Hypertension
Conditions
Keywords
Genotype, CYP2D6, ADRB1
Brief summary
The investigators will prospectively follow a population of patients with uncontrolled high blood pressure beginning metoprolol succinate therapy to determine the drug effect in an observational clinical trial. The investigators will determine each individual's genotype for both CYP2D6 and Adrenoceptor Beta 1 (ADRB1). Metabolomic markers will be identified to determine if specific metabolites are associated with drug response. The investigators' overall objective is to determine if genetics predicts metoprolol succinate response better than clinical factors such as age, race, body mass index, dose, and medication co-ingestion.
Interventions
DRUGmetoprolol succinate
GENETICGenotyping
CYP2D6 only clinically pertinent pathway of metoprolol metabolism and polymorphisms have been associated with altered levels of metoprolol. ADRB1 is the drug target and polymorphism in this receptor has been associated with variable drug response. Genotyping will occur after the treatment phase is complete. Thus the investigator, the subject, and the outcomes investigator will be blind to the intervention.
PROCEDURECYP2D6 Phenotyping
Phenotype can be discordant from what is predicted by genotype due to variability in absorption, hepatic blood flow, drug interaction and drug elimination. These factors can be accounted for by utilizing a phenotyping assay that determines area under the curve of the probe since the probe is affected by the same variables dictating metabolism phenotype of the therapeutic drug. Investigators will be blind to the patient blood pressure outcome for this intervention.
Sponsors
National Institute of General Medical Sciences (NIGMS)
University of Colorado, Denver
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects between age \>30 years and \< 80 years 2. Subjects have diagnosis of uncontrolled essential hypertension.
Exclusion criteria
1. end stage liver disease, 2. end stage renal disease, 3. pregnant females, 4. American Society of Anesthesiologists (ASA) classification of \>3, 5. wards of the state, prisoners, 6. decisionally challenged, 7. HR\<60 bpm, 8. AV block\>240 msec, 9. active reactive airway disease, 10. illicit drug abuse in the preceding 30 days, 11. hypersensitivity to metoprolol or its derivatives 12. severe peripheral arterial circulatory disorders. Subjects will have a screening physical exam performed by Dr. Monte prior to enrollment in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Blood Pressure Decline | 4-6 weeks status post initiation | Participants with at least a 10% decrease in SBP |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Heart Rate Decline | 4-6 weeks | 10 % decline from pre-initiation heart rate will considered a HR decline success. Number of of participants with at least 10% decline is reported. |
| Adverse Drug Events: CYP2D6 Metabolizer Status | 6 weeks | Occurrence of adverse drug events will be captured and stratified by CYP2D6 metabolizer status (Poor Metabolizer (PM), Extensive Metabolizer (EM), Intermediate Metabolizer (IM), and Ultra rapid Metabolizer). |
| Adverse Drug Events: ADRB1 Genotype | 6 weeks | Occurrence of adverse drug events will be captured and stratified by ADRB1 genotype (strong responder, good responder, non-responder). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Metabolomic Factors | 0-6 weeks | The top 5 metabolomic factors associated with SBP decline will be captured and stratified by CYP2D6 genotype and phenotype groups. |
Countries
United States
Participant flow
Pre-assignment details
322 participants screen failed or withdrew after consent, but prior to starting the study & receiving the intervention
Participants by arm
| Arm | Count |
|---|---|
| Metoprolol Succinate, Genotyping, Clinical Factors, and Phenotyping The parent study will integrate covariates to predict metoprolol effectiveness for SBP decline of 10%. All patients will receive metoprolol. The following covariates will be used to predict metoprolol effectiveness: clinical variables (Age, sex, race/ethnicity, co-medications, and BMI) CYP2D6 genotype, CYP2D6 phenotype, and metabolomic factors.
metoprolol succinate
Genotyping: CYP2D6 only clinically pertinent pathway of metoprolol metabolism and polymorphisms have been associated with altered levels of metoprolol. ADRB1 is the drug target and polymorphism in this receptor has been associated with variable drug response. Genotyping will occur after the treatment phase is complete.
CYP2D6 Phenotyping: Phenotype can be discordant from what is predicted by genotype. CYP2D6 henotyping using dextromethorphan will be used. Investigators will be blind to the patient blood pressure outcome for this intervention. | 140 |
| Total | 140 |
Baseline characteristics
| Characteristic | Metoprolol Succinate, Genotyping, Clinical Factors, and Phenotyping |
|---|---|
| Age, Continuous | 52.12 years STANDARD_DEVIATION 11.05 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 116 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 60 Participants |
| Race (NIH/OMB) More than one race | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 70 Participants |
| Region of Enrollment United States | 140 participants |
| Sex: Female, Male Female | 55 Participants |
| Sex: Female, Male Male | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 140 |
| other Total, other adverse events | 0 / 140 |
| serious Total, serious adverse events | 0 / 140 |
Outcome results
Primary
Blood Pressure Decline
Participants with at least a 10% decrease in SBP
Time frame: 4-6 weeks status post initiation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metoprolol Succinate, Genotyping, Clinical Factors, and Phenotyping | Blood Pressure Decline | 85 Participants |
Secondary
Adverse Drug Events: ADRB1 Genotype
Occurrence of adverse drug events will be captured and stratified by ADRB1 genotype (strong responder, good responder, non-responder).
Time frame: 6 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Metoprolol Succinate, Genotyping, Clinical Factors, and Phenotyping | Adverse Drug Events: ADRB1 Genotype | ADRB1 genotype: Strong Responder | 1 participants with events |
| Metoprolol Succinate, Genotyping, Clinical Factors, and Phenotyping | Adverse Drug Events: ADRB1 Genotype | ADRB1 genotype: Good Responder | 2 participants with events |
| Metoprolol Succinate, Genotyping, Clinical Factors, and Phenotyping | Adverse Drug Events: ADRB1 Genotype | ADRB1 genotype: Non-responder | 0 participants with events |
Secondary
Adverse Drug Events: CYP2D6 Metabolizer Status
Occurrence of adverse drug events will be captured and stratified by CYP2D6 metabolizer status (Poor Metabolizer (PM), Extensive Metabolizer (EM), Intermediate Metabolizer (IM), and Ultra rapid Metabolizer).
Time frame: 6 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Metoprolol Succinate, Genotyping, Clinical Factors, and Phenotyping | Adverse Drug Events: CYP2D6 Metabolizer Status | CYP2D6 metabolizer status: EM | 3 participants with events |
| Metoprolol Succinate, Genotyping, Clinical Factors, and Phenotyping | Adverse Drug Events: CYP2D6 Metabolizer Status | Other Metabolizer Statuses | 0 participants with events |
Secondary
Heart Rate Decline
10 % decline from pre-initiation heart rate will considered a HR decline success. Number of of participants with at least 10% decline is reported.
Time frame: 4-6 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metoprolol Succinate, Genotyping, Clinical Factors, and Phenotyping | Heart Rate Decline | 67 Participants |
Other Pre-specified
Metabolomic Factors
The top 5 metabolomic factors associated with SBP decline will be captured and stratified by CYP2D6 genotype and phenotype groups.
Time frame: 0-6 weeks