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

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ClinicalTrials.gov Identifier: NCT00925119
Recruitment Status : Terminated
First Posted : June 19, 2009
Results First Posted : December 22, 2017
Last Update Posted : January 23, 2018
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Amber Beitelshees, University of Maryland

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 Type : Interventional  (Clinical Trial)
Actual Enrollment : 31 participants
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 : December 2009
Actual Primary Completion Date : June 2013
Actual Study Completion Date : May 2014

Resource links provided by the National Library of Medicine

U.S. FDA Resources

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



Primary Outcome Measures :
  1. Change in Diastolic Function (Annular Tissue Velocity [Em]) [ Time Frame: 8 weeks ]
  2. Change in Free Fatty Acid Kinetics [ Time Frame: 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 [ Time Frame: Baseline and Week 8 ]
    (Post atenolol triglycerides - Pre atenolol triglycerides)

  2. Change in Insulin Sensitivity [ Time Frame: 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 [ Time Frame: Baseline and Week 8 ]
    Glucose effectiveness as measured by insulin-modified IV glucose tolerance test using the MINMOD model.

  4. Change in HDL [ Time Frame: Baseline and Week 8 ]
  5. Change in Insulin [ Time Frame: Baseline and Week 8 ]
    fasting insulin (post - pre atenolol)



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Ages Eligible for Study:   21 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00925119


Locations
United States, Maryland
University of Maryland
Baltimore, Maryland, United States, 21201
Sponsors and Collaborators
University of Maryland
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Amber L. Beitelshees, PharmD, MPH University of Maryland

Responsible Party: Amber Beitelshees, Principal Investigator, University of Maryland
ClinicalTrials.gov Identifier: NCT00925119     History of Changes
Other Study ID Numbers: HP-00040291
K23HL091120 ( U.S. NIH Grant/Contract )
First Posted: June 19, 2009    Key Record Dates
Results First Posted: December 22, 2017
Last Update Posted: January 23, 2018
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Amber Beitelshees, University of Maryland:
Diabetes
Atenolol
Genetic

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Adrenergic beta-Antagonists
Atenolol
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Adrenergic beta-1 Receptor Antagonists