Examining Genetic Influence on Response to Beta-Blocker Medications in People With Type 2 Diabetes

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00925119
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 31
• Location: 1
• Arm: 1
• Duration (Months): 53
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

Beta-blockers are medications used to treat cardiovascular disease (CVD) symptoms, including high blood pressure and chest pain. People with diabetes who receive beta-blockers may experience adverse health effects, but the exact cause of why this happens remains unknown. This study will examine the genetic factors that may influence how atenolol, a beta-blocker medication, affects fat breakdown, blood sugar levels, and heart function in people with type 2 diabetes.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: Atenolol	Phase 4

Detailed Description

People with diabetes who develop CVD have worse health outcomes than people without diabetes who develop CVD. Beta-blockers are medications used to treat high blood pressure, angina (i.e., chest pain), arrhythmias, and other CVD conditions. While beta-blockers are effective at treating these conditions, they may also have damaging effects on cholesterol or glucose levels, thereby possibly lessening their ability to prevent CVD events in people with diabetes. It is important to identify which patients may not benefit from receiving beta-blocker medications. Genetic factors may influence how people respond to beta-blocker medications. The purpose of this study is to evaluate the influence of genetic variation on beta-blocker-induced changes in insulin sensitivity, fat breakdown, and heart function in people with type 2 diabetes.

This study will enroll people with type 2 diabetes. At a series of up to three baseline study visits, participants will have a blood collection, a glucose tolerance test, an echocardiogram to obtain images of the heart, and biopsies of muscle from the thigh and fat from the stomach. All participants will then receive atenolol once a day for 8 weeks. During Week 1, participants will receive a low dose of atenolol. They will then attend a study visit at the end of Week 1, and study researchers will examine how well participants are tolerating the medication. If the atenolol is well tolerated, the dose will be increased. Study researchers will call participants 1 week after any dosage changes to monitor for side effects. Blood collection will occur again at a study visit at Week 4. At Week 8, participants will then attend up to three study visits for repeat baseline testing. Participants will then be slowly tapered off of atenolol over a 1-week period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Uncoupling Protein Polymorphisms and Cardiometabolic Responses to Beta-Blockers
• Study Start Date: Dec 1, 2009
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Atenolol Participants will receive atenolol for 8 weeks.	Drug: Atenolol; 12.5 mg twice daily of atenolol for 1 week; increased to 25 mg twice daily for a total of 8 weeks, if the medication is well tolerated

Outcome Measures

Primary Outcome Measures

1. Change in Diastolic Function (Annular Tissue Velocity [Em]) [8 weeks]

2. Change in Free Fatty Acid Kinetics [Baseline and Week 8]

   Estimate of peripheral lipolysis using modeling of free fatty acid levels collected during an IV glucose tolerance test. The change in threshold for insulin action (post-atenolol minus pre-atenolol) is the primary variable from this modeling that we analyzed.

Secondary Outcome Measures

1. Change in Triglycerides [Baseline and Week 8]

   (Post atenolol triglycerides - Pre atenolol triglycerides)

2. Change in Insulin Sensitivity [Baseline and Week 8]

   As measured by the Homeostatic model assessment of insulin resistance (HOMA2-IR) (post atenolol - pre atenolol). he Homeostatic model assessment (HOMA) is a method for assessing insulin sensitivity from fasting glucose and insulin. A higher HOMA value indicates higher insulin resistance. The widely-used formulae available for HOMA1 provide only linear approximations of HOMA_%B and HOMA_IR, the inverse of HOMA_%S. These are: HOMA1_IR = [FPI (uU/ml) x FPG (mmol/l) ]/22.5 HOMA1_%B = (20 x FPI)/(FPG - 3.5) The results obtained for HOMA2 may differ considerably from HOMA1 computer-calculated values, especially for more extreme glucose and insulin values. For this reason, no attempt has been made to provide linear approximations of HOMA2 calculated values of HOMA_%B, HOMA_IR and HOMA_%S. The software needed to calculate HOMA2 values is available on this website: https://www.dtu.ox.ac.uk/homacalculator/download.php, subject to the conditions specified on the downloads page.

3. Change in Glucose Effectiveness [Baseline and Week 8]

   Glucose effectiveness as measured by insulin-modified IV glucose tolerance test using the MINMOD model.

4. Change in HDL [Baseline and Week 8]

5. Change in Insulin [Baseline and Week 8]

   fasting insulin (post - pre atenolol)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Type 2 diabetes

• Pre-Diabetes

Exclusion Criteria:

• Insulin therapy

• Treatment with any beta-blocker in the 30 days before study entry

• Asthma

• Chronic obstructive pulmonary disease (COPD)

• Greater than first degree heart block

• Heart rate less than 60 bpm

• Systolic blood pressure less than 90 mm Hg

• Raynaud's phenomenon

• Known history of angina, heart attack, heart failure, coronary revascularization, or automatic implantable cardioverter defibrillators

• Pregnant

• Creatinine clearance less than 35 ml/min

• Hematologic dysfunction (white blood cell [WBC] count less than 3000 or hematocrit less than 28%)

• Allergy to amide anesthetics

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Maryland	Baltimore	Maryland	United States	21201

Sponsors and Collaborators

• University of Maryland, Baltimore
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Amber L. Beitelshees, PharmD, MPH, University of Maryland, Baltimore

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Amber Beitelshees, Principal Investigator, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT00925119
• Other Study ID Numbers: HP-00040291; K23HL091120
• First Posted: Jun 19, 2009
• Last Update Posted: Sep 26, 2019
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Amber Beitelshees, Principal Investigator, University of Maryland, Baltimore: Diabetes; Atenolol; Genetic
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Atenolol

Study Results

Participant Flow

Arm/Group Title	Atenolol
Arm/Group Description	Participants will receive atenolol for 8 weeks. Atenolol: 12.5 mg twice daily of atenolol for 1 week; increased to 25 mg twice daily for a total of 8 weeks, if the medication is well tolerated
Period Title: Overall Study
STARTED	31
COMPLETED	19
NOT COMPLETED	12

Baseline Characteristics

Arm/Group Title	Atenolol
Arm/Group Description	Participants will receive atenolol for 8 weeks. Atenolol: 12.5 mg twice daily of atenolol for 1 week; increased to 25 mg twice daily for a total of 8 weeks, if the medication is well tolerated
Overall Participants	19
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57 (11)
Sex: Female, Male (Count of Participants)
Female	11 57.9%
Male	8 42.1%

Outcome Measures

1. Primary Outcome

Title	Change in Diastolic Function (Annular Tissue Velocity [Em])
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Data were not able to be collected from the echocardiography.

Arm/Group Title	Atenolol
Arm/Group Description	Participants will receive atenolol for 8 weeks. Atenolol: 12.5 mg twice daily of atenolol for 1 week; increased to 25 mg twice daily for a total of 8 weeks, if the medication is well tolerated
Measure Participants	0

2. Primary Outcome

Title	Change in Free Fatty Acid Kinetics
Description	Estimate of peripheral lipolysis using modeling of free fatty acid levels collected during an IV glucose tolerance test. The change in threshold for insulin action (post-atenolol minus pre-atenolol) is the primary variable from this modeling that we analyzed.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Modeling data not available in all subjects

Arm/Group Title	Atenolol
Arm/Group Description	Participants will receive atenolol for 8 weeks. Atenolol: 12.5 mg twice daily of atenolol for 1 week; increased to 25 mg twice daily for a total of 8 weeks, if the medication is well tolerated
Measure Participants	5
Mean (Standard Deviation) [mU/mL]	2.02 (16.5)

3. Secondary Outcome

Title	Change in Triglycerides
Description	(Post atenolol triglycerides - Pre atenolol triglycerides)
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Data available in 17 subjects

Arm/Group Title	Atenolol
Arm/Group Description	Participants will receive atenolol for 8 weeks. Atenolol: 12.5 mg twice daily of atenolol for 1 week; increased to 25 mg twice daily for a total of 8 weeks, if the medication is well tolerated
Measure Participants	17
Mean (Standard Deviation) [mg/dL]	17 (65)

4. Secondary Outcome

Title	Change in Insulin Sensitivity
Description	As measured by the Homeostatic model assessment of insulin resistance (HOMA2-IR) (post atenolol - pre atenolol). he Homeostatic model assessment (HOMA) is a method for assessing insulin sensitivity from fasting glucose and insulin. A higher HOMA value indicates higher insulin resistance. The widely-used formulae available for HOMA1 provide only linear approximations of HOMA_%B and HOMA_IR, the inverse of HOMA_%S. These are: HOMA1_IR = [FPI (uU/ml) x FPG (mmol/l) ]/22.5 HOMA1_%B = (20 x FPI)/(FPG - 3.5) The results obtained for HOMA2 may differ considerably from HOMA1 computer-calculated values, especially for more extreme glucose and insulin values. For this reason, no attempt has been made to provide linear approximations of HOMA2 calculated values of HOMA_%B, HOMA_IR and HOMA_%S. The software needed to calculate HOMA2 values is available on this website: https://www.dtu.ox.ac.uk/homacalculator/download.php, subject to the conditions specified on the downloads page.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Post and Pre atenolol data available in 17 subjects

Arm/Group Title	Atenolol
Arm/Group Description	Participants will receive atenolol for 8 weeks. Atenolol: 12.5 mg twice daily of atenolol for 1 week; increased to 25 mg twice daily for a total of 8 weeks, if the medication is well tolerated
Measure Participants	17
Mean (Standard Deviation) [arbitrary units]	-0.05 (0.84)

5. Secondary Outcome

Title	Change in Glucose Effectiveness
Description	Glucose effectiveness as measured by insulin-modified IV glucose tolerance test using the MINMOD model.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Data could not be determined because assumptions for MINMOD model were not met.

Arm/Group Title	Atenolol
Arm/Group Description	Participants will receive atenolol for 8 weeks. Atenolol: 12.5 mg twice daily of atenolol for 1 week; increased to 25 mg twice daily for a total of 8 weeks, if the medication is well tolerated
Measure Participants	0

6. Secondary Outcome

Title	Change in HDL
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atenolol
Arm/Group Description	Participants will receive atenolol for 8 weeks. Atenolol: 12.5 mg twice daily of atenolol for 1 week; increased to 25 mg twice daily for a total of 8 weeks, if the medication is well tolerated
Measure Participants	19
Mean (Standard Deviation) [mg/dL]	-3.5 (5.8)

7. Secondary Outcome

Title	Change in Insulin
Description	fasting insulin (post - pre atenolol)
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atenolol
Arm/Group Description	Participants will receive atenolol for 8 weeks. Atenolol: 12.5 mg twice daily of atenolol for 1 week; increased to 25 mg twice daily for a total of 8 weeks, if the medication is well tolerated
Measure Participants	17
Mean (Standard Deviation) [mU/mL]	-0.55 (6.03)

Adverse Events

Arm/Group Title	Atenolol
Arm/Group Description	Participants will receive atenolol for 8 weeks. Atenolol: 12.5 mg twice daily of atenolol for 1 week; increased to 25 mg twice daily for a total of 8 weeks, if the medication is well tolerated
All Cause Mortality
	Atenolol
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Atenolol
	Affected / at Risk (%)	# Events
Total	0/19 (0%)
Other (Not Including Serious) Adverse Events
	Atenolol
	Affected / at Risk (%)	# Events
Total	4/19 (21.1%)
Cardiac disorders
Bradycardia	4/19 (21.1%)
General disorders
Fatigue	2/19 (10.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.