Diabetes Mellitus, Type 2, Hypertension
Conditions
Keywords
Type 2 Diabetes Mellitus, Hypertension, Carvedilol CR, Beta-blocker, Oxidative stress, Inflammation, Vascular benefits
Brief summary
To determine whether addition of Carvedilol CR to diabetic patients with hypertension who are receiving the ACEi,Lisinopril,will provide added benefits to blood vessels when compared to treatment with Lisinopril alone.It is believed that carvedilol provides added benefits by suppressing free radicals(charged substances that cause damage to the body ) and inflammation.
Detailed description
Type 2 diabetes is an atherosclerotic, pro-inflammatory and pro-oxidative stress.Both vascular oxidative stress and inflammation are CVD risk factors and impact endothelial function. Carvedilol has been demonstrated in preclinical and clinical studies (although limited in size) to exert anti-inflammatory and antioxidant properties: (1) reduce the inflammation markers such as high sensitivity C-reactive protein (hsCRP); (2) reduce oxidative stress via dually eliminating existing reactive oxygen species (ROS) and suppressing the generation of ROS; (3) prevent lipid peroxidation in myocardial cell membrane; (4) protect endothelial and vascular muscle cells from oxygen radical-mediated injury. This project is about studying the effect of carvedilol CR on blood vessels of diabetic hypertensive patients as compared to Lisinopril alone. This study involves weaning patient off their current antihypertensive medications and starting them on Lisinopril with Carvedilol CR or lisinopril alone for 6 months and studying the effects of the drugs during this period and thereafter.
Interventions
DRUGCarvedilol Controlled Release (CR)
lisinopril starting dose in all patients 10 mg QD for 1 week then increase to 20 mg QD throughout the study. Initial dose: Carvedilol CR (20 mg QD, dose level 1) Titration: If tolerated, increase the dosage to 20 mg QD, 40 mg QD, and 80mg QD orally over successive intervals of at least 2 weeks to achieve target blood pressure sSBP \<130 and sDBP \< 80
DRUGlisinopril
lisinopril starting dose in all patients 10 mg QD for 1 week then increase to 20 mg QD throughout the study
Sponsors
GlaxoSmithKline
University at Buffalo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Is male or female \>= 18 and \<= 70 years of age * Has a documented history of type 2 diabetes mellitus for a minimum of four months prior to the screening visit * Has a documented history of or current presentation with Stage 1 or Stage 2 hypertension and meets one of the following criteria: * Has controlled hypertension (sSBP \<130 mmHg AND sDBP \<80 mmHg) on \>=2 antihypertensive medications NOTE: A combination drug containing two antihypertensive agents represents two antihypertensive medications OR * Has uncontrolled hypertension (sSBP \>=130 and \<=170 mmHg AND/OR sDBP \>=80 and \<=105 mmHg) on one or two antihypertensive medications OR * Has newly diagnosed or previously untreated hypertension (sSBP \>=130 and \<=170 mmHg AND/OR sDBP \>=80 and \<=105 mmHg * At Randomization, sitting systolic blood pressure (sSBP) \>= 130 mmHg or sitting diastolic blood pressure (sDBP) \>= 80 mmHg and sSBP \<= 170 mmHg and sDBP \<= 105 mmHg * Has been on a stable dose of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) for a minimum of four months prior to the screening visit
Exclusion criteria
* Has any clinically significant abnormality identified in the screening physical examination, laboratory tests or electrocardiogram which, in the judgement of the investigator, would preclude safe completion of the study * Is female of childbearing potential * Has any of these cardiac conditions: uncontrollable or symptomatic arrhythmias, unstable angina, sick sinus syndrome or second or third degree heart block (unless treated with a permanent, functioning pacemaker), bradycardia (heart rate \<55 bpm), and stroke within three months of study screening, and history of myocardial infarction. * Has Congestive Heart Failure NYHA (New York Heart Association) class II-IV * Has type 1 diabetes mellitus * Has newly diagnosed type 2 diabetes (within 4 months of screening visit) * Has HbA1c \> 8.5% * Has the following, as it relates to subject's antidiabetic therapy:Initiated or changed dosage or formulation of thiazolidinediones (TZDs) within 6 months of screening visit. * A history of acute or chronic acidosis, including diabetic ketoacidosis * Has current clinical diagnosis of chronic obstructive pulmonary disease (COPD, e.g., chronic bronchitis) or asthma * Has a history of bronchospastic disease not undergoing active therapy in whom, in the investigator's opinion, treatment with study medication could provoke bronchospasm * Has evidence of any of the following clinically significant diseases that could impair the absorption, metabolism, or excretion of orally-administered medication: * renal disease defined as estimated Glomerular Filtration Rate (eGFR) \<60mL/min per 1.73 m2 using the Modification of Diet in Renal Disease (MDRD) formula below: GFR (mL/min/1.73m2) = 186 x \[Serum Creatinine (umol/L) x 0.0113\]-1.154 x Age(years)-0.203 (x 0.742 if female) * hepatic disease (i.e., ALT or AST levels greater than three times the upper limit of normal range, history of hepatic impairment, or by clinical assessment) * Chronic biliary disorders * Has endocrine disorders (e.g., pheochromocytoma, active and untreated hypo or hyperthyroidism) * Has any known contraindication to ACE inhibitors, alpha- or beta-blocker treatment * Has systemic disease, including cancer, with reduced (\<12 months) life expectancy * Has used an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication * Has a history of a psychological illness or any condition that would interfere with the subject's ability to understand or complete the requirements of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Brachial Artery Vascular Reactivity | 6 months | Percent change from baseline in Brachial artery vascular reactivity at 6 months calculated as: (brachial reactivity at 6 months-brachial reactivity at 0 months)/brachial reactivity at 0 month \*100 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Oxidative Stress in Mononuclear Cells (MNC) | 6 months | Percent change from baseline in Reactive Oxygen species (ROS) generation in MNC at 6 months calculated as: (ROS at 6 months-ROS at 0 months)/ROS at 0 month \*100 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Carvedilol carvedilol
carvedilol: carvedilol | 7 |
| Lisinopril lisinopril
lisinopril: lisinopril | 7 |
| Total | 14 |
Baseline characteristics
| Characteristic | Lisinopril | Total | Carvedilol |
|---|---|---|---|
| Age, Continuous | 59 years STANDARD_DEVIATION 11 | 57 years STANDARD_DEVIATION 10 | 56 years STANDARD_DEVIATION 10 |
| Body mass index (BMI) | 36 Kg/m^2 STANDARD_DEVIATION 4 | 35 Kg/m^2 STANDARD_DEVIATION 3 | 35 Kg/m^2 STANDARD_DEVIATION 3 |
| diastolic blood pressure | 89 mmHg STANDARD_DEVIATION 5 | 89 mmHg STANDARD_DEVIATION 4 | 88 mmHg STANDARD_DEVIATION 5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 4 Participants |
| systolic blood pressure | 137 mmHg STANDARD_DEVIATION 7 | 136 mmHg STANDARD_DEVIATION 7 | 134 mmHg STANDARD_DEVIATION 8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 7 |
| other Total, other adverse events | 0 / 7 | 0 / 7 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 |
Outcome results
Primary
Change in Brachial Artery Vascular Reactivity
Percent change from baseline in Brachial artery vascular reactivity at 6 months calculated as: (brachial reactivity at 6 months-brachial reactivity at 0 months)/brachial reactivity at 0 month \*100
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Carvedilol | Change in Brachial Artery Vascular Reactivity | 28 percentage of change | Standard Error 20 |
| Lisinopril | Change in Brachial Artery Vascular Reactivity | 19 percentage of change | Standard Error 17 |
Secondary
Change in Oxidative Stress in Mononuclear Cells (MNC)
Percent change from baseline in Reactive Oxygen species (ROS) generation in MNC at 6 months calculated as: (ROS at 6 months-ROS at 0 months)/ROS at 0 month \*100
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Carvedilol | Change in Oxidative Stress in Mononuclear Cells (MNC) | -15 percentage of change | Standard Error 9 |
| Lisinopril | Change in Oxidative Stress in Mononuclear Cells (MNC) | -10 percentage of change | Standard Error 11 |