is the change in this ratio after the first intervention phase compared to after the second intervention phase.
Time frame: Change from three months to seven months
Population: All completers were included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Carvedilol CR + Lisinopril, Then Lisinopril +HCTZ | Change in Reactive Hyperemic Index by Period (Carvedilol CR + Lisinopril vs. Lisinopril + HCTZ) | -0.26 Ratio | Standard Deviation 0.59 |
| Lisinopril + HCTZ, Then Carvedilol CR + Lisinopril | Change in Reactive Hyperemic Index by Period (Carvedilol CR + Lisinopril vs. Lisinopril + HCTZ) | -0.14 Ratio | Standard Deviation 0.18 |