Pharmacogenetic Prediction of Metoprolol Effectiveness

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.

Study Overview

• Status: Terminated
• Conditions: Hypertension
• Intervention / Treatment: Drug: metoprolol succinate; Genetic: Genotyping; Procedure: CYP2D6 Phenotyping

• Study Type: Interventional
• Enrollment (Actual): 462
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver; Emergency Department

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: QUADRUPLE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Metoprolol succinate, CYP2D6 Genotyping, CYP2D6 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.

Drug: metoprolol succinate; Other Names: Lopressor; Genetic: 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. Thus the investigator, the subject, and the outcomes investigator will be blind to the intervention.; Other Names: CYP2D6 genotyping and ADRB1 genotyping; Procedure: CYP2D6 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.; Other Names: Dextromethorphan probe of CYP2D6

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Pressure Decline	Participants with at least a 10% decrease in SBP	4-6 weeks status post initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	4-6 weeks
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).	6 weeks
Adverse Drug Events: ADRB1 Genotype	Occurrence of adverse drug events will be captured and stratified by ADRB1 genotype (strong responder, good responder, non-responder).	6 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metabolomic Factors	The top 5 metabolomic factors associated with SBP decline will be captured and stratified by CYP2D6 genotype and phenotype groups.	0-6 weeks

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Institute of General Medical Sciences (NIGMS)
• Investigators: Principal Investigator: Andrew Monte, MD, University of Colorado, Denver

Publications and helpful links

General Publications

• Brocker CN, Velenosi T, Flaten HK, McWilliams G, McDaniel K, Shelton SK, Saben J, Krausz KW, Gonzalez FJ, Monte AA. Metabolomic profiling of metoprolol hypertension treatment reveals altered gut microbiota-derived urinary metabolites. Hum Genomics. 2020 Mar 11;14(1):10. doi: 10.1186/s40246-020-00260-w.

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (ACTUAL): August 23, 2017
• Study Completion (ACTUAL): August 23, 2017

Study Registration Dates

• First Submitted: November 13, 2014
• First Submitted That Met QC Criteria: November 17, 2014
• First Posted (ESTIMATE): November 18, 2014

Study Record Updates

• Last Update Posted (ACTUAL): September 16, 2021
• Last Update Submitted That Met QC Criteria: August 18, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Genotype; CYP2D6; ADRB1
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Respiratory System Agents; Antitussive Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Dextromethorphan; Metoprolol
• Other Study ID Numbers: 13-3174; 1K23GM110516-01 (NIH)