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| ID | Type | Description | Link |
|---|---|---|---|
| U01GM074492-06 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of General Medical Sciences (NIGMS) | NIH |
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There are many medications available for the treatment of high blood pressure (hypertension), but finding the right one for a specific patient can be challenging. In fact, it is estimated that less than 50% of people with hypertension have their blood pressure under control. The hypothesis is that genetic differences between individuals influence their response to antihypertensive medications. This study is aimed at determining the genetic factors that may influence a person's response to either a beta-blocker or a thiazide diuretic. The hope is that through this research, the investigators may someday be able to use an individual's genetic information to guide the selection of their blood pressure medicine, leading to better control of blood pressure, and less need for the current trial and error process.
The proposed work should help move toward the long-term goal of selection of antihypertensive drug therapy based on a patient's genetic make-up. Hypertension (HTN) is the most common chronic disease for which drugs are prescribed, and the most prevalent risk factor for heart attack, stroke, renal failure and heart failure. Responses to antihypertensive drug therapy exhibit considerable interpatient variability, contributing to poor rates of HTN control (currently about 40-50% in the US), and frequent nonadherence and dropout from therapy. We propose to identify genetic predictors of the antihypertensive and adverse metabolic responses to two preferred and pharmacodynamically contrasting drugs, a beta-blocker (metoprolol) and a thiazide diuretic (chlorthalidone) in a sequential monotherapy design in 400 hypertensive individuals. Data collected will include home and clinic blood pressure, blood samples for testing for adverse metabolic effects and other biomarkers, RNA, and DNA and urine sample. We will conduct genome-wide association single nucleotide polymorphism (SNP) genotyping and data from the study will be used for replication of findings from the previous PEAR trial, along with new discoveries. The primary aims are to define the genetic determinants of the antihypertensive response and adverse metabolic responses (e.g. changes in glucose, triglycerides and uric acid). The proposed research is significant because genetically-targeted antihypertensive therapy could lead to dramatically higher response rates and fewer adverse effects than the usual trial-and-error approach. This would likely lead to higher rates of HTN control, less need for polypharmacy, reduced health care costs, and improved outcomes.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Metoprolol + Chlorthalidone | Experimental | Study participants in this group had their current hypertension treatment withdrawn, baseline labs drawn and hypertension documented. Participants were initiated on metoprolol tartrate 50 mg twice daily for two weeks, followed by dose titration to 100 mg twice daily for six additional weeks if blood pressure (BP) > 120/70 mmHg. BP measures were again recorded. Participants entered a washout where metoprolol was titrated, then discontinued, and the patient's hypertension was re-established. After another set of identical baseline labs, study participants were initiated on chlorthalidone 25 mg four days per week (Monday, Wednesday, Thursday, Saturday) 15 mg daily for two weeks, followed by 25 mg daily for an additional six weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metoprolol | Drug | Metoprolol 50 mg twice daily titrated to 100 mg twice daily Note: due to discontinuation of the manufacture of chlorthalidone 15 mg, effective Jan 1, 2013; the starting dose of chlorthalidone will be 25 mg 4 times per week (Mon, Wed, Thur, Sat) with subsequent titration to 25 mg daily. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Blood Pressure From Baseline to Treatment | Response to blood pressure medication will be assessed by measuring blood pressure before and after treatment | after 6-8 weeks of treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse Metabolic Effects | Change in glucose after treatment with study medication | after 6-8 weeks treatment |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Julie A Johnson, PharmD | University of Florida | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Florida | Gainesville | Florida | 32610 | United States | ||
| Emory University School of Medicine |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24637943 | Background | Hamadeh IS, Langaee TY, Dwivedi R, Garcia S, Burkley BM, Skaar TC, Chapman AB, Gums JG, Turner ST, Gong Y, Cooper-DeHoff RM, Johnson JA. Impact of CYP2D6 polymorphisms on clinical efficacy and tolerability of metoprolol tartrate. Clin Pharmacol Ther. 2014 Aug;96(2):175-81. doi: 10.1038/clpt.2014.62. Epub 2014 Mar 17. | |
| 38747311 | Derived | Mehanna M, McDonough CW, Smith SM, Gong Y, Gums JG, Chapman AB, Johnson JA, Cooper-DeHoff RM. Integrated metabolomics analysis reveals mechanistic insights into variability in blood pressure response to thiazide diuretics and beta blockers. Clin Transl Sci. 2024 May;17(5):e13816. doi: 10.1111/cts.13816. |
| Label | URL |
|---|---|
| PEAR study website | View source |
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Healthy volunteers with mild to moderate primary hypertension between the ages of 18-70 were eligible for the study. Subjects were washed-out from their hypertension medication prior to beginning study protocol. Participants with elevated systolic blood pressure greater than 180 mmHg after wash-out were excluded from the study.
The first subject was recruited on 8/10/10 and the final patient was recruited on 9/30/2013. Subjects were recruited from family medicine clinics and were identified through providers daily schedules, medical records, and encounter forms.
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| ID | Title | Description |
|---|---|---|
| FG000 | Metoprolol + Chlorthalidone | This group was assigned the following: (Metoprolol 8 weeks): Metoprolol tartrate 50 mg twice daily for two weeks. After two weeks subjects will be seen in clinic and will have the dose doubled to 100 mg twice daily if either their home blood pressure (HBP) average or office blood pressure (OBP) is > 120/70 mmHg. They will continue on this dose for an additional 6 weeks. (Washout 2 weeks): Then will washout from all study medication. (Chlorthalidone 8 weeks): participants will initiate chlorthalidone 25 mg four times per week (Monday, Wednesday, Thursday, Saturday) for two weeks, then 25 mg daily of chlorthalidone for 6 weeks. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Metoprolol 8 Weeks |
|
| ||||||||||||||||||
| Washout 2 Weeks |
| |||||||||||||||||||
| Chlorthalidone 8 Weeks |
|
Approximately 1000 males or females with mild to moderate primary HTN, of any race or ethnicity, between the ages of 18 and 65 will be enrolled into the PEAR2 protocol. Prospective study participants will be those with newly diagnosed HTN, untreated HTN or known HTN currently treated with antihypertensive drugs.
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| ID | Title | Description |
|---|---|---|
| BG000 | Metoprolol + Chlorthalidone | This group was assigned to the following: Metoprolol tartrate 50 mg twice daily for two weeks. After two weeks subjects will be seen in clinic and will have the dose doubled to 100 mg twice daily if either their HBP average or OBP is > 120/70 mmHg. They will continue on this dose for an additional 6 weeks. Then will washout from all study medication. After washout, participants will initiate chlorthalidone 25 mg four times per week (Monday, Wednesday, Thursday, Saturday) for two weeks, then 25 mg daily of chlorthalidone for 6 weeks. Metoprolol: Metoprolol 50 mg twice daily titrated to 100 mg twice daily Chlorthalidone: Chlorthalidone 25 mg 4 times per week titrated to 25 mg daily Note: due to discontinuation of the manufacture of chlorthalidone 15 mg, effective Jan 1, 2013; the starting dose of chlorthalidone will be 25 mg 4 times per week (Mon, Wed, Thur, Sat) with subsequent titration to 25 mg daily. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Blood Pressure From Baseline to Treatment | Response to blood pressure medication will be assessed by measuring blood pressure before and after treatment | All patients with antihypertensive response data. 282 patients completed all 3 study periods. 369 patients completed only period 1. 328 patients completed only period 3. | Posted | Mean | Standard Deviation | mmHg | after 6-8 weeks of treatment |
|
Adverse events were recorded during subject participation in the study. Participation lasted between 3 and 4 months.
Adverse events were not recorded according to intervention.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | All Study Participants | Study participants had their current hypertension treatment withdrawn, baseline labs drawn and hypertension documented. Participants were initiated on metoprolol tartrate 50 mg twice daily for two weeks, followed by dose titration to 100 mg twice daily for six additional weeks if blood pressure (BP) > 120/70 mmHg. BP measures were again recorded. Participants entered a washout where metoprolol was titrated, then discontinued, and the patient's hypertension was re-established. The subjects were initiated on chlorthalidone 25 mg four days per week (Monday, Wednesday, Thursday, Saturday) 15 mg daily for two weeks, followed by 25 mg daily for an additional six weeks. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Vascular disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bradycardia | Cardiac disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Julie A. Johnson | University of Florida | (352) 273-6309 | johnson@cop.ufl.edu |
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| ID | Term |
|---|---|
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D008790 | Metoprolol |
| D002752 | Chlorthalidone |
| ID | Term |
|---|---|
| D050198 | Phenoxypropanolamines |
| D011412 | Propanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
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|
|
| Chlorthalidone | Drug | Chlorthalidone 25 mg 4 times per week titrated to 25 mg daily |
|
|
| Atlanta |
| Georgia |
| 30322 |
| United States |
| Mayo Clinic, Division of Hypertension | Rochester | Minnesota | 55905 | United States |
| 38353215 | Derived | Chekka LMS, Tantawy M, Langaee T, Wang D, Renne R, Chapman AB, Gums JG, Boerwinkle E, Cooper-DeHoff RM, Johnson JA. Circulating microRNA Biomarkers of Thiazide Response in Hypertension. J Am Heart Assoc. 2024 Feb 20;13(4):e032433. doi: 10.1161/JAHA.123.032433. Epub 2024 Feb 14. |
| 30753254 | Derived | Mehanna M, Wang Z, Gong Y, McDonough CW, Beitelshees AL, Gums JG, Chapman AB, Schwartz GL, Bailey KR, Johnson JA, Turner ST, Cooper-DeHoff RM. Plasma Renin Activity Is a Predictive Biomarker of Blood Pressure Response in European but not in African Americans With Uncomplicated Hypertension. Am J Hypertens. 2019 Jun 11;32(7):668-675. doi: 10.1093/ajh/hpz022. |
| 29925376 | Derived | Sa ACC, Webb A, Gong Y, McDonough CW, Shahin MH, Datta S, Langaee TY, Turner ST, Beitelshees AL, Chapman AB, Boerwinkle E, Gums JG, Scherer SE, Cooper-DeHoff RM, Sadee W, Johnson JA. Blood pressure signature genes and blood pressure response to thiazide diuretics: results from the PEAR and PEAR-2 studies. BMC Med Genomics. 2018 Jun 20;11(1):55. doi: 10.1186/s12920-018-0370-x. |
| 29523524 | Derived | Singh S, McDonough CW, Gong Y, Alghamdi WA, Arwood MJ, Bargal SA, Dumeny L, Li WY, Mehanna M, Stockard B, Yang G, de Oliveira FA, Fredette NC, Shahin MH, Bailey KR, Beitelshees AL, Boerwinkle E, Chapman AB, Gums JG, Turner ST, Cooper-DeHoff RM, Johnson JA. Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients. J Am Heart Assoc. 2018 Mar 9;7(6):e007339. doi: 10.1161/JAHA.117.007339. |
| 28115488 | Derived | Shahin MH, Sa AC, Webb A, Gong Y, Langaee T, McDonough CW, Riva A, Beitleshees AL, Chapman AB, Gums JG, Turner ST, Boerwinkle E, Scherer SE, Sadee W, Cooper-DeHoff RM, Johnson JA. Genome-Wide Prioritization and Transcriptomics Reveal Novel Signatures Associated With Thiazide Diuretics Blood Pressure Response. Circ Cardiovasc Genet. 2017 Jan;10(1):e001404. doi: 10.1161/CIRCGENETICS.116.001404. |
|
| NOT COMPLETED |
|
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Metorprolol Only | Study participants had their current hypertension treatment withdrawn, baseline labs drawn and hypertension documented. Participants were initiated on metoprolol tartrate 50 mg twice daily for two weeks, followed by dose titration to 100 mg twice daily for six additional weeks if blood pressure (BP) > 120/70 mmHg. BP measures were again recorded. |
| OG002 | Chlorthalidone Only | Study participants were initiated on chlorthalidone 25 mg four days per week (Monday, Wednesday, Thursday, Saturday) 15 mg daily for two weeks, followed by 25 mg daily for an additional six weeks. |
|
|
|
| Secondary | Adverse Metabolic Effects | Change in glucose after treatment with study medication | All patients with change in glucose data | Posted | Mean | Standard Deviation | mg/dL | after 6-8 weeks treatment |
|
|
|
|
| 3 |
| 839 |
| 114 |
| 839 |
| Heart Attack | Cardiac disorders | Systematic Assessment |
|
| Chest Pain | Cardiac disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Dizziness | Ear and labyrinth disorders | Systematic Assessment |
|
| Dyspnea | Nervous system disorders | Systematic Assessment |
|
| Headache | Vascular disorders | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Other | General disorders | Systematic Assessment |
|
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| D009930 |
| Organic Chemicals |
| D020005 | Propanols |
| D000588 | Amines |
| D000096926 | Benzenesulfonamides |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D001577 | Benzophenones |
| D010797 | Phthalimides |
| D007094 | Imides |
| D007659 | Ketones |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D054833 | Isoindoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
Mean glucose change after treatment with metoprolol
| t-test, 1 sided |
| 0.049 |
P-value for one sided t-test for mean glucose change before and after treatment with metoprolol was 0.049. |
| 2-Sided |
| Superiority or Other |